When should bisphosphonates be started in patients with osteoporosis, particularly postmenopausal women and older adults?

When to Start Bisphosphonates in Osteoporosis

Bisphosphonates should be started immediately upon diagnosis of primary osteoporosis in postmenopausal women (T-score ≤ -2.5 or history of spine/hip fracture), as they are the first-line pharmacologic treatment with high-certainty evidence for fracture reduction. 1

Postmenopausal Women with Osteoporosis

Start bisphosphonates now if any of the following criteria are met:

• Bone mineral density T-score ≤ -2.5 at the hip or spine 1, 2
• History of osteoporotic spine or hip fracture, regardless of BMD 1, 2
• FRAX score indicating ≥3% 10-year hip fracture risk OR ≥20% major osteoporotic fracture risk 3

The American College of Physicians provides a strong recommendation for bisphosphonates as initial therapy in postmenopausal women with osteoporosis, based on high-certainty evidence showing 50% reduction in vertebral fractures and 40-50% reduction in hip fractures over 3 years 1, 4. Benefits begin accruing within 12.4 months, with 1 nonvertebral fracture prevented per 100 women treated 5.

Preferred Bisphosphonate Regimens

Choose one of these first-line options:

• Alendronate 70 mg orally once weekly (or 10 mg daily) 6
• Risedronate 35 mg orally once weekly (or 5 mg daily, or 150 mg monthly) 6
• Zoledronic acid 5 mg IV annually 6

Generic oral bisphosphonates are preferred over brand-name formulations due to equivalent efficacy at significantly lower cost 6.

Men with Osteoporosis

Start bisphosphonates in men meeting the same diagnostic criteria (T-score ≤ -2.5 or prior osteoporotic fracture), though the recommendation strength is conditional due to lower-certainty evidence 1. Bisphosphonates reduce radiographic vertebral fractures in men, though hip fracture data are limited 1.

Postmenopausal Women with Osteopenia (Low Bone Mass)

Take an individualized approach—do NOT automatically start bisphosphonates in osteopenia (T-score between -1.0 and -2.5) 1.

Consider starting bisphosphonates only if:

• FRAX score meets treatment thresholds (≥3% hip fracture risk or ≥20% major fracture risk) 3
• Multiple additional risk factors present (age >65, prior fracture, glucocorticoid use, family history) 3

The evidence for treating osteopenia is very low-certainty, with only zoledronate showing potential benefit in select high-risk osteopenia patients 1, 3. Most women with osteopenia should receive calcium (1,000-1,200 mg/day), vitamin D (600-800 IU/day), and lifestyle modifications rather than pharmacologic therapy 3.

Very High-Risk Patients Requiring Anabolic Therapy First

Start with anabolic agents (romosozumab or teriparatide) BEFORE bisphosphonates if:

• Age >74 years with osteoporosis 6
• Recent fracture within 12 months 6
• Multiple prior osteoporotic fractures 6
• T-score ≤ -3.0 6
• Fracture occurring despite ongoing bisphosphonate therapy 6

After completing 12 months of romosozumab or up to 24 months of teriparatide, patients must transition to bisphosphonate therapy to maintain bone density gains and prevent rapid bone loss 6, 7.

Glucocorticoid-Induced Osteoporosis

Start bisphosphonates immediately in patients receiving:

• Prednisone ≥7.5 mg/day for ≥6 months with moderate-to-high fracture risk 1
• Very high-dose glucocorticoids (prednisone ≥30 mg/day with cumulative dose >5 gm/year) in adults ≥30 years 1

For adults <40 years, start bisphosphonates only if there is a history of osteoporotic fracture OR hip/spine BMD Z-score <-3 OR bone loss ≥10%/year 1.

Essential Pre-Treatment Requirements

Before starting bisphosphonates, ensure:

• Vitamin D sufficiency (25-OH vitamin D >20 ng/mL, ideally >32 ng/mL) to prevent hypocalcemia 4, 6
• Adequate calcium intake (1,000-1,200 mg/day) 6, 8
• Dental evaluation completed if high-risk dental procedures are needed (to minimize osteonecrosis of jaw risk, though this remains rare at <1 per 10,000 patient-years) 4
• Creatinine clearance ≥30 mL/min (bisphosphonates not recommended in severe renal impairment) 8

Critical Administration Instructions

For oral bisphosphonates, instruct patients to:

• Take in the morning immediately after breakfast (for delayed-release formulations) or on an empty stomach with plain water (for immediate-release) 8
• Use at least 4 ounces (120 mL) of plain water 8
• Remain upright (standing or sitting) for 30 minutes after taking the medication to prevent esophageal complications 8, 4
• Avoid taking with calcium supplements, antacids, PPIs, H2 blockers, or iron as these interfere with absorption 8

When NOT to Start Bisphosphonates

Absolute contraindications:

• Esophageal abnormalities (stricture, achalasia) that delay esophageal emptying 8
• Inability to stand or sit upright for 30 minutes 8
• Uncorrected hypocalcemia 8
• Known hypersensitivity to bisphosphonates 8
• Severe renal impairment (CrCl <30 mL/min) 8

Use denosumab 60 mg subcutaneously every 6 months as second-line therapy if bisphosphonates are contraindicated or not tolerated 1, 6. However, never discontinue denosumab without transitioning to bisphosphonates, as this causes severe rebound bone loss and multiple vertebral fractures 6, 4.

Treatment Duration and Reassessment

Initial treatment duration: 5 years for oral bisphosphonates or 3 years for IV zoledronic acid 6, 9.

After initial treatment period, reassess fracture risk:

• High-risk patients (age >65, hip T-score <-2.5, prior major fracture, or fracture on therapy): Continue treatment up to 10 years (oral) or 6 years (IV) 9, 6
• Low-to-moderate risk patients: Consider a drug holiday of 2-3 years with periodic reassessment 9, 6

The residual antifracture effects persist after bisphosphonate discontinuation due to prolonged bone retention, making drug holidays feasible in lower-risk patients 2, 9.

Common Pitfalls to Avoid

• Never start bisphosphonates without correcting vitamin D deficiency first—this substantially increases hypocalcemia risk, particularly with IV formulations 4
• Do not confuse osteopenia with osteoporosis—most osteopenia patients do not require pharmacologic treatment 3
• Do not use denosumab, estrogen, raloxifene, or other agents as first-line therapy when bisphosphonates are appropriate 1, 6
• Never implement drug holidays in very high-risk patients without careful risk stratification 6
• Do not apply drug holiday concepts to denosumab—it requires continuous therapy or transition to bisphosphonates 6