What are the recommended first‑line and alternative treatment options for an adult with osteoporosis (post‑menopausal woman or older man) with a DXA (dual‑energy X‑ray absorptiometry) T‑score ≤ ‑2.5 or high fracture risk?

Treatment Options for Osteoporosis

Oral bisphosphonates (alendronate 70 mg weekly or risedronate 35 mg weekly) are the mandatory first-line pharmacologic treatment for adults with osteoporosis, combined with calcium 1,200 mg daily and vitamin D 800 IU daily. 1

First-Line Pharmacologic Treatment

Bisphosphonates are the cornerstone of osteoporosis therapy based on high-certainty evidence demonstrating a 50% reduction in hip fractures and 47-56% reduction in vertebral fractures over 3 years, with the most favorable balance of efficacy, safety, and cost. 1, 2, 3

Specific Bisphosphonate Options:

• Alendronate 70 mg once weekly (oral) 1
• Risedronate 35 mg once weekly (oral) 1
• Zoledronic acid 5 mg IV annually for patients unable to tolerate oral formulations 1

The choice among these agents should be based on patient tolerance, convenience, and cost—all three have comparable efficacy. 4 Generic bisphosphonates are more cost-effective than newer agents for initial therapy. 2

Essential Supplementation (Non-Negotiable)

All patients must receive calcium 1,200 mg daily and vitamin D 800 IU daily, as pharmacologic therapy is significantly less effective without adequate supplementation. 1, 2 Target serum 25-hydroxyvitamin D level ≥20 ng/mL. 1

For documented vitamin D deficiency (25-OH-D <20 ng/mL), prescribe high-dose repletion: vitamin D₂ 50,000 IU weekly for 8-12 weeks followed by monthly dosing, or vitamin D₃ 2,000 IU daily for 12 weeks then 1,000-2,000 IU daily for maintenance. 1

Treatment Duration and Monitoring

• Initial treatment duration is 5 years with oral bisphosphonates or 3 years with zoledronic acid 1, 3
• Do not monitor bone density during the initial 5-year treatment period—bisphosphonates reduce fractures even when BMD does not increase or actually decreases 1, 2
• After 5 years, reassess fracture risk to determine if continued therapy is warranted; patients at lower risk may be considered for a drug holiday 1, 3

This approach is critical because benefits are retained after discontinuation of bisphosphonates due to their long skeletal half-life. 3

Second-Line Treatment Options

Denosumab 60 mg subcutaneously every 6 months is the recommended alternative for patients with contraindications to or intolerance of bisphosphonates. 1, 2, 4

Critical warning: Never discontinue denosumab abruptly without transitioning to bisphosphonate therapy—abrupt discontinuation is associated with rebound bone turnover and multiple vertebral fractures in some patients. 1, 2

Anabolic Agents for Very High-Risk Patients

Anabolic medications should be reserved for very high-risk individuals only (recent vertebral fractures, hip fracture with T-score ≤-2.5, or multiple fractures), followed by transition to an antiresorptive agent. 5

Anabolic Options:

• Teriparatide (reduces nonvertebral and vertebral fractures) 3, 4
• Abaloparatide 80 mcg subcutaneously once daily (indicated for postmenopausal women and men with osteoporosis at high risk for fracture; treatment limited to 2 years maximum during patient's lifetime) 6, 4
• Romosozumab 210 mg subcutaneously monthly for 12 months (limited to 12 monthly doses due to waning anabolic effect; contraindicated in patients with myocardial infarction or stroke within the preceding year) 7, 4, 5

Important safety consideration: Abaloparatide caused dose-dependent osteosarcoma in rats; it is unknown whether this occurs in humans. 6 Romosozumab carries a boxed warning for increased risk of myocardial infarction, stroke, and cardiovascular death. 7

Agents to Avoid

Strongly avoid menopausal estrogen therapy, estrogen plus progestogen therapy, or raloxifene for osteoporosis treatment due to unfavorable benefit-harm balance. 1, 2

Mandatory Lifestyle Modifications

All patients require the following non-pharmacologic interventions regardless of medication use: 1

• Weight-bearing aerobic exercise (walking, jogging) for ≥30 minutes on ≥3 days per week 1
• Resistance and muscle-strengthening exercises to reduce fall risk 1, 5
• Balance-training programs especially in older adults 1
• Smoking cessation—tobacco accelerates bone loss 1, 5
• Limit alcohol to ≤1-2 standard drinks per day 1, 5
• Maintain healthy body weight within recommended range 1

Evaluation for Secondary Causes

All patients with osteoporosis require comprehensive workup for secondary causes of bone loss, including: 1

• Vitamin D deficiency
• Hypogonadism/estrogen deficiency
• Glucocorticoid exposure
• Malabsorption disorders (celiac disease, inflammatory bowel disease)
• Hyperparathyroidism
• Hyperthyroidism
• Chronic alcohol or opioid misuse
• Chronic kidney or liver disease 5

Laboratory screening should include: serum calcium, phosphorus, 25-hydroxyvitamin D, alkaline phosphatase, and parathyroid hormone—this panel detects secondary causes with approximately 92% sensitivity. 1

When a reversible secondary cause is identified, initiate targeted therapy for that condition before or concurrently with anti-osteoporotic pharmacotherapy. 1

Safety Profile and Adverse Effects

High-certainty evidence from randomized trials shows bisphosphonates cause no difference in serious adverse events compared to placebo at 2-3 years. 1 Common mild adverse effects include upper GI symptoms, influenza-like symptoms, myalgias, arthralgias, and headaches. 1

Rare but serious adverse effects with prolonged bisphosphonate use include osteonecrosis of the jaw and atypical femoral fractures—these are exceedingly uncommon but increase with treatment duration beyond 5 years, which is why reassessment and potential drug holidays are recommended. 1, 3, 5

Special Populations

For glucocorticoid-induced osteoporosis, therapy should be considered at a higher BMD threshold (T-score <-1.5) because fractures occur at higher BMD levels than in postmenopausal osteoporosis. 8 In patients aged ≥65 years on chronic glucocorticoids, bone protective therapy can be initiated without DEXA since the vast majority will have T-score ≤-1.5. 8