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Bisphosphonates

Bisphosphonates bind strongly to bone mineral

When osteoclasts attempt to resorb bone, the drug is internalized → inhibits osteoclast activity → induces osteoclast apoptosis

Serious side effects:

- Atypical femoral shaft fractures

-Osteonecrosis of the jaw (ONJ)

-renal and kidney impairment

Patients on oral bisphosphonates for 5 years or IV bisphosphonates for 3 years should have their fracture risk re-evaluated.

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

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Often silent until fracture occurs

Fragility fractures (hip, wrist, spine) → seen in this patient (wrist fracture)

Height loss (≥2–3 cm) → patient lost 3 inches

Kyphosis (“dowager’s hump”) → due to vertebral compression

Chronic back pain → from vertebral collapse

Consequences: Decreased mobility, Low quality of life, possible respiratory/GI compromise

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Differentiate with Other Spinal Diseases

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Differentiate with Other Spinal Diseases

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Alendronate + GERD/gastritis → esophageal irritation risk

Alendronate + calcium carbonate → ↓ absorption if taken together (separate timing)

Etoricoxib (NSAID) + gastritis/GERD → ↑ GI bleeding risk

Prednisolone (past use) → secondary osteoporosis contributor

Omeprazole (previous) → ↓ calcium absorption → switched to ranitidine

Atorvastatin → rare myopathy, ↑ fall risk

Extra: food interactions (milk/coffee ↓ alendronate absorption), long-term bisphosphonate risks (atypical fracture, osteonecrosis of jaw)

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GR’s Chinese background → possible VDR / CYP2C8 polymorphisms affect bisphosphonate response.

Pharmacist role: flag poor responders, suggest pharmacogenomic testing, adjust therapy if fractures persist.

Ensures therapy is personalized, not “one‑size‑fits‑all.”

Source : https://www.nature.com/articles/tpj201052

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Genetic/Family History

Family history of osteoporosis or hip fracture → increases personal risk.

Gender

Women are more prone (especially postmenopausal), but men with low testosterone are also at risk.

History of Previous Fractures

Past fractures (especially low-trauma fractures) strongly predict future fractures.

Medications

Prednisolone (chronic use): Glucocorticoids decrease bone formation and increase bone breakdown.

Omeprazole (long-term use): Proton pump inhibitors reduce calcium absorption.

NSAIDs (ibuprofen): May worsen gastric issues, limiting calcium/vitamin D absorption.

Underlying Diseases

Asthma → required corticosteroid therapy (adds to bone loss).

Hypercholesterolemia → sometimes linked to poor bone quality.

GERD/Gastritis → dietary restrictions, reduced nutrient absorption.

Chronic Diseases (NOT IN THE CASE)

Endocrine disorders: Hyperthyroidism, Cushing’s syndrome, diabetes.

Rheumatological diseases: Rheumatoid arthritis, lupus.

Malabsorption syndromes: Celiac disease, inflammatory bowel disease (IBD)

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Home safety counseling: advise patient to remove loose rugs, install grab bars, and ensure good lighting at home.

Footwear counselling: recommend supportive, non-slip shoes instead of slippers or high heels.

Medication review: identify drugs that increase fall risk (e.g., sedatives, antihypertensives causing dizziness) and discuss with doctors if adjustments are needed.

https://pmc.ncbi.nlm.nih.gov/articles/PMC4125318/

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Drug-related falls in older patients: implicated drugs, consequences, and possible prevention strategies

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Falls are the leading cause of injuries among older adults, aged 65 years and older. Furthermore, falls are an increasing public health problem because of ageing populations worldwide due to an increase in the number of older adults, and an increase…

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Hip protectors
→ Special padded garments worn under clothing to reduce hip fracture risk during falls.

Back braces / posture-correcting devices
→ Help relieve pain, support spine, and reduce kyphosis progression.

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Alendronate, Risedronate, Ibandronate, Zoledronic acid

They are the first choice in postmenopausal osteoporosis.

binds to bone surfaces and inhibits bone resorption by osteoclasts, possibly by inhibiting the mevalonate pathway.

It has been shown to be effective in the treatment of women or men with corticosteroid-induced osteoporosis and in the prevention of osteoporosis in postmenopausal women

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Definition (MOH CPG):

“Osteoporosis is defined as a skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength reflects the integration of bone density and bone quality. Bone density (g/cm² or g/cm³) is determined by peak bone mass and amount of bone loss. Bone quality refers to the architecture, turnover, damage accumulation, and mineralisation of the bone.”

This definition highlights that fracture risk is not only about ‘how much bone’ (density) but also ‘how good the bone is’ (quality).”

The most common sites of fractures are spine, wrist and hip, and that hip fractures carry high morbidity and mortality (up to ~20 % mortality in first year) in Malaysia.

Osteopenia refers to low bone mass, with a T-score between –1.0 and –2.5 (i.e. not yet low enough for osteoporosis).

Osteoporosis is diagnosed when the T-score ≤ –2.5 (or via clinical diagnosis if fragility fracture present).

In other words, osteopenia is an intermediate stage — a “risk state” of lower than normal bone mass but not yet reaching the threshold for osteoporosis. People with osteopenia may progress to osteoporosis if bone loss continues, especially if other risk factors are present.

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

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Signs & Symptoms of Menopause

Vasomotor symptoms (VMS): hot flushes, night sweats, palpitations

Genitourinary Syndrome of Menopause (GSM): vaginal dryness, irritation, itching, dyspareunia, recurrent UTIs, urinary urgency.

Psychological/Neurocognitive: irritability, low mood, anxiety, depression, sleep disturbance, forgetfulness, reduced concentration.

Somatic & Musculoskeletal: Joint pain, stiffness, fatigue, headaches, weight gain, changes in skin and hair (dryness, thinning).

Long-term risks (from estrogen deficiency): osteoporosis, cardiovascular disease, cognitive decline/dementia, urogenital prolapse.

https://www.moh.gov.my/moh/resources/Penerbitan/CPG/Women%20Health/CPG_Management_of_Menopause_2022_e-version-1.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC4890704/

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explain importance of avoiding sudden movements, bending from the waist, or lifting heavy objects incorrectly.

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1) Raloxifene (SERM – Selective Estrogen Receptor Modulator)

Regimen:

60 mg orally once daily (with or without food).

MOA (easy):

Acts like estrogen on bones → slows down bone loss.

Blocks estrogen in breast/womb → lowers cancer risk there.

Side Effects:

Hot flushes, leg cramps.

↑ Risk of venous thromboembolism (VTE: DVT/PE).

Mild flu-like symptoms.

NOTES:

Works mainly for vertebral fractures, not hip.

Good option in postmenopausal women at breast cancer risk.

Avoid in history of VTE, stroke, or severe liver disease.

Encourage mobility (prolonged immobility raises clot risk).

https://www.mims.com/malaysia/drug/info/raloxifene?mtype=generic

2) Teriparatide (Parathyroid Hormone analogue, anabolic agent)

Regimen:

20 µg subcutaneous injection once daily (thigh or abdomen).

Maximum 2 years lifetime use (osteosarcoma risk in animals).

After stopping → must use anti-resorptive (e.g. bisphosphonate/denosumab) to maintain bone density.

MOA (easy):

Small daily dose of “PTH copy” → activates bone-building cells (osteoblasts) → new bone formed.

Side Effects:

Hypercalcemia, hypercalciuria.

Dizziness, nausea, headache.

Leg cramps.

Rare: osteosarcoma (very rare in humans).

NOTES:

For severe osteoporosis (T-score ≤ –3.0 or multiple fragility fractures).

Avoid in bone cancers, Paget’s disease, hypercalcemia, or ↑ ALP.

Monitor calcium (blood and urine).

Expensive, reserved for very high-risk patients.

https://www.mims.com/malaysia/drug/info/teriparatide?mtype=generic

3) Strontium Ranelate (restricted use now)

Regimen:

2 g orally once daily (granules mixed in water, at bedtime, away from calcium-rich food/supplements).

MOA (easy):

Two jobs in one:

Helps bone-building cells (osteoblasts) → more bone made.

Slows bone-breaking cells (osteoclasts) → less bone lost.

Side Effects:

Nausea, diarrhea.

↑ Risk of venous thromboembolism (VTE).

↑ Cardiovascular risk (MI, stroke).

Rare: severe skin reactions (DRESS).

NOTES:

Dual action (formation ↑ + resorption ↓).

Only if other drugs unsuitable (due to CV risk).

Avoid in past/current VTE, ischemic heart disease, uncontrolled hypertension.

Must take calcium + vitamin D if diet is lacking.

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Significant: Increased serum triglycerides (particularly in patients with history of estrogen-induced hypertriglyceridaemia); vaginal bleeding.
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, flatulence.
General disorders and administration site conditions: Peripheral oedema.
Investigations: Increased blood pressure, weight gain.
Musculoskeletal and connective tissue disorders: Leg cramps, arthralgia, muscle spasms, myalgia, tendinopathy.
Nervous system disorders: Headache, migraine.
Psychiatric disorders: Depression, insomnia.
Renal and urinary disorders: UTI.
Reproductive system and breast disorders: Breast pain, enlargement, or tenderness; leukorrhoea, uterine or endometrium disease.
Respiratory, thoracic and mediastinal disorders: Flu syndrome, bronchitis, sinusitis, pharyngitis, pneumonia, laryngitis.
Skin and subcutaneous tissue disorders: Rash, sweating.
Vascular disorders: Hot flushes, superficial vein thrombophlebitis.
Potentially Fatal: Increased risk of venous thromboembolic events, including DVT, pulmonary embolism, and retinal vein thrombosis; stroke.

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Raloxifene: Belongs to the class of selective estrogen receptor modulators. Our drug directory offers in-depth details on its uses, side effects, and more. Get the latest medication information and prescription drug insights today!

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1. Primary Osteoporosis

Type I (Postmenopausal osteoporosis):

Occurs within 15–20 years after menopause.

Due to estrogen deficiency → increased osteoclast activity, accelerated trabecular bone loss.

More common in women, leads to vertebral & wrist fractures.

Type II (Senile osteoporosis):

Occurs after ~70 years of age.

Due to aging, reduced osteoblast function, calcium/vitamin D deficiency.

Affects both cortical and trabecular bone, common fractures = hip, pelvis.

2. Secondary Osteoporosis

Due to underlying conditions or medications.

Examples:

Endocrine: hyperthyroidism, hyperparathyroidism, diabetes.

GI/malabsorption: celiac disease, inflammatory bowel disease.

Drugs: glucocorticoids (prednisolone), proton pump inhibitors (omeprazole), anticonvulsants.

Lifestyle: smoking, alcohol excess, immobility.

Secondary osteoporosis should always be ruled out in younger patients or when risk factors are present.

Case relevance (GR, 53 y/o, fragility fracture, T-score –2.6)

GR fits Primary Type I (Postmenopausal osteoporosis) because she is ~1 year post-menopause, with fragility fracture and low BMD.

She also has secondary contributors → previous prednisolone therapy, smoking, vegetarian diet (possible calcium/vitamin D deficiency), and chronic PPI (omeprazole) use.

So GR’s osteoporosis is a mixed case: postmenopausal (primary) with secondary risk factors.

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Osteoporosis = systemic skeletal disease

Characterized by low bone mass + microarchitectural deterioration

Osteoclasts: bone resorption

Osteoblasts: bone formation

Osteocytes: key regulators (signal balance)

Controlled by hormones, cytokines, and mechanical loading

1. Pathophysiological Imbalance

Osteoporosis occurs when:

Bone resorption > bone formation

Results: net bone loss, weak trabecular bone, fractures

2. Cellular & Molecular Mechanisms

(A) Osteoclast Activation (Bone Resorption ↑)

RANKL–RANK–OPG axis

↑ RANKL / ↓ OPG → ↑ osteoclast differentiation

Key pathways: NF-κB, MAPK, PI3K/Akt, NFATc1

Cytokines: IL-1, TNF-α enhance osteoclastogenesis

MALT1: boosts osteoclast activation

(B) Osteoblast Suppression (Bone Formation ↓)

Osteoblast differentiation impaired from MSCs

Pathways involved:

Wnt/β-catenin → inhibited by sclerostin

BMP/Smad → needed for Runx2 & osterix

Hedgehog → directs MSCs to osteoblasts

Notch → context dependent, can suppress osteoblasts

Osteocytes secrete sclerostin → blocks Wnt signaling

3. Systemic Regulators

Hormones

Estrogen (Postmenopausal osteoporosis)

Normally: Estrogen suppresses osteoclasts by ↑ OPG and ↓ RANKL

Loss of estrogen → unchecked RANKL activity → excessive osteoclastogenesis

Leads to rapid bone loss, especially in trabecular bone

Testosterone & aromatization also important in men

PTH ↑ → stimulates bone resorption

Calcitonin → inhibits osteoclasts

Vitamin D → regulates Ca²⁺ absorption + bone metabolism

Nutrients & Cytokines

Ca²⁺ deficiency → bone loss

IL-6, TGF-β modulate bone turnover

4. Emerging Factors

Non-coding RNAs (miRNA, lncRNA, circRNA): regulate osteoblast/osteoclast gene expression

Bone marrow MSCs: shift from osteogenesis → adipogenesis

Bone marrow adipocytes: secrete SFRP-1, inhibit Wnt signaling

Bone vasculature: angiogenesis coupled with osteogenesis (HIF-1α, SLIT3)

Bone innervation: neural signals regulate bone cells

Gut microbiota: influence Ca²⁺ absorption, immune signaling, bone metabolism

https://cmbl.biomedcentral.com/articles/10.1186/s11658-022-00371-3

https://www.ncbi.nlm.nih.gov/books/NBK441901/

https://pmc.ncbi.nlm.nih.gov/articles/PMC7415937/

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Red blood count

Haemoglobin

Check to identify if there is anaemia in the patient. Studies showed that postmenopausal women with anaemia are at a higher risk of bone fractures. The reduced blood volume would increase the proliferation of haematopoietic cells, such as osteoclasts. Proliferated osteoclasts would increase bone resorption. Although osteoblast is also stimulated, the resorption in bone would affect the bone remodelling. Hypoxemia in anaemia patients would also cause osteoporosis. Severe hypoxia would increase the oxidative stress and acidify the extracellular bone matrix, impairing the bone metabolism. The osteoblast formation would decrease. Hypoxia would reduce the bone mineral density in human.

Reference:

Bone Density Loss Is Associated with Blood Cell Counts - PMC

Association between Osteoporosis and Low Hemoglobin Levels: A Nested Case–Control Study Using a National Health Screening Cohort

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✉Address correspondence to JYW: 300 Pasteur Dr., S-025, Stanford, CA 94305, TEL: 650-736-9654, jywu1stanford.edu

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Bone Density Loss Is Associated with Blood Cell Counts

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Hematopoiesis depends on a supportive microenvironment. Preclinical studies in mice have demonstrated that osteoblasts influence the development of blood cells, particularly erythrocytes, B lymphocytes, and neutrophils. However, it is unknown…

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https://pmc.ncbi.nlm.nih.gov/articles/PMC10721754/

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

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Menopausal hormone therapy (MHT, also called menopausal or hormone replacement therapy) is the most effective treatment for vasomotor symptoms (hot flushes/night sweats) and genitourinary syndrome of menopause (GSM). It also prevents bone loss and reduces fracture risk in postmenopausal women

Types of MHT

1) Systemic Estrogen-only therapy (ET)

Forms: oral tablets (conjugated estrogens, estradiol), transdermal patches, gels, sprays.

Use: most effective for vasomotor symptoms and helps prevent bone loss. Only for women who have had a hysterectomy (no uterus)

2) Combined Estrogen + Progestogen Therapy (EPT / combined MHT)

Forms: systemic estrogen (oral/transdermal) + oral progestogen (medroxyprogesterone acetate, micronized progesterone, norethisterone) OR intrauterine levonorgestrel system (LNG-IUS) for endometrial protection.

Use: for women with an intact uterus who need systemic estrogen for vasomotor symptoms or bone protection. Progestogen prevents endometrial hyperplasia/cancer. Choice of progestogen and route (oral vs LNG-IUS) is individualized.

3) Tibolone

Form: oral synthetic steroid with estrogenic, progestogenic and androgenic activity.

Use: relief of vasomotor symptoms, GSM, and bone protection in some cases; often considered when conventional MHT not tolerated or not desired. Caution around vascular risks in older or high-risk women.

4) Local (vaginal) estrogen therapy

Forms: creams, tablets, rings, low-dose local preparations.

Use: genitourinary syndrome of menopause (vaginal dryness, dyspareunia, recurrent urinary symptoms). Minimal systemic absorption — can be used when systemic therapy is not indicated or when only GSM is present.

5) Tissue-selective approaches / SERMs / Combination (e.g., bazedoxifene + conjugated estrogen)

Use: alternative for those who need symptom control with different risk profile (e.g., bazedoxifene + estrogen combo to avoid progestogen).

Relating options to GR’s case

Key facts: Age 53 (<60), within 10 years post-menopause, osteoporosis (fragility fracture), smoker, unclear uterus status.

Offer MHT as an option. Prefer a transdermal estradiol regimen combined with endometrial protection if uterus intact — e.g.:
Transdermal estradiol (low dose patch/gel) + levonorgestrel IUS (LNG-IUS) — preferred option if LNG-IUS acceptable/available.

Rationale: GR is within the favorable window for MHT (age/timing), has symptomatic menopause potential and bone benefit. Because she smokes, transdermal route reduces VTE risk versus oral estrogen. If uterus is present, LNG-IUS provides endometrial protection with minimal systemic progestin exposure

If MHT contraindicated or declined: use non-hormonal options for vasomotor symptoms (SSRI/SNRI, gabapentin) and continue targeted osteoporosis therapy (bisphosphonate/denosumab/teriparatide as appropriate). MHT is not a substitute for anti-osteoporotic drugs for established osteoporosis.

https://www.moh.gov.my/moh/resources/Penerbitan/CPG/Women%20Health/CPG_Management_of_Menopause_2022_e-version-1.pdf

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Use Tech + Family Support for GR

1. Mobile apps & digital reminders

Medication reminder apps (e.g. Medisafe, MyTherapy, MediSafe Pill Reminder):

These send push notifications when it’s time for her alendronate, inhaler, or calcium.

They allow tracking missed doses so she can see adherence over time.

Some apps even let you log supplements (like calcium & vitamin D) and generate a simple report for her doctor or pharmacist.

https://multiculturalcaregiving.com/medisafe-pill-reminder-medication-tracker-app-review-can-medisafe-help-seniors-and-caregivers/#google_vignette

Smart pillboxes / alarms: Devices that beep or flash if she forgets a dose — helpful if she struggles with routine.

Wearables (smartwatch reminders): If she uses a smartwatch/fitness tracker, alarms can sync to remind her of medications or even prompt exercise.

2. Nutrition tracking (important since she’s vegetarian)

Apps like MyFitnessPal or CalorieKing allow logging calcium and protein intake from food.

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(“Adultifying” the Home)

Lighting: Ensure hallways, stairs, and bathrooms are well lit (motion sensor lights at night).

Floor safety: Remove loose rugs/carpets, secure electrical cords, use anti-slip mats in bathroom/kitchen.

Supportive fittings: Install grab bars near toilets, showers, and stairs; railings on both sides of staircases.

Furniture placement: Arrange furniture so walkways are clear; avoid clutter that increases trip risk.

Footwear: Encourage sturdy, non-slip shoes instead of slippers or heels.

Emergency plan: Keep phone or alert system accessible in case of falls.

“Just like parents baby-proof a home for safety, we adult-proof GR’s home to reduce fall risk and protect her fragile bones.”

https://www.nia.nih.gov/health/aging-place/home-safety-tips-older-adults#:~:text=Install%20a%20ramp%20with%20handrails,surfaces%20that%20may%20get%20wet.

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Immune dysfunction would cause osteoporosis. Osteoporosis is normally related to inflammatory disease. The lymphocyte ratio would decrease with the increase of bone loss and increase osteoporosis severity. The monocyte and neutrocyte ratio would increase with increase of bone loss and osteoporosis severity. The inflammatory marker would affect the osteoclast by surrounding the cytokine that find in bone formation and destruction. The high RANKL production by T-cell and B-cell, and overactivation of T-lymphocytes and B-lymphocytes could affect osteoporosis in postmenopausal women.

Reference:

A correlative studies between osteoporosis and blood cell composition: Implications for auxiliary diagnosis of osteoporosis - PMC

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A correlative studies between osteoporosis and blood cell composition: Implications for auxiliary diagnosis of osteoporosis

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Osteoporosis is defined as a metabolic skeletal disease characterized by a decrease of the bone mass per unit volume, caused by a variety of reasons. Increasing evidence indicate that the host inflammatory response was correlated with the occurrence…

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Oxidised lipids stimulate the RANKL increasing the osteoclast differentiation and bone resorption. Cholesterol would bind to smoothen protein, and activate the Hedgehog signalling pathway, inhibiting osteoblast differentiation. High cholesterol would decrease the bone mineral density and the use of statin would increase the bone mineral density.

Reference:

The role of lipid metabolism in osteoporosis: Clinical implication and cellular mechanism - PMC

High Cholesterol Deteriorates Bone Health: New Insights into Molecular Mechanisms - PMC

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Abstract

In recent years, researchers have become focused on the relationship between lipids and bone metabolism balance. Moreover, many diseases related to lipid metabolism disorders, such as nonalcoholic fatty liver disease, atherosclerosis, obesity, and menopause, are associated with osteoporotic phenotypes. It has been clinically observed in humans that these lipid metabolism disorders promote changes in osteoporosis-related indicators bone mineral density and bone mass. Furthermore, similar osteoporotic phenotype changes were observed in high-fat and high-cholesterol-induced animal models. Abnormal lipid metabolism (such as increased oxidized lipids and elevated plasma cholesterol) affects bone microenvironment homeostasis via cross-organ communication, promoting differentiation of mesenchymal stem cells to adipocytes, and inhibiting commitment towards osteoblasts. Moreover, disturbances in lipid metabolism affect the bone metabolism balance by promoting the secretion of cytokines such as receptor activator of nuclear factor-kappa B ligand by osteoblasts and stimulating the differentiation of osteoclasts. Conclusively, this review addresses the possible link between lipid metabolism disorders and osteoporosis and elucidates the potential modulatory mechanisms and signaling pathways by which lipid metabolism affects bone metabolism balance. We also summarize the possible approaches and prospects of intervening lipid metabolism for osteoporosis treatment.

Keywords: Bone homeostasis, Cross-organ communication, Lipid metabolism, Osteoclast, Osteoporosis

Introduction

Disorders of lipid metabolism are qualitative and quantitative changes in lipids and their metabolites in blood or other tissues, including total cholesterol, triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein, phospholipids, fatty acids, and lipid oxides.¹ Metabolic disorders, obesity, and insulin resistance are the risk factors for dyslipidemia and lipid metabolism disorders,² producing many diseases associated with abnormal lipid metabolism, such as nonalcoholic fatty liver disease (NAFLD), atherosclerosis, and cardiovascular diseases. NAFLD and atherosclerosis frequently occur together with osteoporosis. It has been demonstrated clinically in humans that abnormalities of lipid metabolism cause changes in osteoporosis-related indicators like bone mineral density (BMD) and bone mass in diseases such as NAFLD and atherosclerosis. Consequently, it is essential to comprehend the role and mechanism of lipid metabolism in osteoporosis development.

Osteoporosis is a progressive bone disease characterized by bone mass loss and changes in the bone microstructure, affecting bone strength and increasing fracture risk.³ Osteoporosis is prevalent among the elderly and postmenopausal women.⁴ Risk factors for osteoporosis include aging, estrogen deficiency, lipid metabolism disorders, and obesity. The association between lipids and bone has received more attention in recent years. The disorder of lipid metabolism might be a major cause of osteoporosis, and in particular, many studies were conducted on oxidized lipids and plasma cholesterol. Oxidized lipids are modified lipids via oxidation and lipid metabolism disorders could lead to an increase in oxidized lipids.

Furthermore, oxidized lipids promote lipogenic differentiation of mesenchymal stem cells (MSCs) primarily by activating the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway.⁵ Elevated plasma cholesterol levels down-regulate the Wnt signaling pathway, affecting MSC differentiation towards osteoblasts.⁶,⁷ Besides, oxidized lipids and cholesterol interfere with the balance of osteogenic and osteoclastic bone remodeling. Oxidized lipids stimulate osteoblasts to secrete receptor activator of nuclear factor-kappa B ligand (RANKL), causing excessive osteoclasts differentiation and bone resorption.⁸ Cholesterol binds with Smoothened protein and activates the Hedgehog signaling pathway, inhibiting osteoblast differentiation.⁹,¹⁰ Lipid metabolism disorders can affect bone microenvironment homeostasis, resulting in osteoporosis.

In this review, we discussed the potential link between lipid metabolism disorders and osteoporosis and elucidated the potential molecular mechanisms and signaling pathways by which lipid metabolism affects the occurrence and development of osteoporosis. This study may contribute to developing novel preventative medications, therapeutics, and predictive value for osteoporosis treatment. Finally, we summarized several strategies for preventing and treating osteoporosis, including diet and exercise, lipid interventions, and molecular targeted therapy. This review will add to our understanding of the function of lipid metabolism in osteoporosis and present innovative concepts for the therapeutic development of osteoporosis.

Adverse effects of lipid metabolic diseases on bone

Clinical findings

Osteoporosis phenotype in nonalcoholic fatty liver disease

NAFLD is a metabolic liver disease characterized histologically by the accumulation of triglycerides in hepatocytes, which can progress from mild hepatic steatosis to nonalcoholic steatohepatitis with liver inflammation and cirrhosis.¹¹,¹² Evidence suggests that free fatty acids and cholesterol are involved in key metabolic and inflammatory pathways in the pathogenesis of NAFLD; free fatty acids are a major source of triglycerides in the liver, and free cholesterol levels can lead to nonalcoholic steatohepatitis. 13, 14, 15 Furthermore, triglycerides can be packaged into very-low-density lipoprotein in addition to accumulating in lipid droplets; increased very-low-density lipoprotein secretion due to high lipid content in the liver is a chief reason for dyslipidemia associated with NAFLD.¹⁵ In conclusion, hepatic steatosis, caused by lipid apoptosis, disrupts systemic metabolism and adversely affects various organs.¹⁶

Given the rising prevalence of NAFLD and osteoporosis and their propensity to occur in the elderly, osteoporosis is anticipated to be an important complication of NAFLD. Recent epidemiological studies confirmed that the incidence of osteoporosis is significantly higher in patients with liver disease than in those without liver disease.¹⁷ Li et al¹⁸ explored whether NAFLD was associated with osteoporotic fractures by selecting 7797 adults aged 40 or older in the Jiading district of Shanghai, China. They conducted a questionnaire to collect the fracture history of the NAFLD patients and reported that the prevalence of osteoporotic fractures was significantly higher in men with NAFLD than those without NAFLD, but no difference was found in women. In another study examining the correlation between liver fat content and serum alanine aminotransferase and BMD in an elderly population, researchers used dual-energy X-ray bone densitometry to measure lumbar spine, hip, and whole-body BMD in 1659 adults (755 men and 1028 postmenopausal women) in the Changfeng community of Shanghai. The results found that subjects with higher liver fat content had significantly lower BMD at all skeletal sites and that BMD at all bone sites was significantly and synergistically worse when NAFLD and alanine aminotransferase levels were elevated together.¹⁹ However, the above study had some limitations and might not apply to the entire population. Moreover, the main pathological and physiological factors of NAFLD impacting bone density and bone mass that led to osteoporosis include hormones, inflammatory factors, proteins, and lipids. Among them, lipids comprise vitamin D, triglyceride, cholesterol, etc. ⁴ Overall, NAFLD may have a negative effect on bone mass and BMD, which in turn promotes osteoporosis.

Atherosclerosis and osteoporosis in humans

Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation in the artery wall, and the major hallmarks are lipid metabolism disorders and hypercholesterolemia.²⁰ The main source of lipids accumulating in atherosclerotic plaques is circulating LDL.²¹ Furthermore, under oxidative stress, polyunsaturated fatty acid phospholipids and cholesterol esters contained in cell membranes and lipoproteins can form complex lipid oxidation products through free radical-induced lipid peroxidation, and these oxidized lipids can impair normal physiological functions and stimulate atherogenesis.²²,²³ Moreover, the evidence suggests osteoporosis and atherosclerosis have the same risk factors or pathophysiological processes, implying that the occurrence of atherosclerosis and osteoporosis may be related.

Possible common risk factors for atherosclerosis and osteoporosis include aging, estrogen deficiency, dyslipidemia, oxidized lipid products, diabetes, hypertension, and chronic inflammation.²⁴,²⁵ In a study cohort of Finnish young adults based on cardiovascular risk followed in 2007, investigators used liquid chromatography-tandem mass spectrometry to analyze the serum lipidome to identify tightly linked lipid species associated with subclinical markers of osteoporosis and atherosclerosis. The results showed that the lipid module was significantly associated with subclinical markers of osteoporosis and atherosclerosis, and among the 37 significantly associated lipids, the top three were triglycerides (18:0/18:0/18:1), triglycerides (18:0/18:1/18:1), and triglycerides (16:0/18:0/18:1).²⁶ Besides, glycerophospholipids, sphingolipids, and cholesterol are also included.²⁶ Furthermore, in a study examining the relationship between atherosclerosis and BMD in 332 men without a history of cardiovascular disease, researchers assessed atherosclerosis and BMD-related metrics; among the healthy middle-aged and older men without a history of cardiovascular disease, the positive association between atherosclerosis and BMD was explained primarily through body weight, of which body fat mass was a component, and that excess fat could promote osteoporosis.²⁷ Research also demonstrates that among the prevalent risk factors for atherosclerosis and osteoporosis, lipid oxidation products such as minimal oxidized LDL promote arterial calcification and their accumulation in the subendothelial space of skeletal arteries inhibiting bone formation. To summarize, these results revealed that lipids play a crucial role in atherosclerosis and osteoporosis development.

Obesity-induced osteoporosis

Obesity is a worldwide epidemic. According to the World Health Organization, overweight and obesity are considered abnormal or excessive fat accumulation that can be detrimental to health. Obesity or excess weight increases the risk of coronary artery diseases, hypertension, type 2 diabetes (T2D), and osteoporosis. 28, 29, 30 Furthermore, dyslipidemia due to obesity is characterized by high levels of triglyceride-rich lipoproteins and low levels of high-density lipoprotein cholesterol (HDL-C).³¹ In addition, a study assessing obesity and lipid levels in 10-year-old children over 27 years found that obese children had significantly higher total cholesterol, triglyceride, and non-high-density lipoprotein cholesterol levels and lower high-density lipoprotein levels than non-obese children.³² Most clinical studies have shown the association between obesity and osteoporosis risk.

A trial on the effects of obesity on bone metabolism, microarchitecture, and strength in 112 obese male patients with and without type 2 diabetes assessed bone turnover and biochemical markers and compared data between obese patients with and without type 2 diabetes. The results showed that obese men with type 2 diabetes had significantly lower osteocalcin and carboxy-terminal collagen cross-linking levels and poorer bone trabecular microarchitecture and strength; obesity and type 2 diabetes resulted in severe bone diseases.³³ In addition, low muscle and high fat give rise to bone function defects and poorer bone health, increasing the risk of falls and fractures, and osteoporosis is prevalent in people with low muscle mass.³⁴ Leslie et al³⁵ studied bone health as a function of estimated total lean and fat mass in 40,050 women and 3600 men under 50 and measured femur and tibia bone density, strength index, cross-sectional area, and other metrics. According to the findings, the increased fat mass did not influence bone density but had a negative effect on femur strength, predicting a higher chance of fracture.

Osteoporosis phenotype in postmenopausal women

Female menopause is the natural cessation of menstruation due to loss of follicular activity, and surgical menopause is also accompanied by loss of estradiol.³⁶ Thus, the distinguishing feature of a naturally or surgically menopausal woman is hormonal changes, such as a decrease in estrogen, a rise in follicle-stimulating hormone (FSH), and an increase in circulating androgens.³⁷ It has been shown that the rise in FSH in menopausal women contributes to adiposity and dyslipidemia. Epidemiologic studies have shown that high FSH levels are positively correlated with total cholesterol and low-density lipoprotein cholesterol (LDL-C) in menopausal women, especially young menopausal women (588 subjects aged 53-73 years).³⁸ As the prevalence of osteoporosis increases in postmenopausal women,³⁹ it is therefore crucial to study the mechanisms of osteoporosis in menopausal women.

In a study evaluating the relationship of antioxidant enzymes and lipid peroxidation products to BMD and bone mass in 87 postmenopausal women (aged 40-65 years without a history of osteoporosis), the investigators concluded from measurements of BMD and related metrics that lipid peroxides may be a key indicator of bone loss in postmenopausal women.⁴⁰ In addition, Yoshida et al⁴¹ explored the effects of ovariectomy on lipid and bone metabolism (62 women, divided into an ovary-preserved group and a bilateral oophorectomy group) and demonstrated that ovariectomized women had significantly higher LDL levels and significantly lower BMD levels. The lack of hormones in menopausal women causes an increase in bone marrow-derived adipocytes, resulting in fat redistribution, which leads to an increase in visceral fat in postmenopausal women, and lipolysis of visceral fat produces large amounts of free fatty acids.³⁷ Mao et al⁴² showed that FSH binds to the follicle-stimulating hormone receptor, which activates the classical cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein pathway, and increased adipocytic PPARγ transcription promotes the production of lipids and a range of lipogenic factors. Therefore, since menopausal women are often accompanied by pathological manifestations such as dysregulation of lipid metabolism and obesity, the development of osteoporosis in menopausal women may perhaps be related not only to estrogen deficiency but also to disorders of lipid metabolism.

Osteoporosis in animal models of a high-fat diet

The osteoporosis phenotype has been noted in several animal models under conditions of disturbed lipid metabolism, suggesting that disturbed lipid metabolism adversely affects the development and course of osteoporosis. Some investigators have studied the phenotype of osteoporosis in a number of high-fat-fed animal models. Investigators assessed the effect of micro-oxidized LDL on osteoblast differentiation and its ability to regulate lipogenesis in mouse bone marrow stromal cells (M2-10B4) after feeding a high-fat and atherogenic diet to C57BL/6 mice and showed that oxidized lipids such as minimal oxidized LDL inhibit the differentiation of MSCs to osteoblasts and promote lipogenic differentiation, thereby promoting osteoporotic bone loss.⁴³ In another study, You et al⁶ explored the effect of a high-cholesterol diet on osteoporosis development in rats and its mechanism by establishing a rat model fed with a high-cholesterol diet. They measured BMD, osteocalcin, carboxy-terminal collagen cross-linking, and gene expression profiles and observed the changes in these indicators and differentiation of osteoblasts in rats. The study reported that femoral BMD and serum osteocalcin levels were significantly lower, and carboxy-terminal collagen cross-linking levels were significantly higher in rats fed a high-cholesterol diet. Likewise, the expression of genes related to bone formation, such as transforming growth factor β/bone morphogenetic protein and Wnt signaling pathway-related proteins, was reduced in rats fed a high-cholesterol diet; the expression of genes related to bone resorption was increased, such as interleukin-6 and Ager. Furthermore, in one study, researchers selected two strains of mice with different susceptibilities to atherosclerosis and examined the effects of an atherogenic high-fat diet and a control diet on the bones of the mice. After four and seven months of the diet, they measured the mineral content and density of the resected femur and lumbar spine and examined the expression of osteocalcin in the bone marrow of the mice after four months of feeding. The results showed that the high-fat diet reduced the mineral content of femurs in atherosusceptible mice by 43%, the mineral density was 15% lower than that of mice on a normal diet, and that osteocalcin expression was reduced in the bone marrow of atherosclerotic mice fed a high-fat diet. That is, an atherogenic high-fat diet can inhibit bone formation.⁴⁴ In summary, hyperlipidemia or hypercholesterolemia is closely associated with osteoporosis, and a high-cholesterol diet increases the osteoporosis risk.

Interorgan communication of bone

Bone is a paracrine and an endocrine organ; bone-derived secretory factors regulate the normal physiological functions of other organs to ensure material balance and health in the body.⁴⁵ Substances released by other vital metabolic organs, in turn, can influence bone formation and development. Thus, bone has a highly common cross-organ connection, and signaling axes exist between other organs and bone that govern their respective functions.⁴⁶ The liver-bone axis and the bone-vascular axis are currently being researched in depth ( Fig. 1).

Figure 1.

The effect of lipid metabolic diseases on osteoporosis. Many diseases, such as NAFLD, atherosclerosis, obesity, and postmenopause can cause lipid metabolism disorders in the body. Lipid metabolism will affect bone metabolism through blood circulation, mainly including lipid promotion of lipogenic differentiation of MSCs and inhibition of osteoblast differentiation. This makes bone resorption greater than bone formation, leading to osteoporosis. NAFLD, nonalcoholic fatty liver disease; MSCs, mesenchymal stem cells; FSH, follicle-stimulating hormone; RANKL, receptor activator of nuclear factor-kappa B ligand; OPG, osteoprotegerin.

Liver-bone crosstalk

The liver is a metabolic center that regulates the homeostasis in the body by interacting with multiple organs. Chronic liver disease patients frequently exhibit reduced BMD, defined as hepatic osteodystrophy,⁴⁷ which is a classic example of the liver as a metabolic organ affecting bone metabolism. Nussler et al⁴⁷ treated C57BL/6 mice with CCL4 for six weeks to establish a liver injury model. The μCT analysis showed a significant decrease in BMD, bone volume, and trabecular number and thickness in the CCL4-treated mice. Serum analysis disclosed decreased 25-OH vitamin D levels and excessive active transforming growth factor β, inhibiting osteoblasts function in vitro. It has been demonstrated that the expression of the intrahepatic phosphatase PP2Aca is up-regulated during hepatic osteodystrophy, leading to the down-regulation of the expression of the hepatic factor lecithin cholesterol acyltransferase; the loss of lecithin cholesterol acyltransferase's function significantly exacerbates the bone loss phenotype in mice with hepatic osteodystrophy.⁴⁶ In addition, hepatocyte-derived insulin-like growth factor binding protein 1 enhances the transcriptional activity of nuclear factor-activated T cell 1 in osteoblasts by binding to the receptor integrin β1 on osteoblast precursors, promoting osteoblast differentiation and bone resorption.⁴⁸

Bone-vascular crosstalk

The vasculature is a multifunctional transport network that plays a key role in tissue oxygenation, substance metabolism, and immune detection. In the skeletal system, the local vascular system has an active role in bone formation and resorption, and thus the connection between cardiovascular disease and bone is particularly strong.⁴⁹ Bone is a mineral reservoir required for vascular integrity. Furthermore, platelet-derived growth factor-BB secreted by the skeleton is a major source of its excess in the circulation during aging and metabolic stress; skeletal-derived platelet-derived growth factor-BB is an important mediator of vascular sclerosis.⁵⁰,⁵¹ The liver and bone or the blood vessels and bone can influence their respective metabolism through substance exchange. Therefore, lipid metabolism abnormalities caused by NAFLD and atherosclerosis may influence bone metabolism via the liver-bone or the vascular-bone axis. Recognition of these tissue axes will broaden our understanding of the pathogenesis of skeletal-related metabolic disorders and degenerative diseases.

Mechanism of oxidized lipids and cholesterol affecting bone metabolism

Oxidized lipids and cholesterol affect MSC differentiation

Bone marrow-derived MSCs are a multispectral cell lineage that can self-renew and differentiate into multiple cell types to maintain skeletal homeostasis.⁵² Adipogenesis and osteogenesis are the two opposite directions of MSC differentiation, and biological, physical, and chemical factors regulate the specific direction of differentiation; the balance of MSC differentiation is affected in different bone marrow microenvironments where lipogenic-inducing factors inhibiting osteoblasts formation and osteogenic-inducing factors blocking adipogenesis.³ The development of age-related osteoporosis is accompanied by decreased bone formation and increased bone marrow fat accumulation. In osteoporosis, MSCs have a decreased ability to differentiate into osteoblasts and an increased capacity to differentiate into adipocytes, leading to decreased bone formation.⁵³ There is evidence that lipids influence MSC differentiation via numerous signaling pathways; thus, lipid metabolism may have a role in the development and progression of osteoporosis ( Table 1 and Fig. 2).

Table 1.

Lipid

Lipid's function

Mechanism

References

Break the homeostasis between osteoblasts and osteoclasts

Act on the receptor EP1/TP on osteoblasts, activate the cAMP-PKA pathway, and promote the release of IL6/RANKL from osteoblasts; act on the receptor EP2/DP on osteoclasts and promote osteoclast differentiation through the cAMP-PKA pathway

8, 64

Induce bone marrow adipocyte senescence

Activate the PPARγ signaling and induce the SASP in bone marrow adipocytes
71

Activate endothelial progenitor cells' autophagic flux and inhibit their proliferation

Increase the expression of STIM1 and intracellular Ca ²⁺ concentration
81

Cholesterol

Promote the differentiation of mesenchymal stem cells into lipoblasts and inhibit osteogenic differentiation

Down-regulate the bone morphogenetic protein/TGF-β pathway and up-regulate plasma sclerostin level and thus down-regulate the Wnt/β-catenin pathway; inhibit Runx2 expression and promote PPARγ/C/EBPα expression due to low-activity Wnt pathway

5, 6, 7, 57, 58

Break the homeostasis between osteoblasts and osteoclasts

Act on Smoothened protein and activate Hedgehog signaling pathway; act on liver X receptors and up-regulate RANKL/OPG level

9, 10, 68, 69

Impair autophagy and polarize towards M1 macrophages

Inhibit the autophagy-related 5 expression
76

Figure 2.

Oxidized lipids and cholesterol affect MSC differentiation. Oxidized lipids bind to and activate the PPARγ/C/EBP signaling pathway, promoting adipocyte differentiation, leading to fat accumulation. It also activates the EGF/MAPK pathway in MSCs and inhibits osteoblast differentiation. Cholesterol activates the BMP/TGF-β pathway and increases serum sclerostin levels, which leads to down-regulation of the Wnt/β-catenin pathway. Low activity of the Wnt pathway down-regulates Runx2 expression, thereby inhibiting osteogenic differentiation. The low-activity Wnt pathway also up-regulates PPARγ and C/EBPα to enhance adipocyte differentiation. MSCs, mesenchymal stem cells; PPARγ, peroxisome proliferator-activated receptor gamma; C/EBP, CCAAT/enhancer binding protein; EGF, epidermal-like growth factors; MAPK, mitogen-activated protein kinase; BMP, bone morphogenetic protein; TGF-β, transforming growth factor β; Runx2, runt-related transcription factor 2.

Oxidative lipids activate the PPARγ signaling

PPARγ is a nuclear receptor and a master regulator of adipogenesis that regulates the transcription of adipocyte-specific genes through ligand binding activation.⁵⁴ Oxidized lipids bind to and activate the PPARγ signaling pathway, and PPARγ activation acts synergistically with CCAAT/enhancer binding protein to differentiate MSCs along the lipogenic pathway, while inhibiting osteoblast differentiation, leading to fat accumulation and inhibiting bone formation.⁵ In addition, some oxidized lipids induce the expression of epidermal-like growth factors by acting on their receptors in bone marrow stromal cells, thereby activating the mitogen-activated protein kinase pathway and inhibiting alkaline phosphatase activity and osteoblast differentiation in bone marrow stromal cells.⁴³

Cholesterol abnormalities down-regulate the Wnt pathway

The Wnt signaling pathway is vital for regulating bone homeostasis, and the classical Wnt-β-catenin signaling pathway is triggered by the binding of Wnt ligands to membrane receptors, including LDL receptor-related protein 5/6 and coiled-coil proteins, which in turn trigger intracellular cascade responses that regulate the differentiation of MSCs to osteoblasts and adipocytes.⁵⁵,⁵⁶ Low activity of the Wnt-β-catenin signaling pathway in MSCs enhanced adipocyte differentiation by up-regulating CCAAT/enhancer binding protein α, and PPARγ leads to fat accumulation while inhibiting osteoblast differentiation by down-regulating runt-related transcription factor 2 (Runx2) expression, thereby suppressing bone formation.⁵ Runx2 is a key transcription factor involved in osteoblast differentiation. Cholesterol can alter Runx2 levels by altering the bone morphogenetic protein/transforming growth factor β/Wnt signaling pathway involved in bone formation, impacting the MSCs' differentiation to osteoblasts and proliferation and maturation of osteoblasts.⁶,⁷ In addition, the investigators found that serum sclerostin levels were positively correlated with LDL cholesterol levels and that high blood cholesterol levels elevate circulating serum sclerostin levels, which act as antagonists of Wnt ligands and down-regulate the Wnt-β-catenin signaling pathway.⁵⁷,⁵⁸ Therefore, cholesterol could stimulate lipogenic differentiation of MSCs while inhibiting osteoblast differentiation, leading to increased bone fat deposition, decreased bone mass, and the development of osteoporosis.

Effects of oxidized lipids and cholesterol on osteoblasts and osteoclasts

Osteoblasts are mainly derived from MSCs inside and outside the periosteum and bone marrow stroma, and multinucleated osteoclasts differentiate from myeloid cells at different stages of maturation.³ The homeostasis of bone mass within healthy adults requires strict control of bone resorption by osteoclasts and bone formation by osteoblasts, and imbalance of bone formation and resorption is the underlying cause of various skeletal diseases including osteoporosis.⁵⁹,⁶⁰ Osteoblasts and osteoclasts communicate with each other mainly through direct cell-to-cell contact or secretion of cytokines to regulate cell growth and differentiation; for example, osteoblasts secrete macrophage colony-stimulating factor and RANKL/osteoprotegerin (OPG) to promote or inhibit the differentiation of osteoclasts.⁶¹ Osteoporosis results from an imbalance in the bone remodeling process through increased osteoclast activity and decreased osteoblast activity.⁶² Several studies have found that lipids can influence the differentiation and maturation of osteoclasts and osteoblasts, disrupting bone homeostasis. Understanding the mechanisms of lipid metabolism of osteoclasts and osteoblasts is thus critical for osteoporosis prevention ( Fig. 3).

Figure 3.

Oxidized lipids and cholesterol break the bone homeostasis between osteogenesis and osteolysis. Oxidized lipids act on the receptor EP1/TP on osteoblasts to induce the cAMP/PKA pathway in osteoblasts, leading to the release of cytokines. Oxidized lipids also act directly on EP2/DP receptors on osteoclasts to promote osteoclast differentiation via the cAMP/PKA pathway. Cholesterol binds to Smoothened protein and activates the Hedgehog signaling pathway, thereby inhibiting osteoblast differentiation. The intermediate metabolite of cholesterol, 27-hydroxycholesterol, acts on liver X receptors (LXRs) and increases the RANKL/OPG ratio, leading to the inhibition of osteoclast differentiation. PKA, cAMP-dependent protein kinase; RANKL, receptor activator of nuclear factor-kappa B ligand; OPG, osteoprotegerin.

Oxidized lipids stimulate the cAMP-PKA cascade

RANKL plays a critical role in osteoclast proliferation and differentiation by binding to RANK receptors located on osteoclast precursor cells; it activates the mitogen-activated protein kinase signaling pathway, triggering various transcription factors and osteoclast differentiation markers such as nuclear factor kappa B, activator protein-1, and nuclear factor-activated T cell 1 downstream, thereby promoting osteoclast differentiation and bone resorption function.⁶³ It has been shown that oxidatively modified bioactive lipids stimulate the production of interleukin-6 and RANKL by osteoblasts and T lymphocytes, inducing the cAMP-PKA pathway in osteoblasts by acting on their receptor EP1/TP, releasing these cytokines. Subsequently, overexpression of interleukin-6 and RANKL promotes osteoclasts over differentiation, encouraging bone resorption.⁸ On the other hand, oxidized lipids directly act on the prostaglandin receptor subtype EP2/DP on osteoclasts, increasing the level of cAMP in osteoclasts and ultimately promoting osteoclast differentiation via the PKA pathway.⁶⁴

Cholesterol activates Hedgehog and LXR signaling

The Hedgehog signaling pathway is essential for osteoblast differentiation and plays an important role in bone homeostasis, and reducing Hedgehog signaling prevents age-related bone loss. 65, 66, 67 Cholesterol binds to Smoothened proteins and activates the Hedgehog signaling pathway.⁹ Li et al¹⁰ investigated the role of exogenous and endogenous cholesterol in osteogenesis and Hedgehog pathway activation using a bone marrow stromal cell line (ST2 cells). The results found that exogenous cholesterol significantly inhibited alkaline phosphatase activity and osteoblast marker gene expression and moderately activated Hedgehog signaling pathway activity under basal osteogenic culture conditions, inhibiting the osteogenic differentiation of ST2 cells. In addition, using molecular and pharmacological approaches, Nelson et al⁶⁸ demonstrated that the major metabolite of cholesterol, 27-hydroxycholesterol, may act on liver X receptors (LXRs). LXRs are a regulator of RANKL expression and RANKL/OPG ratio in osteoblasts. They can reduce osteoblast differentiation and activity, increase osteoclastic factors (tumor necrosis factor and RANKL), enhance osteoclast differentiation, and thus increase bone resorption in mice.⁶⁹

Effects of oxidized lipids and cholesterol on other cells in the bone microenvironment

Bone marrow adipocytes are an important class of cells in the bone marrow microenvironment. Bone marrow adipocytes act directly on other cell types in the bone marrow and secrete cytokines and adipokines that regulate bone remodeling.⁷⁰ A growing body of research indicates that abnormal expansion of bone marrow adipose tissue is critical for the development of postmenopausal osteoporosis.⁷⁰ In addition, bone marrow adipocyte senescence leads to secondary senescence of the bone marrow, which in turn leads to bone loss and osteoporosis.⁷¹ Recent evidence suggests that lipids or their intermediary metabolites are capable of influencing bone marrow adipocyte-related functions. Liu et al⁷¹ found that lipoxides induced bone marrow adipocyte senescence through activation of the PPARγ signaling pathway in a glucocorticoid-induced bone loss model. Senescent bone marrow adipocytes acquired the senescence-associated secretory phenotype, which spread senescence to bone marrow vascular cells and osteoblasts, leading to bone loss. Therefore, lipids could contribute to the development of osteoporosis by directly acting on bone marrow adipocytes, leading to senescence of bone marrow adipocytes or abnormal expansion of adipose tissue ( Table 1).

Macrophages are bone marrow-derived mononuclear phagocytes that change their function and phenotype in response to different signaling stimuli in the bone microenvironment.⁷² Macrophages can be categorized into M1 and M2 subtypes. M1 macrophages are pro-inflammatory cells, and M1 macrophage-associated cytokines (such as tumor necrosis factor-α, interleukin-6, and IL-1β) induced osteoclastogenesis which promotes bone resorption. 72, 73, 74 Thus, different polarization states of macrophages have an important role in bone homeostasis. Recent studies have shown that disorders of lipid metabolism lead to disturbances in macrophage function.⁷⁵ Liu et al⁷⁶ demonstrated that decreased levels of macrophage autophagic flux led to impaired autophagy in high-fat diet-induced obese mice. Inhibition of autophagy-related 5 expression polarized macrophages toward M1 phenotypes, leading to a systemic and tissue inflammatory response. Thus, lipids interfere with macrophage polarization, leading to an inflammatory response in the bone microenvironment and influencing bone remodeling ( Table 1).

Bone is a highly vascularized organ.⁷⁷ Vascular endothelial cells form the inner layer of the vascular system and act as a barrier for the transportation of substances between blood vessels and bone cells.⁷⁸ It has also been found that blood vessels play an important role in the regulation of bone formation. A variety of cell-secreted factors enter the bone marrow microenvironment and promote the formation of type H vessels which produce factors that stimulate the proliferation and differentiation of bone histiocytes and positively direct bone formation.⁷⁹ Therefore, angiogenesis is essential for bone development, bone regeneration, and bone remodeling.⁸⁰ It has been shown that lipids, especially oxidized lipids, can damage vascular endothelial cells, leading to alterations in the structural integrity and function of the endothelial barrier. Yang et al⁸¹ demonstrated that in rat-derived endothelial progenitor cells with oxidized low-density lipoproteins' stimulation mimicking hypercholesterolemia condition, oxidized low-density lipoproteins activated autophagic fluxes of endothelial cells, inhibited the proliferation of endothelial progenitor cells, and impaired angiogenesis. The oxidized low-density lipoproteins increased endothelial cell stromal interaction molecule 1 expression and intracellular Ca ²⁺ concentration.⁸¹ Therefore, lipid metabolism affects angiogenesis by influencing endothelial function, and impairing bone vascularization could lead to the development of a number of bone-related diseases, such as osteoporosis ( Table 1).⁸⁰

In conclusion, lipids, mainly oxidized lipids and cholesterol, promote lipogenic differentiation of MSCs and inhibit differentiation of osteoblasts. Besides, oxidized lipids and cholesterol can also upset the balance of bone remodeling, increase osteoclast activity, and decrease osteoblast activity. These changes ultimately increase bone marrow fat deposits, reduce bone formation, and promote bone resorption and the development of osteoporosis.

Strategies for regulating lipids to treat osteoporosis

Diet and exercise

Exogenous lipids are crucial for the development of osteoporosis. Therefore, in addition to pharmacological treatment, lifestyle modifications, dietary changes, and reasonable exercise can be used to treat osteoporosis or prevent further osteoporotic fractures.⁸² Regarding diet, it is important to reduce the intake of high-fat foods and low calcium intake, and high sodium, alcohol, and cola intake can decrease bone mass.⁸³ Results of a trial evaluating the effects of low-fat low-carb diets on obesity and lipids in 6499 adults showed that low-fat low-carb diets were effective in reducing body weight and improving levels of HLD and triglycerides.⁸⁴ Therefore, current research on diet and bone status encourages a balanced diet, including plenty of fruits and vegetables, adequate dairy products and other protein foods, and limiting foods with low nutrient density.⁸⁵ Moreover, it is crucial to maintain moderate exercise and maintain a normal weight. Lipids are considered an important source of energy during exercise, mainly referring to the oxidation of fatty acids.⁸⁶ Fatty acids may be signaling candidates for regulating the transcription of target genes encoding proteins involved in muscle lipid metabolism.⁸⁷ As obesity is characterized by impaired fatty acid oxidation, fatty acid oxidation capacity is improved in obese individuals during exercise training. Thus, moderate exercise is a potential approach to improve the flexibility of lipid metabolism in obese patients.⁸⁷ Moreover, Baek et al⁸⁸ examined MGAT1 and hepatic adipogenic gene mRNA levels in high-fat diet-induced rats subjected to 6 weeks of regular aerobic exercise. The results showed that aerobic exercise inhibited the MGAT1 pathway, thereby ameliorating high-fat diet-induced NAFLD in obese rats. In addition, numerous studies have shown that exercise therapy can improve quality of life, such as physical function and action, pain, and vitality in postmenopausal women with osteoporosis or osteopenia.⁸⁹ This shows that diet and exercise have an important and positive role in regulating lipid metabolism and preventing osteoporosis.

Investigational agents targeting lipid metabolism and bone formation

Pathological conditions such as NAFLD, atherosclerosis, and obesity can alter the body's lipid metabolism, affecting bone mass and density and leading to osteoporosis. All these studies concluded that lipid metabolism disorders increase the chance of osteoporosis. Therefore, the use of lipid-lowering agents to regulate lipid metabolism in the body may have a role in treating and mitigating osteoporosis ( Table 2).

Table 2.

Agents

Effects

Mechanism

References

Statins

Lower plasma cholesterol levels, especially low-density lipoprotein cholesterol; promote bone anabolism and decrease bone resorption

Inhibit the activity of HMGCR; regulate the sterol regulatory element binding protein-2 pathway; up-regulate bone morphogenetic protein-2 and protect osteoblasts from apoptosis; reduce RANKL/OPG ratio and inhibit osteoclast differentiation

90, 92, 93

Metformin

Regulate blood sugar and lipid; restore damaged bone structure and bone density

Up-regulate expression of osteogenic marker genes; decrease OPG/RANKL ratio and inhibit osteoclast differentiation

94, 95, 96

LT175

Lose weight; lower the levels of blood sugar, cholesterol, insulin, and triglycerides

Interact with a new recognition region of PPARγ
105

Bisphenol A diglycidyl ether

Enhance osteogenesis and inhibit fat formation

Inhibit the PPARγ signaling in mesenchymal stem cells
106

SR1664

Enhance osteogenesis and inhibit fat formation

Block obesity-induced phosphorylation of S273; inhibit the PPARγ pathway
107

Statins

As a lipid-lowering agent, statins can inhibit the activity of HMG-CoA Reductase (HMGCR), effectively reducing plasma cholesterol levels, especially LDL-C.⁹⁰ Low plasma cholesterol levels can increase hepatic LDL receptor (LDLR) expression through the sterol regulatory element binding protein-2-dependent pathway, accelerating the uptake and clearance of LDL-C from plasma.⁹⁰ Statins seem to be a promising drug for the treatment of osteoporosis.⁹¹ According to the present literature, statins' effects on bone may entail several pathways. In addition to their lipid-lowering properties, statins exert their anabolic effects on bone by up-regulating bone morphogenetic protein-2, protecting osteoblasts from apoptosis, and controlling MSCs' commitment to osteoblasts.⁹² Furthermore, statins can increase and decrease the expression levels of OPG and RANKL mRNA in osteoclasts, respectively, reducing bone resorption by decreasing the differentiation and activity of osteoclasts through the OPG/RANKL signaling pathway.⁹³ Thus, statins act as a primary agent to treat cardiovascular disease and thus regulate lipid levels and alleviate osteoporosis. Furthermore, it could play a vital role in the regulation of bone resorption as well as the maintenance of bone metabolism for the therapeutic management of osteoporosis.

Metformin

Metformin, an antidiabetic drug, promotes osteoblast differentiation, inhibits osteoclast differentiation, and prevents bone loss in de-ovalized rats.⁹⁴ Studies have shown that metformin can increase alkaline phosphatase activity and expression of osteogenic marker genes at the mRNA and protein levels.⁹⁵ It may act through multiple mechanistic effects to achieve therapeutic effects in osteoporosis. Nirwan and Vohora⁹⁶ used a high-fat diet to feed C57BL/6 mice for 22 weeks to induce diabetic osteoporosis and treated with oral linagliptin and metformin. They measured femoral and tibial bone microarchitecture and BMD and examined histopathological changes. In addition, bone transformation biomarkers such as bone morphogenetic protein-2, sclerostin, anti-tartrate acid phosphatase, osteocalcin, and alkaline phosphatase were evaluated. Ultimately, the combination of linagliptin and metformin significantly restored damaged bone structure and density and positively modulated bone turnover biomarkers. In addition, Mai et al⁹⁴ established that metformin dose-dependently stimulated OPG in mouse cranial and MC3T3-E1 osteoblasts and decreased RANKL mRNA and protein expression. Therefore, metformin could be used to treat high-glucose and high-fat-induced osteoporosis.

Oxidized lipid antagonists

Numerous studies have established that oxidized lipids adversely impact lipid metabolism in bone, and lipid peroxidation is associated with various diseases and aging. Consequently, oxidized lipid antagonists may be used to prevent and counteract the negative effects of oxidized lipids on bone. Antioxidants can slow the progression of arterial thickening, atherosclerosis, and coronary heart disease.⁹⁷ Vitamins E and C are typical lipophilic and hydrophilic antioxidants, respectively, and vitamin C scavenges free radicals in the aqueous phase. Furthermore, vitamin C intake reduces the effect of high high-cholesterol diet on alveolar bone density and osteoclast differentiation by reducing oxidative tissue damage by neutralizing free radicals and scavenging hydroxyl radicals.⁹⁸ Its antioxidant activity may be clinically useful in hyperlipidemic patients to prevent alveolar bone resorption. Moreover, vitamin E scavenges lipid peroxide radicals.⁹⁹ As a result, consuming certain doses of vitamins C and E can be used to intervene in the oxidative alteration of lipids. However, due to the diversity of lipid oxidation production pathways, including enzymatic oxidation, non-enzymatic free radical-mediated oxidation, and non-enzymatic non-free mediated oxidation,⁹⁹ different countermeasures are required for oxidized lipids produced by different mechanisms, necessitating further exploration and researches.

Drugs for regulating lipid transport

LDL influences the action of cholesterol on osteoclasts and osteoblasts.¹⁰⁰ Perhaps it is feasible to modulate exogenous lipid uptake by blocking lipoprotein receptors on the surface of osteocytes or boost hepatic LDLR expression to reduce plasma LDL-C for changes in bone mass caused by excessive cholesterol or other lipids. Okayasu et al¹⁰¹ used LDL knockout ( LDLR−/−) mice to elucidate the role of LDLR in regulating osteoclast differentiation and showed that bone mass was consistently increased in LDLR−/− mice, accompanied by a decrease in bone resorption parameters, while bone formation parameters were unchanged. Pro-protein convertase subtilisin/kexin 9 (PCSK9) is a serine protease of the proprotein convertase family, mainly produced by the liver and up-regulates plasma LDL-C levels by inhibiting hepatic LDLR recirculation to the cell surface.¹⁰² Thus, PCSK9 inhibitors could increase hepatic LDLR expression by attenuating PCSK9 expression/function, thereby reducing plasma LDL-C. Accordingly, PCSK9 inhibitors are potentially valuable in treating cardiovascular disease and may further mitigate the development of osteoporosis by lowering lipid levels and regulating cholesterol metabolism.

Inhibitors of PPARγ signaling pathway

PPARγ is a major regulator of lipogenesis and a very critical target in MSCs to determine their differentiation direction. Therefore, regulating the activity of PPARγ can regulate lipid levels and thus osteoporosis due to dyslipidemia and disorders of lipid metabolism. Saroglitazar is a novel agonist of PPARγ that improves glucose lipid parameters and insulin sensitivity. In a randomized controlled clinical trial, Gawrieh et al¹⁰³ found that saroglitazar (4 mg) significantly improved alanine aminotransferase levels and atherosclerotic dyslipidemia in patients with NAFLD/NASH. In addition, Kumar et al¹⁰⁴ verified the effect of saroglitazar on improving NASH by establishing a high-fat diet-induced NAFLD model in mice. The results also confirmed that saroglitazar treatment resulted in lower body weight, lower levels of total cholesterol, triglycerides, and alanine aminotransferase, and remission of NASH in mice. LT175 is a novel PPARγ ligand that interacts with a novel recognition region of PPARγ. It was shown that in vivo administration of LT175 to mice on a high-fat diet reduced body weight, adipocyte size, and white adipose tissue mass. In addition, LT175 significantly reduced blood glucose, cholesterol, insulin, triglycerides, and non-esterified fatty acids.¹⁰⁵

In addition, inhibition of PPARγ transcriptional activity in MSCs to enhance osteogenesis and inhibit lipogenesis is also an effective means to alleviate osteoporosis. Li et al¹⁰⁶ studied the effects of bisphenol A diglycidyl ether, an antagonist of PPARγ, on an OVX rat model and showed that early treatment with a 30 mg/kg dose of bisphenol A diglycidyl ether reduced bone marrow obesity and stimulated bone formation in ovary-intact and OVX rats. Marciano et al¹⁰⁷ reported a PPARγ antagonist SR1664, which blocks obesity-induced serine 273 phosphorylation in the absence of classical agonists. Furthermore, they demonstrated that the inhibitory effect of SR1664 on PPARγ promotes osteogenic differentiation in MSCs and is consistent with the ideal bone phenotype observed in an animal model of PPARγ deficiency. Thus, it is evident that PPARγ is a critical regulatory target in osteoporosis triggered by dyslipidemia and lipid metabolism disorders.

Conclusion and prospect

The results of clinical and basic studies revealed that lipids and lipid metabolites significantly influence the progression of osteoporosis. Results from in vivo experiments in animals suggested that lipid metabolism is directly related to the differentiation of MSCs and the homeostasis of bone metabolism. This review discussed the effects of NAFLD, atherosclerosis, and obesity on the occurrence of osteoporosis and attempted to reveal the cellular and molecular mechanisms of oxidative lipids and cholesterol causing osteoporosis. However, because lipid metabolism involves multiple organs and cells and has complex regulatory mechanisms, including many steps of lipid absorption and transport, the relationship between different types of lipids and their metabolism and the development of osteoporosis remain to be further elucidated. Furthermore, the origins of lipid metabolism abnormalities and their relationships with inflammation and other substance metabolism should be addressed, followed by a thorough examination of the mechanisms impacting bone metabolism.

In addition to descriptive investigations, we performed cellular and mechanistic explorations as new therapeutic targets for treating osteoporosis. This review shows that lipid metabolism disorder promotes the differentiation of MSCs toward lipogenic pathways and inhibits osteogenic differentiation. Besides, lipids affect bone homeostasis between osteoblasts and osteoclasts. As a result, in terms of therapeutic strategy development, osteoporosis can be alleviated by regulating lipids, and new therapeutic drugs can be developed based on cellular and molecular mechanisms. Due to the complexity of lipid metabolism, the mechanisms of lipid impacting osteoporosis need to be further explored; therefore, new therapeutic targets for osteoporosis need to be further discovered and studied. In conclusion, increasing evidence supports the close association of lipids and lipid metabolism with the development of osteoporosis, providing new insights that can contribute to the safe and rational selection of drug therapies to prevent and treat these common diseases.

Conflict of interests

The authors declare no conflict of interests.

Funding

The study was sponsored by the Key Program of the National Natural Science Foundation of China (No. 81930067), the Natural Science Foundation of China (No. 82002316), and the Youth Cultivation Project of Army Medical University (China) (No. 2020XQN08).

Footnotes

Peer review under responsibility of Chongqing Medical University.

Contributor Information

Jianmei Li, Email: amyleeljm@163.com.

Shiwu Dong, Email: dongshiwu@163.com.

References

97. Zhang P.Y., Xu X., Li X.C. Cardiovascular diseases: oxidative damage and antioxidant protection. Eur Rev Med Pharmacol Sci. 2014;18(20):3091-3096. [PubMed] [Google Scholar]

Articles from Genes & Diseases are provided here courtesy of Chongqing Medical University

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The role of lipid metabolism in osteoporosis: Clinical implication and cellular mechanism

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In recent years, researchers have become focused on the relationship between lipids and bone metabolism balance. Moreover, many diseases related to lipid metabolism disorders, such as nonalcoholic fatty liver disease, atherosclerosis, obesity, and ...

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Serum creatinine levels can indicate skeletal muscle mass. Sarcopenia, loss of muscle mass would affect the bone mineral density. Subjects with low serum creatinine were at a higher risk for low BMD (T-score ≤ -1.0) at the femur neck, total hip and lumbar spine in men, and at the total hip and lumbar spine in women after adjustment for confounding factors.

Reference:

Lower Serum Creatinine Is Associated with Low Bone Mineral Density in Subjects without Overt Nephropathy - PMC

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Abstract

Background

Low skeletal muscle mass is associated with deterioration of bone mineral density. Because serum creatinine can serve as a marker of muscle mass, we evaluated the relationship between serum creatinine and bone mineral density in an older population with normal renal function.

Methods

Data from a total of 8,648 participants (4,573 men and 4,075 postmenopausal women) aged 45-95 years with an estimated glomerular filtration rate >60 ml/min/1.73 m2 were analyzed from the Fourth Korea National Health and Nutrition Examination Survey (2008-2010). Bone mineral density (BMD) and appendicular muscle mass (ASM) were measured using dual-energy X-ray absorptiometry. Receiver operating characteristic curve analysis revealed that the cut points of serum creatinine for sarcopenia were below 0.88 mg/dl in men and 0.75 mg/dl in women. Subjects were divided into two groups: low creatinine and upper normal creatinine according to the cut point value of serum creatinine for sarcopenia.

Results

In partial correlation analysis adjusted for age, serum creatinine was positively associated with both BMD and ASM. Subjects with low serum creatinine were at a higher risk for low BMD (T-score ≤ -1.0) at the femur neck, total hip and lumbar spine in men, and at the total hip and lumbar spine in women after adjustment for confounding factors. Each standard deviation increase in serum creatinine was significantly associated with reduction in the likelihood of low BMD at the total hip and lumbar spine in both sexes (men: odds ratio (OR) = 0.84 [95% CI = 0.74−0.96] at the total hip, OR = 0.8 [95% CI = 0.68−0.96] at the lumbar spine; women: OR = 0.83 [95% CI = 0.73-0.95] at the total hip, OR=0.81 [95% CI = 0.67-0.99] at the lumbar spine).

Conclusions

Serum creatinine reflected muscle mass, and low serum creatinine was independently associated with low bone mineral density in subjects with normal kidney function.

Introduction

Growing evidence supports cross-talk between bone and muscle because they have common genetic, nutritional, lifestyle, and hormonal determinants [ 1]. Interactions between muscle and bone can affect bone strength [ 2], and it has been previously documented that bone functions as a musculoskeletal unit and adapts to the mechanical loads exerted by skeletal muscle [ 3]. In addition, a progressive decline in bone mineral density (BMD), muscle mass and muscle strength have common key features of the aging process. Accordingly, sarcopenia, the age-related loss of muscle mass, has been suggested as a major risk factor for low BMD and fracture in several epidemiological studies [ 4- 6]. Therefore, identification of sarcopenia is an important factor in older populations suggesting whether individuals have decreased BMD and are therefore at high risk of fragility fracture. Although dual-energy X-ray absorptiometry (DXA) is currently accepted as the gold standard method to measure both muscle mass and BMD, it is expensive and not easily accessible for many populations.

Serum creatinine is primarily a metabolite of creatine phosphate, almost all of which is found in skeletal muscle. Because the amount of creatinine per unit of skeletal muscle mass and the breakdown rate of creatine are both consistent, plasma creatinine concentration is a stable, direct reflection of skeletal muscle mass [ 7]. In addition, because 24-h urinary creatinine excretion is highly correlated with muscle mass estimates determined using DXA [ 8], and serum creatinine is highly correlated with 24-h urine excretion in subjects with normal renal function [ 9], serum creatinine could represent an acceptable and easily measured surrogate marker of muscle mass. Considering that skeletal muscle is a major target tissue of insulin [ 10], several previous studies have reported lower serum creatinine (reflecting lower skeletal muscle) to be associated with metabolic disorders such as insulin resistance and type 2 diabetes [ 11, 12]. From those findings and considering the bone-muscle relationship, we speculated that lower serum creatinine might also be associated with deterioration of BMD, especially in subjects without renal insufficiency. However, few studies have reported the association between serum creatinine and BMD.

Therefore, the aim of the present study was to investigate the associations between serum creatinine and BMD in adults with normal kidney function using data from the general Korean population. We also examined whether those associations differ by sex or skeletal sites. We hypothesized that lower serum creatinine, reflecting low muscle mass, might be related to decreased BMD and that serum creatinine could provide information about an individual's bone health as well as muscle health in subjects without renal insufficiency.

Materials and Methods

Study population and design

The Korea National Health and Nutrition Examination Survey (KNHANES) has been performed periodically since 1998 by the Division of Chronic Disease Surveillance of the Korean Centers for Disease Control and Prevention to assess the health and nutritional status of the civilian, non-institutionalized population of Korea. The KNHANES IV, V was a cross-sectional and nationally representative survey conducted from 2008 to 2010 which are available on the KNHANES website ( https://knhanes.cdc.go.kr/knhanes/sub03/sub03_02_02.do; S1 Dataset). The survey was composed of a health interview survey, a nutrition survey, and a health examination survey. The data were collected by household interviews and by direct, standardized physical examinations conducted in mobile examination centers. Nutritional status and medical history were evaluated using a 24-h recall method. Regular exercise was indicated as "yes" when the subject exercised for more than 20 min at a time more than three times per week. Subjects with any pathological disorders (such as cancer, hyperthyroidism, malabsorption, or hepatic failure) or subjects using medications (such as corticosteroids, heparin, or anticonvulsants) known to alter calcium and bone metabolism were excluded from our analysis. We also excluded subjects who used testosterone, anabolic steroids or antiresorptive agents and who have definite renal insufficiency (estimated glomerular filtration rate <60 ml/min/1.73 m ²). Among those who participated in the survey and met our inclusion criteria, 8,648 participants were 45 years or older (4,573 men and 4,075 postmenopausal women).

Ethics statement

Because the KNHANES IV survey data are publicly available, ethical approval was not required for this study. Prior to the survey, all participants were informed that they had been randomly chosen to participate in the KNHANES IV survey with the right to refuse to be involved in further analyses, and signed informed consents were obtained. The data we used from the KNHANES database were fully anonymized.

Measurements and definitions of sarcopenia

Total body fat and appendicular skeletal muscle mass (ASM) as well as BMD at the lumbar spine (LS) (L1-4) and hip region were measured using DXA (QDR 4500A; Hologic Inc., Waltham, MA). All men and non-pregnant women aged 20 years and older who received a physical examination in the mobile centers were eligible for bone densitometry analysis unless they had previously fractured both hips. Low BMD was defined as a T-score of -1.0 or less. Relative ASM was calculated as the sum of the mass of skeletal muscle in the arms and legs, divided by the square of the height (ASM/ht ² in kg/m ²). A subject was classified as having sarcopenia when he or she had a relative ASM less than one standard deviation (SD) below the sex-specific normal mean for the young reference group (healthy men and women aged 20-39 years) [ 13]. The cutoff point for sarcopenia was 7.86 kg/m ² for men and 5.71 kg/m ² for women.

Biochemical analysis

Collected blood samples were immediately refrigerated, transported to the Central Testing Institute in Seoul, Korea, and analyzed within 24 h. Serum creatinine levels were determined using a Hitachi 7600 automated chemistry analyzer (Hitachi, Tokyo, Japan) with Creatinine plus (Roche Diagnostics). The estimated glomerular filtration rate derived from the Chronic Kidney Disease Epidemiology Collaboration equation was used to assess renal function; this method is more accurate than previous indices, such as the Modification of Diet in Renal Disease Study equation [ 14]. Fasting plasma glucose and cholesterol levels were measured with a Hitachi 700-110 chemistry analyzer (Hitachi). Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured by radioimmunoassay (DiaSorin Inc., Stillwater, MN, USA) using a γ-counter (1470 Wizard; PerkinElmer, Turku, Finland). A chemiluminescence immunoassay (N-tact PTH assay; DiaSorin) was used to measure serum intact parathyroid hormone. Fasting insulin (INS-IRMA; Biosource, Nivelles, Belgium) was measured by an immunoradiometric assay. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated using the following formula: fasting (plasma glucose (mg/dL) x fasting insulin (mIU/mL))/22.5 [ 15].

Statistical analysis

Statistical analyses were conducted using IBM's SPSS version 20.0 for Windows (IBM Corp., Armonk, NY, USA). A receiver operating characteristic curve (ROC) was created to find the cut-off point of serum creatinine for predicting sarcopenia. The optimal cut point was 0.88 in men (sensitivity was 57%; specificity was 57% at this level) and 0.75 in women (sensitivity was 70%; specificity was 40% at this level). We classified subjects into two groups according to this cut-off point value of serum creatinine. An independent, two-sample t-test was used to compare differences in the mean values of baseline parameters among the groups. For categorical variables, a chi-square test was used to compare the frequencies among the groups. Partial correlation analyses were used to evaluate the association between serum creatinine and body composition indices with adjustments made for age. Multiple linear regression analysis was then used to determine the association between serum creatinine and the outcome (total hip, femoral neck and lumbar spine BMD) adjusted for confounding factors. Multiple logistic regression analysis was used to examine the association between sarcopenia and low BMD, with the results expressed as odds ratios (OR) and 95% confidence intervals (CI).

Results

Clinical characteristics of the study population

The demographic and clinical characteristics of the patients, who were classified into two groups according to sex-specific cutoff values of creatinine for sarcopenia (Men: serum creatinine ≤ 0.8 mg/dL, Women: ≤ 0.7 mg/dL), are shown in Table 1. The mean age was 60.16±10.06 years (range, 45-93 years) in men and 62.96±9.07 years (range, 45-95 years) in postmenopausal women. The low creatinine group had lower body mass index, weight, waist circumference and ASM in both sexes. BMD at the total hip (TH), femoral neck (FN), and lumbar spine (LS) was significantly lower in the low creatinine group than in the upper normal creatinine group in men, but only BMD at LS was significantly lower in the low creatinine group in postmenopausal women. Fasting insulin and HOMA-IR were higher in the upper normal creatinine group than in the low creatinine group. The frequency of alcohol consumption and the proportion of current smokers were both higher in the low creatinine group in both sexes.

Table 1. Clinical characteristics of the subjects.

Variable (unit)

Men

Women

Low creatinine (n = 1,189)

Upper normal creatinine (n = 3,384)

P- value

Low creatinine (n = 2,845)

Upper normal creatinine (n = 1,230)

P- value

RASM a (kg/m ²)

7.29 ± 085

7.58 ± 0.87

<0.001

5.93 ± 0.68

6.03 ± 0.71

<0.001

Regular exercise b (%)

216 (18.3)

655 (18.3)

0.994

354 (12.5)

188 (13.2)

0.511

Relationships between serum creatinine, muscle mass and bone density

As shown in S1 Table, we found a positive correlation between serum creatinine and BMD at TH, FN, and LS after adjusting for age (R = 0.162, P < 0.001 at TH; R = 0.221, P < 0.001 at FN; R = 0.274, P < 0.001 at LS). We also found a positive correlation between serum creatinine and total skeletal muscle mass (R = 0.424, P < 0.001), ASM (R = 0.43, P < 0.001) and relative ASM (R = 0.362, P < 0.001). Serum creatinine was also negatively associated with body fat (%) (R = -0.309, P < 0.001). Table 2 presents the independent contribution of serum creatinine to BMD at each site using multiple linear regression analysis. Even after adjustment for all potential confounders, an increase in serum creatinine significantly contributed to an increase of BMD at TH, FN, and LS in both sexes. The association between serum creatinine and BMD was more prominent in men than in women.

Table 2. Multivariate linear regression analysis for bone mineral density in men and women.

Variables

Total hip

Femoral neck

Lumbar spine

β a

SE

P-value

β a

SE

P-value

β a

SE

P-value

Men

Serum creatinine (mg/dL)

0.752

0.115

<0.001

0.503

0.12

<0.001

1.135

0.169

<0.001

Variables

Total hip

Femoral neck

Lumbar spine

β b

SE

P-value

β b

SE

P-value

β b

SE

P-value

Women

Serum creatinine (mg/dL)

0.494

0.141

<0.001

0.323

0.136

0.018

1.102

0.181

<0.001

Sex-specific prevalence of low BMD according to serum creatinine levels

After adjusting for age, the low creatinine group had a significantly elevated OR for low BMD at all sites in both sexes ( Table 3). After further adjusting for other conventional confounding covariates (Models 2 and 3), the low creatinine group of men still had a significantly elevated OR for low BMD at all sites, but the low creatinine group of postmenopausal women had an elevated OR for low BMD at only TH and LS. Each standard deviation increase in serum creatinine was significantly associated with a 16% reduction in the likelihood of low BMD at TH and a 20% at LS in men (OR = 0.84, 95% CI = 0.74−0.96 at TH; OR = 0.8, 95% CI = 0.68−0.96 at LS) ( Fig 1). In women, each standard deviation increase in serum creatinine was significantly associated with a 17% reduction in the likelihood of low BMD at TH and a 19% reduction at LS (OR = 0.83, 95% CI = 0.73−0.95 at TH, OR = 0.81, 95% CI = 0.67−0.99 at LS). However, each standard deviation increase in serum creatinine was not significantly associated with a low BMD at FN in both sexes (OR = 0.83, 95% CI = 0.69-1 in men and OR = 0.85, 95% CI = 0.68-1 in women).

Table 3. Multivariate odds ratio and 95% confidence interval for low bone mineral density a according to serum creatinine.

Men

Women

Upper normal creatinine

Low creatinine

P-value

Upper normal creatinine

Low creatinine

P-value

Incidence b (%)

392 (13.7%)

194 (17.6%)

0.002

566 (39.8%)

995 (35.2%)

0.004

Incidence b (%)

1081 (37.7%)

501 (45.5%)

<0.001

1113 (78.3%)

2115(74.9%)

0.016

Incidence b (%)

1050 (37.3%)

516 (48.1%)

<0.001

1011(73%)

2066 (74.9%)

0.19

Model 1

reference

1.48 (1.28,1.71)

<0.001

reference

1.44 (1.22,1.69)

<0.001

Fig 1. Adjusted odds ratios with 95% confidence interval for the presence of low bone mineral density for each standard deviation (SD) increase in serum creatinine.

*Data were adjusted for age, current smoking status, regular exercise, daily calcium intake (mg/d), HOMA-IR, vitamin D, body fat (%) and estrogen replacement therapy (in women).

Discussion

In this general population-based study of subjects with normal renal function, we found that serum creatinine was closely associated with ASM. Additionally, we demonstrated that significantly decreased BMD was observed in subjects with low serum creatinine (≤ 0.8 mg/dL in men and ≤ 0.7 mg/dL in postmenopausal women). The association between serum creatinine and BMD was more prominent in men than in women. These discoveries provide the first clinical evidence for the notion that subjects with extremely low serum creatinine are at high risk for reduced BMD.

Reduced muscle mass, or sarcopenia, is a well-known risk factor for osteoporosis. Reduced muscle mass affects balance and thereby increases the risk of falls and subsequent fractures [ 16]. In this way, gradual age-related decline in bone and muscle (i.e., osteoporosis and sarcopenia) can result in increased morbidity and mortality [ 17]. Considering the close relationship between sarcopenia and osteoporosis and the effects of muscle mass on fracture risk, identification and treatment of those conditions is important in older populations. Therefore, recent studies have suggested a more inclusive name be given to the combination of sarcopenia and osteoporosis, such as 'dysmobility syndrome,' which integrates their pathogenesis and unites them as a single therapeutic target [ 18]. However, although osteoporosis has been clearly defined, the definition of sarcopenia remains unclear [ 19]. In addition, although DXA is the currently accepted gold standard test for evaluating body composition, including both bone density and muscle mass [ 20], it is not easily accessible or commonly available to general populations because of time and cost. From this background, we hypothesized that serum creatinine, known to be a stable marker of skeletal muscle mass [ 21], could be related to bone health status.

Several studies have reported correlations between serum creatinine and lean body mass, estimated anthropometrically using bioimpedence analysis or DXA [ 22, 23]. Consistent with these findings, we observed that serum creatinine was significantly associated with total and appendicular skeletal muscle mass. Therefore, we further calculated the cut point of serum creatinine for the presence of sarcopenia and it was ≤ 0.8 mg/dL in men and ≤ 0.7 mg/dL in postmenopausal women. Similarly, Harita et al. demonstrated that those who had serum creatinine levels ≤0.6 mg/dl was associated with increased the risk of type 2 diabetes [ 11]. However, they did not assess the risk of lower creatinine for diabetes considering gender differences although skeletal muscle mass might differ between women and men. Taken together, we can speculate that serum creatinine, a cheap and simple method, can be used as a marker to assess individual's skeletal health status and it can be also alternative for body composition analysis in subjects with normal renal function.

Chronic kidney disease, especially stage 3 or over, is a well-known risk factor for low BMD [ 24] and sarcopenia [ 25]. Our study, which excluded subjects with definite chronic kidney disease, demonstrated that the risk for low BMD remained significantly higher in subjects with low serum creatinine. Furthermore, one SD increase in serum creatinine was associated with a significant reduction in the occurrence of low BMD at TH and LS in both men and postmenopausal women. Those results were valid even after adjusting for confounding factors. Thus, serum creatinine could have a beneficial effect on BMD in subjects with normal renal function. The main pathogenesis for the deleterious effects of low serum creatinine on BMD could be that serum creatinine reflects one's physical activity status as well as skeletal muscle mass, and both are important for maintaining bone health [ 26]. In addition, creatinine degradation is stimulated by reactive oxygen species and in particular by the hydroxyl radical. Fernández-Real et al. reported that telomere length of subcutaneous adipose tissue cells was positively associated with serum creatinine but not with GFR. In other words, decreased serum creatinine is associated with a marker of cellular senescence and oxidative stress and consequently decreased serum creatinine may result in deterioration of BMD via oxidative stress [ 27]. Finally, recent evidences suggest that insulin could stimulate osteoblast differentiation and have some anabolic properties for bone [ 28]. In our study, a higher serum insulin levels were detected in the upper normal creatinine group than in the low creatinine group. Therefore, lower serum creatinine group may have low potency of anabolic properties for bone due to increased clearance of insulin.

An interesting point of our study is that the relationship between serum creatinine and BMD was more prominent in men aged 45 years or older than in postmenopausal women. Although we could not elucidate why this association was more prominent in men than in women, it might be explained by the fact that females tend to have lower skeletal muscle mass than males. Additionally, increased body fat in postmenopausal women might alter the bone-muscle (creatinine) relationship. Conversion of androgens to estrogens in adipose tissue could have a modest effect on bone, especially in postmenopausal women [ 29]. However, in men, adipose tissue is not an important sex hormone source and as they have relatively small fat mass, it may not considerably influence on the bone-muscle (creatinine) relationship [ 30]. Those findings suggest that creatinine can differ by sex, and sex differences should be considered and weighed practically.

The major strength of this study is that the data were collected from a large nationwide survey that included 8,648 participants ages 45 to 95 years throughout Korea. This is the first observational study that extensively investigated the sex-specific association of low serum creatinine with BMD focusing on Korea's general population. However, this study also has some limitations. First, given that serum creatinine is closely related to skeletal muscle mass, it could be influenced by other factors, such as drugs and other dietary variation. However, we could not collect all that information. Second, to define sarcopenia, we did not measure muscle strength or walk speed, as described by the European Working Group on Sarcopenia in Older People and the European Society for Clinical Nutrition and Metabolism special interest group [ 31]. Third, because this study used a cross-sectional design and not a longitudinal design, a causal relationship could not be definitively established. Fourth, we could not demonstrate whether this association between serum creatinine and BMD is independent of estimated glomerular filtration rate as there was collinearity in serum creatnine and estimated glomerular filtration rate. Finally, because all participants were single ethnic group, our results may not be representative of the other ethnic population.

In conclusion, our study is the largest population-based study to examine the sex-specific association between serum creatinine and BMD. An excessive decrease of serum creatinine was associated with greater deterioration of BMD in subjects with normal renal function, especially, in men. Our findings suggest that serum creatinine reflects an individual's skeletal health status as well as muscle mass and that we can indirectly assess both bone and muscle health status from serum creatinine level, which can be easily measured. Monitoring serum creatinine could be helpful to the development of sex-specific strategies for the treatment and prevention of sarcopenia and low BMD.

Supporting Information

Acknowledgments

This work was supported by a National Research Foundation (NRF) of Korea grant funded by the Korean government (MEST) (No. 20110001024).

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This work was supported by a National Research Foundation (NRF) of Korea grant funded by the Korean government (MEST) (No. 20110001024).

References

Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

Articles from PLoS ONE are provided here courtesy of PLOS

# data[].attributes.attachment_link.title
Lower Serum Creatinine Is Associated with Low Bone Mineral Density in Subjects without Overt Nephropathy

# data[].attributes.attachment_link.description
Low skeletal muscle mass is associated with deterioration of bone mineral density. Because serum creatinine can serve as a marker of muscle mass, we evaluated the relationship between serum creatinine and bone mineral density in an older population ...

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Thieme E-Journals - Hormone and Metabolic Research / Full Text

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Diagnosis and Management of Osteoporosis | AAFP

# data[].attributes.body
Approved for prevention of osteoporosis (not first-line for treatment)

Relief of vasomotor symptoms and vulvovaginal atrophy associated with menopause

Reduces vertebral & hip fractures, but carries risks: ↑ stroke, MI, breast cancer, VTE

Should only be considered in women with menopausal symptoms, at lowest effective dose, shortest duration

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Treatment goal

Prevent fracture

Increase bone mineral density

Restore bone architecture

Slow or stop bone loss

Treat the cause of osteoporosis

Improve lifestyle modification

Reference:

Goal-directed osteoporosis treatment: ASBMR/BHOF task force position statement 2024 - PubMed

Treatment of osteoporosis; treatment goals and duration of therapy | ECE2016 | 18th European Congress of Endocrinology | Endocrine Abstracts

Osteoporosis: Diagnosis, Treatment, and Steps to Take

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Affiliations

¹ Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, United States.

² New Mexico Clinical Research & Osteoporosis Center, Division of Metabolic Bone Diseases, Albuquerque, NM 87106, United States.

³ Division of Clinical Medicine, University of Sheffield, Sheffield S10 2RX, United Kingdom.

⁴ Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC 3168, Australia.

⁵ Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA 22908, United States.

⁶ Department of Endocrinology, Aarhus University Hospital, Aarhus N 8200, Denmark.

⁷ Department of Clinical Medicine, Aarhus University, Aarhus N 8200, Denmark.

⁸ Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul 03722, South Korea.

⁹ Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, American University of Beirut, Beirut 1107, Lebanon.

¹⁰ Marcus Institute for Aging Research, Hebrew Senior Life, Boston, MA 02131, United States.

¹¹ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.

¹² Division of Research and Evaluation, HealthPartners Institute, Bloomington MN 55425, United States.

¹³ Division of Health Policy and Management, University of Minnesota, Minneapolis, MN 55425, United States.

¹⁴ Brazil Clinical Research Center, Brasilia 71625-175, Brazil.

¹⁵ Department of Medicine and Joint Department of Medical Imaging, University Health Network, Toronto, ON M5G 2C4, Canada.

¹⁶ Centre of Excellence in Skeletal Health Assessment, University of Toronto, Toronto, ON M5G 2C4, Canada.

¹⁷ Department of Medicine, Institute Hospital del Mar of Medical Investigation, Barcelona 08003, Spain.

¹⁸ Department of Obstetrics and Gynecology, Frankfurt Center of Bone Health and Phillipps-University of Marburg, Frankfurt 60313, Germany.

¹⁹ Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

²⁰ Department of Clinical Osteology, Frankfurt Center of Bone Health and Endocrinology, Frankfurt 60313, Germany.

²¹ Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.

²² San Francisco Coordinating Center, CPMC Research Institute, Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158, United States.

Affiliations

¹ Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, United States.

² New Mexico Clinical Research & Osteoporosis Center, Division of Metabolic Bone Diseases, Albuquerque, NM 87106, United States.

³ Division of Clinical Medicine, University of Sheffield, Sheffield S10 2RX, United Kingdom.

⁴ Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC 3168, Australia.

⁵ Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA 22908, United States.

⁶ Department of Endocrinology, Aarhus University Hospital, Aarhus N 8200, Denmark.

⁷ Department of Clinical Medicine, Aarhus University, Aarhus N 8200, Denmark.

⁸ Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul 03722, South Korea.

⁹ Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, American University of Beirut, Beirut 1107, Lebanon.

¹⁰ Marcus Institute for Aging Research, Hebrew Senior Life, Boston, MA 02131, United States.

¹¹ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.

¹² Division of Research and Evaluation, HealthPartners Institute, Bloomington MN 55425, United States.

¹³ Division of Health Policy and Management, University of Minnesota, Minneapolis, MN 55425, United States.

¹⁴ Brazil Clinical Research Center, Brasilia 71625-175, Brazil.

¹⁵ Department of Medicine and Joint Department of Medical Imaging, University Health Network, Toronto, ON M5G 2C4, Canada.

¹⁶ Centre of Excellence in Skeletal Health Assessment, University of Toronto, Toronto, ON M5G 2C4, Canada.

¹⁷ Department of Medicine, Institute Hospital del Mar of Medical Investigation, Barcelona 08003, Spain.

¹⁸ Department of Obstetrics and Gynecology, Frankfurt Center of Bone Health and Phillipps-University of Marburg, Frankfurt 60313, Germany.

¹⁹ Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

²⁰ Department of Clinical Osteology, Frankfurt Center of Bone Health and Endocrinology, Frankfurt 60313, Germany.

²¹ Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.

²² San Francisco Coordinating Center, CPMC Research Institute, Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158, United States.

Abstract

The overarching goal of osteoporosis management is to prevent fractures. A goal-directed approach to long-term management of fracture risk helps ensure that the most appropriate initial treatment and treatment sequence is selected for individual patients. Goal-directed treatment decisions require assessment of clinical fracture history, vertebral fracture identification (using vertebral imaging as appropriate), measurement of bone mineral density (BMD), and consideration of other major clinical risk factors. Treatment targets should be tailored to each patient's individual risk profile and based on the specific indication for beginning treatment, including recency, site, number and severity of prior fractures, and BMD levels at the total hip, femoral neck, and lumbar spine. Instead of first-line bisphosphonate treatment for all patients, selection of initial treatment should focus on reducing fracture risk rapidly for patients at very high and imminent risk, such as in those with recent fractures. Initial treatment selection should also consider the probability that a BMD treatment target can be attained within a reasonable period of time and the differential magnitude of fracture risk reduction and BMD impact with osteoanabolic versus antiresorptive therapy. This position statement of the ASBMR/BHOF Task Force on Goal-Directed Osteoporosis Treatment provides an overall summary of the major clinical recommendations about treatment targets and strategies to achieve those targets based on the best evidence available, derived primarily from studies in older postmenopausal women of European ancestry.

Keywords: DXA, analysis/quantitation of bone; anabolics, therapeutics; antiresorptives, therapeutics; osteoporosis, diseases and disorders of/related to bone; practice/policy-related issues.

Plain language summary

Goal-directed treatment can help healthcare providers recommend the best treatments for individual patients to prevent fractures. The goal-directed strategy considers the site, number, and recency of prior fractures. This may require imaging for spine fractures, which may not have caused pain. Treatment decisions also require bone mineral density (BMD) measurement and consideration of other major risk factors. In contrast to the standard approach, same first treatment for all, treatment selection is tailored to an individual's risk. In patients with recent fractures of the spine, hip, or pelvis, fracture risk is very high and treatment should rapidly reduce that risk. For others, the target is a specific BMD level and should consider the likelihood that the treatment target can be attained within a reasonable period of time, which differs for osteoporosis medications. After initial therapy, BMD should be assessed to determine if the target has been achieved. If so, strategies should focus on maintaining BMD. If the target is not yet achieved, treatment should be intensified, or continued if it is already the most potent option. This position statement represents a consensus of expert recommendations about treatment targets and strategies to achieve those targets based on the best available evidence.

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Conflict of interest statement

F.C.: Amgen: investigator, consultant, advisor, speaker; Radius Health: investigator, consultant, speaker; Enterabio, Biocon, CuraTeQ, Pfizer/Myovant/Sumitomo, Theramex, UCB: consultant.

E.M.L.: Amgen: investigator, consultant, speaker; Radius: investigator, consultant; Ultragenyx: investigator; Kyowa Kirin: consultant, speaker; Angitia and Ascendis: consultant.

R.E.: AstraZeneca, Immunodiagnostic Systems, Sandoz, Samsung, CL Bio, CuraTeQ, Biocon, Takeda, UCB: consultant; Pharmacosmos, Alexion, UCB and Amgen: speaker; Alexion and Osteolabs: grants.

P.R.E.: Amgen: grant funds, speaker; Alexion: grant funds, speaker, consultant; Sanofi: investigator; Kyowa Kirin: speaker.

S.J.d.B.: Ultragenyx: investigator, consultant; Kyowa Kirin: investigator, consultant; Ascendis: consultant; Inozyme: consultant; BridgeBio: investigator; Mereo: Investigator.

B.L.: Amgen: investigator, advisor, speaker; UCB: investigator, advisor, speaker; Gedeon-Richter: advisor, speaker; Astellas; speaker; Astra-Zeneca: speaker.

Y.R.: Amgen: investigator, speaker; Alexion: grant funds; Sanofi: investigator; Kyowa Kirin: investigator, speaker; Daewoong: investigator; Dongkook: investigator; Donga ST: investigator.

D.P.K.: Amgen: grant funds, Radius Health: consultant and grant funds, Agnovos: Data and Safety Monitoring Board.

G.E.H.F.: None.

A.C.: Amge n: investigator, consultant, speaker; Incyte: investigator; Ipsen: investigator, consultant, speaker; Sanofi: investigator.

A.D.P.: Theramex: speaker and advisor.

P.H.: Amgen, Besins, Exeltis, Gedeon Richter, Hexal, Sandoz, Stada, Theramex and UCB: speaker and consultant.

S.T.: Amgen, Asahi Kasei Pharma and Daiichi-Sankyo Co: speaker.

F.T.: Amgen, Fresenius, Gedeon-Richter, Stada, Theramex, UCB: Advisor and speaker; Abbvie, Alexion: speaker.

S.R.C.: Amgen: speaker.

References

Cummings S, Cosman F, Lewiecki E, et al. Goal-directed treatment for osteoporosis: a progress report from the ASBMR-NOF working group on goal-directed treatment for osteoporosis. J Bone Miner Res. 2017;32(1):3-10. 10.1002/jbmr.3039 - DOI - PubMed

Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis-2020 update. Endocr Pract. 2020;26(Suppl 1):1-46. 10.4158/GL-2020-0524SUPPL - DOI - PubMed

Shoback D, Rosen CJ, Black DM, Cheung AM, Murad MH, Eastell R. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society Guideline Update. J Clin Endo Metab. 2020;105(3):587-594. 10.1210/clinem/dgaa048 - DOI - PubMed

Kanis JA, Cooper C, Rizzoli R, Reginster JY, Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the Committees of Scientific Advisors and National Societies of the International Osteoporosis Foundation (IOF) . Executive summary of European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Aging Clin Exp Res. 2019;31(1):15-17. 10.1007/s40520-018-1109-4 - DOI - PubMed

Management of Osteoporosis in Postmenopausal Women: The 2021 Position Statement of the North American Menopause Society Editorial Panel . Management of osteoporosis in postmenopausal women: the 2021 position statement of the North American Menopause Society. Menopause. 2021;28(9):973-997. 10.1097/GME.0000000000001831 - DOI - PubMed

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bone density conservation agents / therapeutic use

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osteoporotic fractures / prevention & control

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national center for biotechnology information

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Goal-directed osteoporosis treatment: ASBMR/BHOF task force position statement 2024 - PubMed

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The overarching goal of osteoporosis management is to prevent fractures. A goal-directed approach to long-term management of fracture risk helps ensure that the most appropriate initial treatment and treatment sequence is selected for individual patients. Goal-directed treatment decisions require as ...

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Female: Women are at a higher risk than men. Women have lower peak bone mass and smaller bones than men.

Aging: Bone density naturally decreases with age. As you age, bone loss happens more quickly, and new bone growth is slower.

Menopause: The significant drop in estrogen levels during menopause accelerates bone loss.

Early menopause: Menopause before age 45 or a hysterectomy with ovary removal at a young age significantly increases risk.

Family history: Having parents or close relatives with osteoporosis or hip fractures raises risk.

Body frame: A small or thin body frame is associated with higher risk. Slender, thin-boned women and men are at greater risk to develop osteoporosis because they have less bone to lose compared to larger boned women and men.

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Activated vitamin D

Calcitriol

Dose:

Calcitriol 0.25 µg bd

MOA

Calcitriol, the active form of vitamin D3 (cholecalciferol), binds to and activates the vitamin D receptors in the intestine, kidneys, parathyroid gland and bone, thus stimulating intestinal Ca transport and absorption. It also stimulates bone resorption and increases renal tubular reabsorption of Ca, thereby decreasing PTH levels and improving Ca-phosphate homeostasis.

Calcitriol could increase the bone mineral density in postmenopausal osteoporosis.

SE:

Hypercalcaemia

Polyuria Polydipsia

Cardiac arrhythmias

Sensory disturbances

Apathy

Nephrocalcinosis

Urinary tract infections

Hypertension

Monitoring Parameter

Serum calcium should be monitored periodically, at minimum before starting therapy, and at 3 to 6 monthly intervals thereafter. In addition, measurement of 24 hour urinary calcium can be considered in those on calcitriol, especially in those with renal impairment.

Reference:

2022_CPG-ManagementofOsteoporosis-final.pdf

Calcitriol - StatPearls - NCBI Bookshelf

Calcitriol: Uses, Dosage, Side Effects and More | MIMS Malaysia

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Low calcium and vitamin D intake: Insufficient dietary intake of these nutrients hinders bone health.

Lack of physical activity: A sedentary lifestyle, especially a lack of weight-bearing exercise, contributes to bone loss. They also leave you in poor physical condition, which can increase your risk of falling and breaking a bone.

Smoking: Nicotine slows bone formation, decreases calcium absorption, and reduces bone blood supply.

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Vertebral compression fractures: The bones in the spine weaken and collapse, causing back pain, loss of height, and a stooped posture.

Hip fractures: Often result from a fall and are the most serious, potentially leading to disability and an increased risk of death within the first year.

Wrist fractures (Colles' fractures): Occur more frequently in women and often result from a protective reflex to a fall.

https://www.ncbi.nlm.nih.gov/books/NBK441901/

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Osteoporosis is defined as low bone mineral density caused by altered bone microstructure, ultimately predisposing patients to low-impact, fragility fractures. Osteoporotic fractures lead to a significant decrease in quality of life, increasing morbidity, mortality, and disability.[1] Over 50% of postmenopausal white women will have an osteoporotic-related fracture. Only 33% of senior women who have a hip fracture will be able to return to independence. In white men, the risk of an osteoporotic fracture is 20%, but the one-year mortality in men who have a hip fracture is twice that of women. Black males and females have less osteoporosis than their white counterparts, but those diagnosed with osteoporosis have similar fracture risks. The aging of the American population is expected to triple the number of osteoporotic fractures.[2][3][4][5]

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Pain and Disability: Fractures can cause significant pain, making it difficult to walk, dress, or perform other daily activities.

Loss of Height and Posture: Vertebral fractures can result in a hunched or stooped posture and a noticeable loss of height.

Loss of Independence: Limited mobility and fractures can prevent individuals from living independently, often leading to long-term care or nursing home placement.

Emotional and Social Impact: Reduced mobility can lead to feelings of isolation, depression, and difficulty in social interactions.

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Salbutamol and prednisolone to salmeterol and fluticasone

Inhaled corticosteroids improve the FEV1 better than systemic corticosteroids. The side effect of inhaled corticosteroids is less than systemic corticosteroid. Systemic corticosteroid is usually use for short term management, inhaled corticosteroid would be better option for long-term asthma management.

LABA (Salmeterol) better than SABA in improving exacerbation and hospitalisation.

Reference:

ROLE OF INHALED CORTICOSTEROIDS VERSUS SYSTEMIC CORTICOSTEROIDS IN THE MANAGEMENT OF ASTHMA | Journal of Population Therapeutics and Clinical Pharmacology

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Journal of Population Therapeutics and Clinical Pharmacology

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Journal of Population Therapeutics and Clinical Pharmacology

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Introduction: The aim of the current study was to analyze the comparison between the Inhaled Corticosteroids and Systemic Corticosteroids in the management of persistent asthma
Methods: In this study demographics analysis was conducted to examined the demographics characteristics of the participants. The descriptive analysis was conducted to examine the categorical variables. The difference between the lung functions test i.e., FEV1(Forced expiratory volume in the first second), FVC (Force vital capacity) and symptoms scores i.e., Asthma control test (ACT) between ICS(Inhaled corticosteroids) and SCS(systemic corticosteroid) groups was compared through t-test and chi-square test. While, multivariate analysis was used to examine the differences between the lung functions test i.e., FEV1, FVC and symptoms scores i.e., ACT between ICS and SCS groups when the potential cofounders were adjusted. Duration of asthma, severity, number of exacerbations in the past year, type of corticosteroid used (ICS or SCS), dosage, and duration of use, lung function tests (FEV1, FVC) and asthma control test (ACT) scores were analyzed through SPSS.
Results: The study found that after controlling for age, gender, BMI, and asthma duration, ICS was linked with significantly greater FEV1 compared to SCS (β coefficient = 0.28, p-value < 0.01). After adjusting for other covariates, the β coefficient for corticosteroid type (ICS vs. SCS) was 0.24, demonstrating a significant connection between ICS and greater FVC compared to SCS (p-value < 0.05). The β coefficient for corticosteroid type between ICS and SCS was 1.5, with a p-value < 0.01, indicating that patients on ICS had significantly higher ACT scores, indicating better asthma control. Longer asthma duration was a significant negative predictor (β = -0.2, p = 0.046), predicting poorer ACT scores. After controlling for relevant confounders, the multivariate analysis showed that ICS is linked with improved lung function (FEV1 and FVC) and asthma control (ACT scores) than SCS.
Conclusion: Exacerbations of persistent asthma are well treated with ICS. The best way to treat these individuals with ICS, how long they should take them for, and whether or not they should take systemic corticosteroids at the same time are all areas that need more investigation.

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Caffeine intake

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.

Alcohol intake

Excessive alcohol intake (>2 units daily) should be avoided as it has been associated with increased rates of any fracture and osteoporotic fracture

Smoking

Smoking increases osteoporotic fracture risk. Current smokers have the highest risk, followed by ex-smokers, when compared to those who have never smoked.

Reference:

2022_CPG-ManagementofOsteoporosis-final.pdf

Diagnosis and Management of Osteoporosis | AAFP

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Smoking cessation: Quit smoking as it speeds up bone loss.

Exercise: Engage in regular weight-bearing activities like walking, hiking, dancing, and running. Perform strength-training exercises to build muscle and bone strength. Include balance and posture exercises, such as Tai Chi or sit-to-stand exercises.

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Dietary & Lifestyle

Reduce salt intake → high sodium increases urinary calcium loss.

Limit soft drinks / carbonated beverages (esp. cola) → excess phosphates can worsen calcium balance.

Adequate micronutrients: magnesium, zinc, vitamin K (esp. K2 in green leafy veg & fermented foods) support bone mineralisation.

Soy isoflavones (plant estrogens) may benefit postmenopausal women.

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Osteoporosis and Kyphosis via Vertebral Compression Fractures (VCFs)

VCFs are the most common osteoporotic fracture, but ~⅔ go undiagnosed.

Pain is often mistaken for muscle strain, general back pain, or normal aging.

Mechanism of Kyphosis in Osteoporosis

Osteoporotic bones are brittle → fracture may occur with minimal stress (lifting, bending, coughing, sneezing, or even turning in bed).

VCFs typically occur as wedge fractures → collapse of the vertebral front while the back remains intact.

Multiple wedge fractures accumulate → forward curvature of the spine (kyphosis).

Progression of Kyphosis

Dependent on cause.

Untreated osteoporosis → continued bone loss → kyphosis worsens over time.

Treated osteoporosis (e.g., medications to improve bone density) → may slow, halt, or prevent further kyphotic progression.

Clinical Impact

Height loss and postural changes (kyphosis)

Chronic back pain often overlooked as aging-related.

Reduced mobility and quality of life.

Severe kyphosis can lead to respiratory compromise due to restricted chest expansion.

Case Relevance (GR)

May have had unnoticed vertebral fractures years earlier, leading to gradual kyphotic posture before formal osteoporosis diagnosis.

https://www.southeasttexasspine.com/blog/the-link-between-osteoporosis-and-kyphosis

https://www.hss.edu/health-library/conditions-and-treatments/list/kyphosis

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education in proper posture

participation in a physical therapy exercise program

https://www.hss.edu/health-library/conditions-and-treatments/list/kyphosis

In more serious case, minimally invasive interventions

Vertebroplasty → bone cement injected into fractured vertebra → hardens, supports spine.

Kyphoplasty → balloon inserted to expand compressed bone → cement injected into expanded area.

Benefits: pain relief, height restoration, reduced spinal deformity.

https://jasonlowensteinmd.com/understanding-osteoporosis-degenerative-kyphosis/

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Spinal fusion permanently joins two or more vertebrae together. This eliminates painful movement between the vertebrae and can strengthen the spine.

https://www.southeasttexasspine.com/blog/the-link-between-osteoporosis-and-kyphosis

https://my.clevelandclinic.org/health/treatments/25168-spinal-fusion

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For severe kyphosis, spinal reconstructive surgery may take the pressure off a pinched nerve and stabilize the spine.

http://southeasttexasspine.com/blog/the-link-between-osteoporosis-and-kyphosis

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Beginning in childhood and into old age, a diet low in calcium and vitamin D can increase your risk for osteoporosis and fractures. Excessive dieting or poor protein intake may increase your risk for bone loss and osteoporosis.

https://www.niams.nih.gov/health-topics/osteoporosis

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National Institute of Arthritis and Musculoskeletal and Skin Diseases

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Overview of Osteoporosis

Osteoporosis is a bone disease that develops when bone mineral density and bone mass decreases, or when the structure and strength of bone changes. This can lead to a decrease in bone strength that can increase the risk of fractures (broken bones).

Osteoporosis is a "silent" disease because you typically do not have symptoms, and you may not even know you have the disease until you break a bone. Osteoporosis is the major cause of fractures in postmenopausal women and in older men. Fractures can occur in any bone but happen most often in bones of the hip, vertebrae in the spine, and wrist.

However, you can take steps to help prevent the disease and fractures by:

Staying physically active by participating in weight-bearing exercises such as walking.

Drinking alcohol in moderation.

Quitting smoking, or not starting if you don't smoke.

Taking your medications, if prescribed, which can help prevent fractures in people who have osteoporosis.

Eating a nutritious diet rich in calcium and vitamin D to help maintain good bone health.

Symptoms of Osteoporosis

Osteoporosis is called a "silent" disease" because there are typically no symptoms until a bone is broken. Symptoms of vertebral (spine) fracture include severe back pain, loss of height, or spine malformations such as a stooped or hunched posture (kyphosis).

Bones affected by osteoporosis may become so fragile that fractures occur spontaneously or as the result of:

Minor falls, such as a fall from standing height that would not normally cause a break in a healthy bone.

Normal stresses such as bending, lifting, or even coughing.

Causes of Osteoporosis

Osteoporosis occurs when too much bone mass is lost and changes occur in the structure of bone tissue. Certain risk factors may lead to the development of osteoporosis or can increase the likelihood that you will develop the disease.

Many people with osteoporosis have several risk factors, but others who develop osteoporosis may not have any specific risk factors. There are some risk factors that you cannot change, and others that you may be able to change. However, by understanding these factors, you may be able to prevent the disease and fractures.

Factors that may increase your risk for osteoporosis include:

Sex. Your chances of developing osteoporosis are greater if you are a woman. Women have lower peak bone mass and smaller bones than men. However, men are still at risk, especially after the age of 70.

Age. As you age, bone loss happens more quickly, and new bone growth is slower. Over time, your bones can weaken and your risk for osteoporosis increases.

Body size. Slender, thin-boned women and men are at greater risk to develop osteoporosis because they have less bone to lose compared to larger boned women and men.

Race. White and Asian women are at highest risk. African American and Mexican American women have a lower risk. White men are at higher risk than African American and Mexican American men.

Family history. Researchers are finding that your risk for osteoporosis and fractures may increase if one of your parents has a history of osteoporosis or hip fracture.

Changes to hormones. Low levels of certain hormones can increase your chances of developing osteoporosis. For example:

Low estrogen levels in women after menopause.

Low levels of estrogen from the abnormal absence of menstrual periods in premenopausal women due to hormone disorders or extreme levels of physical activity.

Low levels of testosterone in men. Men with conditions that cause low testosterone are at risk for osteoporosis. However, the gradual decrease of testosterone with aging is probably not a major reason for loss of bone.

Diet. Beginning in childhood and into old age, a diet low in calcium and vitamin D can increase your risk for osteoporosis and fractures. Excessive dieting or poor protein intake may increase your risk for bone loss and osteoporosis.

Other medical conditions. Some medical conditions that you may be able to treat or manage can increase the risk of osteoporosis, such as other endocrine and hormonal diseases, gastrointestinal diseases, rheumatoid arthritis, certain types of cancer, HIV/AIDS, and anorexia nervosa.

Medications. Long-term use of certain medications may make you more likely to develop bone loss and osteoporosis, such as:

Glucocorticoids and adrenocorticotropic hormone, which treat various conditions, such as asthma and rheumatoid arthritis.

Antiepileptic medicines, which treat seizures and other neurological disorders.

Cancer medications, which use hormones to treat breast and prostate cancer.

Proton pump inhibitors, which lower stomach acid.

Selective serotonin reuptake inhibitors, which treat depression and anxiety.

Thiazolidinediones, which treat type II diabetes.

Lifestyle. A healthy lifestyle can be important for keeping bones strong. Factors that contribute to bone loss include:

Low levels of physical activity and prolonged periods of inactivity can contribute to an increased rate of bone loss. They also leave you in poor physical condition, which can increase your risk of falling and breaking a bone.

Chronic heavy drinking of alcohol is a significant risk factor for osteoporosis.

Studies indicate that smoking is a risk factor for osteoporosis and fracture. Researchers are still studying if the impact of smoking on bone health is from tobacco use alone or if people who smoke have more risk factors for osteoporosis.

Osteoporosis Related Information

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What is osteoporosis? It is a disease in which your bones become weak and are more likely to break. Discover the causes & how to live with it.

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Increasing dorsal kyphosis (Dowager’s hump)

• A low-trauma fracture:

- After a fall from standing height or less.

- Fractures occurring at the site of a typical osteoporotic fracture, i.e. at the hip, spine, forearm, humerus, ribs, tibia (excluding ankle), pelvis and other femoral fractures.

• Historical height loss of >4cm (>1.5 inches).

• Acute back pain following seemingly innocuous activities, e.g. bending, lifting objects, coughing or sneezing.

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Osteoporosis can be diagnosed based on clinical presentation where there is a low-trauma fracture (i.e. fragility fracture) in the absence of other metabolic bone disease and where bone mineral density (BMD) assessment may not be feasible or appropriate. A fragility fracture is one that occurs after a fall from standing height or less. Hence, in this situation, treatment should still be initiated.

Bone mineral density (BMD) measurement:

BMD measurement via dual-energy x-ray absorptiometry (DXA) at the femoral neck, total hip or lumbar spine remains the gold standard recommendation for the diagnosis of osteoporosis. All patients should have BMD at the lumbar spine (L1-L4, posteroanterior) and hip (to include the femoral neck or total hip) measured. Forearm BMD (1/3rd radius of the non-dominant forearm) should be measured when the hip and/or spine cannot be measured or interpreted, in patients with hyperparathyroidism, and/ or in very obese patients (over the weight limit for the DXA table). BMD measurement is also used for determining fracture risk and treatment decisions.

BMD is reported as a T-score or Z-score, both of which are units of standard deviation (SD).

T-score

The T-score represents the number of SDs by which an individual’s BMD diverges from the mean value of young female adults. The recommended reference range* for determining the T-score is the United States of America Centres for Disease Control and Prevention’s National Health and Nutrition Examination Survey (US CDC NHANES) III database for femoral neck measurements in women aged 20-29 years. This classification does not apply to premenopausal women, men <50 years old, and children.

Z-score

The Z-score describes the number of SDs by which the BMD in an individual differs from the mean value expected for age and sex. The Z-score should be used for premenopausal women, men <50 years old and children.

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

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Supplements:

-       1200 mg of calcium (a combination of dietary sources and supplements) is recommended daily for its positive effect on bone mineral density and fracture risk reduction.

-       Adequate Vitamin D supplementation to achieve Vitamin D levels of more than 50 ng/mL is advised in order to maintain skeletal health and reduce the risk of fractures and falls.

Cognitive Behavioural Therapy:

Women experiencing menopausal symptoms may consider alternative therapy such as hypnotherapy, cognitive behavioural therapy, relaxation techniques, sleep hygiene and enforcing positive attitudes to help ease anxiety, sleep and vasomotor symptoms.

https://www.moh.gov.my/moh/resources/Penerbitan/CPG/Women%20Health/CPG_Management_of_Menopause_2022_e-version-1.pdf

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Pharmacists can reassure that fractures can heal, and many patients return to normal activity. Besides, pharmacists can also suggest support groups or counseling if patient feels depressed or anxious after losing independence.

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Proton pump inhibitors (PPIs) increase osteoporotic fracture risk presumably via hypochlorhydria and consequent reduced fractional calcium absorption (FCA).

1. PPIs act mainly toward suppressing gastric acid secretion. The presence of gastric acid and an acidic proximal duodenum are required to free ingested calcium from foodstuffs for absorption to occur in the small intestine.

Lack of sufficient amounts of gastric acid can lead to

secondary hyperparathyroidism

increased rates of osteoclastic bone resorption

skeletal turnover

subsequent reduction in bone mass.

https://www.gastrojournal.org/article/S0016-5085(13)00095-4/fulltext

2. PPI users taking calcium supplements were more likely to have hyperparathyroidism compared to non-users.

Hyperparathyroidism was defined as a parathyroid hormone (PTH) > 65 pg/ml.

Parathyroid hormone (PTH) plays a pivotal role in calcium homeostasis and bone metabolism. PTH maintains serum calcium concentration by releasing calcium from the skeleton through bone resorption, renal tubular calcium reabsorption, and activating vitamin D. PTH has major effects on bone turnover and remodelling. Hyperparathyroidism causes excessive bone remodelling, with bone resorption outpacing formation leading to lower BMD, altered microarchitecture and increased fracture risk

Calcium carbonate is the most commonly used calcium supplement, and reduction of its absorption due to PPI-induced hypochlorhydria is well-described

https://doi.org/10.1007/s00198-023-06867-8

3. chronic use of PPIs is associated with potential adverse drug events, such as hypomagnesaemia, interstitial nephritis, and iron and vitamin B12 malabsorption

https://onlinelibrary.wiley.com/doi/10.1155/2021/8902367

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Rationale to change omeprazole to ranitidine

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Rationale to change omeprazole to ranitidine

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Induction of osteoporosis significantly elevated serum BSALP, decreased serum calcium, bone mineral density and cortical thickness and significantly increased the histopathological score.

Ranitidine treatment resulted in insignificant changes in tested parameters.

Pantoprazole given alone, significantly decreased serum calcium and increased serum BSALP.

Alendronate significantly improved BSALP level, serum calcium, BMD, cortical thickness and histopathological score.

This improvement was not affected by combining ranitidine with alendronate.

pantoprazole with alendronate caused a significant deterioration of tested parameters.

Ranitidine proved safer than pantoprazole for patients with high risk of osteoporosis and in alendronate-treated patients.

https://www.sciencedirect.com/science/article/pii/S1110116417300960

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Healthy diet (fruits, vegetables, fish, poultry, whole grains) → ↓ risk of low BMD & hip fractures.

Milk/dairy diet → ↓ risk of low BMD.

Western/meat diet (processed/red meat, fat, sugar, soft drinks) → ↑ risk of low BMD & hip fractures.

DASH diet (calcium-rich, fruit/veg, low-fat dairy) → ↓ bone turnover (RCT evidence).

https://www.nogg.org.uk/full-guideline/section-5-non-pharmacological-management-osteoporosis

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Section 5: Non-pharmacological management of osteoporosis

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The effect of exercise varies with intensity and duration. Strengthening (resistance) exercise may be more effective if supervised. People at risk of falls, or with vertebral fractures, may need more specific advice and assessment before increasing exercise intensity ( see Section 8 ).

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RANK ligand (RANKL) inhibitor: Denosumab (Human IgG2 monoclonal antibody)

This is an inhibitor that helps slow down bone loss and is approved to treat osteoporosis in:

Postmenopausal women or men with osteoporosis who are at high risk for fracture.

Men who have bone loss and are being treated for prostate cancer with medications that cause bone loss.

Women who have bone loss and are being treated for breast cancer with medications that cause bone loss.

Men and women who do not respond to other types of osteoporosis treatment.

https://www.niams.nih.gov/health-topics/osteoporosis/diagnosis-treatment-and-steps-to-take

Indications and Dosage: Subcutaneous

Adult: 60 mg every 6 mth. Co-administer oral Ca 1,000 mg and vit D >= 400 IU

daily.

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National Institute of Arthritis and Musculoskeletal and Skin Diseases

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Treatment of Osteoporosis

The goals for treating osteoporosis are to slow or stop bone loss and to prevent fractures. Your health care provider may recommend:

Proper nutrition.

Lifestyle changes.

Exercise.

Fall prevention to help prevent fractures.

Medications.

People who develop osteoporosis from another condition should work with their health care provider to identify and treat the underlying cause. For example, if you take a medication that causes bone loss, your doctor may lower the dose of that medication or switch you to another medication. If you have a disease that requires long-term glucocorticoid therapy, such as rheumatoid arthritis or chronic lung disease, you can also take certain medications approved for the prevention or treatment of osteoporosis associated with aging or menopause.

Nutrition

An important part of treating osteoporosis is eating a healthy, balanced diet, which includes:

Plenty of fruits and vegetables.

An appropriate amount of calories for your age, height, and weight. Your health care provider or doctor can help you determine the amount of calories you need each day to maintain a healthy weight.

Foods and liquids that include calcium, vitamin D, and protein. These help minimize bone loss and maintain overall health. However, it's important to eat a diet rich in all nutrients to help protect and maintain bone health.

Calcium and Vitamin D

Calcium and vitamin D are important nutrients for preventing osteoporosis and helping bones reach peak bone mass. If you do not take in enough calcium, the body takes it from the bones, which can lead to bone loss. This can make bones weak and thin, leading to osteoporosis.

Good sources of calcium include:

Low-fat dairy products.

Dark green leafy vegetables, such as bok choy, collards, and turnip greens.

Broccoli.

Sardines and salmon with bones.

Calcium-fortified foods such as soymilk, tofu, orange juice, cereals, and breads.

Vitamin D is necessary for the absorption of calcium from the intestine. It is made in the skin after exposure to sunlight. Some foods naturally contain enough vitamin D, including fatty fish, fish oils, egg yolks, and liver. Other foods that are fortified with vitamin D are a major source of the mineral, including milk and cereals.

The chart below shows how much calcium and vitamin D you need each day.
Definitions: mg = milligrams; IU = International Units Source: National Institutes of Health, Office of Dietary Supplements, November 2018
If you have trouble getting enough calcium and vitamin D in your diet, you may need to take supplements. Talk to your health care provider about the type and amount of calcium and vitamin D supplements you should take. Your doctor may check your blood levels of vitamin D and recommend a specific amount.

Lifestyle

In addition to a healthy diet, a healthy lifestyle is important for optimizing bone health. You should:

Avoid secondhand smoke, and if you smoke, quit.

Drink alcohol in moderation, no more than one drink a day for women and no more than two drinks a day for men.

Visit your doctor for regular checkups and ask about any factors that may affect your bone health or increase your chance of falling, such as medications or other medical conditions.

Exercise

Exercise is an important part of an osteoporosis treatment program. Research shows that the best physical activities for bone health include strength training or resistance training. Because bone is living tissue, during childhood and adulthood, exercise can make bones stronger. However, for older adults, exercise no longer increases bone mass. Instead, regular exercise can help older adults:

Build muscle mass and strength and improve coordination and balance. This can help lower your chance of falling.

Improve daily function and delay loss of independence.

Although exercise is beneficial for people with osteoporosis, it should not put any sudden or excessive strain on your bones. If you have osteoporosis, you should avoid high-impact exercise. To help prevent injury and fractures, a physical therapist or rehabilitation medicine specialist can:

Recommend specific exercises to strengthen and support your back.

Teach you safe ways of moving and carrying out daily activities.

Recommend an exercise program that is tailored to your circumstances.

Exercise specialists, such as exercise physiologists, may also help you develop a safe and effective exercise program.

Medications

Your doctor may prescribe medications for osteoporosis. The U.S. Food and Drug Administration (FDA) has approved the following medications for the prevention or treatment of osteoporosis:

Your health care provider will discuss the best option for you, taking into consideration your age, sex, general health, and the amount of bone you have lost. No matter which medications you take for osteoporosis, it is still important that you get the recommended amounts of calcium and vitamin D. Also, exercising and maintaining other aspects of a healthy lifestyle are important.

Medications can cause side effects. If you have questions about your medications, talk to your doctor or pharmacist.

Bisphosphonates. Several bisphosphonates are approved to help preserve bone density and strength and to treat osteoporosis. This type of drug works by slowing down bone loss, which can lower the chance of fractures.

Calcitonin. This medication is made from a hormone from the thyroid gland and is approved for the treatment of osteoporosis in postmenopausal women who cannot take or tolerate other medications for osteoporosis.

Estrogen agonist/antagonist. An estrogen agonist/antagonist, also known as a selective estrogen receptor modulator (SERM), and tissue-selective estrogen complex (TSEC), are both approved to treat and prevent osteoporosis in postmenopausal women. They are not estrogen, but they have estrogen-like effects on some tissues and estrogen-blocking effects on other tissues. This action helps improve bone density, lowering the risk for some fractures.

Estrogen and hormone therapy. Estrogen and combined estrogen and progestin (hormone therapy) are approved to prevent osteoporosis and fractures in postmenopausal women. Because of potential side effects, researchers recommend that women use hormone therapy at the lowest dose, and for the shortest time, and if other medications are not helping. It is important to carefully consider the risks and benefits of estrogen and hormone therapy for the treatment of osteoporosis.

Parathyroid hormone (PTH) analog and parathyroid hormone related-protein (PTHrP) analog. PTH is a form of human parathyroid hormone that increases bone mass and is approved for postmenopausal women and men with osteoporosis who are at high risk for fracture. PTHrP is a medication that is also a form of parathyroid hormone. It is an injection and is usually prescribed for postmenopausal women who have a history of fractures.

RANK ligand (RANKL) inhibitor. This is an inhibitor that helps slow down bone loss and is approved to treat osteoporosis in:

Postmenopausal women or men with osteoporosis who are at high risk for fracture.

Men who have bone loss and are being treated for prostate cancer with medications that cause bone loss.

Women who have bone loss and are being treated for breast cancer with medications that cause bone loss.

Men and women who do not respond to other types of osteoporosis treatment.

Sclerostin inhibitor. This is a medication that treats osteoporosis by blocking the effect of a protein, and helps the body increase new bone formation as well as slows down bone loss.

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The goals for treating osteoporosis are to slow or stop bone loss and to prevent fractures. Your health care provider may recommend: Proper nutrition. Lifestyle changes. Exercise. Fall prevention to help prevent fractures. Medications. People who develop osteoporosis from another condition should work with their health care provider to identify and treat the underlying cause.

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odanacatib and balicatib

MOA: Inhibit Cathepsin K → block osteoclast-mediated collagen breakdown → ↓ bone resorption while preserving some bone formation.

Indication: Investigated for postmenopausal osteoporosis (effective in increasing BMD & reducing fractures).

Odanacatib: Development discontinued (2016) due to increased risk of stroke and cardiovascular events.

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Ranitidine → reduce gastric acid production → may reduce calcium absorption (switch to calcium citrate if needed).

Calcium citrate is better absorbed with low gastric acid; consider switch if persistent low Ca levels.

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Yoga can support posture, strength, balance, and pain relief in kyphosis from osteoporosis if practiced safely with modifications. It cannot reverse kyphosis, but it can slow progression and improve quality of life.

https://pmc.ncbi.nlm.nih.gov/articles/PMC4851231/

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Abstract

Objective:

Assess the effectiveness of selected yoga postures in raising bone mineral density (BMD).

Methods:

Ten-year study of 741 Internet-recruited volunteers comparing preyoga BMD changes with postyoga BMD changes.

Outcome Measures:

Dual-energy x-ray absorptiometric scans. Optional radiographs of hips and spine and bone quality study (7 Tesla).

Results:

Bone mineral density improved in spine, hips, and femur of the 227 moderately and fully compliant patients. Monthly gain in BMD was significant in spine (0.0029 g/cm ², P = .005) and femur (0.00022 g/cm ², P = .053), but in 1 cohort, although mean gain in hip BMD was 50%, large individual differences raised the confidence interval and the gain was not significant for total hip (0.000357 g/cm ²). No yoga-related serious injuries were imaged or reported. Bone quality appeared qualitatively improved in yoga practitioners.

Conclusion:

Yoga appears to raise BMD in the spine and the femur safely.

Keywords: osteoporosis, yoga

Osteoporosis and osteopenia affect up to 200 000 000 people worldwide today, with numbers likely to grow with our aging population. Many people are without access to medications or professional help after the fractures that are more likely without them. A low-cost, low-risk alternative is desirable.

Annual spinal fractures in the United States exceed 700 000, with more than 300 000 hip fractures. After hip fracture, 25% of Americans will succumb, and another 25% will never leave the nursing institution to which they are admitted following hospitalization. 1- 4 The United States currently spends an estimated $19 billion on the more than 2 million annual fragility fractures and the 500 000 hospitalizations these entail. 1- 2

Some have termed hip fracture a "sentinel event," indicating a general and irreversible decline in many aspects of health, but since the medications themselves are associated with spontaneous fracture, atrial fibrillation, slowed healing, gastric distress, osteonecrosis, and, in the newer intravenous forms, scleritis and episcleritis, some of this general decline actually may be due to pharmaceutical treatment rather than the patient herself or himself. 5- 7

Yoga classes are a dramatically low-cost and less dangerous alternative to medications and the elaborate health care their absence is alleged to engender. The "side effects" of yoga include better posture, improved balance, enhanced coordination, greater range of motion, higher strength, reduced levels of anxiety, and better gait. 8- 17 Improved posture directly addresses spinal fractures, while all of these documented benefits of yoga reduce the risk of falling, which is the main cause of all other osteoporotic fractures. 8- 17 The current study examines the proposition that yoga is a safe and effective means of preventing osteoporosis-related fracture.

Contemporary medicine accounts for bone loss or gain by genetics, nutrition, hormones, medications, and activity. The main preventive measures are based on nutrition, such as vitamin D and calcium supplementation; 18- 20 medications, such as bisphosphonates and serum estrogen receptor manipulation; and activities such as gym workouts, running, and sports. 20

We held other variables as constant as possible to isolate the effect of one activity: yoga, to determine the response of 3 common sites of fracture-the spine, hip, and femur, associated with daily use of a DVD of 12 common yoga poses. We selected the poses specifically for their safety and their calculated effects on those 3 sites, among the most commonly fractured. Qualitative bone quality measurements were performed on the left hips of 18 subjects.

By pitting one group of muscles against another, yoga exposes bones to greater forces and, therefore, might enhance bone mineral density (BMD) more than other means. The advantages of such a program include universal applicability, virtual absence of side effects, and minimal cost.

MATERIALS AND METHODS

Encouraged by a successful pilot study, 21 and approved by Sound Shore Medical Center Institutional Review Board, currently part of Montefiore Medical Center, we devised a 12-minute DVD of 12 yoga poses that we believed would stimulate increasing BMD in the lumbar vertebrae, the hip, and the femoral neck (see Figure 1). We then announced through the Web site " sciatica.org " and at talks and workshops that we would give the DVD without cost to yoga practitioners and nonpractitioners that satisfied the criteria for study entry.

Figure 1.

Poses of the DVD from top left: (1) Vriksasana-tree, (2) Trikonasana-triangle, (3) Virabhadrasana II-warrior II, (4) Parsvakonasana-side-angle pose, (5) Parivrtta Trikonasana-twisted triangle, (6) Salabhasana-Locust, (7) Setu Bandhasana-bridge, (8) Supta Padangusthasana I-supine hand-to-foot I, (9) Supta Padangusthasana II-supine hand-to-foot II, (10) Marichyasana II-straight-legged twist, (11) Matsyendrasana-bent-knee twist, (12) Savasana -corpse pose.

Using the Internet, we collected baseline data, urine, blood chemistries, BMD, and spinal and hip radiographs of volunteers worldwide who intended to perform the 12-minute yoga regimen daily and distributed to them a disk of 12 poses that we had studied in a pilot study 21 accompanied by simultaneous verbal descriptions with each pose (see Figure 1 and 2). We began our pilot study in June 2005, employing an online scoresheet for subjects to report their levels of compliance. Subjects received a periodic newsletter and were encouraged to communicate with each other via a bulletin board. Instructional webinars were held in 2006, 2008, 2011, and 2013, with seminars in 2007 and 2012 in Westchester County and Lenox, Massachusetts, stressing the proper way to do the poses. Changes in BMD over 1 or more years leading up to study inclusion were compared with change in BMD 1 or more years following study entry. Bone quality measurements were taken on 18 patients with long-term yoga practices.

Figure 2.

Study flow diagram. DXA indicates dual-energy x-ray absorptiometry

Inclusion criteria:

1. Dual-energy x-ray absorptiometric (DXA) scan within the 6 months preceding study entry.

2. If the current DXA scan was normal, no laboratory tests were required. If the DXA scan contained osteopenic or osteoporotic values on the T-scale for spine, hip, or femur, then normal values on the following tests were necessary within 6 months of joining the study:

Comprehensive Metabolic Panel (SMA-18)

Thyroid stimulating hormone

Erythrocyte sedimentation rate

Vitamin D, 1, 25 dihydroxy

Urine collagen cross-linkage (NTX).

Completion of a questionnaire including information, such as medical and surgical history, medication usage, and diet, that can be seen on the Web site " sciatica.org."

Agreement to continue the current medication, nutritional and exercise regimen for the following 2 years, and to repeat the DXA scan within or just after that time period. Study subjects were encouraged but not required to submit spinal and hip radiographs obtained within the same time frame, submit previous DXA scans, and further encouraged to enter one of the authors' (GC) bone quality study.

Exclusionary criteria:

1. Abnormal values on the above tests.

2. Metabolic or bone diseases such as osteogenesis imperfecta, or Paget disease.

Individuals with abnormal blood tests, for example, with thyroid stimulating hormone (TSH), were referred to appropriate specialists, an endocrinologist in the case of elevated TSH. Once the value of the test was normal, they naturally became eligible for the study (see Figure 1).

The DVD consisted of 3 versions of each pose, the classical pose, an elementary pose that contained most elements of the classical pose but stressed safety and simplicity, and an intermediate or transitional version. Entry-level poses often used a wall for stabilization and a prop such as a bolster, belt, or chair to reduce the challenges and risks of the posture. All entrants were asked to begin by practicing the elementary poses for 1 week and to progress thereafter as far as they safely could from each elementary pose to the intermediate version of the pose and thereafter to the classical pose. Entrants were asked to perform each pose displayed and described in the DVD for 30 seconds daily and to log their yoga activities on a Health Insurance Portability and Accountability Act-compliant electronic scorecard available on the Internet. Subjects without yoga experience were encouraged to have at least 1 private lesson from a yoga teacher or yoga therapist, preferably one knowledgeable in the Iyengar type of yoga.

The primary measure was mean BMD change during the years before the study began versus mean BMD change following 2 years of daily yoga. Spine, right or left hip, and right or left femur (g/cm ²) constituted the metrics of choice. Because the timing of the DXA scans varied from patient to patient, all comparisons were in BMD changes per month. Secondary measures were based on compliance and self-reported and radiological measures of injury. Bone quality measures were qualitative. All DXA studies and bone quality studies were blinded in the sense that no radiologist was aware of the status of study subjects.

RESULTS

A total of 741 patients joined the study between 2005 and 2015, of whom 227 were identified as compliant with more than every-other-day yoga. Women comprised 202 of these patients. Mean age at joining the study was 68.2 years. Entry DXA scans showed that 174 (83%) of the compliant patients had osteoporosis or osteopenia.

Dropout rate was lower than that in a previous pilot study, 21 in which recruitment was not Internet-based. Many people failed to submit DXA scans from years prior to study entry. Others did not submit subsequent DXA scans; still others offered inadequate information about their in-study yoga practice. Because of the variable information that patients submitted subsequent to their enrollment in the study, data analysis was done in 3 tiers, as a function of the adequacy and relative certainty of the data supplied.

In approximately 4 years preceding study entry, 128, 130, and 125 patients presented prestudy DXA scans that revealed a mean monthly decline in BMD of −0.0036 g/cm ² for the spine, −0.00008 g/cm ² for the hips, and −0.009 for the femora, over a mean 47, 52, and 48 months, respectively; standard deviations/95% confidence intervals = 0.125/0.118, 0.117/0.183, and 0.317/0.192, for spine, hips, and femora, respectively. After practicing the yoga of the DVD over 22, 22, and 24 months, respectively, 72, 81, and 83 of these subjects reported mean gains of 0.048, 0.088, and 0.0003 g/cm ² per month, for spine, hips, and femora; standard deviations/95% confidence intervals = 0.551/0.44, 0.103/0.159, and 0.129/0.133, respectively (see Table 1 and Figures 3- 5).

TABLE 1. Most Recent Changes in BMD Before Yoga vs Those Following Two Years of Yogaa.

Location

Preyogaa

Number

Timingb

SD/CI

Postyoga

Timing

Number

SD

Spine

−0.036

128

47

0.125/0.118

0.048

21.7

71

0.551/0.44

Left hip

−0.017

130

52

0.117/0.183

0.088

22

81

0.103/0.159

Left femur

−0.03

125

48

0.317/0.192

0.003

24

83

0.129/0.133

Compliant patients were classified as having done more than half the poses at the highest level (high level, grade 3), more than half at the lowest level (low level, grade 1), or neither (moderate level, grade 2). We identified 57 patients of moderate to full compliance (grades 2 or 3).

For lumbar spine L1-L4, 29 participants showed average −0.00080 ± 0.00025 g/cm ² change per month over a mean 35 ± 7 months before yoga practice and showed significant improvement with 0.0010 ± 0.00043 g/cm ² change per month over a mean 21 ± 1 month after yoga practice ( P = .002). For total hip, 25 (16 from left hip, 5 from right hip, 2 bilateral) measurements showed mean 0.000082 ± 0.00038 g/cm ² change per month over a mean 38 ± 8 months before and mean 0.00012 ± 0.00031 g/cm ² change per month over 23 ± 2 months after yoga practice, which was nearly a 50% improvement but not significant. For femoral neck, 18 measurements were analyzed (13 from left side, 3 from right side, and both right and left of 1 participant). Bone mineral density fell a mean −0.00090 ± 0.00027 g/cm ² change per month over average 46 ± 12 months before yoga and showed significant improvement with mean 0.00030 ± 0.00048 g/cm ² change per month over average 24 ± 2 months after yoga ( P = .05) (see Table 2).

TABLE 2. Mean Monthly Change Before Yoga vs. After Two Years of Yoga in Moderately and Completely Compliant Patients.

Location

Before Yoga or After Yoga

Number

Time Span in Months/Confidence Interval

Change Per Month/Confidence Interval

P

Spine

Before

29

35 ± 7

−0.00080/0.00025

Total hip

Before

25

38 ± 8

0.000082/0.00038

Femur

Before

18

46 ± 12

−0.00090/0.00027

Selecting only those individuals with complete pre-and poststudy entry data (who sent in the actual DXA reports rather than just sending us the numerical results) and moderate to full compliance, we found that 43 patients-spine (n = 27), hip (n = 16), and femur (n = 14), within a span of 11 to 59, 23 to 59, and 11 to 59 months, respectively-showed monthly BMD gains of 0.001 (±0.0007), 0.0003 (±0.0007), and 0.0009 (±0.0003), g/cm ², respectively. The P values for these changes are .02, .01, and .0002, respectively (see Table 3 and Figure 6).

TABLE 3. Improvements in Fully Documented Patients Who Followed the Daily Regimen for Two Years.

Location

Number

Range of Time Between DXA Scans in Months

Difference in Change Per Month (Before Yoga-After Yoga)/Confidence Interval

P

In all, 109 fractures were reported on prestudy radiographs and in the induction forms, and 19 in subjects postentry. As of this writing, with more than 90 000 hours of yoga practiced largely by people with osteoporosis or osteopenia, there have been no reported or X-ray detected fractures or serious injuries of any kind related to the practice of yoga in any of the 741 participants. Bone quality of the 18 patients completing the study was judged as superior to those without yoga experience.

CONCLUSION

The 12 yoga poses studied here appear to be a safe and effective means to reverse bone loss in the spine and the femur and have weaker indications of positive effects on the total hip measurement of the DXA scan. There is qualitative evidence suggesting improved bone quality as a result of the practice of yoga.

DISCUSSION

Globally, there are 200 000 000 people with osteopenia or osteoporosis. 1- 2, 4 A safe, effective, and stunningly low-cost means of reversing this condition would be welcome for the many people who have neither the means to acquire the recommended medications nor access to the treatment of the fractures that may occur without them.

Mean rate of improvement in total hip BMD increased from baseline by 50% after a mean 23 ± 2 months of yoga, but wide variation in individual improvement caused the confidence intervals to overlap, thus precluding statistical significance. The root cause of this increased variation is possibly due to the wide differences in yoga skills within the study population that was more important in the more difficult twisting, extension, and standing poses in which the hips bear the most pressure. There are also several different formulae used for calculating total hip BMD which might add to the variability in this number.

Some studies suggest that BMD is not as closely associated with fracture as falling itself. 8 By improving posture, balance, range of motion, strength, and coordination, decreasing anxiety and improving gait, 8- 17, 19- 21 yoga opposes falls in ways no medicine can provide. Although some medications do reduce anxiety, they also impair balance.

However, this study suffers from many drawbacks.

Recruitment

People signing up for the study were largely those with already weakened or weakening bones and, very often, people already doing some yoga. Therefore, the study may have selected the very people for whom yoga does not give maximum benefit. The bone-building effects of yoga in younger and in healthier people, without the genetic predisposition that is possibly overrepresented in our sample, might well be greater and at any rate are unknown.

Study focus

Yoga poses were selected specifically to produce torque and bending of the proximal femur, compression of the pelvis, and twisting of the lumbar vertebral bodies. The choice was determined because these are the most common sites of osteoporotic fractures and the anatomical regions measured by the DXA scan. However, osteoporotic fractures frequently occur in the thoracic spine, the forearm, and the ribs. These sites were not studied and might not respond to yoga directed toward them in the same way.

Data

Some subjects used the electronic scorecard incorrectly and/or inadequately, limiting the data on actual compliance. This vitiated the calculation of dose-response curves enough to preclude their utility in this study.

Bone quality

The qualitative measure of bone quality can be supplemented and improved with finite element analysis, which is yet to be performed on this sample.

Study design

This was perforce a crossover study since none of the subjects were doing yoga for osteoporosis before joining the study. However, many were doing yoga for other reasons, reducing the calculated effect of the 12 poses studied here.

SUMMARY

The current study supports the efficacy and safety of yoga as a treatment of osteopenia and osteoporosis. However, its use in prevention, on a wider selection of possible fracture sites, with more precise data for dose-response relationships, improved bone quality measures and with standard randomized, controlled, double-blinded inquiries, requires further investigation. Many of these goals could be accomplished with a younger osteopenia-free population. What is suggested by this study's results is that yoga can reverse bone loss that has reached the stages of osteopenia and osteoporosis.

Footnotes

Dr Fishman funded the study.

References

Articles from Topics in Geriatric Rehabilitation are provided here courtesy of Wolters Kluwer Health

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Twelve-Minute Daily Yoga Regimen Reverses Osteoporotic Bone Loss

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Assess the effectiveness of selected yoga postures in raising bone mineral density (BMD). Ten-year study of 741 Internet-recruited volunteers comparing preyoga BMD changes with postyoga BMD changes. Dual-energy x-ray absorptiometric scans. Optional ...

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https://www.ncbi.nlm.nih.gov/books/NBK493191/

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Hormone replacement therapy (HRT) replenishes women with ovarian hormones diminished during the natural menopausal transition to alleviate associated symptoms, especially hot flashes and night sweats. Traditional HRT typically combines estrogen and progesterone to replicate ovarian hormones. HRT, approved by the Federal Drug Administration (FDA), treats severe vasomotor menopausal symptoms and prevents osteoporosis. Available estrogen therapies are ethinyl estradiol, conjugated equine estrogen (CEE), synthetic conjugated estrogens, and micronized 17β-estradiol. The addition of progesterone helps prevent endometrial hyperplasia in people with an intact uterus. Systemic HRT can be administered orally, vaginally, or transdermally, each with unique benefits and risks. This activity for healthcare professionals is designed to enhance the learner’s understanding of HRT indications, risk-benefit ratios, individualized management, including estrogen and progesterone therapies and administration methods, and the implementation of an appropriate interprofessional management approach to improve patient outcomes.