Osteoporosis

Definition

• Goldman-Cecil Medicine, Chapter 225

Epidemiology

• ~50% of White women will have an osteoporosis-related fracture in their lifetime - greater than their combined risk for breast cancer, heart attack, and stroke.
• 1 in 5 men will also sustain an osteoporotic fracture; ~75% of all fractures occur in women.
• Ethnic variation: Blacks have roughly half the lifetime fracture risk of Whites due to differences in bone size, microarchitecture (thicker trabeculae), and calcium absorption. Asian Americans and Hispanics have intermediate risk.
• Most common fracture site: spine (>750,000 annually in the US). Hip fractures account for ~300,000 annually and ~75% of costs.
• Hip fracture risk increases exponentially after age 65 in women; Colles fractures plateau in the mid-60s. Men lag ~5-10 years behind women in fracture incidence.

Pathophysiology

Bone Remodeling

• RANK-L (Receptor Activator of NF-κB Ligand): expressed on osteoblasts and stromal cells; stimulates osteoclast differentiation and activity.
• Osteoprotegerin (OPG): a decoy receptor that inhibits RANK-L, thereby suppressing osteoclastogenesis.
• Estrogen normally upregulates OPG and suppresses RANK-L - postmenopausal estrogen loss shifts the balance toward resorption.

Peak Bone Mass & Age-Related Loss

• Peak bone mass is achieved by ages 20-30, largely determined by genetics (~60-80%), with modifiable contributions from calcium intake, vitamin D, physical activity, and sex hormones.
• Women lose bone rapidly in the 5-10 years after menopause (up to 2-3% per year at the spine), then slowly thereafter. Men lose bone more gradually with aging.
• Cortical bone becomes thinner and more porous; trabecular bone loses connectivity, reducing structural integrity.

Risk Factors

• Advanced age, female sex, White/Asian ethnicity
• Family history of osteoporosis or fracture
• Small body frame, prior fragility fracture

• Low calcium and vitamin D intake
• Physical inactivity, prolonged immobilization
• Smoking, excessive alcohol (>3 drinks/day)
• Low BMI (<20 kg/m²)

Diagnosis

Bone Mineral Density (BMD)

• All women aged ≥65 years
• Younger postmenopausal women with risk factors
• Men aged ≥70, or younger with significant risk factors
• Any patient on long-term glucocorticoids

FRAX Score

Laboratory Workup

• Serum calcium, phosphate, alkaline phosphatase
• 25-hydroxyvitamin D
• PTH
• TSH
• CBC, ESR/CRP
• 24-hour urine calcium and creatinine
• Serum and urine protein electrophoresis (if myeloma suspected)
• Sex hormones (testosterone in men)
• Cortisol if Cushing's suspected

Bone Turnover Markers

• Resorption markers: serum C-telopeptide (CTX), urine N-telopeptide (NTX)
• Formation markers: serum P1NP (procollagen type I N-terminal propeptide), bone-specific alkaline phosphatase
• Used to monitor treatment response, not for diagnosis.

Clinical Presentation

• Osteoporosis is largely asymptomatic until a fracture occurs.
• Vertebral compression fractures: sudden or insidious back pain, loss of height (>4 cm cumulative suggests multiple fractures), progressive kyphosis ("dowager's hump"). Many (up to 2/3) are clinically silent.
• Hip fracture: typically after a fall, causing groin/thigh pain and inability to bear weight. Associated with ~20% 1-year mortality in elderly patients.
• Colles fracture: distal radius fracture after outstretched hand fall.

Treatment

Non-Pharmacological (Universal)

• Calcium: 1,000-1,200 mg/day total (diet + supplement). Postmenopausal women and men >70 need 1,200 mg/day.
• Vitamin D: 800-1,000 IU/day to maintain 25(OH)D ≥30 ng/mL.
• Weight-bearing exercise (walking, jogging) and resistance training.
• Fall prevention: vision correction, home safety assessment, balance exercises (Tai Chi), avoid polypharmacy/sedatives.
• Smoking cessation, limit alcohol.

Pharmacological Therapy

1. Bisphosphonates (First-line)

• Reduce vertebral fracture risk by ~40-70% and hip fracture risk by ~40-50%.
• Zoledronic acid also reduces mortality after hip fracture.
• Treatment typically continued 3-5 years, then re-evaluate (bisphosphonate holiday for low-risk patients; continue or switch for high-risk).
• Adverse effects: GI irritation (oral), atypical femoral fractures and osteonecrosis of the jaw (rare, mainly with prolonged use), transient flu-like reaction with IV zoledronate.

2. Denosumab

• Mechanism: humanized monoclonal antibody against RANK-L; potently inhibits osteoclastogenesis.
• Route: subcutaneous injection 60 mg every 6 months.
• Effective in postmenopausal women and men with low BMD; preferred in renal impairment (unlike bisphosphonates).
• Reduces vertebral fractures ~68%, hip fractures ~40%.
• Important: discontinuation causes rebound bone loss and increased vertebral fractures - transition to bisphosphonate if stopping denosumab.

3. Anabolic Agents (for severe osteoporosis or treatment failures)

• Recombinant PTH fragment, stimulates osteoblast activity when given intermittently.
• 20 mcg SC daily for up to 24 months.
• Reduces vertebral fractures ~65%, non-vertebral ~35%.

• Similar mechanism to teriparatide; 80 mcg SC daily.
• Reduces new vertebral fractures vs. placebo (ACTIVE trial).

• Inhibits sclerostin, a Wnt pathway inhibitor - stimulates bone formation and inhibits resorption simultaneously.
• 210 mg SC monthly for 12 months, then switch to antiresorptive therapy.
• Reduces vertebral fractures ~73% vs. placebo; cardiovascular risk signal - avoid in patients with recent MI or stroke.
• Approved for postmenopausal women at high fracture risk.

4. Hormonal Agents

• Reduces bone loss and fracture risk but not first-line due to risks of breast cancer, cardiovascular disease, and thromboembolism.
• May be considered in younger postmenopausal women with menopausal symptoms.

• Raloxifene: reduces vertebral (not hip) fracture risk; also reduces breast cancer risk. May increase hot flashes and VTE risk.

5. Calcitonin

• Nasal spray; modest anti-fracture efficacy. Primarily used for analgesia after acute vertebral fracture. No longer a preferred agent for long-term osteoporosis treatment.

Special Situations

Glucocorticoid-Induced Osteoporosis

• Most common form of secondary osteoporosis. Glucocorticoids suppress osteoblastogenesis, increase osteoblast/osteocyte apoptosis, decrease intestinal calcium absorption, and increase urinary calcium loss.
• Treat with calcium + vitamin D and a bisphosphonate (typically risedronate or zoledronate) in any patient expected to take prednisone ≥5 mg/day for ≥3 months who has a high fracture risk.

Male Osteoporosis

• Often underdiagnosed. Secondary causes are more common than in women and should be systematically excluded (hypogonadism, alcohol use disorder, glucocorticoid use, multiple myeloma).
• Treatment principles similar; alendronate, risedronate, zoledronate, and denosumab are all approved for use in men.

Monitoring

• Repeat DXA every 1-2 years during treatment initiation, then every 2-3 years once stable.
• Bone turnover markers (CTX, P1NP) can be checked 3-6 months after starting treatment to confirm biochemical response.
• Assess for new fractures if height loss >2 cm or new back pain (vertebral fracture assessment).

Key Takeaways