What is the recommended pharmacologic and non‑pharmacologic management for osteoporosis?

Osteoporosis Treatment: Pharmacologic and Non-Pharmacologic Management

Oral bisphosphonates (alendronate 70 mg weekly or risedronate) are the first-line pharmacologic treatment for osteoporosis, combined with mandatory calcium 1000-1200 mg daily, vitamin D 800-1000 IU daily, and a structured exercise program including resistance training and balance exercises. 1

Pharmacologic Treatment Algorithm

First-Line: Oral Bisphosphonates

• Prescribe alendronate 70 mg once weekly or risedronate as initial therapy for postmenopausal women and men with osteoporosis at high risk for fracture 1
• These agents reduce vertebral fractures by 52 per 1000 person-years, hip fractures by 6 per 1000 person-years, and non-vertebral fractures significantly 1, 2
• Use generic formulations whenever possible due to significantly lower cost with equivalent efficacy 1
• Treat for 5 years initially, then reassess fracture risk to determine whether to continue or take a drug holiday 1, 3

Treatment Indications (When to Start)

• T-score ≤-2.5 at femoral neck, total hip, or lumbar spine 4, 1
• T-score between -1.0 and -2.5 with 10-year FRAX risk of major osteoporotic fracture ≥20% or hip fracture ≥3% 4, 1
• History of low-trauma fracture, even if DEXA does not indicate osteoporosis 1

After 5 Years of Bisphosphonate Therapy

• If moderate-to-high fracture risk persists: Continue treatment for 7-10 years total, switch to IV bisphosphonate if absorption/adherence is problematic, or consider another drug class 1
• If lower risk after 5 years: Discontinue treatment temporarily (drug holiday) 1, 3
• Continue therapy beyond 5 years only if: History of vertebral fracture, T-score ≤-2.5, or ongoing very high fracture risk 3
• Extending beyond 5 years reduces vertebral fractures but increases long-term harms without reducing hip or other non-vertebral fractures 3

Second-Line: Denosumab

• Prescribe denosumab 60 mg subcutaneously every 6 months for patients with contraindications to or intolerance of bisphosphonates 4, 1
• Critical warning: Denosumab discontinuation causes rebound bone loss and multiple vertebral fractures 1
• Patients must transition to bisphosphonate therapy after stopping denosumab to prevent rebound fractures 1

Very High-Risk Patients: Anabolic Agents First

Initiate anabolic agents (teriparatide, abaloparatide, or romosozumab) before bisphosphonates in patients meeting very high-risk criteria, followed by mandatory transition to antiresorptive therapy 1, 2

Very high-risk criteria include:

• Age >74 years 1
• Recent fracture within 12 months 1
• Multiple prior osteoporotic fractures 1
• T-score ≤-3.0 1
• Fractures despite ongoing bisphosphonate therapy 1

Anabolic agent specifics:

• Teriparatide reduces vertebral fractures by 69 per 1000 patients and clinical fractures by 27 per 1000 patients 1
• Abaloparatide is supported by the strongest BMD data for men with osteoporosis at very high risk 1
• Romosozumab is conditionally recommended for very high-risk postmenopausal women, limited to 12 monthly doses due to waning anabolic effect 1
• Limit anabolic agents to 2 years maximum, then must be followed by antiresorptive therapy to maintain bone gains 1

Special Population: Glucocorticoid-Induced Osteoporosis

• For patients on ≥2.5 mg/day of glucocorticoids for >3 months, perform fracture risk assessment within 6 months of starting therapy 1
• Oral bisphosphonates are strongly recommended for patients at high or very high fracture risk 1
• Anabolic agents (teriparatide or PTH-related protein) are conditionally recommended over antiresorptive agents for very high fracture risk 1

Special Population: Cancer Survivors

• For patients with nonmetastatic cancer with osteoporosis or increased fracture risk, offer oral bisphosphonates, IV bisphosphonates, or subcutaneous denosumab at osteoporosis-indicated dosage 4
• Avoid hormonal therapies (estrogens) in patients with hormonal-responsive cancers 4
• Consider treatment at higher bone density than recommended using FRAX for patients receiving GnRH therapies, aromatase inhibitors, androgen deprivation therapy, bone marrow transplantation, or chronic glucocorticoid use 4

Special Population: Chronic Kidney Disease

• Bisphosphonates, denosumab, teriparatide, and romosozumab have demonstrated increased BMD in patients with CKD G4-G5D 4
• Safety concerns in CKD: For bisphosphonates—nephrotoxicity, osteonecrosis of the jaw, atypical femoral fractures; for denosumab—hypocalcemia (more severe in CKD), rebound bone resorption; for teriparatide/abaloparatide—hypercalcemia and hyperuricemia; for romosozumab—cardiovascular risk 4
• Many agents are off-label in CKD G4-G5D 4

Non-Pharmacologic Interventions (Mandatory for All Patients)

Calcium and Vitamin D Supplementation

• Calcium 1000-1200 mg daily (dietary intake plus supplements if needed) 4, 1, 5, 2
• Vitamin D 800-1000 IU daily (target serum 25(OH)D level ≥20 ng/mL or 50 nmol/L) 4, 1, 6, 7, 2
• Higher vitamin D doses (800 IU or more) are more effective than lower doses for fracture prevention 5
• Vitamin D doses of 800 IU per day present little risk of toxicity regardless of sun exposure, season, or additional multivitamin use 6

Exercise Program

• Prescribe a combination of exercise types: balance training, flexibility/stretching exercises, endurance exercise, and resistance/progressive strengthening exercises 4, 1
• Tailor exercise according to the needs and abilities of the individual patient 4
• Offer medical rehabilitation to patients with impairment hindering gait or balance 4
• Muscle resistance exercises (squats, push-ups) and balance exercises (heel raises, standing on 1 foot) are specifically recommended 2

Lifestyle Modifications

• Smoking cessation (smoking is a risk factor for osteoporosis) 4, 1
• Limit alcohol consumption (excessive alcohol increases osteoporosis risk) 4, 1
• Avoid malnutrition 4
• Implement fall-prevention strategies 4, 1

Special Consideration: Men

• Assess serum total testosterone as part of pre-treatment evaluation 1
• Consider appropriate hormone replacement therapy in men with low levels of total or free serum testosterone 1
• The same treatment algorithm applies to men as to postmenopausal women, with oral bisphosphonates as first-line and denosumab as second-line therapy 1

Monitoring and Follow-Up

Bone Mineral Density Testing

• Perform DEXA scanning in all women aged ≥65 years, postmenopausal women <65 years with risk factors, men aged ≥65 years, and men <65 years with risk factors 1
• During treatment: BMD testing every 1-2 years until stable, then every 2-3 years 1
• Do not perform bone density monitoring during the initial 5-year pharmacologic treatment period 1
• For patients at high risk on cancer-related therapies causing bone loss, offer BMD testing every 2 years, or more frequently if medically necessary (generally not more than annually) 4

Biochemical Monitoring

• Use bone turnover markers to assess adherence to anti-resorptive therapy 1
• Assess for medication side effects at each visit, including rare complications like osteonecrosis of the jaw and atypical femoral fractures 1

Safety Considerations and Adverse Events

Bisphosphonates

• No difference in serious adverse events or withdrawals compared to placebo in randomized controlled trials 3
• Osteonecrosis of the jaw and atypical femoral fractures occur with higher risk after longer treatment duration 3
• Nephrotoxicity is a concern, particularly in CKD 4

Denosumab

• Hypocalcemia risk (more severe in CKD patients) 4, 3
• Osteonecrosis of the jaw and atypical femoral fractures 4
• Rebound bone resorption upon discontinuation is a critical safety issue requiring transition to bisphosphonates 1

Anabolic Agents

• Teriparatide may increase risk of serious adverse events and probably increases withdrawal due to adverse events 3
• Romosozumab followed by alendronate probably does not increase risk for serious harms or withdrawal compared to bisphosphonate alone at 12-36 month assessment 3
• Cardiovascular risk with romosozumab 4
• Hypercalcemia and hyperuricemia with teriparatide and abaloparatide 4

Older Adults

• Older adults (≥65 years) with osteoporosis face increased risk for falls and adverse events due to polypharmacy or drug interactions 3
• Treatment selection must address contraindications and cautions based on comorbidities and concomitant medications 3

Common Pitfalls to Avoid

• Do not extend bisphosphonate therapy beyond 5 years without reassessing fracture risk and documenting strong indications for continuation 3
• Never discontinue denosumab without transitioning to bisphosphonate therapy due to rebound fracture risk 1
• Do not use anabolic agents beyond 2 years without transitioning to antiresorptive therapy 1
• Do not prescribe hormonal therapies (estrogens) in patients with hormonal-responsive cancers 4
• Ensure adequate calcium and vitamin D supplementation to reduce hypocalcemia risk, particularly with denosumab 3
• Do not perform BMD testing more frequently than annually in most cases 4