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Maternal nutrition and the developmental origins of osteoporosis in offspring: Potential mechanisms and clinical implications -Mayer

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Maternal nutrition and the developmental origins of osteoporosis in offspring: Potential mechanisms and clinical implications -Mayer

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Osteoporosis is the most common metabolic disorder of the bone and is influenced by many internal and external factors. There is strong evidence, as presented by Zheng et al., that maternal nutrition has long-lasting influences on bone metabolism through epigenetic modifications. Due to the number of people who suffer from osteoporosis, we need to develop better preventative care and get to the root cause of the pathogenesis. Other papers cited in this study that growth rate of infancy was associated with skeletal size and that birth weight and body weight at one-year old determined the bone mass in a cohort 70 years old. They also showed those that take vitamin D helped support bone metabolism and mineral.

The epigenetic modifications that occur during feeding pre and post-natal such as DNA methylation, histone modifications, and non-coding RNAs play critical roles in determining the bone health for the rest of their life. These epigenetic modifications can be passed on to further generations as well. This is important because bettering overall nutrition has many beneficial long-lasting effects.

Zheng, J., Feng, Q., Zheng, S., & Xiao, X. (2018). Maternal nutrition and the developmental origins of osteoporosis in offspring: Potential mechanisms and clinical implications. Experimental biology and medicine (Maywood, N.J.), 243(10), 836–842. https://doi.org/10.1177/1535370218779024

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. 2018 Jun;243(10):836-842.

doi: 10.1177/1535370218779024.

Affiliations

¹ 1 Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.

² 2 Department of Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.

³ 3 Department of Pediatrics, The Second Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300150, China.

⁴ 4 Department of Spine Surgery, Tianjin Union Medical Center, Tianjin Institute of Spine, Tianjin 300121, China.

Free PMC article

Jia Zheng et al. Exp Biol Med (Maywood).

Free PMC article

. 2018 Jun;243(10):836-842.

doi: 10.1177/1535370218779024.

Affiliations

¹ 1 Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.

² 2 Department of Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.

³ 3 Department of Pediatrics, The Second Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300150, China.

⁴ 4 Department of Spine Surgery, Tianjin Union Medical Center, Tianjin Institute of Spine, Tianjin 300121, China.

Abstract

Osteoporosis, the most frequent metabolic disorder of bone, is a complex disease with a multifactorial origin that is influenced by genes and environments. However, the pathogenesis of osteoporosis has not been fully elucidated. The theory of "Developmental Origins of Health and Disease" indicates that early life environment exposure determines the risks of cardiometabolic diseases in adulthood. However, investigations into the effects of maternal nutrition and nutrition exposure during early life on the development of osteoporosis are limited. Recently, emerging evidence has strongly suggested that maternal nutrition has long-term influences on bone metabolism in offspring, and epigenetic modifications maybe the underlying mechanisms of this process. This review aimed to address maternal nutrition and its implications for the developmental origins of osteoporosis in offspring. It is novel in providing a theoretical basis for the early prevention of osteoporosis. Impact statement Our review aimed to address maternal nutrition and its implications for the developmental origins of osteoporosis in offspring, that can novelly provide a theoretical basis for the early prevention of osteoporosis.

Keywords: Maternal; development; early life; nutrition; offspring; osteoporosis.

Figures

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national center for biotechnology information

# data[].attributes.attachment_link.title
Maternal nutrition and the developmental origins of osteoporosis in offspring: Potential mechanisms and clinical implications - PubMed

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Osteoporosis, the most frequent metabolic disorder of bone, is a complex disease with a multifactorial origin that is influenced by genes and environments. However, the pathogenesis of osteoporosis has not been fully elucidated. The theory of "Developmental Origins of Health and Disease" indicates t ...

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Analyzing the association between fish consumption and osteoporosis in a sample of Chinese men

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Analyzing the association between fish consumption and osteoporosis in a sample of Chinese men

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Li, X., Lei, T., Tang, Z., & Dong, J. (2017). Analyzing the association between fish consumption and osteoporosis in a sample of Chinese men. Journal of Health, Population and Nutrition, 36(1), 1-8.

Clarisa Williams

As the aging population continues to increase the prevalence of osteoporosis is likely to increase. Osteoporosis poses a threat to human health as the risk of fractures increase. The number of global hip fractures are predicted to reach 6.26 million in the year 2050. Of those fractures,  notably 30% will occur in Asia. This article published in the Journal of Health, Population and Nutrition aimed to investigate the relationship between fish consumption and osteoporosis in Chinese men. In a traditional Chinese diet, the major source of protein consumed is fish. Researches had results from the their study that suggested that frequency of fish consumption was significantly and independently associated with Osteoporosis in Chinese men. The prevalence of osteoporosis was 6.1% for those who had a higher fish consumption.  The researchers concluded Chinese men that consumed a higher frequency of fish showed less prevalence of osteoporosis. This finding supports the continuation of evaluating fish consumption as a nutritional recommendation for those at a higher risk of developing osteoporosis. Although this study reports a significance between osteoporosis and fish consumption, not all research shows this dietary habit to be beneficial. Continued research regarding the fish consumption is needed to broaden to confidently make the recommendation beyond Chinese men. This research topic has the potential to support suggesting the dietary intervention of increasing fish consumption and potentially making fish a major protein source in the diets of those at risk of osteoporosis.

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Dietary carotenoid intake and osteoporosis: the National Health and Nutrition Examination Survey, 2005–2018 (Richard Adefioye)

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Dietary carotenoid intake and osteoporosis: the National Health and Nutrition Examination Survey, 2005–2018 (Richard Adefioye)

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While the role of micronutrients like calcium and phosphorus in is well appreciated in the development of osteoporosis, other micronutrients like carotenoids are not quite as discussed.

This study looked at the associations of α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein + zeaxanthin intake with the risk of osteoporosis based on a 2005-2018 survey by the National Health and Nutrition Examination Survey (NHANES).

The complete data on carotenoid intake and bone mineral density (BMD) of the participants (≥ 50 years old) were used for analysis.

The results of this study showed that a higher intake of beta-carotene and β-cryptoxanthin was associated with a reduction in the risk of osteoporosis.

For me, this result further reiterates the fact that nutritional mechanisms are multifaceted. So, it might be a good idea to consider other micronutrients beyond calcium and vitamin D in the management of osteoporosis.

Kan, B., Guo, D., Yuan, B. et al. Dietary carotenoid intake and osteoporosis: the National Health and Nutrition Examination Survey, 2005–2018. Arch Osteoporos 17, 2 (2022). https://doi-org.ezproxy.uky.edu/10.1007/s11657-021-01047-9

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Diet-Induced Obesity and Its Differential Impact on Periodontal Bone Loss - Dierra Doaks 

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Diet-Induced Obesity and Its Differential Impact on Periodontal Bone Loss - Dierra Doaks 

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The article I chose for this week discusses the relationship between diet induced obesity and periodontal bone loss. Periodontitis is an inflammatory disease of the tissue that supports the tooth. This results in progressive loss of bone. There have been studies that showed an association between periodontal disease and obesity. Obesity is the second highest risk factor for periodontal disease after smoking. This study looked at the most abundant saturated and monounsaturated fatty acids in the Western Diet which are palmitic acid and oleic acid. Mice were used in the study. The mice were placed in four groups: palmitic acid high fat diet, oleic acid high fat diet, and normal caloric diet. The mice were orally infected with P. gingivalis. Osteoclasts and osteoblasts were isolated from their bone marrow. The results were interesting. Alveolar bone loss was higher in the mice on the palmitic acid high fat diet. Bone remodeling markers were lowest in this group as well. This study showed how the fatty acid make up of diet can impact bone metabolism which can ultimately impact bone loss.

Muluke, M et al. “Diet-Induced Obesity and Its Differential Impact on Periodontal Bone Loss.” Journal of dental research 95.2 (2016): 223–229. Web

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The effect of a prevention program based on health belief model on osteoporosis.

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The effect of a prevention program based on health belief model on osteoporosis.

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Emalee Haynes
The goal of this study was to determine if a prevention program focused on nutrition and regular exercise (walking goals) would help with osteoporosis in women. Within the study there were 120 participants divided into 2 groups of treatment and control groups. Patients had their bone mineral density recorded at baseline, and then 6 months following trial. The trial concluded that the prevention program was effective in managing bone mass ratings. This is important because it can be used for other patients as a non-pharmacologic intervention for those at increased risk for developing osteoporosis, especially female patients. The clinical implications of this study would be evidence behind balanced diet and regular walking or moderate physical activity benefiting bone health or disease progression. Taking the time to apply this into treatment or lifestyle regimens for patients is important in impacting their quality of life and disease development and severity.

Khani Jeihooni, Ali et al. “The effect of a prevention program based on health belief model on osteoporosis.” Journal of research in health sciences vol. 15,1 (2015): 47-53.

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Affiliations

¹ Department of Health Education and Health Promotion, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. khani_1512@yahoo.com.

² Department of Health Education and health promotion, Shiraz University of Medical Sciences, Shiraz, Iran.

³ Department of Biostatistics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Free article

Free article

Affiliations

¹ Department of Health Education and Health Promotion, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. khani_1512@yahoo.com.

² Department of Health Education and health promotion, Shiraz University of Medical Sciences, Shiraz, Iran.

³ Department of Biostatistics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Abstract

Background: Osteoporosis is one of the most common metabolic bone diseases. The purpose of this study was to investigate the effect of a prevention program based on health belief model on osteoporosis among women.

Methods: In this quasi-case study, 120 patients (60 cases and 60 control), registered under the health centers in Fasa City, Fars Province, Iran were selected in 2014. A questionnaire consisting of demographic information, Health Belief Model (HBM) constructs was used to measure nutrition and walking performance for prevention of osteoporosis before, immediately after the intervention and six months later. Bone mineral density (BMD) was recorded at the lumbar spine and femur before and six months after intervention. Data were analyzed using SPSS19 via chi-square test, independent t-test, and Repeated Measures ANOVA at significance level of 0.05.

Results: Immediately and six months after the intervention, the case group showed a significant increase in the knowledge, perceived susceptibility, perceived severity, perceived benefits, perceived barriers, self-efficacy, internal cues to action, nutrition and walking performance compared to the control group. Six months after the intervention, the value of lumbar spine BMD T-Score in the case group increased to 0.127, while in the control group it reduced to -0.043. The value of the Hip BMD T-Score in the intervention group increased to 0.125 but it decreased to -0.028 in the control group.

Conclusions: This study showed the effectiveness of knowledge, walking and diet on bone mass by HBM model. Hence, these models can act as a framework for designing and implementing educational interventions for the osteoporosis prevention.

Keywords: Health Belief Model; Nutritional Status; walking.

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national center for biotechnology information

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The effect of a prevention program based on health belief model on osteoporosis - PubMed

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1 Department of Health Education and Health Promotion, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. khani_1512@yahoo.com. 2 Department of Health Education and health promotion, Shiraz University of Medical Sciences, Shiraz, Iran. 3 Department of Biostatistics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

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The effect of diets on higher osteoporosis risk in patients taking SSRIs - Julie Rees

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The effect of diets on higher osteoporosis risk in patients taking SSRIs - Julie Rees

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This study looked at over 600 osteoporosis and osteopenia patients and 12,000 controls and evaluated the effects of diet against the effects of SSRIs. It has been found in previous studies that both men and women who had taken SSRIs had an increased risk of developing osteoporosis. Since both osteoclasts and osteoblasts have serotonin receptors, it is believe that these antidepressants have a major effect on bone remodeling. Given the state of the world, more and more people are being prescribed antidepressants and approximately 65% of those are SSRIs. This means nutritionists and dieticians will need to keep this in mind when they see new patients. It was hypothesized that depression itself could result in poor diet choices associated with osteoporosis. This study found that both groups had high percentages of inadequate nutrition. The most interesting finding was that osteoporosis correlated more with zinc levels than calcium. This suggests that increasing zinc intake through foods like nuts and whole grains would be beneficial in preventing osteoporosis.

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Nutrition status, bone mass density, and selective serotonin reuptake inhibitors

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The association between selective serotonin reuptake inhibitor (SSRI) use and bone mass density (BMD) has been debated. Inadequate diet, which may occ…

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Optimal Cutoff Values for ESR and CRP to Diagnose Patients with Diabetes Related Foot Infections-Lydia Duncan

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Optimal Cutoff Values for ESR and CRP to Diagnose Patients with Diabetes Related Foot Infections-Lydia Duncan

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For this weeks article, I chose to look further into Osteomyelitis. The study looks into optimal cutoff values for Erythrocyte Sedimentation Rate (ESR) and C-reactive Protein (CRP) when diagnosing Osteomyelitis in patients with foot infections that are Diabetes related. ESR and CRP are common biomarkers used to determine a diagnosis, and there is no official level for diagnosis (as of the time of this article). We also learned recently that foot infections are common in patients with Diabetes. 1842 patients records from 01/01/10-02/06/17 were examined, and 335 were included in the study. The age of the patients ranged from 18-89. After the data was collected, a (descriptive) statistic analysis was performed. This study is important because because it looked into regulations that have not yet been put in place.

One key finding of this study was their threshold for the diagnosis (Fig. 2 in article). When the Diabetic foot infection is observed, first ESR should be measured. If the ESR levels are above 60 mm/hr, CRP levels should then be measured. If the levels are over 7.9 mg/dL, management of osteomyelitis should be considered. This relates to nutritional sciences because it examines biomarkers in relation to Osteomyelitis and Diabetes. While the study was one of the first of it's kind, it does have limitations. Of course, further research (like a cohort study) is needed before parameters like this can be officially used. A second limitation is the physicians diagnoses, because little rationale was provided for why the physicians performed certain evaluations.

A clinical implication of this study is that parameters for optimal cutoff level for ESR and CRP are needed. This would help to regulate the diagnosis of Osteomyelitis. When Osteomyelitis remains untreated, it can become worse and spread. Setting parameters in place allows for the disease to be observed earlier, because physicians could assess the patient if they are close to the threshold, instead of at the onset of Osteomyelitis.

Citation:
Lavery, L. A., Ahn, J., Ryan, E. C., Bhavan, K., Oz, O. K., La Fontaine, J., & Wukich, D. K. (2019). What are the optimal cutoff values for ESR and CRP to diagnose osteomyelitis in patients with diabetes-related foot infections? Clinical Orthopaedics & Related Research, 477(7), 1594–1602. https://doi.org/10.1097/corr.0000000000000718

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Lawrence A. Lavery, DPM, MPH, Junho Ahn, BS, Easton C. Ryan, BS, Kavita Bhavan, MD, Orhan K. Oz, MD, PhD, Javier La Fontaine, DPM, MS, and Dane K. Wukich, MD

Abstract

Background

Distinguishing osteomyelitis from soft-tissue infection of the foot is important because osteomyelitis is associated with more operations, amputation, and prolonged antibiotic exposure. Both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are routinely ordered inflammatory biomarkers for evaluating foot infection. When initial evaluation is inconclusive, advanced imaging is indicated, and high clinical or radiographic suspicion of osteomyelitis may indicate bone biopsy to identify organisms and antibiotic sensitivity. Although ESR and CRP levels are helpful for distinguishing osteomyelitis from soft-tissue infections in patients with diabetes-related foot infections, parameters regarding optimal cutoff values for those tests have not, to our knowledge, been defined.

Questions/purposes

(1) What are the optimal cutoff values for ESR and CRP to differentiate osteomyelitis from soft-tissue infection in patients with diabetes-related foot infection? (2) Can a diagnostic algorithm be derived to guide interpretation of ESR and CRP to improve recognition of osteomyelitis in the setting of diabetic foot infection?

Methods

The medical records of 1842 patients between 18 and 89 years of age treated at our institution between January 1, 2010 and February 6, 2017 for foot infection were reviewed. For inclusion, patients must have had a diagnosis of diabetes mellitus, moderate or severe infection, ESR and CRP values within 72 hours of admission, either advanced imaging (MRI or single-positron emission computed tomography/computed tomography [SPECT/CT]) or bone biopsy during admission and must not have had comorbidities that could affect ESR and CRP, such as autoimmune disorders. As such, 1489 patients were excluded, and 353 patients were included in the study. Osteomyelitis was diagnosed by positive bone culture or histopathology. Osteomyelitis was considered to be absent if there was a negative MRI or SPECT/CT result, or negative bone culture and histology findings if imaging was inconclusive. We identified 176 patients with osteomyelitis and 177 with soft-tissue infection. A blinded investigator performed the statistics. Optimal cutoffs of ESR and CRP were determined using receiver operative characteristic (ROC) analysis. A diagnostic algorithm was determined using epidemiologic principles of screening evaluations.

Results

An ESR of 60 mm/h and a CRP level of 7.9 mg/dL were determined to be the optimal cutoff points for predicting osteomyelitis based on results of the ROC analysis. The ESR threshold of 60 mm/h demonstrated a sensitivity of 74% (95% confidence interval [CI], 67-80) and specificity of 56% (95% CI, 48-63) for osteomyelitis, whereas the CRP threshold of 7.9 mg/dL had a sensitivity of 49% (95% CI, 41-57) and specificity of 80% (95% CI, 74-86). If the ESR is < 30 mm/h, the likelihood of osteomyelitis is low. However, if ESR is > 60 mm/h and CRP level is > 7.9 mg/dL, the likelihood of osteomyelitis is high, and treatment of suspected osteomyelitis should be strongly considered.

Conclusions

While ESR is better for ruling out osteomyelitis initially, CRP helps distinguish osteomyelitis from soft-tissue infection in patients with high ESR values. Further prospective studies addressing the prognostic value of ESR and CRP are needed, and a more comprehensive diagnostic algorithm should be developed to include other diagnostic tests such as probe-to-bone and imaging.

Level of Evidence

Level III, diagnostic study.

Introduction

Diabetic foot infections are a common cause of diabetes-related hospitalizations [ 4, 26]. Distinguishing osteomyelitis from soft-tissue infection is important because bone infections are associated with more operations, amputation procedures, and prolonged antibiotic exposure, which may increase antibiotic-related complications such as pathogen resistance, gastrointestinal complications, and acute kidney injury [ 2, 8, 20, 21, 29, 32]. An incorrect diagnosis of osteomyelitis in a patient with a soft-tissue infection can lead to treatments that may increase the risk of complications and may even result in unnecessary amputation. Conversely, late recognition of osteomyelitis of the foot can lead to spread of the infection, sepsis or septic shock, and amputation [ 16]. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are inflammatory biomarkers that are evaluated using readily available and relatively inexpensive laboratory tests. Previously reported cutoffs of ESR and CRP for distinguishing osteomyelitis and soft-tissue infection involving the foot in diabetic patients were evaluated separately in small study populations [ 6, 7, 9, 11, 17, 19, 21, 23, 30]. However, these studies did not propose detailed guidelines on how these tests should be interpreted. In addition, most of these studies did not consistently use results of culture or histopathology from bone biopsy as the gold standard evaluation for determining the presence of osteomyelitis, and no studies used both culture and histopathology results to identify the presence of osteomyelitis [ 6, 9, 19, 23]. To our knowledge, the current study is the largest study to examine ESR and CRP cutoffs to distinguish osteomyelitis from soft-tissue infections in diabetes and foot infections. Furthermore, this is the only study to propose a diagnostic algorithm to maximize the utility of both biomarkers for detecting osteomyelitis of the foot rather than simply defining individual cutoffs for ESR and CRP.

Therefore, we asked: (1) What are the optimal cutoff values for ESR and CRP to differentiate osteomyelitis from soft-tissue infection in patients with diabetes-related foot infection? (2) Can a diagnostic algorithm be derived using ESR and CRP cutoffs to guide interpretation and evaluation of inflammatory biomarkers to improve recognition of osteomyelitis in the setting of diabetic foot infection?

Patients and Methods

Study Design and Setting

After receiving institutional review board approval for the protocol of this study, we reviewed the medical records of patients hospitalized for moderate and severe foot infections that raised concerns of osteomyelitis at a safety net hospital between January 1, 2010 and February 6, 2017, the period that the senior investigator has been practicing at our institution. The presence of foot infection was defined based on criteria consistent with the Infectious Diseases Society of America and the International Working Group Diabetic Foot Infection Guidelines [ 15, 16]; that is, the clinical observation of purulence or at least two local signs or symptoms of inflammation. Initially, the medical records of 1842 patients between the ages of 18 and 89 years with moderate and severe foot infection were reviewed. In these patients, ESR and CRP are routinely ordered around the time of admission by hospitalists and emergency department staff at our institution. Indications for advanced imaging through MRI or single-positron emission computed tomography/computed tomography (SPECT/CT) include inconclusive clinical and plain radiographic findings. Based on clinical signs, probe-to-bone examination, plain radiographs and advanced imaging, bone biopsy may be indicated depending on whether there is a high index of suspicion for osteomyelitis to identify causative organisms and determine antibiotic sensitivities. However, patients with exposed bone may undergo bone biopsy without advanced imaging. Naturally, patients who did not have ESR or CRP values assessed within 72 hours of admission, pathology results or radiographic evaluation through MRI or SPECT/CT were excluded. However, we excluded patients with comorbidities that could affect baseline ESR and CRP levels, such as autoimmune diseases. After excluding nondiabetic patients based on the American Diabetes Association diagnostic criteria, 353 patients were included in the study [ 1]. The gold standard for diagnosis of osteomyelitis is bone biopsy. Ideally, every patient, regardless of MRI or SPECT/CT results, would undergo bone biopsy. However, as this study was performed retrospectively, this was not possible as bone biopsy is not standard of care for all foot infections.

Diagnostic Categorization

After we excluded 1489 patients for the reasons listed above, 353 patients were included in the study. Patients were separated into two groups, osteomyelitis or soft-tissue infection, based on a combination of bone culture, histopathology, and imaging results. We used bone biopsy results to confirm the diagnosis of osteomyelitis, and negative MRI, negative SPECT/CT, or negative results on bone biopsy to identify patients without a bone infection [ 3]. In this study, 88 patients had positive culture and histopathological changes consistent with osteomyelitis. Forty-one patients had positive histopathology without cultures results, and five patients had positive cultures without histopathology results reported. Twenty-two patients had positive culture with negative histopathology, and 21 had positive histopathology with negative culture. As long as bone biopsy culture or histopathology was positive, we categorized these patients as having osteomyelitis. As a result, 177 patients were included in the osteomyelitis group.

Patients with negative bone culture results and negative histopathology or negative MRI or SPECT/CT findings without bone biopsy results were considered not to have osteomyelitis and were included in the soft-tissue infection group. Specifically, 129 patients had negative MRI and/or negative SPECT/CT and did not undergo bone biopsy. However, 16 patients with negative MRI and/or negative SPECT/CT underwent bone biopsy based on clinical suspicion of osteomyelitis, but none of these patients had positive culture or histopathology. Seventeen of 19 patients with nonspecific MRI or SPECT/CT findings underwent bone biopsies, which were all negative for osteomyelitis. Two patients with nonspecific MRI underwent SPECT/CT scans that were negative and did not subsequently undergo bone biopsy. Five patients who had positive MRI or SPECT/CT findings underwent bone biopsies that were all negative. Seven patients who did not have MRI or SPECT/CT imaging underwent bone biopsy which demonstrated negative culture and histopathology. As a result, these 176 patients were categorized in the soft-tissue infection group.

The median age of the study patients was 54 years (interquartile range [IQR], 46-61 years). Seventy-five percent were male, and approximately 96% had type II diabetes mellitus. No differences between the groups were identified regarding age (p = 0.411), sex (p = 0.713), or comorbidities, except that there was a lower prevalence of retinopathy (p = 0.018) in patients with soft-tissue infection than in those with osteomyelitis (Table ​(Table1 1 ).

Table 1.

Statistical Analysis

After data collection was completed, a blinded investigator (JA) not involved in data collection was given a coded version of the data for statistical analysis. All continuous variables were tested for normality using a quantile-quantile plot, histogram, and Shapiro-Wilk analysis. Because most of these variables did not have a normal distribution, descriptive statistical analyses were used to determine the median values of continuous variables, with an IQR between the 25th to 75th quartiles, and frequencies and percentages of categorical variables. Continuous variables were compared between groups using either a Student t-test or Mann-Whitney U test, and categorical variables were analyzed using the Pearson χ2 test or Fisher exact test, when appropriate. Contingency tables were used to calculate descriptive epidemiologic measures (odds ratios [OR], sensitivity, and specificity). A receiver operating characteristic (ROC) curve analysis was used for both ESR and CRP to determine the performance of each test in detecting osteomyelitis. The ROC curves were compared through the DeLong test [ 5]. In addition, various cutoff levels of interest for ESR and CRP were evaluated to determine the relationship between increasing values of these inflammatory biomarkers and their sensitivity and specificity. Optimal threshold values for ESR and CRP, defined as those with the lowest rates of false results, were identified by selecting the thresholds with the maximum Youden's J-statistic value and then confirming through the ROC analysis [ 34]. An alpha value of 0.05 was set for all statistical analyses. All statistical analyses were performed using the open source statistical program R version 3.3.1 (R Development Core Team, Vienna, Austria) [ 22].

Results

An ESR of 60 mm/h and CRP level of 7.9 mg/dL were determined to be the optimal cutoff points for predicting osteomyelitis. The ESR threshold of 60 mm/h demonstrated a sensitivity of 74% (95% CI, 66-78) and specificity of 56% (95% CI, 49-64) for osteomyelitis, whereas the CRP threshold of 7.9 mg/dL had a sensitivity of 49% (95% CI, 42-57) and specificity of 80% (95% CI, 73-86). Sensitivity and specificity were also calculated for combinations of ESR and CRP thresholds (Table ). When combined in an "or" fashion, where a suprathreshold value of ESR or CRP is a positive result, and a subthreshold value of ESR and CRP is a negative result, the combination demonstrated high sensitivity (87% [95% CI, 81-92]) and low specificity (45% [95% CI, 37-53]). In contrast, when combining the tests in an "and" fashion, where suprathreshold values of both ESR and CRP are a positive result, and a subthreshold value of one or both tests is considered a negative result, the combination showed low sensitivity (36%; 95% CI, 29-44) but high specificity (91%; 95% CI, 86-95) (Fig. ). The ESR threshold of 60 mm/h had a positive predictive value (PPV) of 63% and a negative predictive value (NPV) of 68%. In comparison, for the CRP threshold of 7.9 mg/dL, the PPV was 70% and the NPV was 61%. However, the highest NPV was seen with an ESR threshold of 30 mm/h (88%), and the highest PPV was seen with the "and" combination of the ESR threshold of 60 mm/h and CRP threshold of 7.9 mg/dL (Table ). In addition, positive likelihood ratios (LR+) and negative likelihood ratios (LR-) followed the same pattern. An ESR threshold of 30 mm/h had the lowest LR- while the "and" combination of both the ESR and CRP thresholds showed the highest LR+. These results suggest that ESR < 30 mm/h had the lowest proportion of false negatives while the "and" combination of both ESR and CRP thresholds above the optimal cutoff values had the lowest proportion of false positives.

Table 2.

Our proposed algorithm for differentiating osteomyelitis from soft-tissue infection is as follows: when the ESR is > 60 mm/h and the CRP level is > 7.9 mg/dL, osteomyelitis is likely (sensitivity, 36%; specificity, 91%; PPV, 0.80; NPV, 0.59; LR+, 4.00; LR-, 0.70). When the ESR is < 30 mm/h, osteomyelitis is unlikely (LR-, 0.14). Because an ESR value > 30 mm/h is highly sensitive (97%; 95% CI, 94-99), CRP only marginally increases the sensitivity (ESR > 30 mm/h and CRP >7.9 mg/dL, sensitivity 98%; 95% CI, 95-99) (Fig. ). Therefore, when the ESR is < 30 mm/h, there is little justification to consider it in combination with CRP. For patients with an ESR value between 30 and 60 mm/h, or when there is high clinical suspicion in the absence of elevated ESR and CRP values, clinicians should consider using imaging or another diagnostic evaluation methods (Fig. ).

Discussion

The presence of foot osteomyelitis in patients with diabetes has major clinical implications because its presence affects treatment outcomes, complication risks, and therapy costs [ 27]. Failure to diagnose osteomyelitis may delay the onset of proper treatment and result in spread of the infection, potentially necessitating more surgeries, proximal amputation, and prolonged antibiotic exposure [ 2, 29]. Although several studies have examined the diagnostic value of ESR for osteomyelitis of the foot in patients with diabetes, few have been performed for CRP [ 7, 9, 19]. In addition, previous reports simply reported optimal cutoff values for ESR and/or CRP without a clear method of using both tests [ 7, 19]. Providing simple cutoff values are not as clinically valuable because they do not specify how physicians should approach certain situations, such as when ESR and CRP values conflict. To the best of our knowledge, this study is the first to describe a flowchart detailing the optimal usage of both ESR and CRP for differentiating osteomyelitis from soft-tissue infection of the foot in patients with diabetes. We found that ESR values less than 30 mm/h are not likely to be associated with osteomyelitis and that CRP only adds diagnostic value when ESR is greater than 60 mm/h (Fig. ).

Optimal Cutoff Values for ESR and CRP to Diagnose Osteomyelitis

We found that both ESR and CRP have optimal cutoff values for differentiating osteomyelitis from soft-tissue infection. The optimal cutoff points for ESR and CRP in the current study were similar to those of Fleischer et al. [ 7]. In addition, that was the only study to evaluate ESR and CRP while also confirming the diagnosis of osteomyelitis through bone histology [ 7]. The conclusions of Fleischer et al. [ 7] were that (1) patients with ESR values greater than 60 mm/h and CRP values greater than 3.2 mg/dL should be quickly recognized as having an increased likelihood of having osteomyelitis, and (2) those with mild-to-moderate elevations of these markers likely have soft-tissue infection. Although the results of the current study corroborate their first conclusion about ESR and CRP values above the optimal threshold values, our results also suggest that ESR and CRP should only be used together in certain situations.

Diagnostic Algorithm

Our proposed clinical decision-making tool uses ESR and CRP in combination to make the diagnosis of osteomyelitis and uses ESR alone to exclude it (Fig. ​(Fig.2). 2 ). A patient with an ESR greater than 60 mm/h should have their CRP level evaluated because it can add to the diagnostic value because an ESR greater than 60 mm/h has low specificity for osteomyelitis (56%), and the CRP threshold of 7.9 mg/dL has much-higher specificity. A CRP level greater than 7.9 mg/dL with a finding of ESR greater than 60 mm/h increases the specificity, making a diagnosis of osteomyelitis likely. However, a CRP level less than 7.9 mg/dL with an ESR greater than 60 mm/h does not suggest presence of osteomyelitis. In patients with a normal ESR (< 30 mm/h), osteomyelitis is unlikely. For values of ESR between 30 and 60 mm/h, the prevalence of osteomyelitis was roughly 50%, and we could not identify any CRP values that helped distinguish osteomyelitis from soft-tissue infection within this range of ESR values.

Limitations

This study had several limitations. Retrospective studies like this one may contain errors in the collection of data, disease definitions, and missing data. However, the key variables assessed in this study, such as the presence of diabetes, laboratory values, bone culture, and pathology findings, were given careful consideration and were confirmed with secondary reports, such as evaluating proportion of glycated hemoglobin for presence of diabetes and a review of patient history. No patients had missing values with regard to these key variables. However, we did not confirm all patient comorbidities such as searching for systolic ejection fraction to confirm reports of heart disease or evaluating antibody titers to confirm reports of autoimmune disease. Furthermore, we were not able to identify the rationale for physicians' decisions to pursue various evaluations. It is difficult to determine if the results of CRP or ESR influenced the decision to get advanced imaging or perform a bone biopsy. However, we noted that advanced imaging and inflammatory markers were frequently ordered at the same time. Furthermore, the cutoff values for CRP and ESR are higher with osteomyelitis of the foot in patients with diabetes compared with other anatomic sites [ 10, 12, 13, 24, 28, 31, 33]. However, these measures are not applicable to the diabetic foot. Therefore, extrapolating biomarker cutoff points from other anatomic sites to the diagnosis of diabetic foot osteomyelitis has little use in guiding clinical decision making. The use of these values may lead to unwarranted, expensive, and/or invasive testing. In addition, neither ESR nor CRP is particularly useful for distinguishing osteomyelitis from soft-tissue infection of the foot in patients without diabetes [ 25]. In our experience, internists and emergency room physicians often rely on advanced imaging with a high index of suspicion for deep abscess or osteomyelitis regardless of ESR or CRP. As such, it is unlikely that these physicians were acutely aware of previous evidence to associate particular ESR values with osteomyelitis of the foot in patients with diabetes. Physicians do not often report their rationale for ordering specific tests, so it was not possible to conclusively determine if inflammatory markers influenced prescriptive behaviour. In addition, although we used the "gold standard" of bone biopsy as the confirmatory test for osteomyelitis based on clinical and imaging findings, the evaluation of histology and cultures is not entirely reliable or accurate. However, interobserver variability in the interpretation of bone histology has been reported to be high and could provide an inconsistent interpretation of histology specimens [ 18]. Lastly, all patients in this study were hospitalized for moderate and severe diabetic foot osteomyelitis, where the pretest probability of osteomyelitis was high (50%-67%). The study results may not be applicable to patients seen in outpatient settings, where the pretest probability of osteomyelitis is low (20%) [ 8, 14]. Therefore, the clinical algorithm presented in this study should be used with caution in patients with diabetes treated in the outpatient setting with mild infections of the foot.

Conclusions

Although ESR is better for excluding the diagnosis osteomyelitis initially, CRP helps distinguish osteomyelitis from soft-tissue infection in patients with high ESR values. Our proposed clinical algorithm can help clinicians to distinguish osteomyelitis from soft-tissue infection in patients with diabetic foot infection using thresholds for ESR and CRP (Fig. ). Further studies addressing the prognostic value of ESR and CRP are needed, and a more comprehensive diagnostic algorithm that includes other diagnostic tests such as probe-to-bone and imaging should be developed. Preferably, the optimal study would be performed prospectively with each patient with diabetes-related foot infection evaluated undergoing the same clinical examination, laboratory testing, radiographic imaging and bone biopsy protocol. In addition to determining ESR and CRP levels, future studies may consider the location of the infection because there could be an effect on ESR and CRP levels.

Footnotes

Each author certifies that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research ® editors and board members are on file with the publication and can be viewed on request.

Clinical Orthopaedics and Related Research ® neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA approval status, of any drug or device before clinical use.

Each author certifies that his or her institution approved the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

References

1. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S13-S27. [[ PubMed] Google Scholar]

2. Berendt AR, Peters EJ, Bakker K, Embil JM, Eneroth M, Hinchliffe RJ, Jeffcoate WJ, Lipsky BA, Senneville E, Teh J, Valk GD. Diabetic foot osteomyelitis: a progress report on diagnosis and a systematic review of treatment. Diabetes Metab Res Rev. 2008; 24( Suppl 1):S145-161. [[ PubMed] Google Scholar]

15. Lipsky BA, Aragon-Sanchez J, Diggle M, Embil J, Kono S, Lavery L, Senneville E, Urbancic-Rovan V, Van Asten S, International Working Group on the Diabetic F, Peters EJ. IWGDF guidance on the diagnosis and management of foot infections in persons with diabetes. Diabetes Metab Res Rev. 2016;32(Suppl 1):45-74. [[ PubMed] Google Scholar]

22. R Development Core Team (2008). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria: ISBN 3-900051-07-0. [ http://www.R-project.org. Google Scholar]

25. Ryan EC, Ahn J, Wukich DK, Kim PJ, La Fontaine J, Lavery LA. Diagnostic utility of erythrocyte sedimentation rate and C-reactive protein in osteomyelitis of the foot in persons without diabetes. J Foot Ankle Surg. [Published online ahead of print January 23, 2019]. DOI: 10.1053/j.jfas.2018.09.025. [ PubMed] [ CrossRef]

Articles from Clinical Orthopaedics and Related Research are provided here courtesy of The Association of Bone and Joint Surgeons

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What are the Optimal Cutoff Values for ESR and CRP to Diagnose Osteomyelitis in Patients with Diabetes-related Foot Infections?

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Lawrence A. Lavery, DPM, MPH, Junho Ahn, BS, Easton C. Ryan, BS, Kavita Bhavan, MD, Orhan K. Oz, MD, PhD, Javier La Fontaine, DPM, MS, and Dane K. Wukich, MD Distinguishing osteomyelitis from soft-tissue infection of the foot is important because osteomyelitis is associated with more operations, amputation, and prolonged antibiotic exposure.

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Osteoporosis and Nutrition - Cole Zetter

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Osteoporosis and Nutrition - Cole Zetter

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For this week's weekly wall, I read an article relating nutrition to the topic of osteoporosis. I found this study to be important because it gave a great background on osteoporosis. The study defined the topic as a condition in which bone mass or density falls more than 2.5 standard deviations below the mean for young adults. It then followed up by stating how these changes can lead to microarchitectural changes in the bone and subsequently increased skeletal fragility and risk of fracture. These changes are especially dangerous for the elderly and can lead to death after bone fracture, or significant life changes, such as moving to assisted living facilities. One key finding that I read within this study was that optimal dietary calcium throughout life, along with weight-bearing exercise, can improve an individual's bone mineral density which would in turn reduce fracture risks later in life. This is very important because if a individual maintains healthy levels of calcium in the diet throughout their life from childhood through adulthood, the risk of developing a disease such as osteoporosis would decrease. Following calcium, this study went on to note the importance of other vitamins and nutrients  such as folic acid, cobalamin, pyridoxine, vitamin K, vitamin C, and vitamin D, boron, and manganese. I would say that the clinical implications of this study would be that it is apparent that there are nutritional and lifestyle affects on osteoporosis therefore prevention is a great medicine, although for those who are diagnosed, I would suggest a healthy and diverse diet that is well supplemented with the vitamins and minerals previously listed, as well as exercise that is healthy for them.

Bourgon, Roberta. “Osteoporosis and Nutrition.” Alternative & complementary therapies 3.6 (1997): 433–440. Web.

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Silicon: A Review of Its Potential Role in the Prevention and Treatment of Postmenopausal Osteoporosis- Tamunoerenomie Inimgba

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Silicon: A Review of Its Potential Role in the Prevention and Treatment of Postmenopausal Osteoporosis- Tamunoerenomie Inimgba

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The purpose of this article is to identify the potential role of silicon in bone formation and maintenance. Previous studies and research have already identified the benefits of calcium and vitamin D supplementation. The goal of the study is to identify additional nutritional components that may be important for bone health. A key finding of the article was that silicon intake helps to improve bone matrix quality and plays an essential role in bone mineralization, therefore increased intake of bioavailable silicon has been shown to increase bone mineral density, as well as improve bone strength. Some of the food sources where silicon can be found include whole grains, cereals, beer, and some vegetables, such as green beans. However, although it has been identified that silicon supplementation is associated with increased bone mineral density, the exact process for how this occurs is yet to be identified. The clinical implications of the article would be to study minerals such as silicon that could improve nutrition, dietary supplementation, and help to better understand and manage postmenopausal osteoporosis.

Price, Koval, K. J., & Langford, J. R. (2013). Silicon: A Review of Its Potential Role in the Prevention and Treatment of Postmenopausal Osteoporosis. International Journal of Endocrinology, 2013, 316783–316786. https://doi.org/10.1155/2013/316783

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Rhoda Inimgba: Smoking-Induced Risk of Osteoporosis Is Partly Mediatedby Cadmium From Tobacco Smoke: The MrOS SwedenStudy

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Rhoda Inimgba: Smoking-Induced Risk of Osteoporosis Is Partly Mediatedby Cadmium From Tobacco Smoke: The MrOS SwedenStudy

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Osteoporosis has to do with low bone mineral density which makes one more likely to have a fracture. There are so many risk factors involved in osteoporosis such as age, genetics. This article focuses on smoking as it could be a cause of osteoporosis and fracture. The purpose of this article is to investigate how cadmium from tobacco smoke can cause osteoporosis. This is important because people who smoke are exposed to cadmium which serves as one of the risk factors that can lead to osteoporosis. Although people could get exposed to cadmium through diet but this article focuses more on smoking.
One of the major finding from this paper was that smoking-induce osteoporosis is therefore mediated by cadmium. This relates to nutritional sciences knowing that cadmium from tobacco smoke could lead to osteoporosis, it is important to advise smokers to majorly include calcium in their diet to therefore increase their bone mineral density as smoking can be a major cause of osteoporosis.
The clinical implications of this study include making sure to make notice of the bone mineral density of smokers as it has been seen that they are more at risk of developing osteoporosis and fractures and this should as well go for people who inhale the smoke through secondary smoking.

Li, Wallin, M., Barregard, L., Sallsten, G., Lundh, T., Ohlsson, C., Mellström, D., & Andersson, E. M. (2020). Smoking-Induced Risk of Osteoporosis Is Partly Mediated by Cadmium From Tobacco Smoke : The MrOS Sweden Study. Journal of Bone and Mineral Research, 35(8), 1424–. https://doi.org/10.1002/jbmr.4014.

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Sidney Harm: Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial

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Sidney Harm: Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial

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For this weeks Padlet on bone health I found this study looking into how the amount of vitamin D within the maternal  diet impacts the infants bone mineral content. It was hypothesized that a mother who had supplemental vitamin D throughout pregnancy the infants hole body bone mineral mass would be greater. This study included pregnant women over the age of 18 and no more than 17 weeks gestation, the earlier they were able to implement the treatment was hypothetically will have the better outcomes. Two groups were within the study; a treatment group who were given 1000 IU/day of cholecalciferol or a placebo. The bone mineral content was assessed in the infants within two weeks of birth by using a dual-energy x-ray absorptiometry.1 The overall findings of the study were unfortunate, the treatment group did not differ from the control group comparing data. This shows that bone mineralization content in infants aren’t dependent on the mothers vitamin D intake. This study could show that there is a placenta transfer issue with vitamin D, which could be the reason that the supplementation group didn’t show any difference between the control.

References:
Cooper, Harvey, N. C., Bishop, N. J., Kennedy, S., Papageorghiou, A. T., Schoenmakers, I., Fraser, R., Gandhi, S. V., Carr, A., D’Angelo, S., Crozier, S. R., Moon, R. J., Arden, N. K., Dennison, E. M., Godfrey, K. M., Inskip, H. M., Prentice, A., Mughal, M. Z., Eastell, R., … Javaid, M. K. (2016). Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. The Lancet. Diabetes & Endocrinology, 4(5), 393–402. https://doi.org/10.1016/S2213-8587(16)00044-9

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Joe Devine: Nutrients and Dietary Patterns Related to Osteoporosis

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Joe Devine: Nutrients and Dietary Patterns Related to Osteoporosis

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Osteoporosis is a chronic condition that results from a decrease in bone density. This decrease in bone density leaves the bones open to increased risk of fractures due to its weakened condition. While more nutritional research is needed to determine its total affect on osteoporosis it is known that Vitamin D and Calcium play vital roles in keeping the bone tissues in homeostasis, but whether or not exogenous supplementation is beneficial to mitigating osteoporosis or decreasing its risks is still under debate. This paper looks at a consensus guideline of proper dietary planning instead of isolated nutrient supplementation as nutritional effects act in complex pathways.

The paper looked mostly at dairy products that had been fortified with Vitamin D, but they were unable to confidently support a correlation between higher intake of dairy products and beneficial impacts on bone. But, they did see a correlation in women with higher serum levels of vitamin D that they seemed to benefit more from higher calcium intake. However, the paper notes that there is not enough studies that look at bone remodeling markers other than BMD or BMC.

Muñoz-Garach, A., García-Fontana, B., & Muñoz-Torres, M. (2020). Nutrients and Dietary Patterns Related to Osteoporosis. Nutrients, 12(7), 1986. https://doi.org/10.3390/nu12071986

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Dietary inclusion of whole soy foods results in significant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal postmenopausal women

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Dietary inclusion of whole soy foods results in significant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal postmenopausal women

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Ellen Reusch
When searching for articles for this week's weekly wall posting, I found several articles discussing the importance of soy in reducing the risk for osteoporosis. This particular article caught my eye, and discusses the importance of soy foods and how when included in a diet they can reduce risk factors for women to develop osteoporosis. (Additionally, this article touched on cardiovascular disease risk, another topic we have covered in this class!).

For this particular study, 42 postmenopausal women were observed. They consumed soy three times daily for 12 weeks, and blood and urine specimens were obtained from each patient at baseline and at the 12 week timepoint. Researchers found that the women's levels of isoflavones increased, HDL levels increased, and osteocalcin levels increased (all clinically significant). The participants' total cholesterol to HDL ratios were generally decreased. Additionally, higher levels of isoflavones correlated with lower levels of LDL and triglycerides. Overall, the study found that the inclusion of soy in a diet on a regular basis could lead to metabolic changes that resulted in lower risk for developing cardiovascular disease or osteoporosis. Osteoporosis is a common disease amongst postmenopausal women, and usually there are not very many treatment options available. Also, osteoporosis can place people at greater risk for severe fractures as they age, meaning that nutritional treatments and management for osteoporosis could be extremely beneficial to the medical community as a whole. Physicians and care providers could use this information from this study to help encourage otherwise normal patients who are at risk for developing osteoporosis (or with a family history of osteopenia or osteoporosis) to increase their daily soy intake.

Scheiber, Michael, et. al., Dietary inclusion of whole soy foods results in significant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal postmenopausal women. Menopause: The Journal of the North American Menopause Society. 2001. Vol. 8, No. 5, pp 384-392. https://journals.lww.com/menopausejournal/Fulltext/2001/09000/Dietary_inclusion_of_whole_soy_foods_results_in.15.aspx

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Ivana Djuricic: Second Hand Smoke and Osteoporosis

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Ivana Djuricic: Second Hand Smoke and Osteoporosis

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Kim, K. H et al. “Secondhand Smoke Exposure and Osteoporosis in Never-Smoking Postmenopausal Women: The Fourth Korea National Health and Nutrition Examination Survey.” Osteoporosis international 24.2 (2012): 523–532. Web.

This study looked at the effects of second hand smoke in postmenopausal Korean women, they excluded current smokes and past smokers because they considered active smoking as a possible confounder. This study is important because we know a lot about how active smoking affects the bones, but it is also important to see how living with a smoker and being around that smoke will affect your health.

The key finding of this study is that second hand smoke increased your risk of developing osteoporosis, as measured by bone mineral density, compared to those who have never been exposed and your bone health declines as the number or frequency of smokers/smoking in the house increases.

This relates to nutritional sciences as part of getting a patients history should include, not only if they are active or past smokers, but also if they live with smokers. Do the people they live with smoke inside the house or outside? This way the nutritional plan for these patients can include higher vitamin D and calcium in the diet to make up for possible bone loss. Clinical implications are that the care plan for these patients, older women who live with smokers, should evaluate them for bone mineral density and take into account the effects of smoke just as you would do for an active smoker when it comes to osteoporosis.

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Specific Collagen Peptides Improve Bone Mineral Density and Bone Markers in Postmenopausal Women

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Specific Collagen Peptides Improve Bone Mineral Density and Bone Markers in Postmenopausal Women

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Posted by Mitchell Watts

This randomized controlled trial investigated the effect of 12 month daily oral administration of 5 gm of FORTIBONE specific collagen peptides (SCP) vs. placebo on bone mineral density (BMD) in 102 postmenopausal women with age-related reduction in BMD. I looked at the FORTIBONE website, and they claim that this supplement stimulates osteoblast activity to increase the production of the extracellular bone matrix. The primary endpoint of this study was the change in BMD in the femoral neck and spine after 12 months, and changes in plasma levels of bone markers - P1NP (measure of bone formation) and CTX 1 (measure of bone resorption). What they found is that SCP supplementation led to a significant increase in BMD of the spine and neck compared to control, P1NP increased significantly in the SCP group, and CTX 1 increased significantly in the control group. Therefore, they concluded that SCP supplementation demonstrated increased BMD and led to a favorable shift in bone markers, indicating increased bone formation and reduced bone degradation. Additionally, another investigation found that using a supplement with a combination of collagen, calcium, and vitamin D led to a substantially lower loss of BMD. Clinically, this is important as this can be an adjunct to other lifestyle changes and pharmacotherapy. While basic changes like increased physical activity, consuming a balanced, calcium-rich diet, and reducing intake of alcohol and nicotine may protect against BMD; this supplement may help lead to bone formation.

1. König, D., et al. (2018). Specific Collagen Peptides Improve Bone Mineral Density and Bone Markers in Postmenopausal Women-A Randomized Controlled Study. Nutrients, 10(1), 97.

2. www.gelita.com/en (FORTIBONE)

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Affiliations

¹ Department for Nutrition, Institute for Sports and Sports Science, University of Freiburg, Schwarzwaldstr. 175, 79117 Freiburg, Germany. Daniel.Koenig@sport.uni-freiburg.de.

² CRI, Collagen Research Institute GmbH, Schauenburgerstr. 116, 24118 Kiel, Germany. steffen.oesser@cri-mail.org.

³ Independent Reasercher, Salinenstr. 8, 83435 Bad Reichenhall, Germany. SScharla@gmx.de.

⁴ Department for Nutrition, Institute for Sports and Sports Science, University of Freiburg, Schwarzwaldstr. 175, 79117 Freiburg, Germany. Denise.Zdzieblik@sport.uni-freiburg.de.

⁵ Department for Nutrition, Institute for Sports and Sports Science, University of Freiburg, Schwarzwaldstr. 175, 79117 Freiburg, Germany. AG@sport.uni-freiburg.de.

Free PMC article

Free PMC article

Affiliations

¹ Department for Nutrition, Institute for Sports and Sports Science, University of Freiburg, Schwarzwaldstr. 175, 79117 Freiburg, Germany. Daniel.Koenig@sport.uni-freiburg.de.

² CRI, Collagen Research Institute GmbH, Schauenburgerstr. 116, 24118 Kiel, Germany. steffen.oesser@cri-mail.org.

³ Independent Reasercher, Salinenstr. 8, 83435 Bad Reichenhall, Germany. SScharla@gmx.de.

⁴ Department for Nutrition, Institute for Sports and Sports Science, University of Freiburg, Schwarzwaldstr. 175, 79117 Freiburg, Germany. Denise.Zdzieblik@sport.uni-freiburg.de.

⁵ Department for Nutrition, Institute for Sports and Sports Science, University of Freiburg, Schwarzwaldstr. 175, 79117 Freiburg, Germany. AG@sport.uni-freiburg.de.

Abstract

Introduction: Investigations in rodents as well as in vitro experiments have suggested an anabolic influence of specific collagen peptides (SCP) on bone formation and bone mineral density (BMD). The goal of the study was to investigate the effect of 12-month daily oral administration of 5 g SCP vs. placebo (CG: control group) on BMD in postmenopausal women with primary, age-related reduction in BMD. Methods: 131 women were enrolled in this randomized, placebo-controlled double-blinded investigation. The primary endpoint was the change in BMD of the femoral neck and the spine after 12 months. In addition, plasma levels of bone markers-amino-terminal propeptide of type I collagen (P1NP) and C-telopeptide of type I collagen (CTX 1)-were analysed. Results: A total of 102 women completed the study, but all subjects were included in the intention-to-treat (ITT) analysis (age 64.3 ± 7.2 years; Body Mass Index, BMI 23.6 ± 3.6 kg/m²; T-score spine -2.4 ± 0.6; T-score femoral neck -1.4 ± 0.5). In the SCP group ( n = 66), BMD of the spine and of the femoral neck increased significantly compared to the control group ( n = 65) (T-score spine: SCP +0.1 ± 0.26; CG -0.03 ± 0.18; ANCOVA p = 0.030; T-score femoral neck: SCP +0.09 ± 0.24; CG -0.01 ± 0.19; ANCOVA p = 0.003). P1NP increased significantly in the SCP group ( p = 0.007), whereas CTX 1 increased significantly in the control group ( p = 0.011). Conclusions: These data demonstrate that the intake of SCP increased BMD in postmenopausal women with primary, age-related reduction of BMD. In addition, SCP supplementation was associated with a favorable shift in bone markers, indicating increased bone formation and reduced bone degradation.

Keywords: SCP; bone marker; collagen hydrolysate; osteoporosis; protein supplementation.

Conflict of interest statement

Daniel König, Steffen Oesser, Stephan Scharla, Denise Zdzieblik and Albert Gollhofer declare that they have no conflict of interest.

References

Hernlund E., Svedbom A., Ivergard M., Compston J., Cooper C., Stenmark J., McCloskey E.V., Jönsson B., Kanis J.A. Osteoporosis in the European Union: Medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA) Arch. Osteoporos. 2013;8:136. doi: 10.1007/s11657-013-0136-1. - DOI - PMC - PubMed

Kreutle V., Blum C., Meier C., Past M., Müller B., Schütz P., Borm K. Bisphosphonate induced hypocalcaemia - report of six cases and review of the literature. Swiss Med. Wkly. 2014;144:w13979. doi: 10.4414/smw.2014.13979. - DOI - PubMed

Kaehling C., Streckbein P., Schmermund D., Henrich M., Burchert D., Gattenloehner S., Howaldt H.P., Wilbrand J.F. Lethal cervical abscess following bisphosphonate related osteonecrosis of the jaw. J. Cranio-Maxillofac. Surg. 2014;42:1203-1206. doi: 10.1016/j.jcms.2014.02.009. - DOI - PubMed

Rachner T.D., Platzbecker U., Felsenberg D., Hofbauer L.C. Osteonecrosis of the jaw after osteoporosis therapy with denosumab following long-term bisphosphonate therapy. Mayo Clin. Proc. 2013;88:418-419. doi: 10.1016/j.mayocp.2013.01.002. - DOI - PubMed

Montagnani A. Bone anabolics in osteoporosis: Actuality and perspectives. World J. Orthop. 2014;5:247-254. doi: 10.5312/wjo.v5.i3.247. - DOI - PMC - PubMed

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dietary carbohydrates / administration & dosage

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dietary proteins / administration & dosage

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national center for biotechnology information

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Specific Collagen Peptides Improve Bone Mineral Density and Bone Markers in Postmenopausal Women-A Randomized Controlled Study - PubMed

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Introduction: Investigations in rodents as well as in vitro experiments have suggested an anabolic influence of specific collagen peptides (SCP) on bone formation and bone mineral density (BMD). The goal of the study was to investigate the effect of 12-month daily oral administration of 5 g S ...

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The Mediterranean Diet in Osteoporosis Prevention: An Insight in a Peri- and Post-Menopausal Population-Ashley Wahlman

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The Mediterranean Diet in Osteoporosis Prevention: An Insight in a Peri- and Post-Menopausal Population-Ashley Wahlman

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In the study I looked at the Mediterranean diet was applied to both pre and post menopausal women. As we know post menopausal women experience osteoporosis due to low estrogen levels. They found in this study that higher levels of mediterranean diet adherence equivocated to an increase in calcium level which is important for bone strength. As we know this relates to nutritional sciences as an increase in a Mediterranean diet has a lot of beneficial effects as we have seen through other studies as well as bone health. This type of diet offers an increase in calcium which is important for bone strength. The clinical implication is that I think this could help women a lot who are going through menopause adhering to a diet such as this could act as preventive measure for osteoporosis and trying strengthen their bones.
References:
Quattrini, S., Pampaloni, B., Gronchi, G., Giusti, F., & Brandi, M. L. (2021). The Mediterranean Diet in Osteoporosis Prevention: An Insight in a Peri- and Post-Menopausal Population. Nutrients, 13(2), 531. https://doi.org/10.3390/nu13020531

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Early diet and peak bone mass: 20 year follow-up of a randomized trial of early diet in infants born preterm - Esraa Zamzami

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Early diet and peak bone mass: 20 year follow-up of a randomized trial of early diet in infants born preterm - Esraa Zamzami

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Although this article is not recent, I found it very interesting. This research is a randomized controlled trial investigating the influence of human milk on bone mass and bone size later in life. Although the study was performed on preterm infants, the authors see no reason for not generalizing the outcomes to all preterm and term infants. The key finding of this study is that infants who consumed a greater amount of breast milk had better bone mass and size when they grew up; the relation is proportional. The rationale behind this effect was thought to be because of all the hormones that human milk contains and not because of the mineral content since human milk is considered low calcium and low phosphorus. The study demonstrates the importance of breastfeeding, and its influence is seen not only within the first few years of life but also in adulthood. Lastly, it is always important to encourage breastfeeding since formula milk cannot replace human milk's benefits.

Fewtrell, M. S., Williams, J. E., Singhal, A., Murgatroyd, P. R., Fuller, N., & Lucas, A. (2009). Early diet and peak bone mass: 20 year follow-up of a randomized trial of early diet in infants born preterm. Bone, 45(1), 142–149. https://doi.org/10.1016/j.bone.2009.03.657

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Osteoporosis and sarcopenia: two diseases or one?

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Osteoporosis and sarcopenia: two diseases or one?

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https://journals.lww.com/co-clinicalnutrition/Fulltext/2016/01000/Osteoporosis_and_sarcopenia__two_diseases_or_one_.7.aspx

Posted by Richard Proudfoot

For this week, the research paper selected is titled: “Osteoporosis and sarcopenia: two diseases or one?” This January 2016, article was published in the Current Opinion in Clinical Nutrition and Metabolic Care, (2016), 31-36, 19(1). The authors are Jean-Yves Reginster, Charlotte Beaudart, Fanny Buckinx, and Olivier Bruye`re Their affiliations are Department of Public Health, Epidemiology and Health Economics and Support Unit in Epidemiology and Biostatistics, University of Lie`ge, Lie`ge, Belgium.

This is article is a review of recently published evidence about common pathways explaining bone and muscle wasting in normal ageing and pathological conditions.

This study is important because numerous studies support the concept of a bone-muscle unit; where constant cross-talking between the two tissues takes place, involving molecules released by the skeletal muscle secretome, which affects bone, and osteokines secreted by the osteoblasts and osteocytes, which, in turn, impact muscle cells.

The key findings from this study are future efforts to find treatments should aim at the concomitantly treating osteoporosis and sarcopenia could be developed by targeting pathways that centrally regulate bone and muscle or emerging pathways that facilitate the communication between the two tissues. These findings relate to nutritional sciences because the authors acknowledge the here is a need to ensure a balanced diet providing enough proteins, vitamin D and key nutrients and to recommend regular physical exercise.

Clinical implication of this study is osteoporosis and sarcopenia pre-dominantly affects elderly patients and are responsible for a major clinical and financial burden. Increase in life expectancy in most countries and in both sexes makes their diagnosis, prevention, and treatment a major social and ethical, yet unmet, medical need.¹  Posted by Richard Proudfoot

1.          Reginster JY, Beaudart C, Buckinx F, Bruyère O. Osteoporosis and sarcopenia: Two diseases or one? Current Opinion in Clinical Nutrition and Metabolic Care. 2016;19(1):31-36. doi:10.1097/MCO.0000000000000230

https://journals.lww.com/co-clinicalnutrition/Fulltext/2016/01000/Osteoporosis_and_sarcopenia__two_diseases_or_one_.7.aspx

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Katelyn Spain: High Vitamin C Intake Is Associated with Lower 4-Year Bone Loss in Elderly Men

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Katelyn Spain: High Vitamin C Intake Is Associated with Lower 4-Year Bone Loss in Elderly Men

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The purpose of this study was to determine if consumption of high levels of vitamin C would significantly decrease bone loss in elderly men. Vitamin C has been found essential for collagen formation and bone development. Previous studies have shown that a diet with higher intake of fruits and vegetables are associated with a more positive effect on bone. Fruits and vegetables contain vitamin C, which is said to decrease oxidative stress and decrease bone-resorption. This leads to the idea that vitamin C could be crucial in preventing osteoporosis. In this study it was found that elerdly men, who did not smoke, were found to have lower femoral neck bone loss with an increased supplementation of dietary vitamin C. This study also looked at elderly women, but could not find significant associations between vitamin C and bone loss. Based on these results, the clinical implications of this study are for physicians to recommend higher intake of vitamin C in elderly, male patients to prevent bone loss. This increased intake can be through diet and/or supplementation. This could potentially decrease the risk of osteoporosis in elderly men and/or if already diagnosed with bone loss, could help with the rebuilding of bone.

Sahni, S., Hannan, M. T., Gagnon, D., Blumberg, J., Cupples, L. A., Kiel, D. P., & Tucker, K. L. (2008). High vitamin C intake is associated with lower 4-year bone loss in elderly men. The Journal of nutrition, 138(10), 1931–1938. https://doi.org/10.1093/jn/138.10.1931

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J Nutr. Author manuscript; available in PMC 2009 Sep 25.

Published in final edited form as:

Abstract

Vitamin C is essential for collagen formation and normal bone development. We evaluated associations of total, supplemental, and dietary vitamin C intake with bone mineral density (BMD) at the hip [femoral neck, trochanter], spine, and radial shaft and 4-y BMD change in elderly participants from the Framingham Osteoporosis Study. Energy-adjusted vitamin C intakes were estimated from the Willett FFQ in 1988-89. Mean BMD and 4-y BMD change was estimated, for men and women, by tertile/category of vitamin C intake, adjusting for covariates. We tested for interaction with smoking, calcium, and vitamin E intake. Among 334 men and 540 women, the mean age was 75 y and mean vitamin D intake was 8.25 µg/d (women) and 8.05 µg/d (men). We observed negative associations between total and supplemental vitamin C intake and trochanter-BMD among current male smokers ( P-trend = 0.01). Among male nonsmokers, total vitamin C intake was positively associated with femoral neck BMD ( P-trend = 0.04). Higher total vitamin C intake was associated with less femoral neck and trochanter-BMD loss in men with low calcium (all P-trend ≤ 0.03) or vitamin E intakes (all P-trend = 0.03). Higher dietary vitamin C intake tended to be associated with lower femoral neck-BMD loss ( P-trend = 0.09). These associations were attenuated but retained borderline significance ( P-trend < 0.1) after adjusting for potassium intake (a marker of fruit and vegetable intake), suggesting that vitamin C effects may not be separated from other protective factors in fruit and vegetables. Null associations were observed among women. These results suggest a possible protective role of vitamin C for bone health in older men.

Introduction

It has been estimated that almost 10 million Americans have osteoporosis ( 1) and low bone mass is a major public health threat for almost 44 million people in the U.S. population aged ≥ 50 y. Studies have consistently shown that higher fruit and vegetable intake has positive effects on bone mineral status ( 2- 9) and that fruit- and vegetable-specific antioxidants, such as vitamin C, may decrease oxidative stress ( 10- 12) arising from reactive oxygen intermediates that may be involved in the bone-resorptive process ( 13- 15). Therefore, vitamin C might help in preventing osteoporosis ( 16). In addition, bone matrix contains over 90% of protein as collagen ( 17) and it is well established that vitamin C is an essential cofactor for collagen formation and synthesis of hydroxyproline and hydroxylysine required for the formation of stable triple helixes ( 18). Furthermore, animal studies have demonstrated that experimental deficiency of vitamin C leads to impaired bone mass, cartilage, and connective tissue ( 19, 20).

Several epidemiologic studies have examined the association of vitamin C in relation to bone mineral density (BMD) ( 21- 26). However, results from these studies have been mixed, indicating a complex association involving interaction of both total and dietary vitamin C with nutritional and nonnutritional factors. Because vitamin C supplements may be used more frequently by individuals with other risk factors for bone loss (e.g. smoking), we sought to examine the effects of vitamin C from both dietary intakes as well as from total vitamin C intakes including supplements. Therefore, in this study, we examined associations between vitamin C intake (total, supplemental, and dietary intake) and cross-sectional, as well as longitudinal, changes in BMD at the hip, spine, and radial shaft in men and women in the Framingham Osteoporosis Study. Furthermore, we examined these associations for effect modification by smoking status, total calcium and vitamin E intake, and current estrogen use (in women).

Methods

The Framingham Osteoporosis Study is an ancillary study of the Framingham Heart Study, a population-based cohort study, which began in 1948 to examine risk factors for heart disease. The original subjects (5209 men and women aged 28-62 y) were selected as a population-based random sample of two-thirds of the households in Framingham, Massachusetts, and have been examined biennially for >50 y ( 27). Of the 1402 surviving subjects from the original cohort, 1164 cohort members participated in the Framingham Osteoporosis Study, when BMD measurements were made at the 20th biennial examination ( Fig. 1 ). We excluded subjects with missing FFQ ( n = 333), with incomplete FFQ (based on the criteria of >12 food items left blank in the FFQ), or with energy intakes <2.51 or >16.74 MJ (<600 or >4000 kcal/d) ( n = 92) at the 20th exam. We further excluded subjects with missing BMD measurements (111 subjects for femoral neck BMD, 123 for trochanter BMD, 91 for radial shaft BMD, and 288 for lumbar spine BMD) and 24 participants were excluded due to missing covariate information (BMI, physical activity index, multivitamin use, smoking status, or estrogen use). There were no study participants taking medications during our baseline examination in 1988-89 that were known to influence bone metabolism other than estrogen use in some women. The final analytic sample for cross-sectional analyses included 334 men and 540 women with a complete FFQ and BMD measurement at exam 20. Longitudinal analyses were confined to 213 men and 393 women who had FFQ at the 20th examination and BMD measurement at examinations 20 and 22. All participants gave informed consent for their participation in the study. The Institutional Review Board for Human Research at Boston University, Hebrew Rehabilitation Center, and Tufts University approved this study.

Assessment of BMD

BMD (g/cm ²) was measured in the original cohort in 1988-89 (exam 20) and 1992-93 (exam 22), at the femur, spine, and radius as previously described ( 28, 29). BMD of the proximal right femur (femoral neck, trochanter) and lumbar spine (average L2 to L4) were measured in g/cm ² using a Lunar DP3 dual-photon absorptiometer at baseline. At the 4-y follow-up exam, BMD was measured using dual X-ray absorptiometry (DPX-L, Lunar Radiation). There were strong correlations between measures taken with dual photon and dual X-ray absorptiometry, but due to a small but consistent shift in BMD values between the 2 methods, femoral BMD were adjusted for a change from dual-photon absorptiometer to dual X-ray absorptiometry technology using published corrections ( 30). BMD at the radial shaft was measured in g/cm ² with a Lunar SP2 single-photon absorptiometer (Lunar Radiation) at both examinations.

Assessment of dietary intake

Usual dietary intake was assessed in 1988-89 with a semiquantitative, 126-item Willett FFQ ( 31). Questionnaires were mailed to the study participants. They were asked to complete them, based on their intake over the previous year, and to bring them to the examination where they were reviewed with participants by clinic staff. This FFQ has been validated for many nutrients and in several populations against multiple diet records and blood measures ( 32, 33). Intake of vitamin C (mg/d), total calcium (mg/d), vitamin D (µg/d), vitamin E (mg tocopherol equivalents (TE)/d), caffeine (mg/d), alcohol (g/d), potassium (mg/d), and total energy (MJ) was assessed using the food list section of the FFQ. Based on their alcohol intake, subjects were categorized as nondrinker, moderate drinker (<13.2 g/d of alcohol for women and <26.4 g/d of alcohol for men), or heavy drinker (≥13.2 g/d of alcohol for women and ≥26.4 g/d of alcohol for men) based on cut-offs recommended by dietary guidelines for Americans ( 34). Intake of multivitamin supplements, as recorded on the supplement section of the FFQ, was coded as a yes-no variable. Intake of vitamin C from supplements was categorized into groups based on the estimated average requirements for vitamin C ( 35) (group 1, nonsupplement users; group 2, intake <75 mg/d among women and <90 mg/d among men; group 3, intake ≥75 mg/d among women and ≥90 mg/d among men).

Potentially confounding factors

Previous studies on this cohort have reported several risk factors for osteoporosis, including age (y), female sex ( 29), BMI ( 36), smoking ( 37), caffeine ( 38), alcohol ( 39), current estrogen use in women ( 29), low physical activity ( 40), and low intake of calcium and vitamin D ( 41, 42). BMI (kg/m ²), a known risk factor for osteoporosis, was calculated in the Framingham Study from measurements of height at exam 1 (1948-1949), measured without shoes, in inches, and measurements of weight taken at the 20th examination in pounds (converted to kilograms) with a standardized balance-beam scale. Because BMI is a measure of relative weight designed to be independent of height, we included both BMI and height at exam 1 (converted to meters) in our equations to adjust for ponderosity and body stature, which may be related to dietary intake and BMD ( 4).

Smoking status was assessed via questionnaire in 1988-89 as current cigarette smoker (smoked regularly in the past year), former smoker, or never smoked. Physical activity was measured with the Framingham physical activity index as an estimated measure of energy expenditure calculated from questions about number of hours spent in heavy, moderate, light, or sedentary activity and number of hours spent sleeping during a typical day ( 4). The physical activity index at the 1986-87 exam (exam 19) was used for the subjects who had a missing physical activity index at the 1988-89 exam (exam 20). Women were divided into 2 groups: those currently using estrogen who had been using continuously for >1 y and those who had never used estrogen, had used it previously, or had used it only for a short time, because there is evidence that past use does not sustain bone benefits ( 43). A previous study by our group supported the hypothesis that alkaline-producing dietary components such as potassium, present in fruits and vegetables, play a beneficial role in bone health ( 6). Therefore, final models were adjusted for potassium intake to examine if the association of vitamin C intake with BMD was independent of this measure of dietary quality. Previous research has indicated that there are seasonal changes in BMD in New England ( 44). Therefore, for the cross-sectional analyses, we created a categorical variable for the time of BMD measurement: July, August, and September were coded as summer; October, November, and December as fall; January, February, and March as winter; and April, May, and June as spring.

Statistical analysis

Total and dietary vitamin C intakes were adjusted for total energy intake using the residual method ( 45). Logarithmic transformation was applied to total vitamin C intake and square root transformation was applied to the dietary vitamin C intake, to achieve normality, before creating residuals.

Mean BMD measures were estimated for men and women combined and separately by tertiles of total and dietary vitamin C intake, and by defined categories of supplemental vitamin C, using the General Linear Models procedure in SAS. We regressed each of the 4 BMD measures onto the continuous and categorical measures of energy-adjusted total vitamin C intake, adjusting for potential confounders and covariates. We also regressed baseline BMD on intake of vitamin C from supplements as well as from diet in the same model. Analyses were adjusted for multiple comparisons using Dunnett's adjustment. Test of trend across tertiles was conducted using the median measure for each of the tertiles. We regressed change in BMD (BMD at exam 22 - BMD at exam 20) onto the continuous and categorical energy-adjusted total vitamin C and then the dietary vitamin C and supplemental vitamin C intake variables, adjusting for potential confounders and covariates.

All models were adjusted for age, BMI, height at exam 1, total energy intake, physical activity index, smoking, and intake of total calcium, total vitamin D, caffeine, and alcohol, multivitamin use, season of BMD measurement (for cross-sectional analyses on BMD only), and estrogen use (in women). Models for supplemental vitamin C were also adjusted for dietary vitamin C intake. All analyses were performed using SAS statistical software (SAS Institute, version 9.1, 2001). A nominal 2-sided P-value <0.05 was considered significant for all the analyses.

We tested the associations for effect modification by sex, smoking status, total calcium intake, total vitamin E intake, and estrogen use. Previous studies identified smoking status, estrogen use ( 21), total calcium intake ( 22), and total vitamin E ( 46) as important effect modifiers. Because we were testing multiple interactions, only those that were significant at P < 0.01 were examined further, to avoid false positives.

Results

Subject characteristics

Women represented two-thirds (62%) of the study sample. The mean age of men and women was 75 y and mean BMI was 24.9 (for women) and 26.2 (for men) ( Table 1 ). Approximately one-third of women and men reported education beyond high school. One-half of the women and two-thirds of the men reported alcohol use, whereas more than one-half of the women and three-fourths of the men reported ever having smoked cigarettes. Most women (95%) reported no estrogen use. Approximately one-fourth of men and women reported multivitamin supplement use. The mean intake of calcium was 831 mg/d in women and 763 mg/d in men.

TABLE 1

Descriptive variables

Men²

Women²

Age, y

75.3 ± 5.0

75.5 ± 5.0

BMI, kg/m²

26.2 ± 3.9

24.9 ± 4.7

Total energy, MJ/d

7.8 ± 2.6

7.0 ± 2.3

Dietary vitamin C, mg/d

140.8 ± 73

158.2 ± 83

Supplemental vitamin C, mg/d

81.8 ± 235

95.1 ± 248

BMD at baseline, ⁵ g/cm²

4-y change in BMD, ⁶ g/cm²

Cross-sectional analyses of BMD

We observed several statistically significant 3-way interactions between vitamin C (total, supplemental, and dietary), sex, and smoking status ( P ranged from 0.003 to 0.02 at 3 of the 4 bone sites examined). Therefore, we continued with separate analyses for men and women. Sex-specific analyses were further tested for interaction with total calcium and vitamin E intake, smoking status, and current estrogen use.

Among men who never smoked, total vitamin C intake was positively associated with femoral neck BMD ( P-trend = 0.04) (data not shown). In contrast, total vitamin C ( Table 2 ) and supplemental vitamin C intake ( Table 3 ) were negatively associated with trochanter BMD among current smokers ( P-trend = 0.01 for total and supplemental vitamin C intake). No cross-sectional associations were observed between vitamin C intake and BMD among women ( P > 0.05).

TABLE 2

Site of BMD (g/cm³)
measurement

n

Tertiles of total vitamin C intake²

P-trend

1st tertile

2nd tertile

3rd tertile

Femoral neck

85

0.86 ± 0.04 ²

0.85 ± 0.03

0.94 ± 0.03

0.04

Trochanter

29

0.94 ± 0.07

0.84 ± 0.08

0.68 ± 0.07*

0.01

TABLE 3

Site of BMD (g/cm²)
measurement

n

Categories of supplemental vitamin C intake³

P-trend

1st tertile

2nd tertile

3rd tertile

4-y change in BMD

Interactions were observed for dietary vitamin C and sex ( P for interaction = 0.05) and for dietary vitamin C and total calcium intake ( P for interaction = 0.009 at radial shaft). We therefore continued with our analyses separately for men and women. Among men, an interaction was observed for total vitamin C and calcium intake (low calcium group: intake < median intake of 661 mg/d, high calcium group: intake > median intake) ( P for interaction = 0.001 at the radial shaft) as well as for total vitamin C and vitamin E intake (low vitamin E group: intake < median intake of 7.7 mg TE/d, high vitamin E group: intake > median intake) ( P for interaction = 0.003 at the radial shaft). No significant interactions were observed with smoking status among men or women or with estrogen use among women at P > 0.01.

Among men with low calcium intake, higher total vitamin C intake was associated with less BMD loss at the femoral neck ( P-trend = 0.03) and trochanter ( P-trend = 0.02) ( Fig. 2 ). Similarly, among men with low total vitamin E intake, higher total vitamin C intake was associated with less BMD loss at the femoral neck ( P-trend = 0.03) and trochanter ( P-trend = 0.03) ( Fig. 3 ). In contrast, no associations were observed among men with high calcium intake, men with high vitamin E intake, or among women. No significant longitudinal associations were observed for supplemental vitamin C intake among men or women ( P > 0.05).

Among men, significant associations were observed for dietary vitamin C (adjusting for supplemental intake of vitamin C) and BMD at multiple bone sites. Higher dietary vitamin C intake was associated with less BMD loss at the trochanter ( P-trend = 0.05) and lumbar spine ( P-trend = 0.04) and tended to be associated with less BMD loss at the femoral neck ( P-trend = 0.09) ( Fig. 4 ). However, no associations were observed among women ( P > 0.05). When these analyses were repeated among nonsupplement users, we observed an interaction of dietary vitamin C intake with total vitamin E intake ( P for interaction = 0.0006 at the radial shaft). Also, higher dietary vitamin C intake tended to be associated with less BMD loss at the trochanter ( P-trend = 0.08) among men with low total vitamin E intake (data not shown). However, no associations were observed at other bone sites among men with high vitamin E intakes or among women.

After adjustment for potassium intake, the negative cross-sectional association between total and supplemental vitamin C intake and trochanter BMD in current smokers did not change. However, the positive association of total vitamin C among those who never smoked lost significance ( P > 0.10). In longitudinal analyses, the protective association of total vitamin C in men with low calcium intake was attenuated ( P-trend = 0.07 for femoral neck and 0.06 for trochanter BMD). The protective association of total vitamin C in men with low total vitamin E intake was attenuated for trochanter BMD ( P-trend = 0.06) but did not change for femoral neck BMD. Similarly, the marginal protective association of dietary vitamin C in men did not change for femoral neck BMD but lost significance at other bone sites ( P > 0.10 for trochanter and lumbar spine BMD). Among nonsupplement-using men with low vitamin E intakes, the protective association of dietary vitamin C lost significance after adjustment for potassium intake ( P > 0.10 for trochanter).

Discussion

We observed an unexpected negative cross-sectional association of total vitamin C and supplemental vitamin C intake with trochanter BMD among men who were current smokers. In contrast, dietary vitamin C appeared to be protective against 4-y losses in BMD among men, whereas total vitamin C appeared to be protective only among men with low calcium or vitamin E intakes. These protective associations were attenuated after adjustment for potassium intake.

Studies have consistently shown that higher fruit and vegetable intakes have positive effects on bone mineral status ( 2- 7). Maggio et al. ( 24) observed that antioxidant defenses are markedly decreased in osteoporotic women. New et al. ( 9) reported lower mean pyridinoline excretion (a marker for bone resorption) with higher intakes of total vitamin C compared with low intakes ( P < 0.02). Fruit- and vegetable-specific antioxidants may, therefore, play a role in osteoporosis prevention or treatment ( 47). Hence, more studies are required to clarify the role of fruit- and vegetable-specific antioxidants such as vitamin C in the prevention of osteoporosis.

Observational studies of vitamin C and bone have reported mixed results. Studies on vitamin C intake from supplements have provided some evidence of a protective role in bone health. However, this association has appeared to be complex, due to interactions with estrogen use and calcium intake. For example, 1 population-based study ( n = 994 postmenopausal women) reported that vitamin C supplement users had higher BMD (3%) at the radius, femoral neck, and total hip ( P < 0.05) than nonusers ( 25). They also reported that women with both estrogen and vitamin C intake from supplements had higher BMD at all sites and women taking supplemental vitamin C plus calcium and estrogen had the highest BMD. Another study ( 23) reported that longer duration of vitamin C supplement use was associated with higher BMD in women who had not used estrogen replacement therapy ( P-trend = 0.02) and among women aged 55-64 y ( P-trend = 0.01). In the latter group, women who used vitamin C supplements for ≥10 y had higher BMD than nonusers in the same age group ( P = 0.02). In contrast, negative cross-sectional associations existed for supplemental vitamin C intake among men who were current smokers, but there were no significant longitudinal associations for supplemental vitamin C in men or women.

In contrast to our findings that vitamin C appeared protective only in those with low calcium or vitamin E intake, the Postmenopausal Estrogen/Progestin Interventions Trial found that dietary vitamin C was associated with BMD at the femoral neck ( P = 0.002) and total hip ( P = 0.01) only in subjects with higher calcium intake ( 22). The Women's Health Initiative Study ( 26) reported no significant association between dietary or total vitamin C and BMD. However, in contrast with our lack of interaction, they reported a beneficial effect of current hormone therapy on BMD at the femoral neck ( P = 0.004), total body ( P < 0.04), spine ( P = 0.03), and total hip ( P = 0.02) that was stronger with higher intakes of total vitamin C (interaction P < 0.01). Similarly, Leveille et al. ( 23) found no evidence of association of dietary or total vitamin C intake with BMD. We observed a positive association between total vitamin C and BMD among those who never smoked. However, we found an unexpected negative association between vitamin C intake (total and supplemental) and BMD among male smokers. It is possible that these observations reflect reverse causation, because smokers, with concomitant low BMD, consciously increase their vitamin C intake in the hopes of mitigating some of smoking's negative effects. It is important to note that the level of dietary intake of vitamin C among subjects in our study was similar to the intake level reported by Hall and Greendale in the Postmenopausal Estrogen/Progestin Interventions Trial study ( 22) as well as by Zhang et al. ( 48) in the Utah Study of Nutrition and Bone Health, a statewide, population-based, case-control study. The level of dietary intake of vitamin C in our study was higher than the levels reported in 2 other studies (a study of Swedish women aged 40-76 y and female participants from the Women's Health Initiative) ( 26, 46). For total vitamin C intake, the level among subjects in our study was ~29% higher than the intake level reported by the Utah Study of Nutrition and Bone Health ( 48) but was ~44% less than the levels reported by the Women's Health Initiative ( 26). Additionally, the intake of fruit and vegetables among men in our study were slightly lower than those reported for men (aged 51-70 y) in the NHANES (1999-2000). However, the intake of fruit and vegetables among women in our study and in the NHANES Survey (1999-2000) was comparable ( 49).

Together, these results suggest that effects of vitamin C on bone appear to be complex and that they may interact with smoking ( 21, 48), estrogen use/hormonal therapy after menopause ( 21, 25, 26), calcium intake ( 22, 25), and vitamin E intake ( 46). We found significant interactions between vitamin C intake (total, supplemental, and dietary), sex, and smoking status in cross-sectional analyses. Significant positive associations were observed for total vitamin C among men who never smoked, with negative associations for total vitamin C among men who currently smoked. However, these interactions did not appear in the longitudinal analyses. Rather, the longitudinal analyses revealed protective effects of total vitamin C intake on 4-y change in femoral neck BMD as well as trochanter BMD, which was most evident in men with low calcium or vitamin E intakes. We also observed a greater protective effect of dietary relative to supplemental vitamin C against bone loss in men. Not surprisingly, adjustment for potassium intake, as a marker of fruit and vegetable intake and dietary quality, led to attenuation of most of these results, suggesting that whatever positive effects of vitamin C we observe may not be able to be separated from those of a good quality diet.

There are, however, physiologic reasons to expect protective effects from vitamin C. Oxidative stress may increase bone resorption through activation of nuclear factor-κB protein, which is a crucial mediator of tumor necrosis factor-α and osteoclastogenetic activity ( 50- 53). Vitamin C is capable of reducing oxidative stress and therefore may affect bone health by inhibiting bone resorption. Furthermore, bone matrix contains over 90% of protein as collagen ( 17) and vitamin C is an essential cofactor for collagen formation and for the synthesis of hydroxyproline and hydroxylysine required for the formation of stable triple helixes ( 18).

The current study is unique in that it used data from a population-based cohort that included men as well as women and has both cross-sectional and longitudinal analyses. However, as in any observational study, residual confounding may occur despite control for several major potential confounders.

In summary, we did not observe any significant effects of vitamin C intake on BMD in women. In men, we observed effects only in interaction with smoking, suggesting that smokers with low BMD are using more vitamin C supplements. Consistent with previous findings of protective effects of fruit and vegetables, we observed protective associations between vitamin C intake and 4-y change in femoral neck BMD as well as trochanter BMD among men with low calcium or vitamin E intakes. The dietary rather than the supplement component of vitamin C intakes appeared most strongly protective against bone loss. Additional adjustment for dietary quality (adjustment for potassium intake) weakened these associations further, suggesting that possible effects of vitamin C may not be able to be separated from other protective factors in fruit and vegetables.

Footnotes

¹ Supported by the USDA Agricultural Research Service, agreement number 58-1950-7-707; NIH R01 AR/AG 41398 and NIH/NHLBI N01-HC-25195.

² Author disclosures: S. Sahni, M. T. Hannan, D. Gagnon, J. Blumberg, L. A. Cupples, D. P. Kiel, and K. L. Tucker, no conflicts of Interest.

Literature Cited

17. Termine JD. Bone matrix proteins and the mineralization process. 1st ed. Kelseyville (CA): American Society for Bone and Mineral Research; 1990. [ Google Scholar]

34. U.S. Department of Health and Human Services and USDA. Dietary guidelines for Americans, 2005. 6th ed. Washington, DC: U.S. Government Printing Office; 2005.

35. Food and Nutrition Board. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, DC: National Academy Press; 2000. [ Google Scholar]

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High Vitamin C Intake Is Associated with Lower 4-Year Bone Loss in Elderly Men

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J Nutr. Author manuscript; available in PMC 2009 Sep 25. Published in final edited form as: Vitamin C is essential for collagen formation and normal bone development. We evaluated associations of total, supplemental, and dietary vitamin C intake with bone mineral density (BMD) at the hip [femoral neck, trochanter], spine, and radial shaft and 4-y BMD change in elderly participants from the Framingham Osteoporosis Study.

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Bone-Protective Effects of Dried Plum in Postmenopausal Women-Andrea Ballinger

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Bone-Protective Effects of Dried Plum in Postmenopausal Women-Andrea Ballinger

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The article I chose this week discusses the potential benefits of incorporating dried plum into ones diet. The study exams not only bone maintenance, but also bone remodeling. Dried plum is a nutrient dense fruit, but it also has phenolic compounds that can induce bone protective effects. The study showed that in rodent models, the use of dried plum prevented bone loss Additionally, rodent models showed restoration of femoral and tibial bone mass after initial bone loss. The last component of the rodent models showed that fructooligosaccharides (prebiotic) in combination with dried plum improved the efficacy of bone restoration. When transitioned to human clinical trials, results indicated that the use of dried plum prevented bone loss in postmenopausal women and additionally correlated with increased serum markers of bone formation. The successful results of the various studies shows the promising use of dried plums as a protective factor for those at risk for bone loss. Not only can it be used as a protective factor, but it can also be incorporated into ones daily routine to increase bone mass after bone loss has already occurred. I'm sure this would be extremely effective in combination with traditional osteoporosis/bone disease recommendations of increased weight bearing exercises. This is also really important for people who are looking for new foods to incorporate into their diets that will offer similar protective features like those of calcium and vitamin d supplements. Additional studies should be conducted to see if the efficacy is also found in premenopausal women.

Arjmandi, Bahram H et al. “Bone-Protective Effects of Dried Plum in Postmenopausal Women: Efficacy and Possible Mechanisms.” Nutrients vol. 9,5 496. 14 May. 2017, doi:10.3390/nu9050496

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Bahram H. Arjmandi, 1, 2,* Sarah A. Johnson, ³ Shirin Pourafshar, 1, ² Negin Navaei, 1, 2, ⁴ Kelli S. George, 1, ² Shirin Hooshmand, ⁵ Sheau C. Chai, ⁶ and Neda S. Akhavan 1, ²

Abstract

Osteoporosis is an age-related chronic disease characterized by a loss of bone mass and quality, and is associated with an increased risk of fragility fractures. Postmenopausal women are at the greatest risk of developing osteoporosis due to the cessation in ovarian hormone production, which causes accelerated bone loss. As the demographic shifts to a more aged population, a growing number of postmenopausal women will be afflicted with osteoporosis. Certain lifestyle factors, including nutrition and exercise, are known to reduce the risk of developing osteoporosis and therefore play an important role in bone health. In terms of nutrition, accumulating evidence suggests that dried plum ( Prunus domestica L.) is potentially an efficacious intervention for preventing and reversing bone mass and structural loss in an ovariectomized rat model of osteoporosis, as well as in osteopenic postmenopausal women. Here, we provide evidence supporting the efficacy of dried plum in preventing and reversing bone loss associated with ovarian hormone deficiency in rodent models and in humans. We end with the results of a recent follow-up study demonstrating that postmenopausal women who previously consumed 100 g dried plum per day during our one-year clinical trial conducted five years earlier retained bone mineral density to a greater extent than those receiving a comparative control. Additionally, we highlight the possible mechanisms of action by which bioactive compounds in dried plum exert bone-protective effects. Overall, the findings of our studies and others strongly suggest that dried plum in its whole form is a promising and efficacious functional food therapy for preventing bone loss in postmenopausal women, with the potential for long-lasting bone-protective effects.

Keywords: bioactive compounds, functional foods, menopause, nutrition, polyphenols, (poly)phenols, prune, osteopenia, osteoporosis

1. Introduction

The postmenopausal period typically occupies one-third of a woman's life [ 1], and it is estimated that by the year 2020, more than 46 million women in the United States (U.S.) will be postmenopausal [ 2]. Menopause is associated with the development of numerous chronic diseases [ 3], due to an abrupt cessation of ovarian hormone production, namely estrogen. Osteoporosis is a chronic and debilitating age-related skeletal disease characterized by the loss of bone mass and a deterioration of the microstructural properties of bone, resulting in an increased propensity for fragility fractures [ 4]. Osteoporosis is responsible for more than 1.5 million fractures per year in the U.S., with most occurring in postmenopausal women [ 5]. Osteoporosis and its related bone fractures are a major public health concern as they are associated with increased morbidity and mortality, a poor quality of life, and a large economic burden [ 6, 7]. Approximately 44 million men and women over the age of 50 have osteoporosis or low bone mass in the U.S. [ 3]. Diminished estrogen levels associated with menopause result in an initial phase of rapid bone loss, followed by a period of a slower deterioration of the skeleton [ 8]. This rapid phase of bone loss occurs within the first five to 10 years following the cessation of menses or the surgical removal of the ovaries [ 9]. As the demographic shifts to a more aged population, the prevalence and incidence of osteoporosis are likely to continue to increase, with affected individuals being at a greater risk of falls, fragility fractures, and therefore morbidity and mortality [ 3]. As such, therapeutic strategies that can delay, slow down, or prevent bone loss in aging individuals, and particularly in postmenopausal women, are critically needed.

Hormone replacement therapy is a logical therapeutic strategy for postmenopausal women since age-related chronic disease development typically begins after the cessation of ovarian hormone production. However, evidence from the Women's Health Initiative indicates that the risks associated with hormone replacement therapy outweigh its benefits, making the exploration of alternative therapies necessary [ 10]. Although the Food and Drug Administration has approved several anti-resorptive pharmacological agents such as bisphosphonates and denosumab, as well as the bone-forming pharmacological agent teriparatide, these drugs are associated with adverse side effects, are costly, and often have low compliance [ 11]. Therefore, it is imperative that safe and cost-effective therapeutic strategies, aside from medications, that can delay, slow down, or prevent bone loss in postmenopausal women be identified, investigated for efficacy, and disseminated for public use.

It is well-known that certain lifestyle factors, including diet and nutrition, play an important role in bone health. In fact, research has demonstrated that certain foods (i.e., functional foods) and their bioactive compounds, including nutrient and non-nutrient compounds, have bone-protective effects [ 12]. Of the functional foods investigated for their bone-protective properties, the most efficacious have typically been in the form of fruits and vegetables. The findings from our studies [ 13, 14, 15] and others [ 16, 17] suggest that dried plum ( Prunus domestica L.) is the most effective in preventing and reversing bone loss among the fruits and vegetables investigated. This has also been demonstrated by Mühlbauer et al. [ 18, 19], who examined the effects of 60 fruits and vegetables on bone. Their findings indicated that onion and dried plum had the most potent bone-protective effects. Though the consumption of fruits and vegetables for general health and well-being is encouraged, in terms of bone health, not all fruits and vegetables offer the same benefits. For instance, while certain fruits such as dried plum and to some extent blueberries exert bone-protective effects [ 20], in our observations [ 14], the same may not be true for other fruits such as raisins and dates. We are using a conditional term for the effectiveness of blueberry on bone, because our findings [ 20], as well as those of Zhang et al. [ 21, 22], are preliminary at this point and await confirmation in human studies. The reasons for these discrepancies in the efficacy among fruits and vegetables remain unknown.

Due to the bioactive compound content and composition of dried plum, as well as promising preclinical and clinical research findings, dried plum has been and continues to be investigated as a potential functional food with respect to bone health. Numerous studies in cells, rodent models of postmenopausal osteoporosis, and postmenopausal women have demonstrated its efficacy and have identified possible mechanisms of action. Studies have aimed to identify specific bioactive compounds in dried plum responsible for its bone-protective properties. The present review provides an overview of dried plum, including its nutritional and bioactive compound composition, and provides evidence from preclinical and clinical studies supporting the efficacy of dried plum in preventing and reversing bone loss in postmenopausal women, as well as evidence to support possible mechanisms of action, and bioactive compounds in dried plum responsible for its efficacy. Additionally, gaps in the research and promising new areas of investigation are discussed.

A literature search was performed using the PubMed database and Google Scholar. The following keywords, alone and in combination, were used: bone, dried plum, menopause, osteopenia, osteoporosis, ovariectomy, ovariectomized, plum, postmenopausal, and prune. Preclinical studies using rodent models of postmenopausal osteoporosis and clinical trials with postmenopausal women were included in this review.

2. Dried Plum: A Promising Functional Food for Bone Health

The U.S., primarily California, is a major producer of dried plum, with approximately 99% of the U.S. and 40% of the world supply grown in California. Dried plum was previously referred to as prunes until a formal name change was requested and approved by the Food and Drug Administration in 2001 [ 23]. It is most commonly known for its effects on gastrointestinal motility and research has been and continues to be conducted with respect to gastrointestinal health to support these observations. In addition, dried plum has been investigated for its antimicrobial, cancer-preventive, cardiometabolic, neurological, and bone-protective effects [ 24, 25].

To date, the most notable research has been in the area of bone metabolism and health. The unique ability of dried plum to promote bone health is likely related to its bioactive compound composition. Dried plum is rich in nutrient bioactive compounds including dietary fiber, vitamin K, boron, copper, magnesium, manganese, among others, many of which are known to positively influence bone [ 23, 24, 25]. It is also rich in non-nutrient bioactive compounds including (poly)phenols such as chlorogenic acids (e.g., chlorogenic acid, neochlorogenic acid, cryptochlorogenic acid) and proanthocyanidins [ 24, 25]. Dried plum has been ranked as having one of the highest oxygen radical absorbance capacities among the commonly consumed fruits and vegetables. It has been suggested that this is likely to be primarily due to its (poly)phenolic compound composition and content, as dried plum is low in ascorbic acid, carotenoids, and vitamin E [ 23]. In addition, previous research has demonstrated that phenolic compounds, including those found in dried plum, exert bone-protective effects and profoundly affect bone metabolism [ 25]. For instance, rutin, a flavonoid commonly found in plums and various berries, has been reported to inhibit ovariectomy-induced bone loss in a rat model of osteoporosis [ 26]. Nonetheless, the question still remains as to which bioactive component(s) of dried plum are responsible for its bone-protective effects. The answer may simply be that the whole fruit is more efficacious than its isolated components due to the additive and/or synergistic effects of these components within the food matrix.

3. Dried Plum and Bone Health: Rodent Models of Postmenopausal Osteoporosis

Previous studies investigating the role of dried plum on bone health in rodent models of postmenopausal osteoporosis are summarized in Table 1 . Our laboratory [ 27] was the first to report the bone-protective effects of dried plum both in general, and specifically in an established rat model of postmenopausal osteoporosis [ 28]. We showed that ovariectomy led to significant declines in the bone mineral density (BMD) of the 4th lumbar vertebrae and femurs, as well as a decrease in the tibial trabecular bone area compared to sham-operated (Sham) rats. However, ovariectomized (Ovx) rats that received 25% of the diet as dried plum for 45 days did not lose bone, while those receiving 5% of the diet as dried plum lost bone similarly to Ovx rats not receiving dried plum ( Figure 1 ). Despite this, we also found that dried plum dose-dependently increased circulating insulin-like growth factor-I (IGF-I) levels, while having no effect on tartrate-resistant acid phosphatase-5b (TRAP-5b) levels. At that time, TRAP-5b was considered to be a biomarker of bone resorption. Therefore, these results suggested that dried plum prevented bone loss, in part, by increasing the rate of bone formation, but not through inhibiting bone resorption.

Table 1

Reference

Model

Number

Groups

Duration

Primary Outcomes

Primary Findings

Arjmandi et al., 2001 [ 27]

Sham and Ovx female 90-day old Sprague-Dawley rats

48

(1) Sham control,
(2) Ovx control,
(3) Ovx + 5% dried plum,
or (4) Ovx + 25% dried plum

45 days

BMD and % mineral content of right femur and 4th lumbar vertebrae; trabecular total area and bone area; cortical total area, bone area, marrow space, endosteal perimeter, and periosteal perimeter; serum ALP, TRAP, and IGF-1

Compared to Ovx control:
4th lumbar vertebrae and femur BMD and trabecular bone area were significantly ↑ in the 25% dried plum group

Deyhim et al., 2005 [ 38]

Sham and Ovx female 90-day old Sprague-Dawley rats

80

(1) Sham control,
(2) Ovx control,
(3) Ovx + 17β-estradiol,
(4) Ovx + 5% dried plum,
(5) Ovx + 15% dried plum,
(6) Ovx + 25% dried plum

60 days

BMD of femur, left tibiae, and 4th lumbar; biomechanical properties (length, cortical area, unit yield force, and unit ultimate force); trabecular microarchitectural properties (BV/TV), Tb N, Tb S, Tb Th, ConnDens, SMI); serum IGF-1, ALP, and TRAP; urinary Dpd

Compared to Ovx control:
Femur and tibia BMD were ↑ in all dried plum groups, 4th lumbar BMD tended to be significantly and was significantly ↑ in the 15% and 25% dried plum groups, respectively; unit yield force tended to be significantly ↑ in all dried plum groups; Tb S was significantly ↑ in all dried plum groups while Tb N and Tb Th were significantly ↑ in 15% and 25% dried plum groups and BV/TV and ConnDens were significantly ↑ in 25% dried plum group; urinary Dpd tended to be significantly ↓ in all dried plum groups

Arjmandi et al., 2010 [ 14]

Sham and Ovx female 90-day old Sprague-Dawley rats

180

(1) Sham control,
(2) Ovx control,
(3) Ovx + 2% FOS,
(4) Ovx + 5% FOS + 7.5% dried plum,
(5) Ovx + 2% FOS + 5% dried plum,
(6) Ovx + 2% FOS + dried plum polyphenols,
(7) Ovx + 2% FOS + dried plum juice,
(8) Ovx + 2% FOS + dried plum puree,
or (9) Ovx + 2% FOS + dried plum pulp/skins

60 days

BMD and BMC of whole body, right femur, and 4th lumbar vertebrae; bone histomorphometric parameters (BV/TV, Tb N, Tb S, Tb Th, ConnDens, and SMI); 4th lumbar calcium content; serum osteocalcin and IGF-1; serum and urinary calcium, magnesium, and phosphorus; urinary Dpd

Compared to Ovx control:
4th lumbar vertebrae and femur BMD were significantly ↑ in 5% FOS + 7.5% dried plum group with tendency to significantly ↓ loss of lumbar vertebrae calcium, and significantly ↓ trabecular separation

Johnson et al., 2011 [ 15]

Sham and Ovx female 90-day old Sprague-Dawley rats

72

(1) Sham control,
(2) Ovx control,
(3) Ovx + soy,
(4) Ovx + soy + dried plum, Ovx + soy + FOS,
or (5) Ovx + soy + dried plum + FOS

60 days

BMD and BMC of the whole body, right femur, and 4th lumbar vertebrae; femoral strength; bone histomorphometric parameters (BV/TV, Tb N, Tb S, Tb Th, and MS/BS); serum total ALP; urinary creatinine and Dpd

Compared to Ovx control:
Whole body and 4th lumbar BMD tended to be significantly ↑ in Ovx + soy + dried plum group and was significantly increased in Ovx + soy + dried plum + FOS group, and right femur BMD was significantly ↑; Tb Th tended to be significantly ↑ and Tb Sp, and MS/BS tended to be significantly ↓ in Ovx + soy + dried plum + FOS group; serum ALP and urinary Dpd tended to be significantly ↓ in Ovx + soy + dried plum group and urinary Dpd was significantly ↓ in Ovx + soy + dried plum + FOS group

Rendina et al., 2012 [ 16]

Sham and Ovx female 90-day old C57BL/6J mice

59

(1) Sham control,
(2) Ovx control,
(3) Ovx + 5% dried plum,
(4) Ovx + 15% dried plum,
(5) Ovx + 25% dried plum

4 weeks

BMA, BMC, and BMD of the 4th to 5th lumbar vertebrae; bone microarchitecture parameters of tibia and 4th lumbar vertebrae (BV/TV, Tb N, Tb S, Tb Th, ConnDens, and SMI); biomechanical properties of trabecular bone (total force, stiffness, size-independent stiffness, and Von Mises stresses); plasma PINP and IGF-1; Runx2, osteocalcin, and NFATc1 bone gene expression

Compared to Ovx control:
BMC and BMD were significantly ↑ in 25% dried plum group; BV/TV and vertebra Tb N were significantly ↑ in 15% and 25% dried plum groups, tibia Tb N was increased in 25% dried plum group, tibia Tb S was significantly ↓ in 15% and 25% dried plum groups while vertebra Tb S was significantly decreased in 25% dried plum group; vertebra ConnDens and SMI were significantly ↑ and ↓, respectively, in 15% and 25% dried plum groups while vertebra apparent mean/density tended to be ↑ in 15% dried plum group and was significantly ↑ in 25% dried plum group; tibia ConnDens and SMI, were significantly ↑ and ↓, respectively, in 15% and 25% dried plum groups while apparent mean density was increased in 25% dried plum group; vertebra total force, stiffness, and size-independent stiffness were significantly ↑ and Von Mises stresses was significantly ↓ in 15% and 25% dried plum groups; PINP, NFATc1, and Runx2 were significantly ↓ in all dried plum groups while IGF-1 was significantly ↑ in 15% dried plum group and osteocalcin was significantly decreased in 15% and 25% dried plum groups

Rendina et al., 2013 [ 36]

Sham and Ovx female 90-day old C57BL/6J mice

68

(1) Sham control,
(2) Ovx control,
(3) Ovx + 25% dried plum,
(4) Ovx + 25% dried apple,
(5) Ovx + 25% dried apricot,
(6) Ovx + 25% dried grape,
(7) Ovx + 25% dried mango

8 weeks

BMA, BMC, and BMD of the whole body and 4th and 5th lumbar vertebrae; bone microarchitecture parameters of tibia and 4th lumbar vertebrae (BV/TV, Tb N, Tb S, Tb Th, ConnDens, SMI, and trabecular density); biomechanical properties of trabecular bone (total force, stiffness, size-independent stiffness); plasma GPx; bone marrow gene expression of NFATc1, Col1a1, ALP, osteocalcin, Bak1; flushed femur expression of Bak1, Casp3, Casp9

25% dried plum compared to Ovx control: Whole body and vertebra BMA, BMD, and BMC were significantly ↑, vertebra and tibia BV/TV were significantly ↑; vertebra Tb N, Tb Th, Tb Sp, ConnDens and trabecular density were significantly ↑ and SMI was significantly ↓; proximal tibia Tb N and trabecular density were significantly ↑; vertebra total force, stiffness, and size independent stiffness and tibia size independent stiffness were significantly ↑; plasma GPx was significantly ↑; NFATc1 was significantly ↓ and Col1a1 tended to be ↑, bone marrow Bak1 was significantly ↑, and Casp9 was significantly ↓

Smith et al., 2014 [ 37]

Sham and Ovx female 6-month old Sprague-Dawley rats

84

(1) Sham control,
(2) Ovx control,
(3) Ovx + 5% dried plum,
(4) Ovx + 15% dried plum,
(5) Ovx + 25% dried plum,
(6) Ovx + PTH

6 weeks

BMA, BMC, and BMD of the whole body, femur, and 4th and 5th lumbar vertebrae; bone microarchitecture parameters of tibia and 4th lumbar vertebrae (BV/TV, Tb N, Tb S, Tb Th, ConnDens, and SMI); dynamic bone histomorphometry (proximal tibia metaphysis BFR, MS/BS, and MAR; tibial cancellous MS/bone area, and BFR/BV; tibial cortical bone periosteal BFR, periosteal MS, periosteal MAR, endocortical BFR, endocortical MS, and endocortical MAR), plasma PINP; urinary Dpd; bone gene expression of NFATc1, Col1a1, ALP, osteocalcin, Runx2, BMP 2 and 4, IFG-1, RANKL, OPG

Compared to Ovx control:
Whole body and femur BMD was significantly ↑ in all dried plum groups; vertebral BMD was significantly ↑ in 15% and 25% dried plum groups and tended to be significantly increased in 5% dried plum group; vertebral BV/TV and Tb N significantly ↑ and Tb S and ConnDens significantly ↓ in all dried plum groups, whereas Tb Th and SMI ↑ and ↑, respectively, in 15% and 25% dried plum groups; proximal tibia metaphysis Tb Sp ↓ in 15% and 25% dried plum groups; tibial mid-diaphysis cortical thickness ↑ in all dried plum groups while cortical area tended to be significantly ↑ in 5% dried plum group; plasma PINP was significantly ↓ in all dried plum groups; urinary Dpd tended to be significantly decreased and was significantly decreased in 5% and 15% dried plum groups, respectively; proximal tibial metaphysis BFR tended to be significantly ↓ in 5% dried plum group and was significantly ↓ in 15% and 25% dried plum groups, MS/BS was significantly ↓ in 15% and 25% dried plum groups, and MAR was significantly ↓ in 15% dried plum group and tended to be significantly ↓ in 5% and 25% dried plum groups; tibial cancellous MS/bone area and BFR/BV were significantly ↓ in all dried plum groups; tibial endocortical MAR was significantly ↓ in the 5% dried plum group and tended to be significantly reduced in the 15% and 25% dried plum groups; relative abundance of NFATc1 was significantly ↓ and BMP4 was significantly ↑ in all dried plum groups, while Col1a1 tended to be significantly reduced in all dried plum groups and IGF-1 was significantly ↑ in 25% dried plum group and tended to be significantly ↑ in 15% dried plum group

Pawlowski et al., 2014 [ 39]

Ovx female 3-month old Sprague-Dawley rats

44

(1) Control,
(2) grape seed extract-high,
(3) grape seed extract-low,
(4) blueberry-high,
(5) blueberry-low,
(6) dried plum-high,
(7) dried plum-low,
(8) grape-high,
(9) grape-low,
(10) resveratrol-high,
(11) resveratrol-low,
(12) soy isoflavone-glycosylated,
(13) soy isoflavone-genistein aglycone

10 days

Urine calcium ( ⁴⁵ Ca and total calcium); serum BALP; urinary NTx

Bone calcium retention was significantly ↑ in dried plum-high group compared to baseline

Léotoing et al., 2016 [ 40]

Ovx female 5-month old Wistar rats

84

(1) Sham control,
(2) Ovx control,
(3) high chlorogenic acid dried plum,
(4) low chlorogenic acid dried plum,
(5) high chlorogenic acid dried plum juice,
(6) low chlorogenic acid dried plum juice,
(7) low chlorogenic acid dried plum + fiber

90 days

Total femoral BMD, metaphyseal BMD, and diaphyseal BMD; total BMC; blood osteocalcin, CPII, CTX-II, and CRI; urinary Dpd and calcium; BRI

Compared to Ovx control:
Total femoral BMD and metaphyseal BMD were significantly ↑ in low chlorogenic acid dried plum + fiber and low chlorogenic acid dried plum juice group and tended to be significantly ↑ in all other dried plum groups; diaphyseal BMD was significantly ↑ in high chlorogenic acid dried plum, low chlorogenic acid dried plum + fiber and the low chlorogenic acid dried plum juice groups; total BMC was significantly ↑ in all low chlorogenic acid dried plum groups and tended to be significantly ↑ in high chlorogenic acid dried plum groups; blood osteocalcin was significantly ↓ in high chlorogenic acid dried plum, low chlorogenic acid dried plum + fiber, and low chlorogenic acid dried plum juice groups and tended to be significantly ↓ in the other dried plum groups; urinary Dpd was significantly ↓ in low chlorogenic acid dried plum + fiber and low chlorogenic acid dried plum juice groups and tended to be significantly ↓ in the other dried plum groups; BRI tended to be ↓ in all high chlorogenic acid dried plum groups and tended to be ↑ in all low chlorogenic acid dried plum groups; all groups had significantly ↑ calciurea; CPII and CRI were significantly ↑ in high chlorogenic acid dried plum group

We next asked the question: could the addition of dried plum to the diet restore bone mass after bone loss has occurred? Toward this end, our laboratory [ 27] used an Ovx rat model of postmenopausal osteoporosis to evaluate the ability of dried plum at different doses to reverse bone loss. In this study, 90-day-old female Sprague-Dawley rats were divided into six groups: Sham control, Ovx control, Ovx + 17β-estradiol (E ₂), Ovx + 5% of the diet as dried plum, Ovx + 15% of the diet as dried plum, and Ovx + 25% of the diet as dried plum for 60 days. Interestingly, the consumption of all doses of dried plum (5%, 15%, and 25%) effectively restored femoral and tibial BMD to the same extent as E ₂, while only the group receiving 25% dried plum showed the restoration of 4th lumbar BMD ( Figure 2 ). At the time in which this study was conducted, the loss of bone volume accompanied by the loss of trabecular connectivity was generally believed to be an irreversible process [ 29]. To our knowledge, our study was the first to demonstrate that an agent of any kind could reverse the loss of trabecular microstructures including the bone volume/total volume, connectivity density, trabecular number, trabecular separation, and structure model index ( Figure 3 ).

We next sought to evaluate the efficacy of several potentially bone-protective functional foods and bioactive compounds (i.e., dried plum, figs, dates, raisins, blueberries, dried plum (poly)phenols, fructooligosaccharides (FOS), and β-hydroxy-β-methylbutyrate, alone and in combination, on the bone mass and quality in Ovx rats after bone loss had already occurred [ 14]. Our findings revealed that the group receiving 5% FOS + 7.5% dried plum in their diet had the greatest reversal of BMD loss in the right femur and 4th lumbar spine, 4th lumbar spine calcium loss, and trabecular separation. Interestingly, none of the treatments altered the serum or urinary markers of bone turnover. The findings of this study suggest that the addition of prebiotic FOS to dried plum improves its efficacy in restoring bone mass and quality after bone loss has occurred. Although the mechanisms remain unknown, FOS has been demonstrated to increase the absorption of minerals, including calcium and magnesium, in the colon [ 30]. Additionally, considering that FOS is a prebiotic, it is likely that the combination of FOS and dried plum worked through gut microbiota-related mechanisms including an increase in mineral absorption. Importantly, the dose of dried plum (i.e., 7.5% of the diet) that was efficacious in combination with FOS was lower than what was previously found to be effective. This suggests that the addition of FOS to dried plum may improve the efficacy of dried plum and should be further investigated. These findings will be particularly important if they can be translated to humans, as it could be a novel strategy for reducing the amount of dried plum an individual would need to consume on a daily basis to achieve the same outcomes.

In addition to demonstrating the bone-protective effects of dried plum alone and in combination with FOS, we have also demonstrated in numerous studies that soy is a potentially efficacious functional food for promoting bone health [ 31, 32, 33, 34, 35]. We therefore sought to determine the efficacy of a soy-based diet in combination with 7.5% dried plum, 5% FOS, or 7.5% dried plum + 5% FOS on reversing bone loss in a rat model of postmenopausal osteoporosis. We found that the combination of a soy-based diet with dried plum, FOS, or both, significantly improved the whole body BMD and femoral BMD, while the combination of all components (i.e., soy, dried plum, and FOS) had the most pronounced effect on lumbar BMD [ 15]. All interventions were noted to improve the biomechanical properties of bone, as demonstrated by the increased ultimate load. The serum biomarker results suggest that these improvements may have been due, in part, to their ability to enhance bone formation and reduce bone resorption, as shown by increases in blood alkaline phosphatase (ALP) and decreased urinary deoxypyridinoline (Dpd).

Other investigators have also demonstrated the bone-protective effects of dried plum in rodent models postmenopausal osteoporosis. Rendina et al. [ 16] showed that feeding 25% of the diet as dried plum for four weeks to female Ovx C57BL/6J mice prevented the loss of BMD and bone mineral content (BMC) of the spine, and trabecular microarchitectural properties of the vertebrae and proximal tibiae, resulting in greater bone strength and stiffness in the vertebrae. Additionally, feeding dried plum in the diet at 15% and 25% doses restored myeloid and lymphoid levels to that of the sham-operated mice and suppressed ex vivo concanavalin A stimulated lymphocyte tumor necrosis factor-α production in splenocytes.

In another study, Rendina et al. [ 36] reported the results of a study comparing the bone-protective effects of dried plum with other fruits (i.e., dried apple, apricot, grape, and mango) in Ovx C57BL/6 mice over an eight-week period. They demonstrated that dried plum had superior anabolic effects on the trabecular bone microarchitectural properties of the vertebrae, was able to prevent tibial bone loss, and restored the trabecular biomechanical properties of the spine when compared with the other fruits. In addition, dried plum was more efficacious than the other fruits in enhancing plasma glutathione peroxidase activity, downregulating osteoclast differentiation, upregulating osteoblast activity, and suppressing Ovx-induced apoptosis.

Smith et al. [ 37] reported the findings of a study out of the same laboratory in which they compared the effects of six weeks of dried plum supplementation to treatment with parathyroid hormone (PTH). Treatment with dried plum at doses of 15% and 25% in the diet restored the whole body and femoral BMD to that of the Sham group and improved the trabecular bone volume and cortical thickness. Systemic blood biomarkers of bone metabolism (i.e., N-terminal procollagen type 1 and Dpd) were reduced, indicating a reduction in bone turnover. Dynamic bone histomorphometric analysis of the tibial metaphysis revealed that dried plum restored the Ovx-induced increase in the cancellous bone formation rate and mineralizing surface to that of the Sham group. Dried plum also upregulated the gene expression of bone morphogenetic protein 2, a regulator of osteogenesis, and IGF-I while downregulating the nuclear factor T cell activator 1, a transcription factor involved in the regulation of osteoclast differentiation. Compared with that of the effects of PTH on bone, dried plum reduced the rate of bone turnover, rather than increasing the rate of bone formation.

In summary, our data and others strongly suggest that dried plum is an efficacious functional food for preventing and reversing the loss of bone mass and structural properties in a rat model of postmenopausal osteoporosis. We have also shown that dried plum dose-dependently increases systemic and local indices of bone formation, e.g., serum and mRNA levels of ALP. These findings suggest that dried plum prevents and reverses bone loss, primarily through enhanced bone formation.

4. Dried Plum and Bone Health: Clinical Trials in Postmenopausal Women

Previously conducted clinical trials investigating the role of dried plum on bone health in postmenopausal women are summarized in Table 2 . To our knowledge, our laboratory was the first to evaluate the bone-protective properties of dried plum in humans. Initially, we reported the findings of a three-month clinical trial evaluating the efficacy of dried plum versus dried apple (comparative control) on the biomarkers of bone formation in postmenopausal women [ 41]. Here, we showed that the consumption of 100 g/day dried plum significantly increased the serum markers of bone formation, namely total ALP, bone-specific ALP (BALP), and IGF-1 by 12, 6, and 17%, respectively. The increase in BALP is important as studies have shown that clinically relevant doses of bone-forming agents such as sodium fluoride, growth hormone, and PTH take several months to moderately increase the serum levels of BALP [ 42]. Interestingly, the serum and urinary biomarkers of bone resorption were not affected by either intervention. These observations further support our hypothesis that dried plum prevents and reverses bone loss through enhanced bone formation.

Table 2

Reference

Design

Population

Number

Intervention

Duration

Primary Outcomes

Primary Findings

Hooshmand et al., 2011 [ 13]

RCT

Postmenopausal women with osteopenia

160

100 g/day dried plum or 75 g/day dried apple (comparative control)

12 months

Whole body, lumbar spine, hip, and forearm BMD; serum BALP, osteocalcin, TRAP-5b, and CRP

↑ ulna and lumbar spine BMD in dried plum group compared to dried apple ( p < 0.05), ↓ BALP in dried plum group compared to baseline

To evaluate whether a longer treatment period would lead to an improvement in bone mass, we conducted a one-year clinical trial comparing the effects of the daily consumption of 100 g dried plum to 75 g dried apple (comparative control) on BMD and the biomarkers of bone turnover in 100 osteopenic postmenopausal women. We found that dried plum consumption significantly improved the BMD of the ulna and lumbar spine compared with the dried apple control ( Figure 4 ) [ 13]. Additionally, dried plum consumption led to significantly decreased serum TRAP-5b and BALP levels. Osteocalcin and C-reactive protein levels were significantly lower in the dried plum group than in the apple group. Although the findings of our initial three-month clinical trial indicated that BALP levels increased following dried plum consumption, this was not observed in our one-year clinical trial. We cannot offer a definitive reason for this discrepancy. However, variation is inherent in bone biomarkers due to intra- and inter-individual variability, analytical reasons, and sample stability. For these reasons, BMD remains the gold-standard for evaluating bone health [ 43].

We later investigated the potential mechanisms of action by which dried plum exerted these effects. We showed that compared to the baseline, dried plum increased receptor activator of nuclear factor kappa-B ligand levels by +1.99% versus +18.33% in the control group, increased the osteoprotegerin levels by +4.87% versus −2.15% in the control group, and decreased serum sclerostin levels by −1.12% in the dried plum group versus +3.78% in the control group [ 44]. While these percent changes did not reach statistical significance, they are clearly promising preliminary findings. Collectively, these findings suggest that dried plum prevents bone loss in postmenopausal women through the suppression of bone turnover.

Next, we [ 45] reported the findings of a six-month clinical trial evaluating the effects of resistance training with and without dried plum at a dose of 90 g in postmenopausal breast cancer survivors. While both groups were found to increase upper and lower body strength, no improvements were observed in the body composition or BMD. Interestingly, both groups displayed improvements in the blood biomarkers of bone turnover, with no added effect of dried plum observed.

Our successive six-month clinical trial evaluated the efficacy of two doses of dried plum (50 g versus 100 g) in preventing bone loss in older postmenopausal women [ 46]. Our findings confirmed dried plums' ability to prevent the loss of total body BMD and indicated that a lower dose of dried plum (i.e., 50 g) may be as effective as 100 g of dried plum. This study also demonstrated a reduction in serum TRAP-5b in both dried plum groups.

Most recently, we evaluated whether or not individuals who received the dried plum intervention in our previous one-year clinical trial conducted five years prior were able to retain BMD to a greater extent than those who received the dried apple intervention. Of the 100 women who completed the initial clinical trial, 20 came back for a follow-up visit. All participants, irrespective of group assignment, reported that they did not regularly consume dried plums. We found that individuals that received the dried plum intervention ( n = 8) in our previous one-year clinical trial retained BMD of the ulna and lumbar spine to a greater extent than those who received the dried apple intervention ( n = 12) (unpublished data, Figure 5 ). Although these findings are preliminary, they suggest that women in the dried plum group retained bone density in the lumbar spine and ulna to a greater extent than those in the dried apple group over the course of five years, even in the absence of regular dried plum consumption. These findings should be interpreted with caution as the influence of other factors including diet, physical activity, and medications have not been evaluated. Nonetheless, these findings are promising and further research is needed to evaluate the extent to which bone density is retained following the cessation of an intervention with dried plum.

5. Bioactive Compounds and Possible Mechanisms of Action

Dried plum is known to contain several bioactive compounds including dietary fiber, vitamins (e.g., vitamin K), minerals (e.g., boron, copper), and (poly)phenolic compounds such as chlorogenic acids (i.e., chlorogenic acid, neochlorogenic acid, and cryptochlorogenic acid) and proanthocyanidins [ 24, 25]. The exact nutrients and/or components contributing to the bone-protective effects of dried plum are unknown. However, many of these compounds are known to exert bone-protective effects and therefore likely work additively and/or synergistically.

Among the compounds found in dried plum is boron, which is a trace element critical for bone health as a deficiency or excess in consumption of boron can be harmful to bone. Dried plum contains a higher amount of boron than most fruits. In fact, the content of boron in 47.7 g dried plum (~5 dried plums) is about 1.1 mg [ 23]. The average daily intake of boron is about 1-2 mg/day, depending on sex and age, among other factors [ 47]. Boron has been shown to stimulate bone growth and bone metabolism [ 48], and play an important role in preserving BMD, bone microarchitecture, and bone strength [ 49, 50, 51]. A study by Chapin et al. [ 52] showed that rats fed diets containing 20 or more mg boron/100 g diet had a significantly improved vertebral strength. These authors also demonstrated that rats fed a boric acid diet of 200 ppm or more for nine weeks not only had a significant increase in the boron content of their bone, but retained their bone boron content three-fold greater than the controls 32 weeks after exposure to the diet ended. This suggests that boron has the ability to accumulate in bone, and though the half-life of boron in bone is uncertain, it may be similar to that of calcium, where the half-life is significantly longer than in tissue. This action of boron may play a role in the maintenance of bone density over long periods of time, even without regular consumption.

Another mineral abundant in dried plum important for bone health is potassium [ 53, 54]. One hundred grams of dried plum contains 732 mg. Tucker et al. [ 55] investigated both the cross-sectional and longitudinal relationships between potassium and BMD using a Framingham Heart Study database and concluded that potassium contributes to the maintenance of BMD in men and women. Additionally, higher intakes of potassium have been shown to reduce bone resorption, particularly in the face of high protein intake [ 56].

Dried plum is also a good source of copper. A 47.7 g serving of dried plum provides 0.13 mg, which is 31.2% of the dietary reference intake. Copper is a cofactor for lysyl oxidase, which is involved in the cross-linking of collagen and elastin [ 24, 57]. In an in vivo study by Yee et al. [ 57], Ovx Sprague-Dawley rats placed on a copper deficient diet had more severe osteopenia than the copper adequate diet. Copper may in part contribute to the beneficial properties of dried plum on bone, giving an additive effect.

Dried plum is rich in vitamin K and a 47.7 g serving of dried plum provides 348 mg vitamin K, or 15.6% of the dietary reference intake [ 53]. Vitamin K is important for bone health as it promotes a calcium balance [ 58]. Additionally, it is a cofactor for the γ-carboxylation of osteocalcin, a bone matrix protein secreted by osteoblasts that promotes normal bone mineralization by regulating the growth of hydroxyapatite crystals [ 58]. A study by Braam et al. [ 59] demonstrated that supplementation with vitamin K at the level of 1 mg daily for three years attenuated the loss of BMD in the lumbar spine.

Among the (poly)phenols found in dried plum, chlorogenic acids (e.g., neochlorogenic acid, cryptochlorigenic acid, and chlorogenic acid) are the most abundant. In fact, 100 g of dried plum is estimated to contain between 108 and 153 mg chlorogenic acids. Previous research has demonstrated that chlorogenic acids are bone-protective. For instance, Zhou et al. [ 60] demonstrated that supplementing Ovx rats with chlorogenic acid led to improved BMD and microarchitecture, and an increased proliferation of osteoblast precursors and osteoblast differentiation, as well as increases in bone formation biomarkers. Despite this, Léotoing et al. [ 40] demonstrated that the bone-protective effects of dried plum is not dependent on the content of chlorogenic acids. As the authors pointed out, it is important to consider that dried plum contains other (poly)phenols such as quercetin, rutin, proanthocyanidins, among others, as well as dietary fiber in the form of soluble and insoluble fiber including pectin, fructans, hemicelluloses, and cellulose [ 23, 40], which may be responsible for the effects of dried plum on bone. (Poly)phenols and their metabolites are known to not only act as antioxidants themselves [ 53, 61, 62], but to also activate endogenous antioxidant and inhibit inflammatory signaling pathways [ 63, 64]. Considering that bone loss has been linked to oxygen-derived free radicals in the bone microenvironment, an imbalance in antioxidant defenses, and oxidative stress [ 65, 66], as well as a pro-inflammatory state [ 67], it is possible that other dried plum (poly)phenols and their metabolites work through this mechanism. In fact, we and others have demonstrated the antioxidant and anti-inflammatory properties of dried plum [ 68, 69]. Dried plum has a high oxygen radical absorbance capacity (ORAC) compared with many commonly consumed fruits and vegetables [ 70]. More recently, Kayano et al. [ 61], have isolated several ortho-diphenolic and mono hydroxyl phenolic compounds with ORAC values as high as 4.68 units of Trolox equivalent per mg of dried plum. Therefore, the beneficial effects of dried plum on bone may be partly mediated through its antioxidant properties.

Importantly, dried plum is rich in soluble and insoluble fibers, including pectin, fructans, hemicelluloses, and cellulose [ 23, 40], which are known to increase mineral absorption (e.g., calcium) [ 71]. For instance, fibers are fermented by colonic bacteria, resulting in the production of short-chain fatty acids (SCFA). SCFAs enhance calcium absorption through reductions in the pH of the intestinal lumen and increasing the solubility of calcium, thereby facilitating passive diffusion through exchanges of luminal calcium with cellular hydrogen, and increasing the permeability of gut epithelial cells and paracellular transport [ 40, 71, 72]. Dietary fiber, including prebiotic dietary fibers, as well as (poly)phenolic compounds, have been shown to alter the microbial composition in the gut [ 71, 73, 74]. As such, it is possible that chronic dried plum consumption induces changes in the gut microbiome, thereby increasing SCFA production. It is also possible that these changes in the gut microbiome promote bone health through other mechanisms including those involving the immune system. However, this has yet to be investigated and is therefore speculative.

Lastly, previous research has shown that dried plum rich in chlorogenic acid increases bone calcium retention in an Ovx rodent model of postmenopausal osteoporosis [ 39]. Although changes in biomarkers of bone turnover were not noted, the observation that bone calcium retention was greater is consistent with the notion that dried plum reduces bone turnover. This is an interesting finding that warrants further investigation.

6. Conclusions

The bone-protective effects of dried plum in postmenopausal women have been supported by several animal studies and confirmed in randomized controlled trials. The exact mechanisms by which dried plum exerts these effects remains unknown. Additionally, it is unclear as to which bioactive compound(s) in dried plum is/are responsible for its bone-protective properties. Considering that many of the bioactive compounds present in dried plum have been shown to modulate bone metabolism, it is likely that there are additive and/or synergistic effects among these compounds. In addition to preventing bone loss in postmenopausal women, our recent findings suggest that the bone-protective effects of dried plum may be long-lasting, thereby contributing to the maintenance of bone density after regular consumption has ceased.

The findings of our previously conducted clinical trials indicate that dried plum is most efficacious in preventing bone loss in the ulna and lumbar spine. Although the reason for this is not currently known, both vertebra and ulna contain more trabecular bone than other sites (e.g., femur). In fact, vertebra and ulna contain more than 60% and up to 50% trabecular bone, respectively. Bone turnover is known to be greater in trabecular bone than cortical bone [ 75, 76]. The body of literature suggests that dried plum slows the rate of bone turnover. As such, it is likely that dried plum has a more pronounced effect of reducing bone loss at these sites through reductions in trabecular bone turnover.

An important point to consider with any nutritional intervention, including functional foods, is caloric intake. The addition of dried plum to the diet contributes approximately 120 kcal and 240 kcal for 50 g and 100 g doses, respectively [ 23]. In our previous clinical trials, study participants were advised to maintain their usual diet and physical activity patterns throughout the duration of the study. We did not observe significant changes in nutritional intake, including calories, nor in body weight. Considering that self-reported dietary intake and physical activity are known to have limitations, including measurement error, it is therefore unknown as to whether our study participants made alterations in their diets or physical activity to maintain their body weight. Dried plum is high in dietary fiber which alters the transit time and may increase satiety, thereby reducing the overall caloric intake. Logically, one would assume that the addition of dried plum to the diet would displace other calories. However, this is speculative and needs future confirmation.

Future research should aim not only to better understand the mechanisms by which dried plum consumption contributes to bone health, including the involvement of the gut microbiome, but also to elucidate the long-term maintenance of such effects, including their role in fracture prevention. With respect to feasibility, we have observed good study participant treatment compliance and retention with long-term dried plum consumption at doses of 50 g (six months) and 100 g (one year). Study participants were generally willing to commit to the regular consumption of dried plum in order to improve their bone health and avoid taking osteoporosis medications. Our study participants were educated on ways to incorporate dried plum into their diets (e.g., in their meals) in an effort to promote compliance. Nonetheless, there are challenges with any long-term dietary intervention. For this reason, it is important that future studies aim to establish the lowest dose of dried plum or alternative dosing methods (e.g., intermittent dosing regimens) that provide the same efficacy as 100 g/day. Additionally, the combination of other foods and/or bioactive compounds that show promise for bone health, such as FOS, with dried plum should be further investigated, as this may enhance its efficacy. Finally, many of the previously conducted clinical trials evaluating the bone-protective effects of dried plum had small sample sizes, which may have contributed to null findings. Therefore, future large-scale clinical trials are needed to further establish the bone-protective effects of dried plum in postmenopausal women.

Acknowledgments

This work was funded in part by the California Dried Plum Board and the United States Department of Agriculture.

Conflicts of Interest

The authors declare no conflict of interest.

References

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Articles from Nutrients are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

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Bone-Protective Effects of Dried Plum in Postmenopausal Women: Efficacy and Possible Mechanisms

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Osteoporosis is an age-related chronic disease characterized by a loss of bone mass and quality, and is associated with an increased risk of fragility fractures. Postmenopausal women are at the greatest risk of developing osteoporosis due to the cessation ...

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Nutrients and Dietary Patterns Related to Osteoporosis - Seonwook Kim 

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Nutrients and Dietary Patterns Related to Osteoporosis - Seonwook Kim 

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My selected article for this week is an overall review of nutrients and dietary patterns related to osteoporosis. Osteoporosis is a common chronic disease characterized by a decrease in bone mineral density, impaired bone strength, and an increased risk of fragility fracture. Of course, calcium and vitamin D are for bone metabolism. But I think comprehensive nutrition status is also important for osteoporosis patients. This research group reviewed the Mediterranean diet, Western diet, Asian diet, and Vegetarian diet. Mediterranean diet, Asian diet, and Vegetarian diet are beneficial to the bone mineral density and lower the risk of fracture, while the western diet is inversely associated with the bone mineral density. The conclusion of this study is that lifestyle changes for balanced nutrition intakes are imperative for the reduction of osteoporosis risk, alongside regular physical activity. In clinical implications, healthy dietary patterns including fruit, vegetables, whole grains, poultry, fish, nuts, and low-fat dairy products and the avoidance of processed food products will be beneficial for osteoporosis patients.

Muñoz-Garach A, García-Fontana B, Muñoz-Torres M. Nutrients and Dietary Patterns Related to Osteoporosis. Nutrients. 2020 Jul 3;12(7):1986. doi: 10.3390/nu12071986. PMID: 32635394; PMCID: PMC7400143.

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2. Osteoporosis and Related Nutrients

2.1. Calcium, Vitamin D and Dairy Products

Calcium and vitamin D form part of the bone mineral matrix as calcium phosphate (hydroxyapatite crystals) and are required for bone strength. The best way to achieve adequate calcium intake is through adhering to a healthy diet. However, sometimes dietary sources are insufficient or poorly tolerated, and, in those situations, pharmacological calcium supplementation could be useful. This is the recommendation of most clinical practice guidelines [ 4, 5, 6, 7]. However, some authors are critical of this recommendation due to its low efficacy and the possibility of adverse effects [ 7]. The most important sources of calcium in the diet are dairy products (milk, yogurt and cheese), fish (especially sardines with bones), pulses and a few vegetables and fruits (particularly nuts and seeds).

Calcium homeostasis is, predominantly, regulated by vitamin D. A total of 80-90% of vitamin D is obtained from cutaneous synthesis after sunlight exposure, and 10-20%, from a limited number of foods, such as oily fish, mushrooms and some fortified dairy products. Nevertheless, no foods can provide enough vitamin D to meet requirements. There is a potential role for the fortification of different foods to increase vitamin D intakes.

Adequate sunlight exposure is important for preventing and correcting vitamin D insufficiency. Vitamin D deficiency has deleterious consequences for health outcomes, and this vitamin is extremely important for bone health maintenance. In elderly or postmenopausal women, vitamin D deficiency may aggravate osteoporosis. Additionally, adequate concentrations of 25-hydroxyvitamin D (25(OH)D) are necessary for maximizing the efficacy of anti-osteoporotic drugs [ 8]. Furthermore, vitamin D is involved in maintaining muscle mass and strength as well as bone structure. High efficacy has been demonstrated for certain vitamin D-fortified foods, such as reduced-fat cheese and vitamin D-biofortified eggs [ 9, 10].

A recent meta-analysis of the impact of vitamin D-fortified foods on serum 25(OH)D levels, bone mineral density (BMD) and bone turnover markers (BTM) showed significant effects, with an increase in serum 25(OH)D and BMD and decrease in parathormone (PTH) levels. No significant beneficial effect on BTM was found [ 11].

Dairy products are the main food sources providing bone-beneficial nutrients, such as calcium, phosphorus and magnesium and these elements have a morphological role in bone healthy structure. Dairy products are also a source of protein, vitamin B-12, zinc, potassium and riboflavin. Dairy products could also be considered as a remarkable source of vitamin D if fortified with such. Vitamin D concentrations based on weight are higher in yogurt and cheese than in milk, but the serving sizes are typically smaller for these products than for milk. shows the main nutrient content per 100 g of commonly consumed foods.

Table 1

Therefore, the regular consumption of plain dairy products or those fortified with calcium and/or vitamin D may increase the total body bone mineral content (BMC). However, this association varies depending on ethnicity. In Caucasian and Chinese women, calcium from (fortified) dairy products increased BMD by 0.7-1.8% over 2 years, depending on the site of measurement (lumbar spine, total hip, femoral neck or total body). In adult Caucasian women, a daily intake of 200-250 mL of milk has been associated with a 5% or higher reduction in fracture risk [ 12]. Another large prospective study recently showed a significant 8% reduction in the risk of hip fracture for each daily serving of milk, in men and women combined, which was evaluated every 4 years. Moreover, milk intake was shown to reduce the risk of osteoporotic fractures by 5-15% in an individual patient data cohort, especially in older patients (80 years or more) [ 13]. In a cohort of postmenopausal healthy women, the daily consumption of milk fortified with calcium and vitamin D significantly improved vitamin D status and BMD at the femoral neck, as well as having favorable effects on glucose and lipid profiles [ 14]. The data on this effect in males are more limited.

Fermented milk products, such as yogurt or soft cheese, are also an important source of calcium, phosphorus, and protein. Fermented milk is interesting because it may contain prebiotics and provide probiotics. For example, inulin (a prebiotic) may be added to yogurt. Furthermore, probiotics are able to improve intestinal calcium absorption and bone metabolism. Bone mass balance and the attenuation of sex hormone deficiency-induced bone loss (especially important after menopause) seemed to improve after the intake of calcium, protein, prebiotics and probiotics. These compounds may change the gut microbiota composition and metabolism. Fermented milk product consumption might also be considered as a marker of healthy lifestyle promoting bone maintenance [ 15].

In animal models, probiotics have been shown to inhibit the bone loss associated with estrogen deficiency, diabetes, or glucocorticoid treatments, by regulating both bone resorption and formation [ 16]. In humans, probiotics alter 25(OH)D levels and calcium absorption, and slightly decrease bone loss in elderly postmenopausal women to a similar extent as vitamin D supplements with or without calcium combination [ 17]. Fermented dairy products are an important dietary source of probiotics, which can improve calcium homeostasis, prevent secondary hyperparathyroidism, and inhibit age-related increases in bone resorption and bone loss. Further studies are needed to establish whether probiotics or any other intervention targeting the gut microbiota and its metabolites may be considered as adjuvant treatments for use alongside calcium and vitamin D supplementation or anti-osteoporotic drugs for the management of patients with fragility and low bone mass [ 18].

Unfortunately, a low calcium intake and a suboptimal vitamin D status are very common in the elderly in Europe. The daily consumption of calcium and vitamin D-fortified food products (most commonly yogurt or milk) can help to improve vitamin D intake [ 19]. Yogurt consumption may guarantee a more regular ingestion of dairy products and higher adherence to their consumption, because of various flavors and sweetness levels. However, not enough studies addressing bone remodeling markers, other than BMD or BMC, allowing a good comparison between the effect of dairy products and other food sources on bone quality are available.

Not all of the available information supports the idea of a high intake of dairy products being beneficial for bone [ 20]. In the US, data from the NHANES III population-based survey, including a cohort of nearly 10,000 women and men, showed no correlation between calcium intake and BMD at the hip site, and the correlation was more applicable for subjects with higher levels of 25(OH)D [ 21]. Only women with higher 25(OH)D levels seemed to benefit from a higher calcium intake. Other meta-analyses based on prospective studies were not able to associate a higher milk intake or total dairy product consumption with the risk of hip fracture in women or men [ 22, 23]. The Study of Women's Health Across the Nation (SWAN) recently tried to demonstrate the benefits of dairy intake for bones, but its results were not positive for long-term bone health. It is important to mention that this study was a multicenter, multi-ethnic, community-based longitudinal cohort project that included women during their middle years around the menopause transition period [ 24]. The benefit of dairy consumption for preserving BMD or preventing fractures could not be established. However, when interpreting these results, the authors reported that dairy intake was low among SWAN participants, and this fact could have influenced their results.

The potential beneficial role of dairy products in the prevention of fractures is controversial [ 25]. Moreover, a higher consumption of milk or yogurt could be related with a lower risk of hip fracture although with some differences between populations with different characteristics [ 26]. The inconsistent results found regarding the possible association between milk consumption and the risk of hip fracture could be partially explained by the differences in policies about vitamin D fortification across different countries.

In conclusion, the beneficial role of dairy products in bone health has been more extensively established in Chinese and Caucasian girls and women [ 27], but these results could not be replicated for other populations. Nevertheless, the available evidence is insufficient because studies on calcium alone and other dairy products are limited in size, number, and duration and advanced research on the influence of dairy products within the context of bone health-promoting diets in specific ethnic groups, other than the above-mentioned studies, is needed [ 27].

In summary, it is very difficult to differentiate between the effects of dairy intake and those of other components of diet and lifestyle. No large randomized clinical trials evaluating dairy intake over long periods of time are available. Therefore, we must assume this limitation and establish our recommendations based on the best observational studies and on the previously known biological premises.

2.2. Other Minerals

Other minerals, such as potassium or magnesium, also have an important role in bone health.

Dietary potassium may reduce the acid load and, thus, calcium depletion from bones. Apart from its role in the maintenance of an alkaline state in the body, potassium can also increase the accumulation of calcium in the kidneys. In a nationwide Korean population study, the highest intake of potassium was associated with greater lumbar, total hip, and femur neck BMD in men older than 50 years and postmenopausal women [ 28]. This association was demonstrated in a population with a low calcium intake. The meta-analysis performed by Lambert et al. confirmed that supplementation with alkaline potassium salts was associated with a significant reduction in renal calcium excretion and acid excretion. These salts significantly lowered the bone resorption marker cross-linked N-telopeptides of type I collagen (NTX) but with no effect on bone formation markers or BMD. The reduction in bone resorption indicates a potential advantage for bone health [ 29].

Magnesium is also necessary for calcium metabolism [ 30]. After potassium, magnesium is the second most abundant intracellular cation, with a concentration of 10-30 mM in the human body. Magnesium is found in most whole foods, such as green leafy vegetables, legumes and nuts. The recommended daily allowances of magnesium are 310-360 mg and 400-420 mg for women and men, respectively. The requirements vary between individuals according to age, sex and previous nutritional status [ 31].

Magnesium is also involved in the exchange of calcium and potassium ions across cell membranes, and it is essential for neuronal activity and muscle contractions. Approximately 50-60% of the total body magnesium content is accumulated in the bone. In the bone's structure, magnesium ions bind at the surface of the hydroxyapatite crystals, improve the solubility of phosphorous and calcium hydroxyapatite and, thereby, influence crystal size and formation. Furthermore, magnesium induces osteoblast proliferation; therefore, its deficiency is associated with reduced bone formation [ 32]. Magnesium is also necessary for the activation of vitamin D because most of the enzymes involved in vitamin D metabolism require magnesium [ 33].

Populations that consume more processed food (more refined grains, sugars and fats) have lower levels of magnesium, as is typical in the United States [ 34]. A significant problem arises from the soil used for agriculture, which is becoming increasingly deficient in essential minerals such as magnesium.

No randomized studies evaluating the effect of magnesium on bone disease are available, but small-size studies have associated low serum magnesium levels with osteoporosis [ 35, 36]. In older subjects, a low intake of magnesium causes excessive calcium release from the bone, which further worsens bone fragility and increases the risks of fractures and falls [ 37]. A cross-sectional analysis of a cohort of subjects in the UK evaluating the influence of dietary magnesium and potassium intakes on bone density and fracture risk found a lower hip fracture risk in both men and women with a higher intake of these minerals, but these results did not hold after adjustment for multiple testing [ 38]. summarizes the main influence of some important nutrients on bone health.

2.3. Protein Intake

Protein intake is also essential for bone health. Approximately 50% of bone volume and about a third of bone mass is composed of proteins. They are integrated into the organic matrix of bone as part of the collagen structure when mineralization occurs. Dietary proteins also affect the secretion and action of insulin-like growth factor I (IGF-I), an orthotropic hormone important for bone formation. The IGF-I hormone improves calcium and phosphorus absorption in the gut; it is involved in the synthesis of calcitriol, and it increases the rate of phosphate reabsorption from the kidney. An adequate amount of dietary protein is therefore required for the maintenance of bone health. The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) recommends a dietary protein intake of 1.0-1.2 g/kg body weight/day, with at least 20-25 g of high-quality protein at each main meal [ 39]. The main sources of protein in healthy diets come from meat, fish, poultry, eggs and dairy products. Adequate protein intake is imperative for bone matrix formation and maintenance. However, it was previously believed that excessively high protein intake might induce a negative calcium balance, based on the "nutritional acid load hypothesis". This hypothesis relates a higher protein intake (especially that of animal origin, with more sulfur amino acids) to increased acid production and bone resorption, and thus, the development of deleterious hypercalciuria and bone loss, leading to osteoporosis and an increased risk of fragility fractures [ 40]. More recent meta-analyses have reported that a higher protein intake-more than 0.8 g/kg body weight/day, higher than the general dietary recommendations-is associated with a higher BMD, reduced risk of hip fracture and slower rate of bone loss. It is especially important in older people with osteoporosis and must always be accompanied by adequate dietary calcium intakes [ 41]. It is also important to take into account the anabolic effect of protein intake that, together with physical activity, is a main driver of muscle protein synthesis. When practicing exercise, muscle mass and strength improve, and the combination of adequate protein intake and exercise induces a greater degree of muscle protein accretion than either intervention alone. In the same way, a balanced dietary protein intake in combination with resistance exercise is an important contributor to the maintenance of bone strength.

It has been demonstrated that there is no adverse effect of higher protein intakes on bone. Furthermore, they are beneficial in attenuating age-related bone loss and reducing hip fracture risk in older subjects [ 42]. No significant differences in hip fracture outcomes between animal and vegetable protein consumption within the limits of a balanced diet have been found. However, as previously mentioned, all of these positive outcomes depend on adequate calcium intakes. Dairy product intake is probably very helpful because these products are a source of both proteins and calcium, since 1 L of milk provides 32 g of protein and 1200 mg of calcium. Furthermore, in some countries, yogurts are supplemented with milk powder, resulting in a 50% increased content of these nutrients compared with that in yogurt prepared from plain milk. The combination of protein and calcium in dairy products has positive effects on calciotropic hormones. They produced a reduction in circulating PTH, an increase in IGF-I and, consequently, a decrease in bone resorption markers, as well as improving BMD [ 15]. Therefore, much more severe problems are found for diets with inadequate protein than for those with an excess.

In terms of the nutrients required for good bone health, fruit and vegetables are rich in the previously mentioned nutrients, such as potassium and magnesium, and in vitamin C, vitamin K, folate and carotenoids [ 44, 45].

2.4. Vitamins K and C

Vitamin K is involved in bone matrix formation during mineralization. It acts as a cofactor for the microsomal γ-carboxylase, which facilitates the post-translational conversion of glutamyl to γ-carboxyglutamyl residues in osteocalcin, and it also influences other vitamin K-dependent proteins. In its γ-carboxylated state, osteocalcin is a calcium-binding protein in bone, facilitating the mineralization process. Vitamin K comprises a family of different molecular forms: vitamin K1 is a single form synthesized by plants, whereas the group of vitamins K2 comprises multiple forms, mainly synthesized by bacteria. Vitamin K1 is the major type found in human diets. A special feature of cheese is the presence of vitamin K2. A recent meta-analysis performed in 2019, including more than 11,000 patients, was conducted mainly in postmenopausal or osteoporotic patients [ 46]. It concluded that vitamin K supplementation appeared to have little clinically significant effect on BMD and vertebral fracture outcomes for these patients-in part, related to the heterogenicity in studies included, especially concerning the treatment regimes. Regarding postmenopausal women and osteoporotic patients, clinical fractures were less frequent in the vitamin K-supplemented group, but the effect appeared to be smaller when the analysis was restricted to low-risk-of-bias studies. Unfortunately, very few trials are available; therefore, it is difficult to draw conclusions for other populations based on this meta-analysis. Another systematic review found that the clinical use of oral vitamin K antagonists as part of anticoagulant therapy was neither related to nor reduced BMD, nor was it associated with an increased risk of fracture [ 47]; this supported previously reported results suggesting the absence of a clinically meaningful effect of vitamin K on BMD.

Vitamin C can improve bone health because of its antioxidant properties. It is able to suppress osteoclast activity [ 48]. It also acts as a cofactor for osteoblast differentiation and participates in collagen formation. Vitamin C is a marker of a healthy dietary pattern rich in fruit and vegetables. A systematic review and meta-analysis that compiled observational studies concluded that a greater dietary vitamin C intake was positively associated with BMD at the femoral neck and lumbar spine, although this review reported remarkable between-study heterogeneity at the femoral neck. This heterogeneity was caused by differences regarding study design, sex and age. A higher dietary vitamin C intake was correlated with a lower risk of hip fracture and osteoporosis, as well as higher BMD, at both the femoral neck and lumbar spine sites [ 49]; a more recent meta-analysis strongly reinforces the idea that increasing dietary vitamin C intake could decrease the risk of hip fractures in both males and females [ 50]. Although these bone benefits are remarkable, there is little information in clinical practice guidelines in terms of vitamin C intake recommendations, and this should be taken into account.

2.5. Omega-3 Polyunsaturated Fatty Acids and Other Nutrients

There is conflicting evidence regarding the effects of omega-3 polyunsaturated fatty acids (PUFA) on bone metabolism. The consumption of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may influence bone growth and remodeling in humans through the inhibition of bone resorption and also by stimulating bone formation [ 51]. The mechanism by which PUFAs may affect bone turnover is not well known, but it is hypothesized that both EPA and DHA may exert their benefits by regulating osteoprotegerin (OPG)/receptor activator of nuclear factor kB (RANK), with a balance towards bone formation [ 52]. Fish and seafood are rich in PUFAs, especially n-3 FAs, which are known to have an anti-inflammatory effect that improves bone quality [ 53]. A meta-analysis conducted by Shen et al. showed that omega-3 fatty acids reduced osteocalcin serum levels in postmenopausal women, but no significant decrease in bone-specific alkaline phosphatase was found [ 54]. A study performed with a dairy product enriched in PUFAs, calcium, oleic acid and vitamins to evaluate their effects on bone metabolism in postmenopausal women showed favorable changes in some bone metabolism markers, such as an increase in vitamin D levels and a decrease in both PTH and RANKL, but did not show changes in other bone turnover markers or serum OPG [ 55]. Another Spanish study showed that the dietary intake of PUFAs was positively associated with BMD in both healthy and osteopenic Spanish women, at both the hips and lumbar spine [ 56]. A systematic review published in 2019 revealed a significant inverse association between the dietary intake of n-3 PUFAs through fish consumption and the risk of hip fracture, and that they might have protective effects on bone health [ 57].

Folate and vitamin B-12 might also influence bone by reducing homocysteine concentrations; homocysteine is linked to lower BMD and a higher risk of fracture [ 58]. A recent meta-analysis including 7475 individuals from four prospective studies showed a 4% lower fracture risk for each 50 pmol/L increase in vitamin B-12 concentration [ 59].

Zinc can be found in beans, nuts and whole grains, but the phytate in these foods makes it less bioavailable than zinc from animal-based sources. Lower serum and bone zinc concentrations have been described in patients with osteoporosis [ 60].

3. Recent Studies on Reference Dietary Patterns

Dietary pattern approaches unify contributions from various aspects of the diet. They are more useful than single-nutrient and food studies for elucidating the effects of different nutrients alone on bone health and can paint a more comprehensive picture.

In general, a dietary pattern with a high intake of fruit, vegetables, low-fat dairy products, whole grains, poultry, fish, nuts and legumes has been demonstrated to have a positive effect on bone health and directly associated with a better BMD and lower risk of fracture. Moreover, it is inversely associated with levels of bone resorption markers [ 61, 62]. In an Asian population, a dietary pattern including higher intake of fruits, vegetables and soy was associated with a lower risk of fractures and also a lower risk of osteoporosis [ 63].

3.1. Mediterranean Diet

The latest studies have shown that adherence to the Mediterranean diet (Med-Diet) is protective against osteoporosis [ 64]. Animal studies have suggested that antioxidant-rich fruits have a marked effect, increasing trabecular bone volume, number, and thickness, and decreasing trabecular separation through the stimulation of bone formation and suppression of bone resorption [ 65].

Those subjects with a higher adherence to Med-Diet showed an independent association, with an increase in 25(OH)D, suggesting that higher vitamin D levels could mediate the protective effect of the Med-Diet against osteoporosis. In postmenopausal women, it has been reported that higher Med-Diet scores were associated with a higher BMD and lower risk of hip fracture [ 66, 67]. In a cohort of Spanish premenopausal women, the evaluation of BMD showed that all, total, trabecular, and cortical bone density were positively associated with higher adherence to the Med-Diet [ 68]. These positive bone results were also demonstrated in a cohort of Italian subjects, where higher T-scores were positively associated with higher adherence to the Med-Diet [ 69]. In another study including postmenopausal women, those with higher adherence to Med-Diet had better BMD at the lumbar spine and improved muscle mass, also important for the prevention of osteoporosis and fractures [ 70]. Greater adherence to this diet was associated with a lower risk of fracture as well as a higher mean BMD, according to the meta-analysis of four effect sizes, obtained from three studies by Malmir et al. [ 71].

Considered to be at the core of the Mediterranean diet, olive oil has been reported as beneficial for bone status. Published evidence suggests that olive oil, with a high proportion of phenols, can be beneficial by preventing the loss of bone mass [ 72]. It has been demonstrated that the phenolic compounds can modulate the growing capacity and cell maturation of osteoblasts by increasing alkaline phosphatase activity and contributing to the creation of the extracellular matrix. The dietary intake of olive oil was significantly associated with higher BMD in a cohort of Spanish women across a wide range of ages [ 73]. Furthermore, it was associated with a higher total osteocalcin concentration and an increase in procollagen I N-terminal propeptide in a group of men, suggesting the protective effects of olive oil on bone [ 74]. A cohort of subjects was analyzed as part of the PREDIMED study, and those participants with the highest intake of extra-virgin olive oil had the lowest risk of osteoporosis-related fractures [ 75].

3.2. Western Diet

Regarding the situation in Europe, as suggested by the "Framingham study", individuals with diets high in processed protein foods (with a high percentage of protein intake from cheese, processed meat, pastries, pizza, French fries, snacks and refined grains) have shown a lower BMD compared to other groups of subject [ 76]. Furthermore, all studies alert about the risks of the unhealthy Western dietary pattern and the importance of promoting a decrease in the consumption of processed food products, sweets and desserts, soft drinks, fried foods, meat and refined grains. The risks of Western diets should be reinforced, as they are associated with lower BMD and a higher risk of fractures [ 77]. As an example, an English traditional dietary pattern-including a high intake of fried fish and potatoes, legumes, red and processed meats, and savory pies-was inversely associated with BMD in the femoral neck [ 78]. Moreover, a high fat intake, derived mostly from refined carbohydrates and fat products, can directly interfere with intestinal calcium absorption and also increase fat accumulation and obesity, which lead to a decrease in osteoblast differentiation and bone formation [ 79]. Sodium intake induces higher calciuria, which is presumed to increase bone loss and bone remodeling [ 80]. An excessive intake of inorganic phosphorus, present in processed food additives, induces a disruption of the calcium-phosphorus ratio, affecting the endocrine regulation of calcium homeostasis [ 81]. This is deleterious for bone health. However, it might be taken into consideration that this detrimental relationship between the Western dietary pattern and bone health is, in part, confounded by high net endogenous acid production. In an acidic environment, bone acts as a provider of alkali to maintain the acid-alkali balance, which leads to progressive bone loss [ 82].

3.3. Asian Diet

Asian populations have dietary patterns in which soy and fish intake are high compared to that in Western populations. They have a significantly lower incidence of osteoporotic fractures. Indeed, several meta-analyses have demonstrated that the supplementation of soy isoflavones with omega-3 fatty acids improved bone health status in women [ 83]. Evidence from epidemiological studies supports the idea that dietary soy isoflavone intake attenuates the bone loss induced by menopause, improving bone formation and decreasing bone resorption [ 84]. Another study in a Korean population showed that an increased consumption of fruits and dairy products as part of the traditional Korean diet, consisting mainly of white rice and vegetables, might decrease the risk of osteoporosis in Korean postmenopausal women [ 85] compared to the consumption of a diet rich in meat, alcohol and sugar. Furthermore, those subjects with higher intakes of white rice, kimchee and seaweed had a higher risk of osteoporosis in the lumbar spine. Another study in a cohort of Japanese postmenopausal women found that natto (fermented soybeans) consumption was positively associated with lumbar spine BMD, and its intake could be recommended for preventing postmenopausal bone loss [ 86].

A systematic review of dietary patterns involving a higher consumption of meat or processed meat (Meat Diet) or a higher consumption of fish and seafood (Fish Diet) suggested that these diets did not alter BMD or the risk of fractures. This study indicated that protein intake from fish or meat is not harmful to bone. The Meat Diet showed negative effects on bone metabolism in the setting of a Western Diet, but these could not be demonstrated in the context a Mediterranean or Asian Diet [ 87].

3.4. Vegetarian Diets

Vegetarian diets have been proven to contain lower amounts of calcium, vitamin D, vitamin B-12, protein and n-3 fatty acids, all of which have important roles in maintaining bone health. However, healthy vegetarian diets usually contain greater quantities of several protective bone-related nutrients such as magnesium, potassium, vitamin K, and antioxidant and anti-inflammatory phytonutrients. Unfortunately, the limited available evidence suggests that, on balance, vegetarians-especially vegans-may be at higher risk of low BMD and fractures [ 88]. A meta-analysis in 2009 by Ho-Pham comparing vegetarians and omnivores, including more than 2500 subjects, showed a 4% lower BMD at both the femoral neck and lumbar spine in vegetarians than in omnivores [ 89]. From this study, a subgroup analysis found that the difference was greater for vegans, who had a 6% lower BMD than omnivores.

There are few studies available examining vegetarian diets and related fractures. A prospective study of fracture risk in the United Kingdom found that fracture risk was higher in vegans as they had lower calcium intakes (<525 mg/day), but no difference was found between meat/fish eaters and lacto-ovo-vegetarians [ 90]. Vegan populations should obtain calcium from other sources-such as tofu, fortified soy products or fortified orange juice-but care is required to ensure an adequate intake. A careful selection of foods or the addition of fortified foods or supplements is needed to avoid a potential nutrient shortfall and to help ensure a healthy bone balance and reduce fracture risk in those individuals who adhere to vegetarian diets.

In the most recent meta-analysis published last year by Fabiani et al., the dietary pattern named as the "Meat/Western" pattern-characterized by a high consumption of red and processed meat, refined grains, and sweets-was positively associated with a lower BMD and a higher fracture risk. This dietary pattern was compared to "Healthy" patterns, characterized by a high consumption of fruit and vegetables, and the "Milk/Dairy" pattern, and these two patterns were associated with a decreased risk of low BMD. Moreover, the "Healthy" pattern had a significant preventive effect on fracture risk, whereas the "Meat/Western" pattern significantly increased the fracture risk [ 91]. A summary of larger studies relating bone status to each dietary pattern is found below in .

Table 2

Dietary Pattern

Name of the Study

No. Participants (Sex),
Mean Age/Age Range

Effect on BMD

Effect on Fracture Risk

Mediterranean Diet

EPIC Study [ 61]

188,795
(139,981 women and 48,814 men)
48.6 years (±10.8)

7% decrease in hip fracture incidence

CHANCES Project [ 62]

140,775
(116,176 women, 24,599 men)
60 years and older

4% decrease in hip fracture risk

Meta-analysis, Malmir et al. [ 71]

358,746
13-80 years

Positive association with lumbar spine, femoral neck and total hip BMD

21% reduced risk of hip fracture

Asian Diet

Singapore Chinese Health Study [ 63];
vegetables-fruit-soy

63,257
(35,241 women and 27,913 men)
45-74 years

34% reduced risk of hip fracture

Osteoporosis
Korean Health and
Nutrition Examination
Survey 2008-10 [ 85]

3735
(postmenopausal Women)
64 ± 9 years

Dairy and fruit pattern decreased the risk of osteoporosis of the lumbar spine (53%); white rice, kimchi and seaweed dietary pattern was negatively associated with bone health

Western Diet

Co-twin controlled study,
United Kingdom [ 78]

4928
(postmenopausal Women)
56 ± 12 years

Inversely associated with BMD in femoral neck

Framingham Offspring
Study, United States,
[ 76]

2740
(1534 women and 1206 men)
29-86 years

Higher intakes of red meat and processed food were inversely associated with femoral neck BMD

Vegetarian Diet

Bayesian meta-analysis
[ 89]

2749
(1880 women and 869 men)
20-79 years

4% lower BMD (95% CI: 2%, 7%) at femoral neck and lumbar spine

EPIC Oxford study [ 90]

34,696
(26,749 women and 7947 men)
20-89 years

Fracture incidence rate ratios: 1.00 (0.89-1.13) for vegetarians and 1.30 (1.02-1.66) for vegans

Unfortunately, we have to point out that the majority of studies developed to elucidate the association between bone mineral status or fracture risk and dietary patterns had a cross-sectional design, and this fact may have influenced their results and further conclusions.

Interdependencies among nutrients could be a part of the explanation for the heterogeneity of the results from different studies and meta-analyses. These studies based on dietary patterns are very important for translating knowledge and facilitating recommendations for practice, and they should complement studies of single nutrients and particular foods in relation to bone health. Nutrients are consumed together in one meal rather than in isolation, and often, their effects will not be visible when the intakes of other nutrients are suboptimal.

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Nutrients and Dietary Patterns Related to Osteoporosis

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Calcium and vitamin D form part of the bone mineral matrix as calcium phosphate (hydroxyapatite crystals) and are required for bone strength. The best way to achieve adequate calcium intake is through adhering to a healthy diet. However, sometimes dietary sources are insufficient or poorly tolerated, and, in those situations, pharmacological calcium supplementation could be useful.

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The Effectiveness of Physical Exercise on Bone Density in Osteoporotic Patients- Cole Cincinelli

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The Effectiveness of Physical Exercise on Bone Density in Osteoporotic Patients- Cole Cincinelli

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Exercise is an effective preventative measure and treatment for many diseases. Along with diet, exercise can reduce the risk of cardiovascular disease, diabetes, and many others. For this week's wall post is about the effectiveness of physical exercise on bone density in osteoporotic patients.Two types of exercise were found to be helpful in improving bone density in osteoporotic patients, weight-bearing aerobic exercises, which includes walking, stair climbing, and jogging. Also, Strength and resistance exercises such as lifting weights, swimming, and cycling. Strength and resistance training were determined to increase site specific bone density particularly at the neck of the femur and the lumbar of the spine. Aerobic exercises mostly determined no gain in bone density rather it limited the loss of bone density. This information can be used in the clinical setting for men and women near menopause age, as well as elderly patients at high risk for osteoporosis. In my opinion, the best recommendation for elderly patients is to incorporate swimming into their exercise plan. Not only is strength and resistance training the most effective exercise for bone density and muscle tone but it also limits the stress on joints.

Benedetti MG, Furlini G, Zati A, Letizia Mauro G. The Effectiveness of Physical Exercise on Bone Density in Osteoporotic Patients. Biomed Res Int. 2018;2018:4840531. Published 2018 Dec 23. doi:10.1155/2018/4840531

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Interaction of Nutrition and Exercise on Bone and Muscle- Jaida Garrett

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Interaction of Nutrition and Exercise on Bone and Muscle- Jaida Garrett

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I saw fit for this article because I am all about promoting awareness and seeking prevention in chronic diseases. Musculoskeletal diseases become more of a risk factor as you age, therefore, nutritional and physical health should be adequate. Several dietary components can affect osteocyte function in a positive or negative way. Osteocytes in bone tissue sense fluid shear stress for mechanical loading, and translating that stress into production of biochemical signaling molecules to regulate proper bone formation. So, someone suffering from osteoporosis suffers from osteoclasts and terminally differentiated osteoblasts, which are osteocytes, being underproduced compared to the constant microtrauma. As supported, poor nutrition and physical health can lead to a slew of issues. For clinical use, researchers have looked into circulating 25-hydroxyvitamin D and moderate physical activity and compared that to several different studies. The most significant finding was creatine supplementation that improves muscle mass and strength however, if you look at further data this is just a supporting role and should not be main source of change. One should focus on physical activity, calcium, and protein intake to build bone mass. More clinical trials should be done across aged populations.

Laskou, F., & Dennison, E. (2019). Interaction of Nutrition and Exercise on Bone and Muscle. European endocrinology, 15(1), 11–12. https://doi.org/10.17925/EE.2019.15.1.11

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Nutrients and Dietary Patterns Related to Osteoporosis -Cassie Craig

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Nutrients and Dietary Patterns Related to Osteoporosis -Cassie Craig

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The study I chose for this week is a review that focuses on the development and advancement of osteoporosis in terms of different nutritional patterns and dietary choices. The researchers focused on not only individual impacts of nutrients, but the overall complexity of a consistent dietary pattern. It was found that specific nutrients are important on their own in theory, but it is significantly more important to develop a balanced dietary pattern of many different nutrients, paired with healthy lifestyle choices to prevent the development of osteoporosis. This is related to nutritional sciences because it validates the complexity of nutrient intake and shows that more research needs to be done in how these nutrients work together to combat disease pathology. Clinical implications of this could include different recommendations to patients that are at risk for osteoporosis. As I mentioned, more research should be done in this area, but the researchers of this paper recommend that causality is determined between calcium, vitamin D and protein consumption from dairy and an increased level of bone health. This conclusion would allow for physicians to implement dairy consumption (along with increased physical activity) into patients’ diet when they are at risk for osteoporosis.

Muñoz-Garach, A., García-Fontana, B., & Muñoz-Torres, M. (2020). Nutrients and Dietary Patterns Related to Osteoporosis. Nutrients, 12(7), 1986. https://doi.org/10.3390/nu12071986