What are the first line treatments for osteoporosis?

First-Line Treatment for Osteoporosis

Bisphosphonates are the first-line pharmacologic treatment for osteoporosis in both postmenopausal women and men, with oral alendronate or risedronate preferred due to high-certainty evidence for fracture reduction and significantly lower cost with generic formulations. 1, 2, 3

Treatment Algorithm by Risk Stratification

Standard Risk Osteoporosis (Most Patients)

Start with oral bisphosphonates as initial therapy:

• Alendronate or risedronate are the preferred agents, available as once-weekly formulations (alendronate 70 mg or risedronate 35 mg) for improved convenience and adherence 1, 2, 3
• Zoledronic acid (intravenous, once yearly) is an alternative for patients who cannot tolerate oral formulations 2, 3
• This is a strong recommendation with high-certainty evidence for postmenopausal women, reducing hip fractures by 6 per 1000 patients, clinical vertebral fractures by 18 per 1000, and radiographic vertebral fractures by 56 per 1000 1
• For men, this is a conditional recommendation with low-certainty evidence, primarily extrapolated from studies in women 1, 2
• Generic formulations should be prescribed whenever possible due to equivalent efficacy at significantly lower cost 2, 3

Note: Ibandronate should be avoided as there is no evidence it reduces hip fractures 1

Very High-Risk Osteoporosis (Anabolic Agents First)

Initiate anabolic agents BEFORE bisphosphonates, followed by mandatory transition to antiresorptive therapy:

Very high-risk criteria include 4, 3:

• Age >74 years
• Recent fracture within 12 months
• Multiple prior osteoporotic fractures
• T-score ≤-3.0
• Fractures despite ongoing bisphosphonate therapy
• High FRAX scores (≥20% for major osteoporotic fracture or ≥3% for hip fracture)

Anabolic agent options:

• Teriparatide reduces vertebral fractures by 69 per 1000 patients and any clinical fractures by 27 per 1000 patients 4, 3
• Romosozumab is conditionally recommended for very high-risk postmenopausal women, limited to 12 monthly doses due to waning anabolic effect 4, 3
• After completing anabolic therapy, patients MUST transition to bisphosphonates or denosumab to maintain bone gains 4, 3

Second-Line Treatment

Denosumab 60 mg subcutaneously every 6 months is reserved for patients with:

• Contraindications to bisphosphonates
• Adverse effects from bisphosphonates 1, 2, 3

This is a conditional recommendation with moderate-certainty evidence for postmenopausal women and low-certainty evidence for men 1, 3

Critical Denosumab Warning

Denosumab discontinuation causes rebound bone loss and multiple vertebral fractures—patients MUST transition to bisphosphonate therapy after stopping denosumab 3, 5

Essential Adjunctive Measures for ALL Patients

Every patient requires the following regardless of pharmacologic choice 4, 2, 3:

• Calcium 1000-1200 mg daily
• Vitamin D 800-1000 IU daily (target serum level ≥20 ng/mL)
• Weight-bearing and muscle resistance exercises
• Balance exercises and fall prevention counseling
• Smoking cessation
• Alcohol reduction

Treatment Duration and Monitoring

• Treat with bisphosphonates for 5 years initially, then reassess fracture risk to determine whether to continue or take a drug holiday 2, 3
• Do not perform bone density monitoring during the 5-year treatment period 3
• Reassess fracture risk at 5 years to guide continuation decisions 3

Important Safety Considerations

Bisphosphonate-Specific Risks

While bisphosphonates show no difference from placebo in serious adverse events in randomized trials 1, observational studies demonstrate:

• Increased risk of osteonecrosis of the jaw (incidence 0.01%-0.3%) and atypical femoral fractures after 2-3 years of use (adjusted risk ratio 3.4) 1
• These events remain uncommon but require patient counseling 2, 3

Denosumab-Specific Risks

• Severe hypocalcemia risk, especially in patients with advanced chronic kidney disease—requires laboratory testing before initiation 5
• Mandatory transition to bisphosphonates upon discontinuation to prevent rebound vertebral fractures 3, 5

Common Pitfalls to Avoid

• Do not use ibandronate as it lacks evidence for hip fracture reduction 1
• Do not start anabolic agents in standard-risk patients—reserve for very high-risk only 4, 3
• Do not discontinue denosumab without transitioning to bisphosphonates—this causes dangerous rebound bone loss 3, 5
• Do not forget calcium and vitamin D supplementation—pharmacologic therapy alone is insufficient 4, 2, 3