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What evidence for bisphosphonate drug holidays?


Review of: Nayak S, Greenspan SL. A systematic review and meta-analysis of the effect of bisphosphonate drug holidays on bone mineral density and osteoporotic fracture risk. Osteoporosis Intl 2019;30:705–720.

  • adverse effects
  • adherence

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Key learning points

  • Concerns about long-term treatment of osteoporosis with bisphosphonates have prompted consideration of using ‘drug holidays’.

  • A systematic review included data from four clinical trials and four cohort studies on the impact on bone mineral density of discontinuing bisphosphonate treatment compared with long-term treatment.

  • The effect on clinical and morphometric vertebral fractures was based on secondary or exploratory outcome data.

There is very limited evidence to guide recommendations on the optimal duration of bisphosphonate treatment and the role of drug holidays.1


This systematic review assessed the evidence of the effect of interrupting bisphosphonate treatment (‘drug holiday’) for osteoporosis on bone mineral density (BMD) and fracture risk.1 It included any controlled trial or cohort study involving patients with osteopenia or osteoporosis who had received osteoporosis treatment for at least 3 years. Studies needed to have at least two treatment groups (one of which continued treatment and one of which discontinued treatment) and report on the effects of drug discontinuation compared with treatment continuation on BMD or fracture risk. Eight studies met the inclusion criteria: four extension studies of randomised controlled trials (RCTs) and four cohort studies. All included women only and all but one was carried out in the USA. Two RCTs used alendronate, one used zoledronic acid and one used etidronate. The cohort studies used a range of bisphosphonates. The authors summarised the evidence on the effect of drug holidays on BMD and/or fracture risk.

In one extension study, the risk of clinical vertebral fracture was lower in women who had 10 years of alendronate therapy compared with women who stopped treatment after 5 years (relative risk 0.45, 95% CI 0.24 to 0.85).1 There was no difference in other types of fracture between treatment groups. In another extension study that compared discontinuation with a 3-year extension of treatment with zoledronic acid, there were fewer morphometric vertebral fractures in the group that had extended treatment (OR 0.51, 95% CI 0.26 to 0.95). In the other two extension studies, continued improvements in BMD were reported for women who kept taking bisphosphonates but differences in fracture risk between groups were not statistically significant. Meta-analysis of data from the four cohort studies (number of participants was not stated) found no statistically significant differences in the risk of hip fracture or any clinical osteoporotic fracture.

The authors concluded that it might be reasonable to consider bisphosphonate discontinuation for women who do not have a low hip BMD score after receiving treatment for 3–5 years.1

(The authors were funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging. No conflicts of interest were reported.)


Bisphosphonates inhibit bone turnover and are retained in bone for over 10 years.2 Uncertainty over the long-term benefit of bisphosphonates in the management of osteoporosis and concerns over rare adverse effects (eg, osteonecrosis of the jaw and atypical femoral fractures) have highlighted the need to regularly review their use.1 2 The Medicines and Healthcare products Regulatory Agency has advised that clinicians should periodically review the need for continued bisphosphonate treatment taking into account the benefits and potential risks for each patient, particularly after 5 years of use.3

However, optimal duration of bisphosphonate therapy is not known.2 3 In 2017, a consensus guideline from the National Osteoporosis Guideline Group recommended continuation of bisphosphonate treatment in those aged ≥75 years, those with a previous hip or vertebral fracture, those who had a low-impact fracture during treatment (despite good adherence) and those receiving ≥7.5 mg prednisolone per day.4 These recommendations were largely based on posthoc analyses from bisphosphonate extension studies.

The authors of this review have qualitatively described the effect of long-term bisphosphonate treatment (>3–5 years) based on extension studies that assessed BMD as the primary outcome.1 Although there was a suggestion that the incidence of clinical and morphometric vertebral fractures was reduced with long-term bisphosphonate treatment, these were secondary or exploratory outcome measures. The results highlight the paucity of high-quality evidence to help patients and clinicians decide on the optimal duration of bisphosphonate treatment.



  • Contributors DTB Team.

  • Provenance and peer review Commissioned; internally peer reviewed.