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Ann Intern Med. 2019 Jul 2;171(1):37-50. doi: 10.7326/M19-0533. Epub 2019 Apr 23.

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

Author information

University of Minnesota and Minneapolis VA Health Care System, Minneapolis, Minnesota (H.A.F., R.M., K.E.E., K.U., B.C.T., T.J.W.).
University of Minnesota, Minneapolis, Minnesota (M.L.F., C.E.R., V.A.N., M.B., C.M.O., M.B.).
University of Minnesota, Minneapolis, and HealthPartners, Bloomington, Minnesota (J.T.S.).



Optimal long-term osteoporosis drug treatment (ODT) is uncertain.


To summarize the effects of long-term ODT and ODT discontinuation and holidays.

Data Sources:

Electronic bibliographic databases (January 1995 to October 2018) and systematic review bibliographies.

Study Selection:

48 studies that enrolled men or postmenopausal women aged 50 years or older who were being investigated or treated for fracture prevention, compared long-term ODT (>3 years) versus control or ODT continuation versus discontinuation, reported incident fractures (for trials) or harms (for trials and observational studies), and had low or medium risk of bias (ROB).

Data Extraction:

Two reviewers independently rated ROB and strength of evidence (SOE). One extracted data; another verified accuracy.

Data Synthesis:

Thirty-five trials (9 unique studies) and 13 observational studies (11 unique studies) had low or medium ROB. In women with osteoporosis, 4 years of alendronate reduced clinical fractures (hazard ratio [HR], 0.64 [95% CI, 0.50 to 0.82]) and radiographic vertebral fractures (both moderate SOE), whereas 4 years of raloxifene reduced vertebral but not nonvertebral fractures. In women with osteopenia or osteoporosis, 6 years of zoledronic acid reduced clinical fractures (HR, 0.73 [CI, 0.60 to 0.90]), including nonvertebral fractures (high SOE) and clinical vertebral fractures (moderate SOE). Long-term bisphosphonates increased risk for 2 rare harms: atypical femoral fractures (low SOE) and osteonecrosis of the jaw (mostly low SOE). In women with unspecified osteoporosis status, 5 to 7 years of hormone therapy reduced clinical fractures (high SOE), including hip fractures (moderate SOE), but increased serious harms. After 3 to 5 years of treatment, bisphosphonate continuation versus discontinuation reduced radiographic vertebral fractures (zoledronic acid; low SOE) and clinical vertebral fractures (alendronate; moderate SOE) but not nonvertebral fractures (low SOE).


No trials studied men, clinical fracture data were sparse, methods for estimating harms were heterogeneous, and no trials compared sequential treatments or different durations of drug holidays.


Long-term alendronate and zoledronic acid therapies reduce fracture risk in women with osteoporosis. Long-term bisphosphonate treatment may increase risk for rare adverse events, and continuing treatment beyond 3 to 5 years may reduce risk for vertebral fractures. Long-term hormone therapy reduces hip fracture risks but has serious harms.

Primary Funding Source:

National Institutes of Health and Agency for Healthcare Research and Quality. (PROSPERO: CRD42018087006).


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