What is the recommended treatment for severe osteoporosis?

Treatment of Severe Osteoporosis

For severe osteoporosis at very high risk of fracture, initiate treatment with anabolic agents (romosozumab or teriparatide) followed by mandatory transition to bisphosphonates or denosumab to maintain bone gains. 1, 2

Defining Very High Risk

Very high risk for fracture includes patients with: 2

• 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)

First-Line Treatment for Severe Osteoporosis

Anabolic Agents (Preferred Initial Therapy)

Romosozumab 1, 2

• Administered as monthly subcutaneous injections
• Limited to 12 monthly doses maximum due to waning anabolic effect
• Conditionally recommended for very high-risk postmenopausal women with low-certainty evidence
• Probably does not increase serious harms or withdrawal due to adverse effects compared with bisphosphonate alone

Teriparatide 1, 2, 3

• Dosage: 20 mcg subcutaneously once daily
• Duration: Maximum 24 months during patient's lifetime
• Reduces vertebral fractures by 69 per 1000 patients and any clinical fractures by 27 per 1000 patients
• Administered into thigh or abdominal region
• Critical contraindications: open epiphyses, Paget's disease, bone metastases, prior skeletal radiation, hereditary disorders predisposing to osteosarcoma
• May increase risk for serious adverse events and withdrawal due to adverse events

Critical Pitfall: Sequential Therapy is Mandatory

After completing anabolic therapy, patients MUST transition to bisphosphonate or denosumab to maintain bone density gains and prevent rapid bone loss. 1, 2 Failure to do so results in rebound bone loss and increased fracture risk, particularly multiple vertebral fractures with denosumab discontinuation. 4

Alternative Treatment Pathway

When Anabolic Agents Are Not Appropriate

Bisphosphonates remain first-line for most patients even with severe osteoporosis if very high-risk criteria are not met: 1, 2

Oral Bisphosphonates (Preferred) 1, 2

• Alendronate: 70 mg once weekly or 10 mg daily
• Risedronate: 35 mg once weekly, 5 mg daily, 75 mg on two consecutive days per month, or 150 mg monthly
• Generic formulations strongly recommended due to significantly lower cost with equivalent efficacy
• High-certainty evidence for reducing hip and vertebral fractures

Intravenous Zoledronic Acid 2, 5, 6

• 5 mg IV annually for treatment
• Most effective bisphosphonate with highest adherence rates
• Reduces vertebral, hip, and other fractures in postmenopausal osteoporosis
• Generally more acceptable to patients than oral bisphosphonates
• Cost-effectiveness limited by hospital administration costs

Bisphosphonate Safety Considerations

Long-term risks (observational studies, low-certainty evidence): 1

• Osteonecrosis of the jaw (higher risk with longer duration)
• Atypical femoral fractures (higher risk with longer duration)
• Treatment duration: Initially 5 years, then reassess fracture risk to determine continuation versus drug holiday

Second-Line Treatment

Denosumab 1, 2, 4

• 60 mg subcutaneously every 6 months
• Reserved for patients with contraindications to bisphosphonates or who experience adverse effects
• Moderate-certainty evidence for postmenopausal women; low-certainty evidence for men
• CRITICAL WARNING: Discontinuation causes rebound bone loss and multiple vertebral fractures—patients must transition to bisphosphonate therapy after stopping

Essential Adjunctive Measures

All patients require: 1, 2, 4

• Calcium: 1000-1200 mg daily (dietary plus supplementation if needed)
• Vitamin D: 800-1000 IU daily (target serum level ≥20 ng/mL)
• Weight-bearing and muscle resistance exercises (squats, push-ups)
• Balance exercises (heel raises, standing on one foot)
• Fall prevention counseling
• Smoking cessation
• Alcohol reduction

Treatment Algorithm for Severe Osteoporosis

1. Confirm diagnosis: T-score ≤-2.5 on DEXA scan plus very high-risk criteria 2, 4

2. Assess for very high-risk features: 2

   • If present → Start anabolic agent (romosozumab 12 months or teriparatide up to 24 months)
   • If absent → Start bisphosphonate (oral preferred; IV if contraindications)

3. After anabolic therapy completion: Mandatory transition to bisphosphonate or denosumab 1, 2

4. If bisphosphonates contraindicated or not tolerated: Use denosumab as second-line 1, 2

5. Monitor adherence at 3 months using bone turnover markers (P1NP reduction >38%, CTX reduction >56%) 1

6. After 5 years: Reassess fracture risk to determine continuation versus drug holiday 2, 4

Agents NOT Recommended

The following are strongly contraindicated for osteoporosis treatment: 2

• Estrogen therapy
• Estrogen plus progestogen
• Raloxifene

These carry unfavorable risk-benefit profiles including cardiovascular events, thromboembolic complications, and stroke with moderate-quality evidence. 2