Bisphosphonates in Fracture Management: Evidence-Based Guidelines

Primary Recommendation

Oral bisphosphonates (alendronate 70 mg weekly or risedronate 35 mg weekly) are the first-line pharmacologic treatment for fracture prevention in postmenopausal women with osteoporosis and a history of osteoporotic fractures, with strong evidence demonstrating reduction in hip fractures (6 fewer per 1000 patients), clinical vertebral fractures (18 fewer per 1000 patients), and radiographic vertebral fractures (56 fewer per 1000 patients) compared to placebo. 1, 2

Patient Selection Criteria

High-Risk Patients Requiring Treatment

Bisphosphonates are indicated for patients meeting any of the following criteria:

T-score ≤-2.5 on bone mineral density testing 3
History of vertebral or hip fracture 3
Multiple prior osteoporotic fractures 3
10-year fracture risk ≥20% for major osteoporotic fracture or ≥3% for hip fracture on FRAX assessment 4, 3
Age >74 years with osteoporosis 4

Very High-Risk Patients (Consider Anabolic Agents First)

Patients with the following features should be considered for anabolic therapy (teriparatide or romosozumab) followed by mandatory transition to bisphosphonates:

Recent vertebral fractures with T-score ≤-2.5 4, 3
Multiple prior osteoporotic fractures with severe osteoporosis (T-score ≤-3.0) 4
Hip fracture with T-score ≤-2.5 4

Pre-Treatment Requirements

Mandatory Vitamin D Repletion

Before initiating bisphosphonates, vitamin D deficiency must be corrected to prevent hypocalcemia and optimize treatment efficacy, particularly for intravenous formulations. 5

Target serum 25(OH)D level: ≥32 ng/mL 5

Repletion Protocols:

For 25(OH)D >15 ng/mL: Vitamin D3 2,000 IU daily for 12 weeks, then 1,000-2,000 IU daily for maintenance 5
For 25(OH)D <15 ng/mL or secondary hyperparathyroidism: Vitamin D2 50,000 IU weekly for 8-12 weeks, then monthly thereafter 5

Rationale: Hypocalcemia has been specifically reported in patients with unrecognized vitamin D deficiency who started intravenous bisphosphonates, with highest risk for IV formulations (zoledronic acid, ibandronate) due to rapid bone uptake and acute suppression of bone turnover. 5

Treatment Protocol

First-Line Bisphosphonate Selection

Generic oral bisphosphonates are strongly recommended due to significantly lower cost with equivalent efficacy: 2

Alendronate 70 mg orally once weekly 2
Risedronate 35 mg orally once weekly 2
Zoledronic acid 5 mg IV annually (if oral formulations contraindicated) 1, 6

Note: Ibandronate is not recommended as there is no evidence it reduces hip fractures. 1

Concurrent Supplementation (Mandatory)

All patients on bisphosphonate therapy require:

Calcium: 1,000-1,200 mg daily 2, 5, 3
Vitamin D: 800-1,000 IU daily for maintenance 2, 5, 3
Weight-bearing and muscle resistance exercises 2, 3
Fall prevention counseling 2, 3
Smoking cessation and alcohol reduction 2, 3

Treatment Duration and Drug Holidays

Initial Treatment Period

Treat with bisphosphonates for 5 years initially before reassessing fracture risk. 2, 7, 8

Reassessment After 5 Years

At 5 years, evaluate for drug holiday based on fracture risk stratification: 2, 7, 8

Low-Risk Patients (Consider Drug Holiday):

No new fractures during treatment 7, 8
Stable or improved bone mineral density 7, 8
T-score improved to >-2.5 8
No high-risk features (age <75, no prior hip/vertebral fracture) 8

Drug holiday duration: 1-2 years with monitoring, can extend if BMD remains stable and no fractures occur 8

High-Risk Patients (Continue Treatment):

History of hip or vertebral fracture 7, 8
T-score remains ≤-2.5 7, 8
Age >75 years 8
New fractures during treatment 8

Continue treatment for up to 10 years total, then reassess for drug holiday of no more than 1-2 years 8

Evidence: Extending bisphosphonate therapy beyond 5 years probably reduces vertebral fractures but not other fractures, with increased risk for long-term harms. 2

Second-Line Treatment Options

Denosumab (RANK Ligand Inhibitor)

Denosumab is reserved as second-line therapy for patients with contraindications to or adverse effects from bisphosphonates. 1, 2

Indications for denosumab:

Renal impairment (creatinine clearance <30 mL/min) 5
Esophageal disorders or inability to tolerate oral bisphosphonates 5
Failure of bisphosphonate therapy 1

Dosing: 60 mg subcutaneously every 6 months 1

Critical warning: Denosumab discontinuation is associated with multiple vertebral fractures in some patients; transition to bisphosphonate therapy is mandatory if denosumab is stopped. 1, 5

Monitoring and Safety

Clinical Monitoring Schedule

Baseline: Serum calcium, 25(OH)D level, creatinine clearance 5
1 month after initiation: Serum calcium and urinary calcium 2, 5
Annually: Clinical assessment for adherence, side effects, new fractures 2
Every 1-3 years: Reassessment of fracture risk 5

Common Adverse Effects

High-certainty evidence shows no differences between bisphosphonates and placebo in serious adverse events and withdrawals due to adverse events at ≥3 years. 1

Rare but Serious Adverse Effects

Osteonecrosis of the Jaw

Incidence: 0.01-0.3% of bisphosphonate users 1, 2
Risk increases with longer treatment duration 1
Adjusted risk ratio: 3.4 (95% CI, 1.9-5.2) compared to untreated osteoporosis patients 1

Atypical Femoral Fractures

Risk increases with longer treatment duration 1
Higher risk in Asian women (595 per 100,000 person-years) compared to non-Hispanic White women (109 per 100,000 person-years) 1
Adjusted risk ratio: 3.4 (95% CI, 1.9-5.2) at ≥2-3 years of treatment 1

Clinical pitfall: These rare adverse effects support the rationale for drug holidays after 5-10 years in appropriate patients. 7, 8

Special Populations

Men with Primary Osteoporosis

Bisphosphonates are conditionally recommended for men with primary osteoporosis, with the same first-line agents (alendronate, risedronate, zoledronic acid) as for postmenopausal women. 1, 2

Evidence: Bisphosphonates probably reduced radiographic vertebral fractures but not any clinical fractures at 12-36 months in men (moderate certainty). No RCTs evaluated hip fractures after bisphosphonates in men. 1

Postmenopausal Women with Low Bone Mass (Osteopenia)

An individualized approach is recommended regarding whether to start bisphosphonate treatment in women over 65 with low bone mass, balancing fracture risk against harms and costs. 1

Evidence: Very uncertain evidence about the effect of bisphosphonates (zoledronic acid) on hip fractures in women with low bone mass; may reduce clinical vertebral fractures without higher risk for serious adverse events. 1

Contraindications to Bisphosphonates

Absolute Contraindications

Creatinine clearance <30 mL/min (for IV bisphosphonates) 5
Hypocalcemia (must correct before initiating) 5
Inability to stand or sit upright for 30-60 minutes (for oral formulations) 9
Esophageal abnormalities that delay esophageal emptying 9

Relative Contraindications

Active upper gastrointestinal disease (consider IV formulation or alternative agent) 5
Vitamin D deficiency (must correct before initiating) 5

Clinical Algorithm for Post-Fracture Management

Immediate Post-Fracture Assessment

Confirm osteoporotic fracture (low-trauma fracture at hip, spine, wrist, humerus, pelvis) 3
Obtain bone mineral density testing (if not done within past year) 3
Check serum 25(OH)D level, calcium, creatinine clearance 5
Assess for very high-risk features (recent vertebral fracture, hip fracture with T-score ≤-2.5, multiple fractures) 4

Treatment Initiation Pathway

For very high-risk patients:

Start anabolic agent (teriparatide 20 mcg subcutaneously daily for 18-24 months) 4
Mandatory transition to bisphosphonate or denosumab after anabolic therapy completion 4

For high-risk patients (not meeting very high-risk criteria):

Correct vitamin D deficiency if 25(OH)D <32 ng/mL 5
Start oral bisphosphonate (alendronate 70 mg weekly or risedronate 35 mg weekly) once vitamin D repleted 2, 5
Initiate concurrent calcium (1,000-1,200 mg daily) and vitamin D (800-1,000 IU daily) 2, 5

Role of Fracture Liaison Services

Comprehensive inpatient or outpatient fracture liaison services increase medication initiation and adherence by 38% compared with 17% for patients without these services (risk difference 20%, 95% CI 16-25%), which may reduce subsequent fracture rates. 3

Key Clinical Pitfalls to Avoid

Starting bisphosphonates without correcting vitamin D deficiency - increases risk of hypocalcemia, particularly with IV formulations 5
Failing to provide adequate calcium and vitamin D supplementation - reduces bisphosphonate efficacy 2, 5
Continuing bisphosphonates indefinitely without reassessing fracture risk - increases risk of rare adverse effects (osteonecrosis of jaw, atypical femoral fractures) without clear additional benefit after 5-10 years 1, 7, 8
Discontinuing denosumab without transitioning to bisphosphonate - associated with multiple vertebral fractures 1, 5
Using ibandronate for hip fracture prevention - no evidence of hip fracture reduction 1
Treating low bone mass (osteopenia) without considering individual fracture risk - benefits may not outweigh harms and costs in lower-risk patients 1

What are the guidelines for using bisphosphonates in fracture management for older adults with a history of osteoporotic fractures or significant osteoporosis?

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