What is the best approach to treat a patient with osteoporosis?

Treatment of Osteoporosis

Bisphosphonates are the first-line pharmacologic treatment for osteoporosis in both postmenopausal women and men, combined with calcium (1,000-1,200 mg/day) and vitamin D (600-1,000 IU/day) supplementation, plus lifestyle modifications including weight-bearing exercise, smoking cessation, and fall prevention strategies. 1, 2

Initial Pharmacologic Treatment Algorithm

First-Line Therapy: Oral Bisphosphonates

• Oral bisphosphonates (alendronate, risedronate) are strongly recommended as initial treatment for postmenopausal women with primary osteoporosis (T-score ≤-2.5 or history of fragility fracture). 1, 2
• For men with primary osteoporosis, bisphosphonates are conditionally recommended as first-line therapy, with evidence extrapolated from postmenopausal women studies. 1
• Bisphosphonates reduce vertebral fractures by 52 per 1,000 person-years and hip fractures by 6 per 1,000 person-years compared to placebo. 3
• Generic formulations should be prescribed when possible to reduce costs. 1

Second-Line Therapy: Denosumab

• Denosumab (60 mg subcutaneously every 6 months) is recommended as second-line treatment for patients who have contraindications to or experience adverse effects from bisphosphonates. 1, 2
• Denosumab reduces vertebral fractures by 68%, hip fractures by 40%, and nonvertebral fractures by 20%. 4, 3
• Denosumab is particularly appropriate for patients with renal impairment (creatinine clearance <60 mL/min) as it is not renally cleared. 4

Very High-Risk Patients: Anabolic Agents First

• For women with very high fracture risk (recent vertebral fracture, hip fracture with T-score ≤-2.5, or multiple fractures), anabolic agents (romosozumab, teriparatide, or abaloparatide) should be initiated first, followed by transition to a bisphosphonate. 1, 2, 3
• Romosozumab has moderate-certainty evidence; teriparatide has low-certainty evidence for this indication. 1
• Critical: Patients initially treated with anabolic agents must be transitioned to an antiresorptive agent after discontinuation to preserve gains and prevent rebound vertebral fractures. 1, 4

Essential Foundational Measures (All Patients)

Calcium and Vitamin D

• Calcium intake of 1,000-1,200 mg/day (dietary plus supplementation if needed). 1, 2
• Vitamin D supplementation of 600-1,000 IU/day (some guidelines recommend 800-1,000 IU/day). 1, 2
• Adequate calcium and vitamin D are mandatory to prevent hypocalcemia, particularly with denosumab or teriparatide. 4, 5

Lifestyle Modifications

• Weight-bearing and resistance training exercises to reduce fracture risk from falls. 1, 2
• Balance training and flexibility exercises, tailored to individual patient abilities. 1
• Smoking cessation and limiting alcohol consumption (both are independent risk factors for osteoporosis). 1, 2
• Fall prevention counseling and evaluation, particularly for older adults. 1

Treatment Duration and Monitoring

Bisphosphonate Duration

• Bisphosphonates should typically be continued for 3-5 years, then reassessed for drug holiday consideration. 1, 2
• Evidence suggests that extending bisphosphonate therapy beyond 5 years reduces vertebral fractures but not other fractures, with increased risk of long-term harms. 1
• Patients at high risk (T-score still in osteoporosis range, history of fragility fracture) should continue therapy beyond 5 years. 1, 6

Denosumab Duration

• Denosumab fundamentally differs from bisphosphonates: it cannot be safely discontinued without immediate transition to another antiresorptive agent. 4
• Long-term studies support continuous denosumab treatment for up to 10 years with sustained fracture reduction. 4
• Never discontinue denosumab without planning immediate transition to bisphosphonate therapy within 6-7 months, as this can cause catastrophic rebound vertebral fractures. 4

Monitoring Recommendations

• Bone mineral density reassessment at 1-2 year intervals during treatment (though not required before each authorization during first 5 years). 2, 4
• Clinical assessment for new fractures, adherence, and adverse effects at regular intervals. 1

Special Populations

Glucocorticoid-Induced Osteoporosis

• Oral bisphosphonates are first-line therapy for patients with high fracture risk receiving glucocorticoid treatment. 1, 2
• Teriparatide or denosumab are alternatives for patients who cannot tolerate bisphosphonates. 1

Cancer Survivors with Nonmetastatic Disease

• Bone-modifying agents (oral bisphosphonates, IV bisphosphonates, or denosumab) should be offered to patients with T-score ≤-2.5 or 10-year fracture probability ≥20% for major osteoporotic fractures or ≥3% for hip fractures. 1
• Hormonal therapies are generally avoided in patients with hormone-responsive cancers. 1

Osteopenia (Low Bone Mass)

• An individualized approach is recommended for women over 65 with osteopenia regarding whether to initiate bisphosphonate therapy. 1
• Treatment decisions should be based on absolute fracture risk using tools like FRAX, not T-score alone. 3, 7

Critical Safety Considerations and Contraindications

Bisphosphonates

• Contraindicated in patients with esophageal abnormalities, hypocalcemia, or severe renal impairment (creatinine clearance <30-35 mL/min). 2
• Rare but serious adverse effects include osteonecrosis of the jaw and atypical femoral fractures (risk increases with duration of therapy). 4, 6
• Patients should be instructed to take oral bisphosphonates with full glass of water, remain upright for 30-60 minutes, and take on empty stomach. 8

Denosumab

• Requires dental examination before initiating therapy to minimize osteonecrosis of the jaw risk. 4
• Monitor for signs of infection (risk ratio 1.26 compared to placebo). 4
• Evaluate any new thigh, hip, or groin pain to rule out atypical femoral fractures. 4
• Critical warning: Rebound vertebral fractures occur after denosumab discontinuation without transition therapy. 4

Teriparatide

• Contraindicated in patients with open epiphyses, Paget's disease, prior skeletal radiation, bone metastases, or hereditary disorders predisposing to osteosarcoma. 2, 5
• Black box warning for osteosarcoma risk (based on rat studies; not confirmed in humans). 5
• Limited to 2 years of lifetime use due to theoretical osteosarcoma risk. 5
• Monitor for hypercalcemia symptoms (nausea, vomiting, constipation, lethargy, muscle weakness). 5
• Patients should sit or lie down during/after injection if experiencing lightheadedness or palpitations. 5

Common Pitfalls to Avoid

• Do not apply bisphosphonate drug holiday concepts to denosumab—the pharmacology is fundamentally different and requires continuous treatment or immediate transition. 4
• Do not transfer teriparatide from delivery device to syringe—this results in incorrect dosing. 5
• Do not discontinue anabolic agents without transitioning to antiresorptive therapy—this causes rapid bone loss and increased fracture risk. 1, 4
• Do not prescribe teriparatide for more than 2 years lifetime use due to theoretical osteosarcoma risk. 5
• Avoid using multiple antiresorptive agents simultaneously without clear evidence of benefit. 9