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Monitoring the Safety : Complications of Alendronate

# data[].attributes.subject
Monitoring the Safety : Complications of Alendronate

# data[].attributes.body
Atypical femoral fractures (AFFs)

*stress type fractures originating in the lateral shaft of the femur

The risk of AFFs increases with duration of bisphosphonate use.

STATISTIC: The age-adjusted incidence rate of AFFs has been estimated to be 1.78 per 100,000 person- years in patients on bisphosphonate use <2 years and the incident rate increases to 113.1 per 100,000 person-years with >8 years’ duration.

-Though it has been shown that Asians on bisphosphonate therapy may have an increased risk of AFFs compared to Caucasians

Overall, the benefit of reducing further osteoporotic fractures with bisphosphonate treatment is much greater than the small absolute risk of AFFs.

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Clinical Practice Guidelines: Management of Osteoporosis (page 23)

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https://www.moh.gov.my/moh/resources/Penerbitan/CPG/Rheumatology/221115_MOS_CPG-Management_of_Osteoporosis-ed3_PREVIEW.pdf

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- Alendronate at 10 mg daily for three years increases lumbar spine BMD by up to 8.8% and femoral neck BMD by 5.9% compared to placebo.

-Vertebral and hip fractures are reduced by 50% in women wih or without prior fracture.

-Wrist fracture is reduced by 50% in patients with prior vertebral fracture.

-Fracture reduction is seen after one year of treatment.

-Pooled analysis found an overall reduction in risk of hip fracture of 45% to 55% in patients receiving alendronate therapy.

DOSE: Alendronate 70 mg weekly has similar efficacy to alendronate 10 mg daily in the treatment of postmenopausal osteoporosis.

-Continuous use of alendronate, for up to 10 years, if clinically indicated, produces a sustained increase in BMD and a 55% significant reduction in spine fracture with a good safety profile.

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Nutrition

Adequate calcium and vitamin D is important for peak bone mass attainments and osteoporosis prevention in adults and postmenopausal women

Smoking

Smoking increases osteoporotic fracture risk

Hip Protectors

Reduce, absorb and/or shunt the impact on the hip during a fall to prevent a fracture occurring. They range from a hard shell to a dense foam padding which are worn in an undergarment to cover the trochanteric area of the hip.

Ref : https://www.moh.gov.my/moh/resources/Penerbitan/CPG/Rheumatology/221115_MOS_CPG-Management_of_Osteoporosis-ed3_PREVIEW.pdf

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Plaster of Paris or calcium sulphate has found other uses as well

It has been used as bone graft substitute and to fill up bone defects

It has been used in spinal surgery as a bone graft substitute.

Advantages

Plaster can be tucked or pleated. Plaster requires less tension for application. Gloves are not required.

Plaster absorbs fluids, including pus, blood, and sweat.

If a cast saw is not available, the plaster cast may be removed by soaking and unrolling or using simple hand-cutting instruments.

Disadvantages

Compared with fibreglass, plaster may be difficult to store in high humidity and is more difficult to keep clean.

Plaster casts are heavier than fibreglass, exhibit more breakdown for short-leg casts, and are judged to be more restrictive and less comfortable

However in a country like India where the cost considerations come in to play POP still remains the choice of material in casting

Ref : https://pmc.ncbi.nlm.nih.gov/articles/PMC3880430/

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Inhibit the synthesis of prostaglandins, which are known to stimulate the resorption of bone by osteoclasts

Regular NSAIDs users had a higher fracture risk compared with non-NSAID controls.

Ref : https://www.sciencedirect.com/science/article/abs/pii/S8756328200003616

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Rationale in changing omeprazole to ranitidine

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Rationale in changing omeprazole to ranitidine

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This is a good choice.

A research had hypothesized that Proton Pump Inhibitor (PPI) are bone-specific phosphatase (PHOSPHO1) inhibitors but not for Histamine-2 Receptor Antagonist (H2RA) in animal studies. (mentioned below as 1)

Other research (mentioned below as 2) shown that PPI does not affect bone mineral density.

Vetebral and non-vetebral fracture risk (mentioned below as 3) was increased upon long term PPI usage. Possible mechanisms are visual impairment, vitamin B12 deficiency or their neurologic associated consequences such as numbness of the feet.

Reference:

1. https://link.springer.com/article/10.1007/s00223-021-00882-9#Sec1

2. https://www.gastrojournal.org/article/S0016-5085(09)02030-7/fulltext

3. https://pmc.ncbi.nlm.nih.gov/articles/PMC9504265/#sec6-ijms-23-10733

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Proton Pump Inhibitors Inhibit PHOSPHO1 Activity and Matrix Mineralisation In Vitro

Abstract

Proton pump inhibitors (PPIs) have been associated with an increased risk of fragility fractures in pharmaco-epidemiological studies. The mechanism is unclear, but it has been speculated that by neutralising gastric acid, they may reduce intestinal calcium absorption, causing secondary hyperparathyroidism and bone loss. Here we investigated that hypothesis that the skeletal effects of PPI might be mediated by inhibitory effects on the bone-specific phosphatase PHOSPHO1. We found that the all PPIs tested inhibited the activity of PHOSPHO1 with IC50 ranging between 0.73 µM for esomeprazole to 19.27 µM for pantoprazole. In contrast, these PPIs did not inhibit TNAP activity. We also found that mineralisation of bone matrix in primary osteoblast cultures was inhibited by several PPIs in a concentration dependent manner. In contrast, the histamine-2 receptor antagonists (H2RA) nizatidine, famotidine, cimetidine and ranitidine had no inhibitory effects on PHOSPHO1 activity. Our experiments show for the first time that PPIs inhibit PHOSPHO1 activity and matrix mineralisation in vitro revealing a potential mechanism by which these widely used drugs are associated with the risk of fractures.

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Introduction

Proton pump inhibitors (PPIs) are amongst the most commonly prescribed drugs and are used in the treatment of gastroesophageal reflux disease (GORD), peptic ulcer disease and dyspepsia [ 1]. In the UK alone, more than 60 million PPI prescriptions were issued during 2017 [ 2]. The safety records of PPI's are generally favourable, but pharmaco-epidemiological evidence has consistently shown a positive association between PPI use and bone fractures. For example, large scale studies conducted in Denmark, UK and Canada all reported an increased risk of osteoporosis related fractures including fractures to the hip and spine with chronic PPI therapy [ 3, 4, 5].

The most commonly accepted explanation is that PPIs predispose to fractures by neutralising gastric acid. This in turn is thought to impair intestinal calcium absorption, secondary hyperparathyroidism and increased osteoclastic bone resorption with bone loss [ 6, 7, 8]. However, in healthy subjects, short-term treatment with the PPI omeprazole was not found to have inhibitory effects on calcium absorption [ 9, 10]. Furthermore, epidemiological studies with histamine 2 receptor antagonists (H2RAs), which also supress gastric acid secretion, have not shown an association with fractures [ 3, 11, 12, 13, 14, 15]. Likewise, a recent meta-analysis reported that the use of PPIs, but not H2RAs, is associated with an increased risk of hip fracture [ 16]. These conflicting data suggest that PPI use may increase fracture incidence by a mechanism that distinct from effects on intestinal calcium absorption.

PHOSPHO1, a member of the haloacid dehalogenase superfamily, is a cytosolic phosphatase highly expressed by osteoblasts which is essential for bone mineralisation [ 17]. It liberates inorganic phosphate (P i) through the hydrolysis of phospholipid substrates within the matrix vesicle (MV) membrane [ 17, 18, 19]. Within this protected environment, Pi accumulates and chelates with Ca ²⁺ which is enriched in MVs to form mineral crystals which subsequently invade and mineralise the organic collagenous scaffold [ 17, 18, 19, 20, 21, 22]. Deletion of PHOSPHO1 in mice results in bowed long bones and spontaneous greenstick fractures, decreased cortical BMD and accumulation of osteoid in trabecular bone [ 23]. Similarly, osteoblasts treated with a PHOSPHO1-specific inhibitor and cultures of Phospho1 deficient primary osteoblast both revealed reduced matrix mineralising ability, whereas matrix mineralisation was increased by osteoblasts overexpressing PHOSPHO1 [ 24, 25]. A critical role for PHOSPHO1 in the mineralisation process was confirmed in a comparison of the bone phenotype of; Alpl−/−; Phospho1−/− double knockout mice to that of Alpl−/− and Phospho1−/− mice. The skeleton of both single gene knockouts was impaired, whereas the double ablation led to the complete absence of skeletal mineralisation and embryonic lethality. These experimental data are consistent with the notion that PHOSPHO1 and TNAP have independent, non-redundant roles during the mineralisation process [ 23].

We previously identified, through a screen of chemical libraries containing over 50,000 compounds, the PPI, lansoprazole as a PHOSPHO1-specific inhibitor [ 18]. Indeed, lansoprazole non-competitively inhibited recombinant human PHOSPHO1 activity by over 70% and caused a 57% inhibition of osteoblast MV calcification, but had no effect on tissue non-specific alkaline phosphatase (TNAP) activity [ 18]. Furthermore, in vivo studies disclosed that lansoprazole administration to developing chick embryos completely inhibited mineralisation of all leg and wing long bones [ 26].

Considering the fact that PHOSPHO1 plays a critical role in bone mineralisation, we hypothesise that the association between PPI use and bone fractures is possibly due to their inhibitory effect on PHOSPHO1 activity. To address this hypothesis, we used in vitro approaches to evaluate the potential of commonly prescribed PPIs and H2RAs to inhibit both PHOSPHO1 enzyme activity and osteoblast matrix mineralisation.

Materials and Methods

PPI and H2RAs

The PPIs lansoprazole, omeprazole, pantoprazole and esomeprazole (Cayman Chemicals, Michigan, USA) were used at varying concentrations (0-100 µM) in the phosphatase activity and in vitro mineralisation assays detailed below. Similarly, the H2RAs nizatidine, famotidine, cimetidine and ranitidine (Selleckchem, Munich, Germany) were also used at 0-100 µM.

Primary Osteoblast Isolation

Primary calvarial osteoblasts were obtained from 4-day-old wild-type C57Bl/6 mice. Primary osteoblasts were isolated by sequential enzyme digestion of excised calvarial bones using a four-step process as has previously been described [ 7, 8] [1 mg/ml collagenase type II in Hanks' balanced salt solution (HBSS) for 10 min; 1 mg/ml collagenase type II in HBSS for 30 min; 4 mM EDTA for 10 min; 1 mg/ml collagenase type II in HBSS for 30 min]. The first digest was discarded and the cells were re-suspended in growth medium consisting of a-MEM (Invitrogen, Paisley, UK) supplemented with 10% (v/v) FBS and 1% gentamycin (Invitrogen). Osteoblasts were seeded at a density of 1 × 10 ⁴ cells/cm ² and grown to confluency at which point 2 mM β-glycerophosphate and 50 µg/ml ascorbic acid was added along with a PPI (0-50 µM) as described in the results. Media was changed every 2-3 days for the duration of the 28-day experiments.

Assessment of Primary Osteoblast Matrix Mineralisation

After 28 days, primary cell cultures were fixed in 4% paraformaldehyde for 5 min at room temperature. Cell monolayers were stained with aqueous 2% (w/v) Alizarin red solution for 5 min at room temperature. The bound stain was solubilised in 10% cetylpyridinium chloride and the optical density of the resultant eluted solution measured by spectrophotometry at 570 nm.

Phosphatase Assays

Recombinant human PHOSPHO1 (50 ng) was generated as previously described [ 27] and incubated with varying concentrations of the aforementioned PPIs and H2RAs in experimental assay buffer (20 mM Tris, 2 mM MgCl ₂ & 25 µg/ml BSA) at 37 °C for 15 min. Using the BIOMOL® Green assay (Enzo, Exeter, UK), standards (0-2 nM) and samples were then incubated with 2.5 mM β-glycerol phosphate for 30 min at 37 °C with gentle agitation [ 27]. The reaction was stopped using 100 µl BIOMOL® Green and after being left for 30 min at room temperature, the absorbance was read using spectrophotometry at 630 nm. For TNAP, 2 ng recombinant human TNAP (R&D Systems, Abington, UK), was incubated with varying concentrations of the aforementioned PPIs and H2RAs in experimental assay buffer (1 M diethylamine hydrochloride, 1 mM MgCl ₂ and 20 µM ZnCl ₂). Using the BIOMOL® Green assay, standards (0-2 nM) and samples were then incubated with 0.5 mM p-nitrophenyl phosphate (pNPP) for 30 min at 37 °C with gentle agitation. The reaction was stopped using 100 µl BIOMOL® Green and after being left for 30 min at room temperature, the absorbance was read using spectrophotometry at 630 nm.

Statistical Analysis

The data are expressed as the mean ± standard error of the mean (S.E.M) of at least three independent experiments. Statistical analysis was performed by one-way analysis of variance (ANOVA). P < 0.05 was considered to be significant and noted as *; P values of < 0.01 and < 0.001 were noted as '**' and '***' respectively.

Results

PPIs are Potent Inhibitors of PHOSPHO1 Activity

In accordance with our previous results, lansoprazole inhibited PHOSPHO1 activity (IC ₅₀ = 2.767 µM; Fig. 1A). Similarly, here we show for the first time that the PPIs omeprazole (IC ₅₀ = 2.803 µM) and esomeprazole (IC ₅₀ = 0.726 µM) are potent inhibitors of PHOSPHO1 activity (Fig. 1B, C). Whilst pantoprazole also inhibited PHOSPHO1 activity, its IC ₅₀ was 19.27 µM, suggesting that this PPI is the least potent PHOSPHO1 inhibitor tested (Fig. 1 D).

PHOSPHO1 Activity is Not Inhibited by H2RAs

We next sought to examine whether PHOSPHO1 activity is similarly inhibited by four commonly prescribed H2RAs. At all concentrations tested, there was no inhibition of PHOSPHO1 activity upon addition of nizatidine (Fig. 2A), famotidine (Fig. 2B), cimetidine (Fig. 2C) and ranitidine (Fig. 2 D).

PPIs and H2RAs Have No Effect on TNAP Activity

We next determined whether the aforementioned PPIs are able to inhibit TNAP activity. At all concentrations tested, lansoprazole, omeprazole, esomeprazole and pantoprazole did not inhibit TNAP activity (Fig. 3A-D). Similarly, there was no inhibition of TNAP activity by the H2RAs (Fig. 4 A-D).

PP1s Inhibit Primary Osteoblast Matrix Mineralisation

To examine whether the inhibition of PHOSPHO1 by PPIs has an effect on matrix mineralisation, we cultured primary osteoblasts in the presence of different concentrations of lansoprazole, omeprazole, esomeprazole and pantoprazole. We found that whilst control cultures formed mineralised nodules after 28 days in culture, the addition of 5 µM and 10 µM lansoprazole significantly decreased matrix mineralisation (Fig. 5A-C). Despite this, nodules were clearly visible throughout the cultures suggestive that collagen deposition is still occurring and therefore the effects seen are directly on the mineralisation of this matrix (Fig. 5A). Similarly, omeprazole and esomeprazole significantly inhibited matrix mineralisation at concentration of 10 µM (Fig. 5A-C). In concordance with the higher IC ₅₀ of pantoprazole, culture of primary osteoblasts with 5 µM and 10 µM pantoprazole was not sufficient to inhibit matrix mineralisation (Fig. 5A-C). We therefore cultured cells with 50 µM pantoprazole and indeed saw a significant decrease in matrix mineralisation (Fig. 5 D).

The effects of proton pump inhibitors (PPIs) on primary osteoblast matrix mineralisation. Primary osteoblasts were cultured for 28 days in the presence of 0-10 µM lansoprazole, omeprazole, esomeprazole and pantoprazole. A Microscopic images of alizarin red stained mineral associated with nodule formation. Scale bars are 200 μm. B Alizarin red staining. Images are representative of three individual experiments. C Quantification of alizarin red staining, D Alizarin red staining of primary osteoblasts treated with 50 µM pantoprazole. The data are represented as mean ± S.E.M. ( n = 3 wells/treatment) P < 0.05*, P < 0.01**, P  < 0.001***

Discussion

In this study, we report that all the PPIs tested were inhibitors of PHOSPHO1 activity whilst they had no effect on TNAP activity. The most potent inhibitor was esomeprazole which gave 50% inhibition in the sub-micromolar range, followed by lansoprazole, omeprazole and pantoprazole Consistent with this, the PPIs we tested inhibited mineralisation of bone matrix in vitro in low micromolar concentrations, except pantoprazole which did not have inhibitory effects until higher concentrations of 50uM were used. Conversely, we tested several H2RAs and these had no effect on PHOSPHO1 or TNAP phosphatase activity.

Several studies have shown an association with between PPIs use and fractures. Indeed, a large-scale meta-analysis has reported a significant increase in relative risk (RR) of fractures at the hip [RR = 1.26, 95% CI = 1.16-1.36] spine [RR = 1.58, 95% CI = 1.38-1.82] and any-site fractures [RR = 1.33, 95% CI = 1.15-1.54] in PPI users as compared to controls [ 28].

The PPIs reduce gastric acid secretion through inhibition of H + /K + -ATPases located in stomach parietal cells [ 29]. In view of this it has been speculated that calcium malabsorption mediated by neutralisation of gastric acid may cause secondary hyperparathyroidism and bone loss [ 6, 7, 8]. Other potential mechanisms include (i) impaired bone resorption resulting in altered bone remodelling and (ii) hypergastrinemia resulting in parathyroid hyperplasia and decreased bone mineral density [ 30, 31]. The H2RAs are also widely used to suppress gastric acid production in the treatment of GORD, dyspepsia and peptic ulcers these have not been associated with fractures in epidemiological studies which calls into question the hypothesis that the association between fractures and PPI used is mediated by reduced calcium absorption due to achlorhydria [ 3, 11, 12, 13, 14, 15]. The data presented here is consistent with this and suggests that inhibition of PHOSPO1 may be an alternative mechanism by which PPIs, affect bone health. The PHOSPHO1 enzyme is a bone-specific phosphatase that is highly expressed at sites of mineralization and essential for the formation of mechanically competent bone [ 17]. It is biochemically active within MVs [ 18] and it has been proposed that the accumulation of Pi within MVs is a consequence of PHOSPHO1s intravesicular activity and also intravesicular trafficking of TNAP‐generated Pi via a Type III Na‐Pi co‐transporter, PiT1 [ 32, 33, 34]. We have previously shown that MV mineralisation is reduced in Phospho1−/− mice [ 33, 35] and that lansoprazole treatment of MVs isolated from osteoblasts impairs their mineralisation [ 26]. It is therefore possible that PPI inhibition of PHOSPHO1 activity disrupts the biochemical machinery needed to establish the appropriate inorganic pyrophosphate to Pi ratio required to initiate the formation of HA mineral within MVs [ 34, 36]. Our in vitro cell culture work is also consistent with a previous study in which lansoprazole, esomeprazole and omeprazole decreased the ability of osteoblasts to mineralise their matrix, whilst also inhibiting osteoblast gene expression [ 37]. Therefore, it is plausible that the PPIs could also be having a negative effect on osteoblast differentiation and so to ensure that the mineralisation inhibitory effects observed here are solely due to PHOSPHO1 inhibition, it would be expected that the PPIs would exert the same effect if they were added only to the latter stages of the culture period, rather than throughout. However, we saw no effect on nodule formation, suggesting that our osteoblast cultures are still producing a collagenous matrix and it is indeed the mineralisation of this matrix which is being inhibited. These observations at the cell and MV level are consistent with, and explain, the reduced bone mineral content and BMD in rodents administered omeprazole [ 38, 39].

Interestingly, the data of this present study indicated no effect of PPIs on TNAP phosphatase activity; a result that is consistent with our previous study that reported lansoprazole and other small molecule inhibitors of PHOSPHO1 had no effect on TNAP activity [ 18]. The importance of TNAP in the mineralisation process is well accepted [ 40, 41]. Indeed, in patients with hypophosphatasia and also in Alpl−/− mice, extravesicular crystal propagation is retarded due to an accumulation of inorganic pyrophosphate in the extracellular matrix [ 42]. These data imply that the inhibition of osteoblast matrix mineralisation by the PPIs is via their inhibition of PHOSPHO1, and not TNAP activity. A note of caution in the interpretation of these data is nevertheless warranted; other in vitro studies have reported that lansoprazole can inhibit porcine TNAP activity albeit with a Ki value of ~ 100 times higher than that reported for the inhibition of recombinant human PHOSPHO1 with lansoprazole [ 18, 43]. An explanation for these different results is unclear.

We have previously shown TNAP expression and activity to be decreased in PHOSPHO1 knockout osteoblasts, with a concomitant increase in inorganic pyrophosphate levels [ 23]. However, the contribution of lowered TNAP levels to the decreased mineralisation noted in the absence of PHOSPHO1 is debatable, as transgenic overexpression of TNAP did not correct the bone hypomineralisation of Phospho1 knockout mice, despite normalisation of their plasma inorganic pyrophosphate levels [ 23]. Therefore, it is likely that the main cause of the hypomineralisation seen in our PPI treated cell cultures is indeed due to inhibition of PHOSPHO1 activity, as also indicated in our phosphatase assays.

The order of potency (based on our IC ₅₀ data) of PPI inhibition of PHOSPHO1 activity is esomeprazole > omeprazole = lansoprazole > pantoprazole (Fig. 2), which precisely mimics our data in mineralising primary osteoblasts, but also their ability (based on omeprazole equivalents) to inhibit acid production [ 44, 45]. Intriguingly, this suggests that the structure of the more potent acid suppressive PPIs accounts for their PHOSPHO1 inhibitory properties. Also, pantoprazole, the PPI least able to inhibit PHOSPHO1 enzyme activity was also a poor inhibitor of matrix mineralisation. Knowing the molecular model of PHOSPHO1 [ 21], it would be of interest to perform ligand docking studies to gain more information as to how the different PPIs associate with the enzyme and temper its biological activity. This has the potential to equip industry with the knowledge to generate modified and improved PPIs without the undesired off target bone effects.

In summary, we have shown that commonly prescribed PPIs, but not H2RAs, inhibit the activity of the bone-specific phosphatase, PHOSPHO1 in vitro in a dose-dependent manner and at concentrations that are similar to those used clinically. We have also shown that different PPIs differ by more than 25-fold in their ability to inhibit PHOSPHO1 activity when compared with a sevenfold difference in potency for inhibition of acid production [ 44]. This indicates that there is a > threefold difference in the ability of PPIs to inhibit PHOSPHO1 activity as compared with their ability to suppress gastric acid production.

Considering the fact that PHOSPHO1 plays a critical role in bone mineralisation, we hypothesise that the association between PPI use and bone fractures is possibly due to their inhibitory effect on PHOSPHO1 activity. Although this remains to be confirmed by further research it could have clinical implications in allowing clinicians to select PPIs with the least inhibitory effect on PHOSPHO1 activity as the preferred drug in this class in patients at high risk of fragility fractures.

Data Availability

Data are available on reasonable request from the corresponding authors.

References

1. Prescription Cost Analysis - NHS Digital. https://digital.nhs.uk/data-and-information/publications/statistical/prescription-cost-analysis. Accessed 12 Mar 2021

2. Insogna KL (2009) The effect of proton pump-inhibiting drugs on mineral metabolism. Am J Gastroenterol 104:S2-4

3. Huesa C, Houston D, Kiffer-Moreira T et al (2015) The functional co-operativity of tissue-nonspecific alkaline phosphatase (TNAP) and PHOSPHO1 during initiation of skeletal mineralization. Biochemi Biophys Rep 4:196-201. https://doi.org/10.1016/j.bbrep.2015.09.013

Article Google Scholar

4. Sachs G, Shin JM, Hunt R (2010) Novel approaches to inhibition of gastric acid secretion. Curr Gastroenterol Rep 12:437-447

Article Google Scholar

5. Yadav MC, Bottini M, Cory E et al (2016) Skeletal mineralization deficits and impaired biogenesis and function of chondrocyte-derived matrix vesicles in Phospho1-/- and Phospho1/P i t1 Double-Knockout Mice. J Bone Miner Res 31:1275-1286. https://doi.org/10.1002/jbmr.2790

6. Cui L, Houston DA, Farquharson C, MacRae VE (2016) Characterisation of matrix vesicles in skeletal and soft tissue mineralisation. Bone 87:147-158

7. Yanagihara GR, de Paiva AG, Neto MP et al (2015) Effects of long-term administration of omeprazole on bone mineral density and the mechanical properties of the bone. Revista Brasileira de Ortopedia (English Edition) 50:232-238. https://doi.org/10.1016/j.rboe.2015.03.002

Article Google Scholar

8. Anderson HC (2003) Matrix vesicles and calcification. Curr Rheumatol Rep 5:222-226

Article Google Scholar

9. Kirchheiner J, Glatt S, Fuhr U et al (2009) Relative potency of proton-pump inhibitors-Comparison of effects on intragastric pH. Eur J Clin Pharmacol 65:19-31

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Funding

We are grateful to Medical Research Scotland for a Vacation Scholarship (KM) and the Society for Endocrinology for a Summer Studentship (KL). We are also grateful to the Biotechnology and Biological Sciences Research Council (BBSRC) for Institute Strategic Programme Grant Funding BB/J004316/1.

Author information

Authors and Affiliations

1. School of Pharmacy and Biomolecular Sciences, University of Brighton, Lewes Road, Brighton, BN2 4GJ, UK

Katherine A. Staines

2. The Roslin Institute, The University of Edinburgh, Edinburgh, UK

Katherine Myers, Kirsty Little & Colin Farquharson

3. Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK

Stuart H. Ralston

Contributions

Conception and design of the study: KS, SR, CF. Acquisition of data: KS, KM, KL. Interpretation of data: KS, CF. Drafting the manuscript: KS, CF. Revising the manuscript and final approval, and agreement to be accountable for all aspects of the work: all authors.

Corresponding author

Correspondence to Katherine A. Staines.

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Conflict of interest

Katherine A. Staines, Katherine Myers, Kirsty Little, Stuart H. Ralston, Colin Farquharson state that they have no conflicts of interest.

Ethical Approval

All experimental protocols were approved by Roslin Institute's Animal Users Committee and the animals were maintained in accordance with UK Home Office guidelines for the care and use of laboratory animals, and with the ARRIVE guidelines.

Informed Consent

For this type of study, no informed consent is required.

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Staines, K.A., Myers, K., Little, K. et al. Proton Pump Inhibitors Inhibit PHOSPHO1 Activity and Matrix Mineralisation In Vitro. Calcif Tissue Int 109, 696-705 (2021). https://doi.org/10.1007/s00223-021-00882-9
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# data[].attributes.attachment_link.title
Proton Pump Inhibitors Inhibit PHOSPHO1 Activity and Matrix Mineralisation In Vitro - Calcified Tissue International

# data[].attributes.attachment_link.description
Proton pump inhibitors (PPIs) have been associated with an increased risk of fragility fractures in pharmaco-epidemiological studies. The mechanism is unclear, but it has been speculated that by neutralising gastric acid, they may reduce intestinal calcium absorption, causing secondary hyperparathyroidism and bone loss.

# data[].attributes.body
1. Ranitidine

Certain Ranitidine products have been recalled and effectively banned in Malaysia because of these products containing a potential carcinogen called N-nitrosodimethylamine (NDMA).

An alternative H2 blockers could be recommended, such as Famotidine.

https://www.npra.gov.my/index.php/en/component/content/article/418-english/announcement-main/announcement-2020/1527065-maklumat-terkini-status-produk-ranitidine-berkaitan-impuriti-n-nitrosodimethylamine-ndma-kemaskini-12-2-2020.html?Itemid=1391

https://www.sinarharian.com.my/article/54724/berita/nasional/kkm-tarik-balik-10-produk-mengandungi-ranitidine

2. Alendronate

Contraindication --> Alendronate is not to be taken by patients with low calcium levels (Hypocalcemia).

Alendronate, in the short term, can lower serum Calcium levels further in someone, because less Calcium is released from the bone into the blood.

In GH's case:

Even though her Calcium levels are not stated in the lab results, given her vegan diet, past use of PPI, and history of steroid use --> She is/could be at high risk of Calcium deficiency.

That is likely why the ward prescribed GH with Calcium Carbonate + Calcitriol together --> To ensure her Calcium levels are adequate before and during Alendronate therapy.

So this raises concern of --> If GH actually has Hypocalcemia, Alendronate should be delayed until Calcium levels are corrected. And that justifies the ward giving Calcium and Vitamin D supplements to GH. This combination helps to maintain normal Calcium and prevent Alendronate-induced Hypocalcemia.

However, there are some monitoring recommendations that can be given:

Check serum Calcium levels before starting Alendronate (Not done in this case, but is a recommendation)

Continuous periodic monitoring of GH's Calcium and Vitamin D levels within 1-2 weeks of starting therapy.

-> https://medlineplus.gov/druginfo/meds/a601011.html

-> https://www.ncbi.nlm.nih.gov/books/NBK526073/#article-17348.s7

-> https://www.mims.com/singapore/drug/info/apo-alendronate?type=full

# data[].attributes.attachment_link.description
1. Berdasarkan penilaian dan ujian makmal oleh Kementerian Kesihatan Malaysia (KKM) dan syarikat pemegang pendaftaran produk ke atas produk-produk ranitidi…

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This image best explains how smoking can lead to Osteoporosis.

# data[].attributes.body
Based on the image above and the details presented in this case, we can link some of her lifestyle habits/choices and past medical history to her having Osteoporosis:

1. Gonadal Hormone effect (Post-menopause + Smoking)

GH is in the post-menopause stage for a year now -> Low estrogen levels

Smoking further reduces free Estradiol levels

Low estrogen -> High IL-6 levels -> Stimulates Osteoclast activity -> Higher bone resorption.

GH's bone is broken down faster than it is built.

2. Calciotropic Hormone effect (Vitamin D & Calcium)

Smoking decreases 25-OH-D and 1,25-(OH)2-D [active Vitamin D].

Reduces intestinal Calcium absorption, worsened by GH's vegetarian diet (likely consisting of low Calcium intake).

Low Calcium -> Activates secondary Parathyroid hormone -> More bone resorption to maintain serum Calcium.

Bone mineralization becomes impaired.

3. Adrenocortical Hormone effect (Cortisol)

Smoking raises Cortisol levels.

Cortisol suppresses Osteoblasts -> Reduces bone formation.

Less bone building + More bone breakdown

This reduces her skeleton's ability to repair microdamage -> Chronic fractures (e.g., Height loss, Back pain)

4. Frailty & fall risk

Smoking contributes to muscle wasting and frailty.

GH is already underweight (Low BMI).

Increased risk of falls → Increases fracture incidence, like her recent forearm fracture.

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A condition where your spine curves outward more than it should.

This can happen because of multiple reasons:

1. Weak muscles & poor posture

2. Changes in the bone structure

Osteoporosis

Growth problems

3. Degeneration

4. Others

Trauma

Congenital (Birth) deformities

Conditions affecting connective tissues

Ehlers-Danlos syndrome

Rheumatoid Arthritis

Sarcomas

There are multiple different types of Kyphosis:

1. Postural Kyphosis: Most common type, which happens during your teen years, and affects girls more than boys. This is due to slouching or poor posture that stretches the ligaments and muscles holding your vertebrae in place -> Pulls the vertebrae out of their normal position -> Causes a rounded shape in the spine.

2. Scheuermann's Disease: When the vertebrae has a different shape than normal. The wedge-shaped bones curve forward, making the spine look rounded.

3. Congenital Kyphosis: Kyphosis present at birth. When the spine doesn't develop completely when the baby is in the uterus.

4. Cervical Kyphosis (Military Neck): This type occurs when the cervical spine (the part of the spine at the bottom of the head to the upper back) curves toward the front instead of the natural curve to the back.

5. Hyperkyphosis: A severe forward curvature of the spine, which is more than 50 degrees. This type is more common after the age of 40.

Treatment/Management:

1. Physical therapy

2. Medications (To ease pain and increase ROM)

3. Bracing (To control the progress of the spinal curve while a child is still growing)

Applies corrective force to the spine, helping to hold the spine in a more upright and aligned position -> Improves overall posture and function.

4. Spinal Fusion surgery

A surgery where the surgeons will join 2 or more vertebrae (spinal bones) together so they heal into a single, solid bone.

By attaching metal rods, screws, and wires to the spine, that will hold the bones in a corrected position.

Over time, these bones grow together and fuse the vertebrae into one solid piece.

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Also known as bone densitometry

Uses a very small dose of ionizing radiation to produce pictures of the inside of the body (usually the lower or lumbar spine and hips) to measure bone loss

Commonly used to diagnose osteoporosis, to assess an individual's risk for developing osteoporotic fractures

DXA is simple, quick and noninvasive

Ref : https://www.radiologyinfo.org/en/info/dexa

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Based on this study,

In a sample of Chinese adults aged 40–75, those in the highest diet of fruit + vegetable (FV) intake had higher bone mineral density (BMD) at multiple skeletal sites (whole body, lumbar spine, total hip, femur neck) compared to those who ate less vegetables and fruits

FUN FACT :When they looked separately, fruit intake showed somewhat stronger or more consistent beneficial associations with BMD and osteoporosis risk than total vegetables or vegetable subgroups.

Why Vegetables & Fruits Might Help Bone Health

1. Minerals and Alkaline Load

• Vegetables and fruits are rich in minerals such as potassium and magnesium. These contribute to an alkaline environment (less acid load) which may reduce bone resorption (i.e. less leaching of calcium from bone).

• In contrast, diets high in acid-producing foods (e.g. large quantities of meat, processed foods) may lead to low-level chronic acidosis, prompting bone to release alkaline minerals (calcium, magnesium) to buffer the acid, which could worsen bone loss.

2. Vitamins, Antioxidants & Phytochemicals

• Fruits and vegetables supply vitamins (C, K, E), B-complex vitamins, carotenoids, and other antioxidants or bioactive compounds. These may help by neutralizing oxidative stress, reducing inflammation, and supporting collagen formation and bone remodeling.

• Some of the phytochemicals may inhibit osteoclast activity (cells that break down bone) and/or stimulate osteoblast activity (cells that build bone).

3. Inflammation & Oxidative Stress Reduction

• Chronic inflammation and oxidative stress are implicated in bone loss. Because vegetables and fruits are anti-inflammatory and antioxidant, they may help mitigate these processes, thus protecting bone.

4. Synergy with Other Nutrients

• Vegetables and fruits may enhance absorption of nutrients beneficial for bone (e.g. vitamin C helps with collagen cross-linking, which is part of bone matrix).

• They may also improve gut health (microbiome) which can affect mineral absorption.

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2020 study

The review suggests that vegetarian diets (particularly strict vegan diets) may be associated with a modestly increased risk of lower bone mass / osteoporosis / fractures, primarily when key nutrients are not adequately provided.

But it also highlights that risk is not uniform: lacto-ovo vegetarians may fare better, and plant diets that are carefully planned (with fortification / supplementation) can mitigate much of the risk.

*Lacto → includes dairy products (milk, cheese, yogurt, butter).

Ovo → includes eggs.

The evidence is not definitive, and many studies have methodological limitations, so the relationship is best viewed as potential risk if not well managed, rather than a guarantee of harm.

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The effects of vegetarian diets on bone health: A literature review

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In these recent years many people are adopting a vegetarian type diet due to the numerous positive health effects of this regimen such as the reduction of the incidence of many chronic disorders like diabetes, hypertension, obesity and cancer.…

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5. Vegetarians should pay particular attention to consuming calcium-rich plant foods, fortified foods, and possibly supplements where needed.  Also emphasizes ensuring sufficient vitamin D and protein intake to complement the mineral intake.

https://www.sciencedirect.com/science/article/pii/S0002916523048980

Calcium

Daily Requirement: 700 mg for adults.

Sources:

Dairy products (milk, cheese, yogurt)

Green leafy vegetables (broccoli, cabbage, okra)

Soya beans and tofu

Fortified plant-based drinks (e.g., soya drink)

Nuts and seeds

Fortified bread and cereals

Fish with edible bones (e.g., sardines, pilchards)

Note: Spinach contains calcium but also oxalates, which reduce calcium absorption.

Vitamin D

Daily Requirement: 10 micrograms (400 IU) for adults.

Sources:

Oily fish (salmon, sardines, mackerel)

Egg yolks

Fortified foods (e.g., some fat spreads, breakfast cereals)

Sunlight: The body produces vitamin D from sunlight exposure.

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1. Osteoclast - causes bone resorption

( breakdown bone)

Osteoblast - Bone formation

2. Serum Ca2+ levels

controlled by Parathyroid hormone

( PTH), calcitonin, calcitriol ( Vitamin D)

Low Ca = PTH released by PTH gland

-> Increases bon resorption -> releases calcium into the blood

High Ca= Thyroid gland releases Calcitonin -> Promotes bone formation and decrease bone resorption

Vitamin D = Promotes Ca absorption in the gut -> Increase serum Ca -> Promotes Bone formation

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11. Drugs affecting bone mineral homeostasis (L1 & L2)-14

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When osteoclast break down bones faster than osteoblast can build it -> lowering of bone mass ->osteoporosis

*Osteomalacia bones that are soft due to insufficient mineralization (bone softening) vs Osteoporosis which is low bone density and weakened, porous bones (bone loss), which increases fracture risk

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From WHO, the definition is : Osteoporosis is a progressive disease that weakens bones, increasing the risk of fractures. From NCBI , Osteoporosis is defined as low bone mineral density caused by altered bone microstructure, ultimately predisposing patients to low-impact, fragility fractures. https://www.ncbi.nlm.nih.gov/books/NBK441901/ https://www.who.int/westernpacific/articles/item/simple-ways-to-prevent-osteoporosi.

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Helps regulate calcium absorption in the body → important for maintaining bone density.

During menopause, lower estrogen = higher risk of osteoporosis and fractures. Adequate vitamin D reduces this risk.

Vitamin D receptors found in brain → role in mood regulation.

Low vitamin D associated with depression and mood swings (common in peri- and post-menopause).

Recommended dosage:

1,000 IU daily

or 25,000 IU biweekly (doctor’s prescription)

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Vitamin D3 → increases intestinal absorption of calcium and phosphorus.

Vitamin K2 → directs calcium into bones and teeth (activates osteocalcin) and prevents calcium from depositing in arteries/soft tissues.

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Cholesterol influences osteoclast differentiation via interaction with estrogen-related receptor α (ERRα) and coactivator PGC-1α.

The balance of cholesterol efflux mechanisms (via transporters, and nuclear receptors like LXR/RXR) within osteoclasts may regulate their survival / apoptosis.

Accumulation of lipids in osteoclast precursors increases resorptive activity.

References:

https://www.mdpi.com/2673-396X/6/2/19?utm (MDPI) Cholesterol and Bone Resorption

https://pmc.ncbi.nlm.nih.gov/articles/PMC4617053/ (NCBI) High Cholesterol Deteriorates Bone Health

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Psychological Approach & Smoking-Linked Anxiety

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Psychological Approach & Smoking-Linked Anxiety

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Role of the Pharmacist

Provide empathetic counseling and active listening.

Educate patient on the link between smoking, nicotine withdrawal, and anxiety.

Use motivational interviewing to encourage behavior change.

Teach simple stress-management techniques (breathing, mindfulness, lifestyle tips).

Offer smoking cessation therapy (nicotine replacement, medications, behavioral support).

Help set realistic quit goals and monitor progress.

Refer to psychologists or doctors if anxiety is severe.

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-Caffeine increases faecal and urinary calcium excretion and may induce a negative calcium balance if dietary calcium intake is insufficient.

- High caffeine intake (>330 mg caffeine/day) has been associated with increased risk of fragility fracture.

*330mg is equivalent to 2 medium Zus coffee cup ( 16 oz = 180 mg )

- However, the effect of caffeine appears to be mitigated by increasing calcium intake (40 mg calcium for every 177.5 ml cup of coffee).

- Patients that regularly consume caffeinated drinks should be advised to increase their calcium intake accordingly.

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1. On exercise

2. Prevention of falls

3. Encourage screening at least once a year -> Evaluate risk of falling

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Eg: Severe back pain(she had chronic), loss of height (3 inches), spine malformation (kyphosis), fragile bone(broke her humerus and distal forearm)

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Treatment Algorithm for menopause & osteoporosis.

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Treatment Algorithm for menopause & osteoporosis.

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2022_CPG-ManagementofOsteoporosis-final.pdf

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Mediated primarily by the estrogen receptors ERa, and ERb. Found expressed in osteocytes, osteoblast, BM-MSCs, and osteoclast.

Inhibition of the secretion of RANKL and promotes the secretion of osteoclast-inhibiting factors such as growth hormone, GLP-1, and osteoprotegerin (OPG), thereby inhibiting bone resorption, estrogen promotes osteogenic differentiation of MSCs and maintains the number of osteoblasts.

Osteoporosis pathogenesis and treatment: existing and emerging avenues | Cellular & Molecular Biology Letters | Full Text

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CPG_Management_of_Menopause_2022_e-version-1.pdf

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Synthetic hormone with estrogenic, progestogenic, and androgenic properties and is indicated for the relief of menopausal symptoms and the prevention of osteoporosis in postmenopausal women.

Efficacy of tibolone

For postmenopausal osteoporotic women aged 60 – 85 yrs-old. 1.25mg significantly increased lumbar and hip BMD, and greater absolute reduction among women with prior vertebral fracture.

Safety: not for older women due to increased risk of stroke. (women who have HTN, smoke, diabetes, and atrial fibrillation à risk of stroke)

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Raloxifene (2nd Gen) à reduces new vertebral fractures in women with or without prior fracture.

Synthetic non-steroidal molecules that bind to estrogen receptors throughout the body. They act as an estrogen agonist or antagonist depending on the target organ.

Efficacy: RLX increase BMD by 2-3% at the lumbar spine and femoral neck and reduced incidence of vertebral fracture by 40-50% after 3 years. There were also 22% decrease incidence of major osteoporotic fractures in women.

Safety: Hot flushes, leg cramps, and peripheral oedema.

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·       Overall risk-benefits > positive

·       Not for eGFR < 30ml/min (chronic Kidney stage 4-5)

·       Zoledronic acid is CI in patient with eGFR < 35ml/min

·       Review the efficacy after 3-5 years of treatment to decide whether continue.

·       Potent inhibitors of bone resorption.

a.      Alendronate at 10 mg daily for 3 years.

b.      Risedronate 5 mg daily for 3 years.

c.       Ibandronate 150mg/month

d.      Zoledronic acid à IV infusion 5 mg 15 mins once yearly. May cause flu like symptoms which last for 1 – 7 days. (pre-treat with PCM/Ibuprofen and increase infusion time)

Common side effects: gastrointestinal, nausea.

For patient with gastrointestinal disease use IV ZA or denosumab.

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Effective anti-resorptive therapy.

‘Drug holiday’ not recommended. Rebound in bone turnover may occur.

Treatment reassessment done after 5-10 yrs, severe patient continue.

Human monoclonal antibody (IgG) that inhibits the formation, function, and survival of osteoclast by inhibiting RANK (receptor activator of nuclear factor kappa-B) ligand, thus reducing bone resorption.

6 monthly denosumab 60 mg over 3 years

Low incidence for AE: serious infections, cellulitis, hypocalcaemia, eczema, and malignancy.

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Anabolic agent. Preferred for Low CV risk patient.

12 months followed by anti-resorptive therapy (denosumab or bisphosphonate)

Humanized monoclonal antibody à binds to sclerostin. Change in BTM point to a dual effect on bone remodeling, with a transient increase in formation markers and reduction in resorption, resulting in an increase in bone formation and BMD.

Dose dependent increase in BMD.

AE: major adverse cardiac events (MACE)

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1.      Ca²⁺ and Vit D

Vit D >800 IU/day, Ca2+ (1200mg/day elemental Ca2+)

2.      Activated Vitamin D

Calcitriol (0.25mcg bd) and alfacalcidol (1 mcg od)

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1.

Direct Effects on Bone Cells

Osteoblast inhibition:

Corticosteroids suppress osteoblast proliferation and differentiation.

Increase apoptosis of osteoblasts and osteocytes.

Result → ↓ bone formation.

Osteoclast stimulation:

Initially increase osteoclast survival and activity via upregulation of RANKL and downregulation of osteoprotegerin (OPG).

Result → ↑ bone resorption (especially early in therapy).

2.

Effects on Calcium and Mineral Metabolism

Intestinal absorption:

Corticosteroids reduce calcium absorption from the gut (by antagonizing vitamin D action).

Renal excretion:

Increase urinary calcium excretion.

Result → secondary hyperparathyroidism → enhances osteoclast activity and bone resorption.

3.

Hormonal Alterations

Sex hormones:

Corticosteroids reduce gonadotropin secretion → hypogonadism → ↓ estrogen/testosterone → accelerates bone loss.

Growth factors:

Decrease IGF-1 production → further impairs osteoblast activity.

4.

Muscle and Mechanical Factors

Myopathy:

Corticosteroid-induced muscle weakness decreases mechanical loading on bone → disuse osteoporosis.

5.

Net Effect

Early phase: Rapid bone resorption due to enhanced osteoclast activity.

Chronic phase: Suppressed bone formation due to osteoblast inhibition + decreased sex hormones.

Overall result: Reduced bone mineral density (BMD), deterioration of bone microarchitecture, and increased fracture risk (vertebral > non-vertebral fractures).

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1.

Estrogen Deficiency After Menopause

Ovarian estrogen production drops sharply after menopause.

Estrogen normally protects bone by balancing osteoclast activity (resorption) and osteoblast activity (formation).

2.

Effects on Bone Remodeling

↑ Osteoclast activity:

Estrogen deficiency increases RANKL expression (from osteoblasts and T-cells) and decreases osteoprotegerin (OPG).

This shifts the balance toward osteoclastogenesis → more bone resorption.

↓ Osteoblast survival:

Estrogen normally promotes osteoblast lifespan and function. Its loss increases osteoblast apoptosis → reduced bone formation.

↑ Osteocyte apoptosis:

Weakens bone microarchitecture and reduces mechanosensing ability of bone tissue.

3.

Calcium and Hormonal Factors

Secondary hyperparathyroidism may occur due to reduced calcium absorption (aging + low estrogen → ↓ calcitriol synthesis).

↑ PTH further enhances osteoclast activity and bone loss.

4.

Inflammatory Cytokines

Estrogen deficiency increases IL-1, IL-6, TNF-α from immune cells.

These cytokines further stimulate osteoclast differentiation and survival.

5.

Net Effect

Accelerated bone turnover, with bone resorption >> bone formation.

Rapid loss of trabecular bone (vertebrae, wrist) in the early postmenopausal years.

Progressive loss of cortical bone (hip, long bones) over time.

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Cholesterol directly increased osteoblast functional gene expression in vitro.

hypercholesterolaemia can promote the development of male OP by excessively promoting both osteoclast activity and osteoblast activity, which excessively enhances the bone transformation rate in men.

hypercholesterolaemia damaged the bone microstructure, thus, increasing the risk of osteopenia or OP and reducing bone strength, resulting in a higher risk of fracture.

In vitro studies have shown that cholesterol enhances osteoclast differentiation and osteoclast activity.

In vitro, cholesterol directly upregulated the functions of osteoblasts.

higher risk of high-turnover osteoporosis and future fractures in men.

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Hypercholesterolaemia increases the risk of high-turnover osteoporosis in men

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As the incidence of osteoporosis (OP) and hypercholesterolaemia in men has increased, male OP has drawn more attention from clinicians worldwide. The present study sought to investigate the effects of cholesterol on male bone. Between July 2015 and…

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Osteopenia describes a decrease in bone mineral density (BMD) below normal reference values, yet not low enough to meet the diagnostic criteria for osteoporosis. BMD is diagnosed via dual-energy x-ray absorptiometry (DXA) bone scans. Osteopenia, as defined by the World Health Organization (WHO), is a t-score between -1 to -2.5, while values less than -2.5 are diagnostic for osteoporosis.

https://www.ncbi.nlm.nih.gov/books/NBK499878/

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Continuing Education Activity

Osteopenia describes a decrease in bone mineral density (BMD) below normal reference values, yet not low enough to meet the diagnostic criteria for osteoporosis. BMD is diagnosed via dual-energy x-ray absorptiometry (DXA) bone scans. Osteopenia, as defined by the World Health Organization (WHO), is a t-score between -1 to -2.5, while values less than -2.5 are diagnostic for osteoporosis. This activity describes the pathophysiology, evaluation, and management of osteopenia and addresses the role of the interprofessional team in the care of affected patients.

Objectives:

Review the presentation of osteopenia.

Distinguish osteoporosis from osteopenia based on t-score.

List management considerations for osteopenia.

Explore interprofessional team strategies for improving care coordination and communication to enhance outcomes for patients affected by osteopenia.

Access free multiple choice questions on this topic.
Introduction

Osteopenia is a clinical term used to describe a decrease in bone mineral density (BMD) below normal reference values, yet not low enough to meet the diagnostic criteria to be considered osteoporotic[1]. BMD is diagnosed via dual-energy x-ray absorptiometry (DXA) bone scans. Osteopenia, as defined by the World Health Organization (WHO), is a t-score between -1 to -2.5, while values less than -2.5 are diagnostic for osteoporosis. Decreasing BMD values are reflective of an underlying disruption in the microarchitecture of bone and osteopenia, and osteoporosis is considered quantitative, not qualitative, disorders of bone mineralization. [2]

Etiology

Bone mineral acquisition from birth to adulthood follows a predictable trend specific to an individual's age and sex. With the onset of puberty, bone mineral accretion increases to its maximum level not long after peak height gains are achieved in adolescence. Bone mineral accretion rates remain the greatest for males and females for about four years after the peak accretion rate is achieved, and 95% of the adult bone mass is typically achieved by age 17 for females and 21 for males. Thus, peak bone mass is normally achieved by the third decade of life. Failure to achieve peak bone mass as a young adult results in early-onset conditions of decreased bone mass (osteopenia or osteoporosis) and increased risk of fragility fractures even in adolescence and young adulthood. After age 30, there is a gradual and natural bone mass reduction that takes place over the ensuing decades into later life. [3][4]

While it is estimated that heritable factors dictate up to 80% of our ability to achieve and maintain optimal bone mineralization levels, modifiable factors attributed to the rate of natural bone mass reduction into adulthood include weight-bearing exercises, nutrition status (adequate calcium and vitamin D daily intake), body mass, and hormonal milieu.

The natural bone loss that occurs gradually during adulthood is considered to be the cause of primary forms of osteopenia and osteoporosis. Secondary causes serve to accelerate this process and include lifestyle factors such as alcohol use disorder, smoking, sedentary lifestyle, thin body habitus (BMI under 18.5 kg/m2). White and Asian races are also established risk factors.

Overall disease states and certain medications are considered secondary causes as well. Medical conditions include hyperparathyroidism, anorexia, malabsorption syndromes, hyperthyroidism, chronic renal failure, hypogonadism, amenorrhea/oligomenorrhea, early onset menopause, and chronic conditions resulting in calcium and/or vitamin D deficiencies. Medications implicated in the disease process include excess glucocorticoids/long-term steroid use, valproic acid, proton pump inhibitors, antiepileptics, and chemotherapy agents. [3]

Epidemiology

Currently, 34 million Americans are afflicted with osteopenia. The incidence is expected to exponentially increase as our population becomes older with each ensuing decade. Between 2010 and 2030, the United States population over 65 years of age is expected to increase from 13% to over 20%. By 2020, projections estimate that over 47 million Americans will be afflicted with osteopenia. [5]

Overall, females have a four-fold higher overall prevalence of osteopenia compared to males. However, males are more likely to demonstrate secondary causes of decreased bone mass. While secondary osteopenia and osteoporosis can develop at any age, the incidence of osteopenia in select subgroups demonstrates predictable patterns and trends. In the United States, 54% of postmenopausal women are osteopenic, and an additional 30% are already considered osteoporotic. By age 80, this relative trend predictably shifts in favor of osteoporosis as 27% of women are osteopenic, and 70% are osteoporotic.

Worldwide, Asia has reported the lowest average t-scores by region. Australia reported an incidence rate of osteopenia in 42% of men and 51% of women. In 2005, India reported a 52% overall incidence in its population. Perhaps more important than the population-based absolute BMD values reported is the associated burden of disease, which has been demonstrated in the reported fragility fractures by region worldwide. The greatest number of fragility fractures occur in Europe, followed by the Western Pacific region, Southeast Asia, and the Americas.

Fragility fractures significantly compromise a patient's quality of life and financially devastate the healthcare system. Roughly 2 million fragility fractures occur each year in the United States alone, and by 2025 this number is expected to increase to over 3 million. Worldwide, 9 million fragility fractures occur each year. The overall impact of fragility fractures on the healthcare system is staggering. In 2005, direct costs of care associated with fragility fractures alone tallied $19 billion, and the direct and indirect costs of care are expected to surpass $25 billion by 2025. In addition, fragility fractures significantly decrease the quality of life, and hip fractures alone are associated with a one-year mortality rate of greater than 20%. [6][7][8]

Pathophysiology

Osteopenia occurs secondary to uncoupling of osteoclast-osteoblast activity, resulting in a quantitative decrease in bone mass. Peak bone mass is typically achieved by males and females just prior to or early on in the third decade of life. Beyond age 30, bone resorption gradually becomes favored as dynamic bone remodeling continues into later decades of life. [9][10]

Histopathology

Histologic specimens demonstrate markedly thinned trabeculae, decreased osteon size, and enlarged haversian and marrow spaces. [10]

Toxicokinetics

Bisphosphonates are the most commonly prescribed medication class for treatment. Adverse side effects are well documented in the literature as prolonged use has been linked to two major clinical side effects: osteonecrosis of the jaw (ONJ) and the atypical subtrochanteric femur fracture.

ONJ is rare and is associated with intravenous forms and not oral forms of the medication. Treatment entails immediately stopping the offending agent. Atypical femur fractures also are rare but have significant associated morbidity, and clinicians are cautioned against the chronic, uninterrupted bisphosphonate use beyond 3 to 5 years or in situations when patients report mild thigh discomfort while undergoing treatment. [11]

History and Physical

A comprehensive history and physical includes eliciting potential risk factors attributable to secondary bone loss. A thorough social history also should be obtained with attention to smoking history and chronic alcohol consumption. A family history of osteoporosis also should be noted. The patient should be asked about any prior fractures with focus given to low energy ground-level fall mechanisms and any fractures after the age of 40.

The physical exam is often normal except in certain cases of advanced disease states (i.e., osteoporosis). In healthy individuals without risk factors, most clinicians recommend women approaching menopause (or by age 65 years at the latest) and males at the age of 70 to be screened via a dual x-ray absorptiometry (DXA) scan. However, it should be noted that the United States Preventative Services Task Force (USPTF) has not found sufficient evidence to establish official screening recommendations for men, and systematic population-based screening for osteoporosis has yet to be implemented. [12]

Much attention should be given to the patient sustaining a fragility fracture, and early follow-up with an appropriate practitioner is highly encouraged. Although a standardized follow-up protocol is yet to be recommended, automated follow-up systems and fracture liaison services are two increasingly popular strategies to help improve on the historically reported and strikingly low follow-up rates of 1% to 10%.[2]

Women with normal DXA scans do not need follow-up DXA scans, as studies have shown that most women with normal scores did not progress to osteoporosis. Some experts may advocate for follow-up scans upon treatment implementation, but this modality remains controversial as the literature suggests subsequent DXA scans have rarely resulted in interventions or treatment adjustments. [1][5]

Evaluation

The WHO has established DXA scans as the gold standard for assessing BMD levels. DXA scans utilize a single x-ray beam to measure calcified tissue in select regions of the body. Measurements are reported with 1% to 2% precision rates, and DXA scans are considered the most accurate diagnostic imaging modality with the least amount of radiation exposure. The lumbar spine (L2 to L4), the hip (compiled from the femoral neck, trochanters, and intertrochanteric regions), and the wrist are routinely included in the scan. The BMD reported reflects the absolute, patient-specific score determined from these measured anatomic areas.

In addition, the scan also reports a t-score and a z-score. The t-score is measured in standard deviations and reflects the difference between the patient's measured BMD and the mean value of BMD in healthy, young, matched controls (30-year-old women). By definition, a normal BMD measurement is within one standard deviation of the young adult mean. The WHO defines t-scores between -1 and -2.5 as osteopenic and scores below -2.5 as osteoporotic. The z-score is also measured in standard deviations, but the z-score is compared to a healthy, age-matched control group. The z-score is most clinically relevant when obtaining a DXA scan in younger patients when secondary osteoporosis is being considered. A z-score less than -1.5 warrants a comprehensive secondary osteoporosis workup.

Standard laboratory workup includes checking calcium, phosphorus, albumin, alkaline phosphatase, liver function tests, creatinine (serum and urine), 25 hydroxyvitamin D, TSH and free T4, and intact PTH levels. Males should have a free testosterone level checked to rule out hypogonadism.

The routine use of checking bone turnover markers (BTM) is debated. The utility of obtaining markers of bone resorption can be considered if this is being considered the possible underlying cause of secondary osteoporosis. Although reports question the reproducibility of such values, available tests include checking serum or urinary cross-links of type I collagen (deoxypyridinoline), N-telopeptide of type I collagen (NTx), or C-telopeptide of type I collagen (CTx).

The WHO created a fracture risk assessment tool (FRAX score) to predict the 10-year risk of sustaining a hip or other major osteoporotic fracture. These other major fragility fractures include fractures of the spine, wrist, forearm, or humerus. The assessment includes 12 questions weighted by the relative risk associated with a future fragility fracture event. Assessment includes age, sex, personal history of fracture, low BMI, oral steroid use, secondary osteoporosis, parental history of hip fracture, smoking status, and alcohol intake. In addition, optional BMD measurement values can be included from a prior DXA scan (if available) to provide a more comprehensive score report. [13]

The utility of the FRAX score is emphasized, especially in the osteopenic patient. Although fracture risk increases with decreases in BMD, the concept that the vast majority of these fragility fractures occur in osteopenic (as opposed to osteoporotic) patients poses a conflicting treatment paradigm. Thus, clinicians rely on the FRAX score to stratify in which osteopenic patients exceed the risk threshold to warrant more aggressive pharmacologic treatments.

Patients younger than 50 at increased fragility fracture risk are recommended to obtain a DXA scan if one has not been already obtained for another reason. A study from 2013 analyzed the worldwide uptake of FRAX calculation over one year from 2012 to 2013. Nearly 2.5 million calculations from 173 countries were reported, with the USA, UK, Canada, Spain, Japan, France, Belgium, Italy, Switzerland, and Turkey representing over 80% of all calculations.

Treatment / Management

The core treatment options for osteopenic patients involve early education on how to achieve and maintain healthy bone mass levels and extensive education and counseling on the relevant social, environmental, and lifestyle risk factors that compromise bone health.

Lifestyle Modifications

All patients can benefit from lifestyle modifications. Chronic alcohol use has been identified as a significant risk factor for decreased BMD. Clinicians should also routinely encourage smoking cessation and promote weight-bearing physical activities and regular exercise regimens. Yoga and tai chi can help reduce stress and improve balance and agility.

Patients should be educated on the recommended daily intake for calcium and vitamin D. The National Osteoporosis Foundation (NOF) recommends 1,200 to 1500 mg of calcium per day and 800 to 1,000 IUs of daily vitamin D for adults over the age of 50.

Fall Prevention

Falls, mostly in-house, cause over 90% of hip fractures and all distal radius fractures. While the role of exercise programs and physical therapy intervention for the elderly is reported with mixed results on outcomes of fall reduction and reduced rates of subsequent hip and other fragility fractures, some studies advocate multimodal combinations to benefit the elderly. Regular exercise combined with prophylactic measures to remove loose carpets, reduce the use of sleep medicine and other tranquilizers, and correct visual impairment in elderly populations living in the community results in reduced rates of falls. [14]

Risk Stratification of Osteopenic Patients

While the recommendations for pharmacologic intervention in patients diagnosed with osteoporosis are universally accepted, the pharmacologic treatment of osteopenic patients is much more controversial secondary to the much higher number needed to treat (NNT) threshold reported in the literature. Compared to osteoporosis (NNT = 10 to 20 patients), the NNT for osteopenia exceeds 100 patients.

Current guidelines advocate for risk stratification by the ten-year probability of future hip or other fragility fracture risk and reserving pharmacologic intervention to the subgroup of patients most at risk of developing a major osteoporotic fracture. The primary risk factor for subsequent fracture is a prevalent, low energy fracture, irrespective of whether it is clinically apparent or not.

Fragility Fracture Considerations

A major clinical hurdle is ensuring timely patient follow-up after fragility fractures. The re-fracture risk is highest during the first 1 to 2 years after the inciting fragility fracture, and ultimately, about 50% of subsequent fractures occur within 3 to 5 years from the first event. These patients warrant rapid intervention and follow-up to determine the patient's FRAX score and complete a DXA scan to establish a baseline BMD level and t-score value.

Special consideration is given to the detection of current or prior history of vertebral fractures as they represent the most frequent fractures in both men and women over age 50 years. However, many vertebral fractures are initially missed or not diagnosed by a clinician because the patient is relatively asymptomatic. Estimates report 85% of vertebral fractures are due to an underlying bone density that is already diagnostic for osteoporosis. Furthermore, they are associated with significant morbidity, including a five-fold increased risk of subsequent vertebral fracture regardless of an individual's BMD at the time of the index fracture. When symptomatic, vertebral fractures will present with back pain that can last up to 2 to 3 months. Depending on the severity and degree of collapse associated with the fracture(s), the patient classically may develop a progressive kyphotic deformity and complain of loss of height over time. [15]

Pharmacotherapy Recommendations [16][17]

Consensus favors pharmacologic treatment in a patient with spine or hip fractures in addition to a documented low BMD. Treatment recommendations vary for other nonvertebral fractures and include the following:

The National Osteoporosis Society (NOS) recommends starting treatment in all postmenopausal women with a history of any fragility fracture

The National Osteoporosis Foundation (NOF) recommends performing DXA scans on patients sustaining nonvertebral fragility fractures, and the decision to treat or not with pharmacotherapy is based on the patient's t-score; patients considered to be osteopenic (t-score between -1 and -2.5) are not started on drugs.

Pharmacotherapy Options [18]

Pharmacotherapy agents work through either antiresorptive or anabolic means. Bisphosphonates are the most commonly prescribed medication class. These drugs are divided into non-nitrogen and nitrogen-containing compounds. The latter are considered first-line therapy. The nitrogen-containing compounds inhibit farnesyl pyrophosphate synthase and ultimately inhibit osteoclast resorption and induce osteocyte apoptosis. Common agents include:

Alendronate may reduce the rate of hip, spine, and wrist fractures by 50%

Risedronate may reduce vertebral and nonvertebral fractures by 40% over three years

IV zoledronic acid reduces the rate of spine fractures by 70% and hip fractures by 40% over three years

Other Medication Classes

Conjugated estrogen-progestin hormone replacement (HRT)

Estrogen-only replacement (ERT)

Selective estrogen receptor modulators (Raloxifene) - Raloxifene is an agonist to estrogen receptors on bone and reduces osteoclast resorption

Anabolic - Teriparatide is a recombinant form of parathyroid hormone (PTH) that stimulates osteoblasts to produce more bone. Teriparatide is now FDA approved for osteoporosis treatment in males and females

RANKL inhibitors (Denosumab) - Denosumab is a monoclonal Ig2 that targets RANKL and inhibits its ability to bind to RANK and results in the inhibition of osteoclast activation

Treatment and Follow-up Considerations [19]

Treatment duration varies depending on the class of medication utilized. Agents such as teriparatide and hormonal-based therapy require immediate follow-up treatment with another agent upon stopping the medication; otherwise, bone mass is rapidly lost. Clinicians also must remain cautious against the prolonged use of uninterrupted bisphosphonate therapy beyond a 3- to 5-year period. Patients should also be made aware of these potentially morbid adverse events, and they should be counseled to seek immediate care if they are experiencing any symptoms of thigh discomfort.

Any patient on bisphosphonates for any given period and presenting with mild thigh discomfort should have the following treatment workup:

Educate on the risks of and immediately stop all weight-bearing activity.

Obtain full-length femur and hip radiographs. Thigh pain may be indicative of an impending pathologic, atypical femur fracture. Attention should be directed to the subtrochanteric and diaphyseal regions of the femur, particularly the lateral cortex, which often demonstrates evidence of periosteal reaction.

Immediately discontinue bisphosphonate use.

Refer to an orthopedic surgeon for prophylactic surgical fixation.

Enhancing Healthcare Team Outcomes

Osteopenia and osteoporosis and its associated complications constitute a significant source of patient morbidity and mortality, and the treatment of its complications provide an enormous financial and resource burden to the healthcare system [5]. The key is to prevent osteopenia. Thus, this is best done with an interprofessional team with a focus on patient education. All clinicians should educate patients about the morbidity of osteopenia. The nurse practitioner, pharmacist, and primary care provider should encourage the patient to eat a healthy diet rich in calcium. In addition, the patient should be encouraged to exercise, cease smoking, and abstain from alcohol. The pharmacist should educate the patient on the bisphosphonates, their benefits, and adverse effects.

All postmenopausal women should undergo bone densitometry and understand the benefits of this test.

Healthcare providers must all coordinate to ensure that patients initially diagnosed with a fragility fracture receive early follow-up with an appropriate provider experienced in managing low bone mineral density conditions. The latter has been receiving significant attention in the literature over the last few decades, as followup rates have been documented to be extremely low (i.e., in the range of 5% to 15%). The goal is to enhance interprofessional care and prevent further fracture, surgery, morbidity, and associated mortality. Evidence level: Level 2 and Level 3. [20]

References

1.

2.

Porter JL, Varacallo M. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jun 21, 2022. Osteoporosis. [ PubMed: 28722930 ]

3.

Varacallo M, Seaman TJ, Jandu JS, Pizzutillo P. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Apr 30, 2022. Osteopenia. [ PubMed: 29763053 ]

4.

5.

6.

Donnally III CJ, DiPompeo CM, Varacallo M. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Feb 12, 2022. Vertebral Compression Fractures. [ PubMed: 28846351 ]

7.

8.

9.

Varacallo M, Davis DD, Pizzutillo P. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Feb 12, 2022. Osteoporosis in Spinal Cord Injuries. [ PubMed: 30252365 ]

10.

El Sayed SA, Nezwek TA, Varacallo M. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Oct 9, 2021. Physiology, Bone. [ PubMed: 28722997 ]

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

# data[].attributes.attachment_link.description
Osteopenia is a clinical term used to describe a decrease in bone mineral density (BMD) below normal reference values, yet not low enough to meet the diagnostic criteria to be considered osteoporotic[1]. BMD is diagnosed via dual-energy x-ray absorptiometry (DXA) bone scans.

# data[].attributes.body
Osteoporosis CPG

# data[].attributes.body
Recommended for up to 24 months.

For not responsive to other anti-osteoporosis therapy.

Subcutaneously, 20mcg daily for 21 months.

Benefits of anabolic therapy wear off within one year of discontinuation. Recommendation to initiate anti-resorptive therapies, when stopping anabolic therapy. To maintain bone density gains.

Safety: dizziness, leg cramps, and hypercalcemia. Check serum calcium.

CI for patients with open epiphyses. Bone disease other than osteoporosis or pre-existing hypercalcaemia.

# data[].attributes.body
https://www.fraxplus.org/

# data[].attributes.body
Osteoporosis CPG

# data[].attributes.body
- DXA measurement thru DXA scan

- number shows the amount of bone you have compared with a young adult of the same gender with peak bone mass

- -1.1 and -2.4 is classified as osteopenia (low bone mass)

- score of -2.5 and below is defined as osteoporosis.

- GR has -2.6 hence- osteoporosis

- It also has Z score value when compared with other people in your age group and of the same size and gender

- Other lab value are all normal