What are the alternative medications for osteoporosis beyond first-line treatments like bisphosphonates (e.g. alendronate, generic name: alendronic acid)?

Alternative Medications for Osteoporosis Beyond Bisphosphonates

For patients who cannot tolerate or have contraindications to bisphosphonates, denosumab (60 mg subcutaneously every 6 months) is the recommended second-line treatment, with moderate-certainty evidence in postmenopausal women and low-certainty evidence in men. 1, 2

Second-Line Treatment: Denosumab (RANK Ligand Inhibitor)

Denosumab is specifically indicated when bisphosphonates are contraindicated or cause adverse effects. 1, 2

• Dosing: 60 mg subcutaneously every 6 months 2
• Evidence quality: Moderate-certainty for postmenopausal women; low-certainty for men 1
• Efficacy: Favorable long-term net benefit in postmenopausal women with history of osteoporotic fractures and prior bisphosphonate treatment 1

Critical Safety Warning for Denosumab

Never discontinue denosumab without immediately transitioning to bisphosphonate therapy—discontinuation causes rebound bone loss and multiple vertebral fractures. 2, 3

• This is high-certainty evidence and represents a serious clinical pitfall 2
• Patients must be counseled about this mandatory sequential therapy before starting denosumab 3

Anabolic Agents for Very High-Risk Patients

Anabolic agents (teriparatide or romosozumab) should be reserved exclusively for patients at very high risk of fracture, not as routine alternatives to bisphosphonates. 4, 2, 3

Defining Very High Risk

Very high risk includes patients with: 4, 2

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

Teriparatide (Forteo)

• Dosing: 20 mcg subcutaneously daily for up to 24 months 2
• Efficacy: Reduces vertebral fractures by 69 per 1000 patients and any clinical fractures by 27 per 1000 patients 4, 2
• Evidence quality: High-certainty for fracture reduction 2
• Adverse effects: May increase serious adverse events, hypercalcemia, gastrointestinal symptoms, headache, and hypercalciuria 3
• Disadvantages: Daily subcutaneous injections required; requires refrigeration 5

Romosozumab (Evenity)

• Indication: Conditionally recommended for very high-risk postmenopausal women 4, 2
• Evidence quality: Low-certainty evidence 2, 3
• Duration: Limited to 12 monthly doses due to waning anabolic effect 2

Mandatory Sequential Therapy After Anabolic Agents

All patients treated with anabolic agents must immediately transition to bisphosphonates or denosumab after completion to maintain bone density gains—failure to do so causes rapid bone loss and rebound vertebral fractures. 4, 2, 3

• This is non-negotiable and represents high-certainty evidence 2, 3
• Never use anabolic agents in patients who cannot commit to mandatory follow-on antiresorptive therapy 3

Agents NOT Recommended

The American College of Physicians strongly recommends against using estrogen therapy, estrogen plus progestogen, or raloxifene for osteoporosis treatment. 2

• These carry unfavorable risk-benefit profiles including cardiovascular events, thromboembolic complications, and stroke 2
• This is a strong recommendation against use based on moderate-quality evidence 2

Raloxifene Exception

• Raloxifene may be considered only in younger postmenopausal women when all other options are inappropriate 1
• It should be used only for patients with less serious osteoporosis who cannot tolerate other treatments 1
• Dosing: 60 mg per day 1
• Contraindications: Venous thromboembolism, pregnancy, potential pregnancy, breastfeeding 1

Calcitonin

• Calcitonin has weaker data compared with other options 1
• Should be used only in women with less serious osteoporosis who cannot tolerate other treatments 1
• Dosing: 200 IU per day nasal spray 1

Treatment Algorithm for Alternative Medications

1. First, confirm bisphosphonates are truly contraindicated or not tolerated 1

   • Oral bisphosphonates contraindicated by: esophageal abnormalities, inability to remain upright 30 minutes, hypocalcemia 1
   • IV bisphosphonates contraindicated by: creatinine clearance <35 mL/min/1.73m², acute renal impairment, hypocalcemia 1

2. For standard osteoporosis (not very high risk): Use denosumab as second-line 1, 2

   • Counsel patient about mandatory continuation or transition to bisphosphonates 2, 3

3. For very high-risk patients: Consider anabolic agents first 4, 2

   • Ensure patient can commit to mandatory sequential antiresorptive therapy 3
   • Transition to bisphosphonates or denosumab after 12-24 months 4, 2

4. For glucocorticoid-induced osteoporosis: Follow specific hierarchy 1

   • Oral bisphosphonates remain first-line 1
   • If contraindicated: IV bisphosphonates, then teriparatide, then denosumab, then raloxifene (postmenopausal women only) 1

Essential Adjunctive Measures for All Patients

All patients on any osteoporosis medication require calcium (1000-1200 mg daily) and vitamin D (800-1000 IU daily) supplementation. 4, 2, 3

Additional measures include: 4, 2

• Weight-bearing and muscle resistance exercises
• Balance exercises
• Fall prevention counseling
• Smoking cessation
• Alcohol reduction (limit to 1-2 drinks/day)

Common Pitfalls to Avoid

• Never use anabolic agents when patient is not at very high fracture risk—use bisphosphonates or denosumab instead 3
• Never discontinue denosumab or anabolic agents without immediate transition to antiresorptive therapy 2, 3
• Never use raloxifene, estrogen, or calcitonin as routine alternatives—these have inferior efficacy and unfavorable risk profiles 1, 2
• Never forget to assess and optimize calcium/vitamin D status before and during treatment with any agent 2, 3