What are the risks of medications to treat osteoporosis in older adults with a history of fractures or other risk factors?

Risks of Osteoporosis Medications

Osteoporosis medications carry specific risks that vary by drug class, with bisphosphonates causing rare but serious complications like osteonecrosis of the jaw and atypical femoral fractures (particularly with prolonged use beyond 5 years), while denosumab poses severe hypocalcemia risk in patients with advanced kidney disease and dangerous rebound bone loss if discontinued without transitioning to another therapy. 1, 2

Bisphosphonate-Specific Risks

Common and Serious Adverse Events

• Bisphosphonates show no difference in serious adverse events or withdrawals compared to placebo in randomized controlled trials (high to moderate certainty evidence). 1
• Osteonecrosis of the jaw and atypical femoral fractures occur with higher risk after longer treatment duration (low certainty evidence from observational studies). 1
• The risk of these rare complications increases significantly when bisphosphonate therapy extends beyond 5 years. 1

Duration-Related Risks

• Extending bisphosphonate therapy beyond 3-5 years reduces vertebral fractures but increases long-term harms without reducing hip or other non-vertebral fractures. 1
• After 5 years of continuous therapy, clinicians should reassess fracture risk and consider a drug holiday unless the patient has strong indications for continuation (history of vertebral fracture, T-score ≤-2.5, or ongoing very high fracture risk). 1, 3

Denosumab-Specific Risks

Severe Hypocalcemia in Kidney Disease

• Patients with advanced chronic kidney disease (eGFR <30 mL/min/1.73 m²), including dialysis-dependent patients, face severe hypocalcemia risk that can result in hospitalization, life-threatening events, and fatal cases. 2
• The presence of chronic kidney disease-mineral bone disorder (CKD-MBD) markedly increases hypocalcemia risk in these patients. 2
• Prior to initiating denosumab in patients with advanced kidney disease, evaluate for CKD-MBD with intact parathyroid hormone, serum calcium, 25(OH) vitamin D, and 1,25(OH)2 vitamin D. 2
• Treatment should be supervised by a healthcare provider with expertise in CKD-MBD diagnosis and management. 2

Rebound Bone Loss

• Denosumab therapy must never be interrupted without switching to another therapy, as post-treatment bone loss progresses rapidly and dramatically. 4
• This contrasts with bisphosphonates, where progressive bone loss recurs slowly after discontinuation. 4

General Safety Profile

• Denosumab shows no difference in serious adverse events or withdrawals due to adverse events in randomized trials (high to moderate certainty evidence). 1

Anabolic Agent Risks

Teriparatide

• Teriparatide may increase the risk of serious adverse events and probably increases withdrawal due to adverse events (low to moderate certainty evidence). 1
• Long-term safety in humans requires ongoing evaluation. 1

Abaloparatide

• Long-term safety in humans has yet to be determined, making evidence inconclusive for recommendation. 1

Romosozumab

• Romosozumab followed by alendronate probably does not increase risk for serious harms or withdrawal compared to bisphosphonate alone at 12-36 month assessment (moderate to low certainty evidence). 1

Critical Post-Treatment Requirement

• Females initially treated with any anabolic agent must be offered an antiresorptive agent after discontinuation to preserve bone gains and prevent serious risk of rebound and multiple vertebral fractures. 1

Age-Specific Considerations for Older Adults

Polypharmacy and Fall Risk

• Older adults (≥65 years) with osteoporosis face increased risk for falls and adverse events due to polypharmacy or drug interactions. 1
• Treatment selection must address contraindications and cautions based on comorbidities and concomitant medications. 1
• Reassess other drugs associated with higher risk for falls and fractures. 1
• Consider renal function when prescribing (adjust or avoid bisphosphonates if CrCl <35 mL/min). 3

Selective Estrogen Receptor Modulators (SERMs)

• Evidence on benefits and harms of raloxifene and bazedoxifene remains inconclusive for making firm recommendations. 1
• Raloxifene may be considered in women who do not tolerate first-line antiresorptive drugs. 4

Risk Mitigation Strategies

Monitoring Requirements

• All patients require calcium 1000-1200 mg daily and at least 400-800 IU vitamin D daily to reduce hypocalcemia risk. 2, 5, 3
• BMD testing should be performed every 1-3 years during treatment in high-risk patients. 1, 5
• For patients who completed osteoporosis treatment, BMD testing should occur every 2-3 years. 1

Treatment Discontinuation Decisions

• The decision for bisphosphonate holiday and its duration must be individualized based on baseline fracture risk, medication type and bone half-life, benefits versus harms, and higher fracture risk from discontinuation. 1
• Never discontinue denosumab without transitioning to another antiresorptive therapy. 4

Special Population Considerations

• For glucocorticoid-induced osteoporosis, patients receiving very high-dose glucocorticoids (prednisone ≥30 mg/day, cumulative dose >0.5 gm in past year) require more frequent monitoring. 1
• Pregnancy must be ruled out prior to denosumab administration in all females of reproductive potential, as it can cause fetal harm. 2