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Long-Term Drug Therapy and Drug Holidays for Osteoporosis Fracture Prevention: A Systematic Review

Systematic Review Apr 23, 2019
Long-Term Drug Therapy and Drug Holidays for Osteoporosis Fracture Prevention: A Systematic Review


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Purpose of Review

To summarize the effects of long-term osteoporosis drug treatment and of osteoporosis drug treatment discontinuation and holidays.

Key Messages

  • Evidence on the effects of long-term osteoporosis drug treatment and drug continuation versus discontinuation is mostly limited to white, healthy, postmenopausal women.
  • Long-term alendronate reduces radiographic vertebral and nonvertebral fractures in women with osteoporosis; long-term zoledronate reduces vertebral and nonvertebral fractures in women with osteopenia or osteoporosis.
  • Long-term bisphosphonates may increase atypical femoral fractures and osteonecrosis of the jaw, although both are rare.
  • In women with osteoporosis, long-term raloxifene reduces vertebral fractures, but not hip or nonvertebral fractures, and increases venous thromboembolism.
  • Long-term oral hormone therapies reduce hip and clinical fractures but increase multiple serious harms.
  • Evidence is insufficient about the effects of long-term denosumab, risedronate, ibandronate, teriparatide, and abaloparatide on fractures and harms.
  • Continuing bisphosphonates after 3–5 years versus discontinuation reduces some measures of vertebral fractures, but not nonvertebral fractures.

Structured Abstract

Objective. To summarize the effects of long-term osteoporosis drug treatment (ODT) and ODT discontinuation and holidays on fractures and harms.

Data sources. MEDLINE®, Embase®, and Cochrane databases from 1995 to October 2018; ClinicalTrials.gov; bibliographies of relevant systematic reviews.

Review methods. We defined long-term ODT as >3 years and ODT holidays as discontinuation for ≥1 year after ≥1 year of use. Trials were used for incident fractures and harms, and controlled observational studies were included for additional harms. Two investigators rated risk of bias. For studies with low or medium risk of bias, one investigator extracted data and a second verified accuracy. Two investigators graded strength of evidence (SOE).

Results. Sixty-one English-language studies were included. In women with osteoporosis, 4 years of alendronate reduced clinical fractures (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.50, 0.82]) (moderate SOE) and radiographic vertebral fractures (HR 0.50 [95% CI 0.31, 0.82]) (moderate SOE), while 4 years of raloxifene reduced clinical vertebral fractures (relative risk 0.58 [95% CI 0.43, 0.79]) (high SOE), but not hip (moderate SOE) or nonvertebral fractures (high SOE). In women with osteopenia or osteoporosis, 6 years of zoledronate reduced incident clinical fractures (HR 0.73 [95% CI 0.60, 0.90]) (moderate SOE) and clinical vertebral fractures (HR 0.41 [95% CI 0.22, 0.75]) (moderate SOE). In postmenopausal women with unknown osteoporosis or osteopenia status, both long-term oral estrogen and estrogen/progestin reduced clinical fractures (high SOE) and hip fractures (moderate SOE). After 3–5 years of prior treatment, continuation of zoledronate or alendronate versus drug holiday inconsistently reduced incident vertebral fracture outcomes (radiographic only for zoledronate [low SOE], clinical only for alendronate [moderate SOE]), but did not reduce nonvertebral fractures (low SOE). Hormone therapies increased cardiovascular events, mild cognitive impairment or dementia, and other harms. Observational studies showed that long-term bisphosphonates may increase atypical femoral fractures (AFF) (low SOE) and osteonecrosis of the jaw (low SOE in 2 comparisons, insufficient in 1).

Limitations. Most data were from white, healthy, postmenopausal women, limiting generalizability. Trials often had low power for incident clinical fractures. No trials compared active treatments, sequential treatments, or different durations of drug holidays. Harms and controls were inconsistently defined.

Conclusions. Long-term alendronate, zoledronate, and oral hormone therapy reduced nonvertebral fractures in older women, with oral hormone therapy also reducing hip fractures. While absolute reductions in typical fractures with long-term bisphosphonates are large relative to increases in AFF, reduced hip fracture risk with oral hormone therapy appears offset by increased risk of serious harms. Evidence is limited regarding ODT holidays for fractures and harms. Future research is needed, including randomized trials comparing ODT holiday durations and sequential treatments powered for clinical fractures, and controlled cohort studies of ODT holidays to estimate rare harms.


Suggested citation: Fink HA, MacDonald R, Forte ML, Rosebush CE, Ensrud KE, Schousboe JT, Nelson VA, Ullman K, Butler M, Olson CM, Taylor BC, Brasure M, Wilt TJ. Long-Term Drug Therapy and Drug Holidays for Osteoporosis Fracture Prevention: A Systematic Review. Comparative Effectiveness Review No. 218. (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-2015-00008-I) AHRQ Publication No. 19-EHC016-EF. Rockville, MD: Agency for Healthcare Research and Quality; April 2019. Posted final reports are located on the Effective Health Care Program search page. DOI: https://doi.org/10.23970/AHRQEPCCER218.

Project Timeline

Appropriate Use of Pharmacologic Therapies for Osteoporosis Fracture Prevention

Aug 15, 2017
Topic Initiated
Apr 12, 2018
Apr 23, 2019
Systematic Review
Page last reviewed January 2020
Page originally created April 2019

Internet Citation: Systematic Review: Long-Term Drug Therapy and Drug Holidays for Osteoporosis Fracture Prevention: A Systematic Review. Content last reviewed January 2020. Effective Health Care Program, Agency for Healthcare Research and Quality, Rockville, MD.

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