Osteoporosis

• Osteoporosis is a systemic skeletal disorder characterised by low bone mineral density (BMD) and micro-architectural deterioration of bone tissue. These changes result in increased bone fragility and a higher risk of fractures.
• The condition is largely asymptomatic until a fracture occurs, often leading to its designation as a “silent disease”.
• The World Health Organization (WHO) criteria define osteoporosis based on BMD measurements obtained via dual-energy X-ray absorptiometry (DXA).

Primary Osteoporosis

• A rare condition that occurs in children and young adults.
• Typically presents between 8-14 years.
• Associated with abrupt bone pain and fractures following trauma.
• Normal gonadal function.
  
  

• Can occur in both young and middle-aged adults without an identifiable cause.
  
  

• Oestrogen deficiency is the primary cause.
• Accelerated bone loss, primarily affecting trabecular bone.
• Common fracture sites: distal forearm, vertebrae.
  
  

• Occurs in both men and women as bone mineral density (BMD) declines with aging.
• Represents age-related bone loss.
• Fractures involve cortical and trabecular bone, particularly at the wrist, hip, and vertebrae.
  
  

Secondary Osteoporosis

Causes of Secondary Osteoporosis

• Renal hypercalciuria (one of the most important secondary causes, treatable with thiazide diuretics).
• Osteogenesis imperfecta.
• Ehlers-Danlos syndrome.
• Marfan syndrome.
• Glycogen storage disease.
• Hemochromatosis.
  
  

• Cushing syndrome.
• Diabetes mellitus.
• Hyperparathyroidism (leads to increased bone turnover and calcium resorption).
• Hyperthyroidism (excess thyroid hormone accelerates bone loss).
• Hypogonadism (including Turner syndrome and Klinefelter syndrome).
• Acromegaly.
• Pregnancy-related osteoporosis.
  
  

• Calcium and vitamin D deficiency.
• Protein-energy malnutrition.
• Chronic liver disease.
• Inflammatory bowel disease (e.g., Crohn's disease, celiac disease).
• Bariatric surgery (leads to malabsorption of calcium and vitamin D).
  
  

• Rheumatoid arthritis.
• Systemic lupus erythematosus.
• Multiple myeloma.
• Hemophilia.
• Leukemia and lymphoma.
  
  

• Glucocorticoids (≥5 mg/day for ≥3 months)—major cause of medication-induced osteoporosis.
• Anticonvulsants (e.g., phenytoin, carbamazepine) – enhance vitamin D metabolism, leading to deficiency.
• Aromatase inhibitors (used in breast cancer treatment).
• Proton pump inhibitors (PPIs) – reduce calcium absorption.
• Selective serotonin reuptake inhibitors (SSRIs).
• Thiazolidinediones (used in diabetes).
• Sodium-glucose co-transporter 2 (SGLT2) inhibitors.
  
  

• Chronic alcohol use (leads to direct bone toxicity and poor calcium absorption).
• Smoking (reduces osteoblast activity and estrogen levels).
• Prolonged immobilisation (e.g., spinal cord injury, long-term hospitalisation).
• Weightlessness (as seen in astronauts).
  
  

Risk Factors for Osteoporosis

• Advanced age (≥50 years).
• Female sex.
• White or Asian ethnicity.
• Family history of osteoporosis (particularly maternal hip fracture).
• Small body frame (BMI <20 kg/m²).
• Early menopause (before age 45) or late menarche.
  
  

• Smoking.
• Excessive alcohol intake.
• Low dietary calcium and vitamin D intake.
• Sedentary lifestyle (lack of weight-bearing exercise).
• Chronic use of certain medications (glucocorticoids, PPIs, anticonvulsants).
  
  

Bone Remodeling and Its Dysregulation in Osteoporosis

• Bone is a dynamic tissue that continuously undergoes remodeling to maintain skeletal strength and mineral homeostasis. 
• This process is tightly regulated by the balance between bone resorption by osteoclasts and bone formation by osteoblasts. Any disruption in this equilibrium leads to bone loss and structural deterioration, as seen in osteoporosis.
  
  

Normal Bone Remodeling

• Bone remodeling occurs at distinct skeletal sites and involves four sequential phases:
  1. Activation – Conversion of quiescent bone surfaces into active resorption sites.
  2. Resorption – Osteoclasts degrade the bone matrix, creating resorption pits.
  3. Reversal – Osteoclasts undergo apoptosis while osteoblast precursors are recruited.
  4. Formation – Osteoblasts deposit new bone matrix, which undergoes mineralisation.
• Cortical bone (dense outer layer) and trabecular bone (spongy inner network) have distinct remodeling rates, with trabecular bone being more metabolically active and, therefore, more susceptible to osteoporosis-related deterioration.
  
  

Molecular Mechanisms Underlying Bone Loss

• Receptor activator of nuclear factor-kappa B ligand (RANKL), produced by osteoblasts and T cells, binds to its receptor RANK on osteoclast precursors, stimulating their differentiation and activity.
• Osteoprotegerin (OPG), a decoy receptor secreted by osteoblasts, binds RANKL, inhibiting its interaction with RANK and thereby suppressing osteoclast activity.
• In osteoporosis, increased RANKL expression and reduced OPG levels promote excessive osteoclast activity and bone resorption.
  
  

• Oestrogen plays a critical role in suppressing osteoclastogenesis by:
  • Reducing RANKL expression and increasing OPG secretion.
  • Enhancing osteoclast apoptosis.
  • Inhibiting pro-inflammatory cytokines that stimulate bone resorption (e.g., IL-1, IL-6, TNF-α).
• Postmenopausal oestrogen deficiency leads to unchecked osteoclast activity, accelerating bone loss and increasing fracture risk.
  
  

• Pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6, are upregulated in osteoporosis, enhancing osteoclast formation and survival.
• Osteoimmunology – Immune cells, particularly T cells and B lymphocytes, play a role in regulating bone turnover. Increased TNF-α and IL-17 in postmenopausal women contribute to excessive bone resorption.
  
  

Impact of Aging on Bone Homeostasis

• Peak bone mass is achieved by the third decade of life; thereafter, bone resorption gradually exceeds formation.
• Aging results in:
  • Reduced osteoblast function, leading to inadequate bone formation.
  • Increased cortical porosity and trabecular thinning, weakening bone architecture.
  • Deficiencies in calcium and vitamin D, leading to secondary hyperparathyroidism, which exacerbates bone resorption.
    
    

Bone Quality and Microarchitectural Deterioration

• Osteoporotic bone exhibits thinning of trabeculae, loss of connectivity, and cortical porosity, making it prone to fractures.
• Histologic analyses have demonstrated that:
  • Trabecular bone turnover is significantly increased, leading to weakened bone structure.
  • Cortical bone loses density more gradually, but progressive porosity increases fracture risk

Global Prevalence

• Osteoporosis is the most common metabolic bone disease, affecting over 200 million people worldwide.
• In industrialised countries, the prevalence of osteoporosis at the spine or hip is estimated at:
  • 44% in Japan, 20% in the U.S., 41% in Germany, 40% in France, 38% in Italy, 34% in the UK, 38% in Spain, 21% in Canada, and 28% in Australia.
• The highest prevalence rates are seen in:
  • Africa (39.5%) and Asia (24.3%) among older individuals.
  • The Eastern Mediterranean Region (24.4%).
    
    

Prevalence in the United States

• 2010: An estimated 10.2 million adults aged 50+ had osteoporosis, with 43.3 million more having low bone mass.
• 2015: 2.3 million osteoporotic fractures were reported among 2 million Medicare beneficiaries.
• 2018: The estimated numbers remained consistent, with 10.2 million cases of osteoporosis and 43.4 million cases of low bone mass.
  
  

Fracture Risk and Mortality

• Osteoporotic fractures increase with age, with hip fractures being the most fatal:
• 30% mortality rate within 12 months after a hip fracture.
• 15% of patients suffer subsequent fractures within a year of their initial fracture.
  
  

Age and Sex Distribution

• Postmenopausal women (aged 50-70 years) are at the highest risk.
• Senile osteoporosis is most common in individuals aged 70 years and older.
• The female-to-male ratio for osteoporosis is 4:1, but men have a higher prevalence of secondary osteoporosis (hypogonadism, alcoholism, glucocorticoid excess).
• By age 50, 50% of women and 21% of men will experience at least one osteoporosis-related fracture.
  
  

Racial and Ethnic Disparities

• Non-Hispanic white and Asian women have the highest risk of osteoporosis.
• Hispanic women show the fastest increasing risk of osteoporosis among all racial groups.
• Black individuals have lower fracture risk, likely due to higher peak bone mass and different bone geometry.
• By 2050, 50% of all hip fractures are projected to occur in Asia.

Risk Factors to Elicit from History

• Personal history of fracture as an adult.
• Family history of fractures, particularly in first-degree relatives (maternal hip fractures are especially significant).
• White or Asian ancestry, which is associated with higher osteoporosis risk.
• Advanced age (women >50 years, men >65 years).
• Female sex, with a higher risk in postmenopausal women.
• Dementia, which increases the likelihood of falls and fractures.
• Poor overall health or frailty.
  
  

• Current cigarette smoking, which accelerates bone loss.
• Low body weight (<127 lb or BMI <20 kg/m²).
• Oestrogen deficiency, due to early menopause (age <45 years), bilateral ovariectomy, or prolonged amenorrhea (>1 year).
• Low lifelong calcium intake.
• Excessive alcohol consumption (≥3 drinks per day).
• Impaired vision, even with correction, leading to higher fall risk.
• Recurrent falls, a major predictor of osteoporotic fractures.
• Inadequate physical activity, leading to lower bone mass.
• Frailty or chronic illness, impairing mobility and increasing fracture risk.
  
  

Fracture Risk Assessment

• Age, sex, and race – Postmenopausal women and older men (≥65 years) are at the highest risk.
• Family history of osteoporosis, especially fractures in a parent.
• Reproductive history, including menopause age, history of hysterectomy, and use of estrogen replacement therapy.
• Hypogonadal states – Increased risk in men with hypogonadism from genetic or acquired conditions.
• Lifestyle factors – Smoking, alcohol intake, low activity levels, and diet history.
• Use of medications associated with bone loss, including glucocorticoids, anticonvulsants, cyclosporine, heparin, lithium, and proton pump inhibitors.
• History of fragility fractures, defined as fractures from minimal trauma (e.g., a fall from standing height).
• Coexisting conditions that increase fracture risk, such as hyperparathyroidism, rheumatoid arthritis, leukemia, celiac disease, and Cushing syndrome.
• Fall risk factors, including poor balance, lower extremity weakness, orthostatic hypotension, sedative use, poor vision/hearing, and cognitive impairment.
  
  

Fracture Risk Assessment Tools

• FRAX (Fracture Risk Assessment Tool)
  • Estimates 10-year risk of hip and major osteoporotic fractures.
  • Factors include age, sex, prior fractures, BMI, smoking, alcohol use, glucocorticoid therapy, parental hip fractures, and secondary osteoporosis.
  • FRAX scores are widely used but do not account for fall history.
• Garvan Fracture Risk Calculator
  • Similar to FRAX but includes fall risk assessment, making it more suitable for men and individuals with frequent falls.
• QFracture Tool
  • Includes risk factors such as falls, steroid use, smoking, alcohol intake, and secondary osteoporosis but does not use BMD values.
    
    

Fracture History and Differentiation of Fracture Types

• Vertebral Compression Fractures
  • Often asymptomatic or subclinical.
  • May cause kyphosis, loss of height, and chronic back pain.
  • Patients may report acute back pain after bending, lifting, or coughing.
  • Pain is often localised to a specific vertebral level and may radiate to the abdomen.
• Hip Fractures
  • Common symptoms include pain in the groin, thigh, or buttock during weight-bearing.
  • Restricted hip range of motion, particularly in internal rotation.
  • External rotation of the hip in the resting position.
• Pelvic and Sacral Fractures
  • Pain that worsens with weight-bearing.
  • Common in older adults with low BMD.
• Wrist Fractures (Colles’ Fractures)
  • Often the first osteoporotic fracture in postmenopausal women.
  • Typically result from a fall onto an outstretched hand.
    
    

Vertebral Fracture Indicators from History

• Sudden onset of localised back pain, often triggered by minor trauma.
• Pain worsens with movement but improves when lying supine.
• Paravertebral muscle spasms.
• Gradual development of kyphosis and height loss over time.
• Two-thirds of vertebral fractures are asymptomatic, making screening critical.
  
  

Gastrointestinal History in Osteoporosis

• Patients may report lactose intolerance or celiac disease, both of which are associated with osteoporosis.
• Celiac disease is present in up to 5% of osteoporosis cases due to malabsorption of calcium and vitamin D.
  
  

Anthropometric Changes

• Loss of height: Progressive height reduction (>2–3 cm) is common and may indicate vertebral compression fractures.
• Low body weight (BMI <19 kg/m²): Associated with lower bone mass and higher fracture risk.
  
  

Spinal Deformities and Postural Changes

• Thoracic kyphosis ("dowager hump"): Resulting from multiple vertebral compression fractures.
• Exaggerated cervical lordosis: Often seen in conjunction with thoracic kyphosis.
• Loss of lumbar lordosis: Contributes to an altered posture and increased fall risk.
  
  

Signs of Vertebral Compression Fractures

• Point tenderness over vertebrae: Localized pain on palpation suggests a recent or subacute fracture.
• Paravertebral muscle spasms: Common in acute fractures and exacerbated by movement.
• Pain on spinal percussion: Suggests underlying vertebral fractures.
• Restricted range of motion (ROM) in the spine: Particularly in flexion and extension.
  
  

Hip and Pelvic Fracture Signs

• Hip pain with weight-bearing: Typically in the groin, anterior thigh, buttock, or knee.
• Reduced hip ROM, especially internal rotation and flexion.
• External rotation of the hip in resting position: Suggests a femoral neck fracture.
• Pain with the FABER test (Flexion, Abduction, External Rotation): Indicates hip pathology.
• Antalgic gait or reduced weight-bearing: Seen in patients with hip fractures.
  
  

Pelvic and Sacral Fractures

• Marked pain with ambulation.
• Tenderness on palpation or percussion of the sacrum or pubic bone.
• Positive sacroiliac joint tests (FABER, Gaenslen, or squish test).
  
  

Distal Fractures (Wrist and Humerus)

• Colles' fracture ("dinner fork deformity"): Suggests a distal radius fracture due to a fall on an outstretched hand.
• Limited wrist movement with pain.
• Pain and deformity of the proximal humerus in humeral fractures.
  
  

Balance and Gait Assessment

• Impaired tandem gait: Difficulty walking heel-to-toe suggests postural instability.
• Poor single-limb stance balance: Associated with fall risk.
• Slow performance on the Timed Up and Go (TUG) test: A validated predictor of fall risk and fracture risk.
  
  

Signs of Collagen Defects (Suggesting Underlying Disorders)

• Short fifth digit.
• Dentinogenesis imperfecta (abnormal tooth structure).
• Hyperlaxity of joints.
• Pes planus (flat feet) and bunions.
• Blue sclerae (associated with osteogenesis imperfecta).
• Hearing loss, which may indicate underlying bone metabolism disorders.
  
  

Risk Factors for Falls and Fractures

• Gait instability.
• Orthostatic hypotension, contributing to syncope and falls.
• Lower extremity muscle weakness.
• Poor vision or hearing.
• Cognitive impairment or dementia.
• Use of sedative medications.
  
  

Primary Investigations

• Gold standard for diagnosing osteoporosis and assessing bone mineral density (BMD).
• DXA measures BMD at the lumbar spine, hip, and proximal femur.
• T-scores define bone density status:
  • Normal: T-score ≥ -1.0.
  • Osteopenia: T-score between -1.0 and -2.5.
  • Osteoporosis: T-score ≤ -2.5.
  • Severe osteoporosis: T-score ≤ -2.5 with fragility fractures.
• Spine DXA in older adults may be misleading due to artefacts such as aortic calcification and osteophytes.
• Forearm DXA is recommended if:
  • Hip and/or spine cannot be measured.
  • Patient has hyperparathyroidism.
  • Patient is severely obese (exceeds DXA table weight limit).
    
    

• Developed by WHO to estimate 10-year probability of osteoporotic fractures.
• Integrates clinical risk factors and femoral neck BMD.
• Limitations:
  • Does not account for recent falls or spinal BMD.
  • Underestimates fracture risk in certain populations.
    
    

Additional Imaging Studies

• Assesses bone strength (not BMD) and is portable and radiation-free.
• Used where DXA is unavailable.
• Not standardised for osteoporosis diagnosis and T-scores for DXA cannot be applied.
  
  

• Detects osteopenia and fractures but cannot diagnose osteoporosis.
• Used to guide DXA assessment in cases of height loss, thoracic kyphosis, or suspected vertebral fractures.
  
  

• Measures true volumetric BMD, high sensitivity for trabecular bone loss.
• Higher radiation exposure than DXA.
• Useful in monitoring age-, disease-, or treatment-related BMD changes.
  
  

• Useful for detecting acute fractures.
• Differentiates osteoporotic fractures from metastatic disease.
• Shows bone marrow edema in acute vertebral compression fractures.
  
  

• Identifies increased osteoblastic activity in compression fractures.
• Useful in metastatic disease evaluation.
  
  

Laboratory Investigations

• Used for monitoring response to osteoporosis treatment, not for diagnosis.
• Bone Formation Markers:
  • Bone-specific alkaline phosphatase (BSAP)
  • Osteocalcin (OC)
  • Procollagen type I N propeptide (P1NP) – recommended reference marker.
• Bone Resorption Markers:
  • Urinary deoxypyridinoline
  • N-telopeptide of type I collagen (NTX)
  • C-terminal telopeptide of type I collagen (CTX-1) – recommended reference marker.
    
    

• Serum Calcium and Phosphate:
  • Hypocalcemia may indicate osteomalacia.
  • Hypercalcemia suggests hyperparathyroidism.
• Serum 25-hydroxy Vitamin D:
  • Deficiency (<20 ng/mL) suggests secondary hyperparathyroidism.
• Serum Parathyroid Hormone (PTH):
  • Elevated in primary hyperparathyroidism.
• Thyroid Function Tests (TSH, T4, T3):
  • Exclude thyrotoxicosis, which increases osteoclastic activity.
• Serum Protein Electrophoresis (SPEP) and Urine Protein Electrophoresis (UPEP):
  • Rule out multiple myeloma in older patients with multiple fractures and anaemia.
• Urinary Free Cortisol:
  • Screen for Cushing’s syndrome in suspected cases.
    
    

Specialised Investigations

• Bone Biopsy:
  • Used when the diagnosis is uncertain or to differentiate osteoporosis from osteomalacia.
  • Tetracycline labeling can help assess bone turnover.

Osteomalacia

• Clinical Features:
  • Diffuse bone pain, proximal muscle weakness, and waddling gait.
  • Commonly associated with vitamin D deficiency or malabsorption syndromes.
  • Unlike osteoporosis, fractures in osteomalacia are often Looser zones (pseudofractures) rather than fragility fractures.
• Investigations:
  • Serum 25-hydroxy vitamin D: Low.
  • Parathyroid hormone (PTH): Elevated (secondary hyperparathyroidism).
  • Serum calcium and phosphate: Low to normal.
  • Alkaline phosphatase: Elevated (due to impaired mineralisation).
  • Bone biopsy: Demonstrates excess osteoid and defective mineralisation.
    
    

Multiple Myeloma

• Clinical Features:
  • Persistent bone pain (especially in the spine, ribs, and pelvis).
  • Symptoms of anemia, renal impairment, and hypercalcemia.
• Investigations:
  • Serum and urine electrophoresis: Presence of monoclonal (M) protein.
  • Skeletal survey (X-ray): "Punched-out" lytic lesions.
  • Bone marrow biopsy: Clonal plasma cell proliferation.
  • Serum free light chain assay: Elevated kappa or lambda chains.
    
    

Chronic Kidney Disease – Bone and Mineral Disorder (CKD-BMD)

• Clinical Features:
  • History of chronic kidney disease (CKD).
  • Bone pain, proximal muscle weakness, and pathological fractures.
• Investigations:
  • Serum creatinine: Elevated.
  • PTH: Elevated (secondary hyperparathyroidism).
  • Serum calcium and phosphate: Often abnormal (low calcium, high phosphate).
  • Bone biopsy: May show osteitis fibrosa cystica (high-turnover bone disease) or adynamic bone disease.

Primary Hyperparathyroidism

• Clinical Features:
  • Symptoms of hypercalcemia: Fatigue, nephrolithiasis, constipation, polyuria, and mood disturbances.
  • Bone pain and fractures, particularly in the subperiosteal regions (hands, clavicles).
• Investigations:
  • Serum PTH: Elevated.
  • Serum calcium: Elevated.
  • X-ray: Subperiosteal bone resorption, osteitis fibrosa cystica.
  • DXA scan: Reduced BMD, particularly in cortical bone sites.
    
    

Metastatic Bone Disease

• Clinical Features:
  • Localised bone pain, unexplained fractures.
  • History of a primary malignancy (breast, prostate, lung, renal).
  • Fractures may occur at atypical sites.
• Investigations:
  • DXA scan: May be normal or show regional osteolysis.
  • CT scan: Detects lytic or sclerotic lesions.
  • Bone scan: Multiple hot spots (osteoblastic activity).
  • Bone biopsy: Confirms metastatic involvement.
    
    

Paget’s Disease of Bone

• Clinical Features:
  • Bone pain, skull enlargement, hearing loss, and deformities (e.g., bowed legs).
  • Common in older adults.
• Investigations:
  • Serum alkaline phosphatase: Elevated.
  • Serum calcium and phosphate: Normal.
  • X-ray: Thickened cortical bone, mixed lytic and sclerotic changes.
  • Bone scan: Increased uptake in affected bones.
    
    

Vertebral Deformities (Osteoarthritis, Scoliosis, Ankylosing Spondylitis)

• Clinical Features:
  • Chronic back pain and postural abnormalities.
  • Progressive kyphosis.
• Investigations:
  • X-ray, MRI: Helps differentiate degenerative changes from osteoporotic fractures.
  • HLA-B27 testing: If ankylosing spondylitis is suspected.
    
    

Mastocytosis

• Clinical Features:
  • Diffuse bone pain, pruritus, flushing, and urticaria pigmentosa.
• Investigations:
  • Serum tryptase: Elevated.
  • Urinary histamine metabolites: Increased.
  • Bone marrow biopsy: Demonstrates mast cell infiltration.
    
    

Scurvy (Vitamin C Deficiency)

• Clinical Features:
  • Poor wound healing, gingival bleeding, and bone pain.
• Investigations:
  • Serum Vitamin C levels: Low.
  • X-ray: Periosteal reactions and subperiosteal hemorrhages.
    
    

Sickle Cell Disease (Osteonecrosis, Bone Infarcts)

• Clinical Features:
  • Bone pain, avascular necrosis of femoral head.
  • History of chronic anemia and vaso-occlusive crises.
• Investigations:
  • Haemoglobin electrophoresis: Confirms sickle cell disease.
  • MRI: Detects bone infarcts and osteonecrosis.
    
    

Non-Pharmacological Management

• Recommended daily intake:
  • Calcium: 1000 mg/day (men <70 years), 1200 mg/day (women ≥51 years, men ≥71 years).
  • Vitamin D: 800-1000 IU/day for adults >50 years.
• Dietary sources: Dairy, leafy greens, fortified foods.
• Supplementation considerations:
  • Some studies show fracture risk reduction, while others report little to no benefit.
  • Excessive calcium intake (>2000 mg/day) may increase the risk of nephrolithiasis and cardiovascular disease.
    
    

• Weight-bearing exercises (e.g., walking, jogging) increase BMD.
• Resistance training (e.g., weightlifting) strengthens bones.
• Balance and coordination exercises (e.g., Tai Chi, yoga) reduce fall risk.
• Avoid high-impact activities in severe osteoporosis to prevent fractures.
  
  

• Environmental modifications: Non-slip rugs, grab bars, well-lit spaces.
• Vision and hearing assessments: Impaired sensory function increases fall risk.
• Medication review: Avoid sedatives, antihypertensives, or other medications that increase fall risk.
  
  

Pharmacological Management

• Drugs: Alendronate, risedronate, zoledronic acid, ibandronate.
• Mechanism: Inhibit osteoclast-mediated bone resorption.
• Benefits:
  • Reduce vertebral, hip, and non-vertebral fractures.
  • Increase bone mineral density (BMD) at the spine and hip.
• Administration:
  • Oral forms require fasting and upright posture for 30-60 minutes to prevent esophageal irritation.
  • Zoledronic acid is administered annually via IV, useful for non-compliant patients.
• Adverse effects:
  • GI symptoms: Esophagitis, gastric ulcers.
  • Osteonecrosis of the jaw (ONJ): Rare, associated with long-term use.
  • Atypical femoral fractures: Increased risk with >5 years of use.
    
    

• Recommended after 3-5 years of bisphosphonate use for low-risk patients.
• High-risk patients may continue therapy for up to 10 years.
  
  

• Mechanism: Monoclonal antibody targeting RANK ligand (RANKL), inhibiting osteoclast activity.
• Dosing: 60 mg subcutaneously every 6 months.
• Benefits:
  • Reduces vertebral, non-vertebral, and hip fractures.
  • Alternative for bisphosphonate-intolerant patients.
• Risks:
  • Hypocalcemia: Monitor serum calcium in patients with renal insufficiency.
  • Fracture rebound: Rapid bone loss upon discontinuation requires transition to another agent (e.g., bisphosphonates).
    
    

• Indications:
  • Severe osteoporosis (T-score ≤ -3.0).
  • Multiple fractures or failure of antiresorptive therapy.
• Mechanism:
  • Stimulates new bone formation via PTH receptor activation.
• Dosing:
  • Teriparatide: 20 mcg daily (subcutaneous) for up to 2 years.
  • Abaloparatide: 80 mcg daily (subcutaneous).
• Considerations:
  • Follow with an antiresorptive agent (e.g., bisphosphonates) to maintain BMD gains.
  • Avoid in patients at risk for osteosarcoma (e.g., Paget’s disease, prior skeletal radiation).
    
    

• Indication: High-risk patients with severe osteoporosis.
• Mechanism:
  • Increases bone formation while inhibiting resorption.
• Dosing: 210 mg subcutaneous injection monthly for 12 months max.
• Considerations:
  • May increase cardiovascular risk (stroke, MI).
  • Transition to an antiresorptive agent after discontinuation.
    
    

Hormone-Based Therapies

• Drugs: Raloxifene, bazedoxifene.
• Benefits:
  • Reduce vertebral fracture risk.
  • Breast cancer risk reduction (in high-risk women).
• Risks:
  • Increased risk of venous thromboembolism (VTE).
  • Does not reduce hip fracture risk.
    
    

• Indications:
  • Women <60 years or within 10 years of menopause with osteoporosis and vasomotor symptoms.
• Risks:
  • Increased risk of breast cancer, stroke, VTE.
  • Not first-line therapy but beneficial for select patients.
    
    

Osteoporosis in Special Populations

• First-line therapy: Bisphosphonates.
• Testosterone therapy: Considered only in men with hypogonadism.
• Denosumab, teriparatide, and abaloparatide can be used if high risk.
  
  

• Risk assessment:
  • Patients on prednisone ≥2.5 mg/day for ≥3 months are at high fracture risk.
• First-line therapy:
  • Oral bisphosphonates (alendronate, risedronate).
  • IV zoledronic acid for non-adherent patients.
• Alternatives: Teriparatide or denosumab for severe osteoporosis.
  
  

Monitoring and Treatment Duration

• Bone mineral density (BMD) reassessment:
  • 1-2 years after treatment initiation, then periodically.
• Duration of treatment:
  • Bisphosphonates: 3-5 years, followed by reassessment.
  • Denosumab: Long-term, with no drug holidays.
  • Anabolic agents: 2-year maximum, then transition to an antiresorptive.
• Discontinuation considerations:
  • Stopping denosumab abruptly leads to rapid BMD loss—transition therapy required.
  • Drug holidays should be considered for bisphosphonates but not other therapies.
    
    

Overall Prognosis

Impact of Fractures on Prognosis

• Most common osteoporotic fractures (~700,000 cases annually).
• Symptoms: Back pain, height loss, kyphosis, restrictive lung disease, and increased risk of pneumonia.
• Mortality risk:
  • Vertebral fractures increase 5-year mortality by ~15%.
  • Women with 5 or more vertebral fractures have a 2.3-fold increased risk of death compared to those without fractures.
    
    

• Estimated 250,000 hip fractures per year due to osteoporosis.
• Mortality risk:
  • 20% die within 1 year following a hip fracture.
  • Men have higher post-fracture mortality than women.
• Functional impact:
  • 50% require long-term nursing care.
  • One-third never regain full independence.
• Secondary complications: Nosocomial infections, deep vein thrombosis, and pulmonary embolism.
  
  

• A prior osteoporotic fracture increases the likelihood of future fractures:
  • 5-fold increased risk of additional vertebral fractures.
  • 20% of postmenopausal women with a new vertebral fracture sustain another within one year.
  • Prior hip fracture increases risk of a second hip fracture by 2 to 10 times.
  • Fractures at sites like the ankle, knee, and lumbar spine increase future hip fracture risk by 1.5 to 4.8 times.
    
    

Fracture Risk Prediction Tools

• Calculates 10-year probability of hip or major osteoporotic fractures.
• Factors included:
  • Age, sex, T-score, smoking, alcohol intake, glucocorticoid use, parental history of hip fracture, and secondary osteoporosis.
• Limitations:
  • Does not include fall history, which is a major predictor of fractures.
  • May underestimate risk in some populations, particularly in diabetics.
    
    

• Accounts for falls, making it more accurate for some populations (e.g., men).
• Does not include parental history of fractures or secondary osteoporosis.
  
  

• Includes history of falls, making it potentially superior for predicting fractures in older adults.
• Does not incorporate BMD, limiting its predictive accuracy in some cases.
  
  

Major Complications

• Most serious complications of osteoporosis.
• Common sites: Hip, spine (vertebral compression fractures), wrist, and ribs.
• Consequences: Significant pain, disability, reduced quality of life, and increased mortality.
• Mortality risk:
  • Hip fractures: 20% mortality in the first year post-fracture.
  • Vertebral fractures: Associated with increased mortality and chronic pain.
    
    

Specific Fracture Types and Their Impact

• Incidence is rising, particularly in aging populations.
• Functional impact:
  • Two-thirds of patients do not regain previous levels of function.
  • 20% require long-term institutional care.
  • 50% of previously independent individuals become partially or fully dependent.
• Complications:
  • Deep vein thrombosis (DVT) and pulmonary embolism due to immobility.
  • Nosocomial infections such as pneumonia.
    
    

• Most common osteoporotic fracture (~700,000 per year).
• Progressive kyphosis leads to:
  • Chronic back pain, reduced mobility.
  • Restrictive lung disease, early satiety, and increased risk of pneumonia.
• Mortality risk increases with the number of vertebral fractures:
  • One vertebral fracture increases 5-year mortality by 15%.
  • Five or more fractures lead to a 2.3-fold increased risk of death.
    
    

• Osteoporosis increases wrist fracture risk by 2.4-fold in adults ≥50 years.
• Predictive of future osteoporotic fractures, especially in postmenopausal women.
  
  

• Common in postmenopausal women with osteoporosis.
• Often result in severe pain and respiratory complications.
  
  

Medication-Related Complications

• Long-term bisphosphonate therapy (median duration ~7 years) increases risk.
• Occurs with minimal or no trauma.
• Preceding symptoms: Thigh or groin pain weeks to months before fracture.
• Risk factors: Concomitant glucocorticoid use, proton pump inhibitors, and antiresorptive agents.
  
  

• Rare but serious complication, particularly in patients on IV bisphosphonates.
• Risk factors:
  • Poor dental hygiene.
  • Dental procedures (extractions, implants, or root canals).
• Estimated incidence: 1 in 10,000 to 1 in 100,000 per year of bisphosphonate use.
  
  

• Increased risk of deep vein thrombosis (DVT) and pulmonary embolism.
• Highest risk in first 4 months of use.
• Mechanism: Raloxifene has estrogen-like effects, increasing coagulability.
  
  

• Common after osteoporotic fractures, particularly in the spine and hip.
• Chronic pain syndromes can lead to:
  • Reduced mobility, loss of independence.
  • Psychosocial effects, including depression, social withdrawal, and reduced self-esteem.
    
    

1. Adams JS, Kantorovich V. Rapid recovery of bone mass in hypercalciuric, osteoporotic men treated with hydrochlorothiazide. Annals of Internal Medicine. 1999;130(8):658-660.
2. Bolland MJ, Grey AB, Gamble GD, Reid IR. Vitamin D supplementation and falls: A trial sequential meta-analysis. Lancet Diabetes & Endocrinology. 2014;2(7):573-580.
3. Cauley JA, Lui LY, Ensrud KE, et al. Bone mineral density and fracture risk in diverse racial/ethnic groups. JAMA. 2005;293(17):2102-2108.
4. Clarke B. Normal bone anatomy and physiology. Clinical Journal of the American Society of Nephrology. 2008;3(Suppl 3):S131-S139.
5. Cooper C, Atkinson EJ, Jacobsen SJ, et al. Population-based study of survival after osteoporotic fractures. American Journal of Epidemiology. 1993;137(9):1001-1005.
6. Demontiero O, Vidal C, Duque G. Aging and bone loss: New insights for the clinician. Therapeutic Advances in Musculoskeletal Disease. 2012;4(2):61-76.
7. Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: An Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism. 2019;104(5):1595-1622.
8. Ensrud KE, Crandall CJ, Larson JC, et al. Effects of osteoporosis and comorbidity on mortality in older women: The study of osteoporotic fractures. JAMA Internal Medicine. 2019;179(3):394-400.
9. Föger-Samwald U, Dovjak P, Azizi-Semrad U, Kerschan-Schindl K, Pietschmann P. Osteoporosis: Pathophysiology and therapeutic options. EXCLI Journal. 2020;19:1017-1037.
10. Holick MF. Vitamin D deficiency. New England Journal of Medicine. 2007;357(3):266-281.
11. Jilka RL, Hangoc G, Girasole G, et al. Increased osteoclast development after estrogen loss: Mediation by interleukin-6. Science. 1992;257(5066):88-91.
12. Kado DM, Browner WS, Palermo L, et al. Vertebral fractures and mortality in older women: A prospective study. Archives of Internal Medicine. 1999;159(11):1215-1220.
13. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet. 2002;359(9321):1929-1936.
14. Kanis JA, Melton LJ, Christiansen C, et al. The diagnosis of osteoporosis. Osteoporosis International. 1994;4(6):368-381.
15. Kelman A, Lane NE. The management of secondary osteoporosis. Best Practice & Research Clinical Rheumatology. 2005;19(6):1021-1037.
16. Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: A systematic review and international consensus. Journal of Bone and Mineral Research. 2015;30(1):3-23.
17. Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA. 2001;285(3):320-323.
18. Leslie WD, Morin SN, Lix LM, Majumdar SR. Bone mineral density and fracture risk: A systematic review. Osteoporosis International. 2012;23(4):1367-1375.
19. Mann GB, Kang YC, Brand C, Ebeling PR. Secondary causes of low bone mass in patients with breast cancer: A need for greater vigilance. Journal of Clinical Oncology. 2009;27(22):3605-3610
20. Melton LJ, Sampson JM, Morrey BF, Ilstrup DM. Epidemiologic features of pelvic fractures. Clinical Orthopaedics and Related Research. 1981;(151):43-47.
21. Morin SN, Lix LM, Majumdar SR, Leslie WD. Temporal trends in the incidence of osteoporotic fractures. Current Osteoporosis Reports. 2013;11(4):263-269.
22. National Osteoporosis Foundation (NOF). Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2020.
23. Park-Wyllie LY, Mamdani MM, Juurlink DN, et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA. 2011;305(8):783-789.
24. Salari N, Ghasemi H, Mohammadi L, et al. The global prevalence of osteoporosis: A comprehensive systematic review and meta-analysis. Journal of Orthopaedic Surgery and Research. 2021;16(1):609.
25. Seeman E, Delmas PD. Bone quality—the material and structural basis of bone strength and fragility. New England Journal of Medicine. 2006;354(21):2250-2261.
26. Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: Report of a Task Force of the American Society for Bone and Mineral Research. Journal of Bone and Mineral Research. 2010;25(11):2267-2294.
27. Tanaka S, Nakamura K, Takahashi Y, et al. Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system. Immunological Reviews. 2005;208:30-49.
28. Vasikaran S, Eastell R, Bruyère O, et al. Markers of bone turnover for fracture risk prediction and monitoring osteoporosis treatment. Osteoporosis International. 2011;22(2):391-420.
29. Vestergaard P, Rejnmark L, Mosekilde L. Increased mortality in patients with a hip fracture—effect of pre-morbid conditions and post-fracture complications. Osteoporosis International. 2007;18(12):1583-1593.
30. Wright NC, Looker AC, Saag KG, et al. Prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. Journal of Bone and Mineral Research. 2014;29(11):2520-2526.