Fink HA, MacDonald R, Forte ML, et al. Long-Term Drug Therapy and Drug Discontinuations and Holidays for Osteoporosis Fracture Prevention: A Systematic Review. Ann Intern Med. 2019 Apr 23. pii: 2731605. doi: 10.7326/M19-0533.

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

Purpose: 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).

Limitation: 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.

Conclusion: 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).

Ratings by Clinicians (at least 3 per Specialty)
Specialty Score
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)
Internal Medicine
Comments from MORE raters

Endocrine rater

Useful information to reassure clinicians and their patients regarding benefits vs risks of OP treatment in treatment-naive patients. However, when to discontinue drug treatment in long-term users remains unclear.

Endocrine rater

The questions that this meta-analysis addresses are very important. In my view, the limited information about fracture outcomes with treatment for osteoporosis (and osteopenia) is not well known by practicing endocrinologists. This article will be very helpful as we counsel and treat our patients with osteoporosis.

Endocrine rater

Clinically this is somewhat hard topic as many of us do not know if data from alendronate extends to risedronate for example and it was not discussed in this analysis. I did feel that not all relevant trials were included in this analysis, for example FREEDOM trial with ~7000 women with extension to 10 years with denosumab was not included. It is unclear why. In all tables they refer to only one study with denosumab, with some 300 or so subjects.

General Internal Medicine-Primary Care(US) rater

It appears that the benefits of bisphosphonates outweigh risks, but whether a "drug holiday" at some juncture in the treatment is beneficial remains (at least for me) an unanswered question.

General Internal Medicine-Primary Care(US) rater

This is an important systematic review of long treatment of osteoporosis. The review addresses many of the concerns of primary care physicians on risk/benefit, duration of treatment, drug Holidays. Unfortunately gaps in research and knowledge still leave questions unanswered. The review and very well written accompanying editorial are a substantive contribution to the literature and armamentarium for a practicing primary care physician to engage patients in shared decision making.

Internal Medicine rater

We may be stopping bisphosphonates too soon due to very low risk of side effects, and it might be better to continue in the high-risk patient.

Rheumatology rater

A useful meta-analysis summarising existing trials that inform the benefits and drawbacks of long-term bisphosphonate therapy in osteoporosis. No new conclusion drawn other than the need for further cohort studies, and that longer-term therapy can be justified if the risks are discussed first.