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Osteoporosis (OPP) - Complete Clinical Guide: Patient Approach, Diagnosis, Management & Treatment

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1. DEFINITION

• Osteopenia (low bone mass): T-score between -1.0 and -2.4 SD
• Osteoporosis: T-score ≤ -2.5
• Severe osteoporosis: T-score ≤ -2.5 + fragility fracture

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2. EPIDEMIOLOGY

• ~50% of White women will develop an osteoporosis-related fracture in their lifetime (greater than breast cancer, MI, and stroke combined)
• 1 in 5 men will have an osteoporosis-related fracture
• Most common fracture site: spine (>750,000/year in the US)
• Hip fractures: ~300,000/year; account for ~75% of costs
• Risk increases markedly with age; hip fracture risk increases exponentially in women after age 65
• Blacks have ~50% lower lifetime fracture risk; Asian Americans and Hispanics are intermediate

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3. PATHOPHYSIOLOGY

1. Osteoclasts resorb old/damaged bone
2. Osteoblasts form new bone matrix
3. The BMU moves at 20-40 µm/day and survives ~6 months

• Estrogen deficiency (menopause) - removes inhibition of RANK-L signaling, increasing osteoclast activity
• Aging - reduced 25(OH)D levels, secondary hyperparathyroidism accelerating cortical bone loss
• Reduction in osteoblast precursors (increased bone marrow adiposity)
• Loss of weight and muscle mass (sarcopenia) - myostatin pathway
• Periosteal bone expansion decreases with low sex steroids

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4. RISK FACTORS

Non-Modifiable

• Advanced age
• Female sex
• White or Asian ethnicity
• Family history of osteoporosis or fragility fracture
• Small body frame

Modifiable

• Low calcium and vitamin D intake
• Physical inactivity / immobilization
• Cigarette smoking
• Excessive alcohol consumption
• Low body weight / BMI

Secondary Causes (identified in >25% of individuals with osteoporosis)

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5. PATIENT APPROACH & CLINICAL PRESENTATION

History

• Often asymptomatic - discovered only after fracture or low BMD on screening
• Height loss >2 inches from maximum (suggests vertebral compression fractures, which are clinically silent in up to 3/4 of patients)
• Back pain (acute = may indicate vertebral fracture; chronic = deformity-related)
• History of low-trauma (fragility) fractures
• Ask about risk factors for secondary causes: menstrual history, steroid use, GI symptoms, thyroid symptoms, renal stones

Physical Examination

• Thoracic kyphosis (Dowager's hump)
• Decreased rib-to-pelvis distance (<2 finger-breadths suggests vertebral fractures)
• Increased wall-to-occiput distance (reflects kyphosis)
• Spinal tenderness to percussion (suggests recent vertebral fracture)
• Signs of secondary causes: blue sclerae (osteogenesis imperfecta), goiter/proptosis (hyperthyroidism), facial plethora/purple striae (Cushing syndrome)

Fragility (Osteoporotic) Fracture Sites

• Most common: Vertebral (often silent), hip, distal radius (Colles), proximal humerus, pelvis
• A prior fragility fracture is a major risk factor for future fractures

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6. DIAGNOSIS

A. Bone Mineral Density (BMD) - DEXA Scan

• Women ≥65 years
• Postmenopausal women <65 with risk factors
• Men ≥70 years
• Men 50-69 with risk factors
• Any adult with fragility fracture
• Patients on glucocorticoids or other high-risk medications
• Patients with conditions associated with bone loss

B. FRAX Tool (Fracture Risk Assessment)

• WHO algorithm calculating 10-year probability of major osteoporotic fracture and hip fracture
• Incorporates clinical risk factors with or without BMD
• Guides treatment decisions in patients with osteopenia (T-score -1.0 to -2.5)

1. Hip or vertebral fragility fracture
2. T-score ≤ -2.5 at femoral neck or spine (after ruling out secondary causes)
3. Low bone mass (T-score -1.0 to -2.5) AND FRAX 10-year hip fracture probability ≥5% OR major osteoporotic fracture ≥20%

C. Laboratory Workup

• Resorption: CTX (C-telopeptide), NTX (N-telopeptide)
• Formation: osteocalcin, bone-specific alkaline phosphatase, P1NP
• Useful for monitoring therapy response; elevated BTMs = increased remodeling

D. Imaging

• Vertebral fracture assessment (VFA): Can be done with DEXA; detects clinically silent vertebral fractures
• Spinal X-rays: If height loss >4 cm or back pain - look for vertebral compression fractures
• CT spine / MRI: When fracture morphology or marrow infiltration needs evaluation

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7. MANAGEMENT & TREATMENT

A. Non-Pharmacologic (Lifestyle Measures) - ALL Patients

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B. Pharmacologic Treatment

1. Antiresorptive (Anticatabolic) Agents

• GI: Gastroesophageal reflux, esophagitis (oral agents)
• Flu-like syndrome after first IV infusion (zoledronic acid)
• Rare: Atypical subtrochanteric femur fracture (after prolonged use >5 years)
• Rare: Osteonecrosis of the jaw (ONJ) - especially with high-dose IV use in cancer patients
• Bisphosphonate holiday: Consider after 5 years oral / 3 years IV use; reassess fracture risk

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• Estrogen (± progestogen): Effective for prevention in postmenopausal women; generally not first-line for osteoporosis due to systemic risks (DVT, stroke, breast cancer in combined HT)
• Consideration: Use when menopausal symptoms coexist

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2. Anabolic (Bone-Building) Agents - For Severe Osteoporosis

• Recombinant PTH fragment; stimulates osteoblast activity
• Reduces vertebral and non-vertebral fractures
• First-line for severe osteoporosis (T-score ≤ -3.5 or multiple vertebral fractures)
• Must be followed by antiresorptive therapy to maintain BMD gains

• PTHrP analogue; 80 µg/day SC x 24 months
• Similar efficacy to teriparatide

• Anti-sclerostin monoclonal antibody; inhibits sclerostin, increasing bone formation AND decreasing bone resorption (dual action)
• 210 mg SC monthly x 12 months
• Highly effective; shown to reduce fracture risk faster than alendronate
• Caution: Black box warning for cardiovascular events (MI, stroke); avoid in patients with recent CV event

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C. Treatment Decision Algorithm

Postmenopausal woman / Man ≥50 with fracture or low BMD
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Exclude secondary causes (labs)
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Calculate FRAX score
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┌─────────────────────────────────┐
│ Treat if:                        │
│ • Hip/vertebral fracture         │
│ • T-score ≤ -2.5                 │
│ • FRAX hip ≥5% or major ≥20%    │
└─────────────────────────────────┘
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First-line: Oral bisphosphonate (alendronate or risedronate)
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Intolerant / Renal impairment? → Denosumab or IV zoledronic acid
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Severe (T-score ≤ -3.5 or multiple fractures)? → Anabolic agent (teriparatide/romosozumab) THEN antiresorptive
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Monitor: BMD DEXA every 1-2 years, BTMs at 3-6 months

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D. Special Populations

• Most common drug-induced osteoporosis
• Any patient on ≥5 mg/day prednisone equivalent for ≥3 months should receive:
  • Calcium + Vitamin D supplementation
  • Bisphosphonate (zoledronic acid preferred) if fracture risk is high
  • FRAX-guided risk assessment; note FRAX underestimates glucocorticoid risk if dose >7.5 mg/day

• Workup includes testosterone level (hypogonadism)
• If hypogonadal: testosterone replacement first
• Alendronate, risedronate, zoledronic acid all FDA-approved for men
• Denosumab also approved in men with prostate cancer on androgen deprivation therapy

• Use Z-score (not T-score): Z-score ≤ -2.0 = "below expected range for age"
• Always investigate for secondary causes
• Bisphosphonates contraindicated in women of childbearing potential (teratogenic)

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8. FRACTURE PREVENTION & FALL PREVENTION

• Exercise: Balance training (e.g., tai chi), resistance exercises reduce fall risk significantly
• Hip protectors: Limited compliance; modest fracture reduction
• Medication review: Reduce polypharmacy, stop sedatives/antihypertensives causing orthostasis
• Vision correction: Cataract surgery reduces fall risk
• Home hazard modification: Remove rugs, improve lighting, grab bars in bathrooms
• Vertebroplasty/kyphoplasty: Consider for painful vertebral compression fractures refractory to conservative management

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9. MONITORING

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• Goldman-Cecil Medicine, Chapters 224 & 225 (Metabolic Bone Disease & Osteoporosis)
• Firestein & Kelley's Textbook of Rheumatology, Chapter on Osteoporosis
• Rheumatology, 2-Volume Set (Elsevier 2022), Chapter on Osteoporosis
• WHO FRAX algorithm (for 10-year fracture risk calculation)