Evidence, Primary Considerations for Bisphosphonate Drug Holidays in Patients With Osteoporosis

Shot of a doctor showing a senior patient a bone scan on a digital tablet while sitting in her office, fracture, osteoporosis
Authors of the review discuss primary considerations and areas for future research regarding bisphosphonate drug holiday duration in patients with osteoporosis.

Evidence and considerations for decision-making and areas for future research regarding bisphosphonate drug holiday duration in patients with osteoporosis were discussed, in a review article published in Journal of Clinical Medicine.

Oral bisphosphonates are considered the current first-line therapy for osteoporosis, with alendronate, risedronate, and zoledronate being the most commonly used bisphosphonates. Bisphosphonates have a strong affinity for hydroxyapatite, a bone mineral, they can accumulate in the bone for many years, and circulation can continue long after therapy discontinuation. However, the risk for most fractures does not exacerbate after discontinuation of long-term alendronate therapy.

Due to these biochemical manifestations, guidelines recommend that patients with osteoporosis with a low to moderate risk for fracture undertake a 2- to 3-year drug holiday from bisphosphonate treatment after 3 to 5 years of therapy. Patients with a high risk for fractures should continue to receive bisphosphonate therapy or switch to another osteoporosis treatment. Of note, the review authors noted that drug holidays with nonbisphosphonate treatments are discouraged, especially with denosumab, which has a short-lived antifracture effect after drug discontinuation.

Other benefits of undergoing drug holidays include reducing medication burden, as well as reducing the risk for serious – but rare – adverse effects of prolonged bisphosphonate use.

In their review, the authors outlined 4 considerations that may contribute to the decisions surrounding bisphosphonate drug holidays.

Treatment Duration and Adherence in Total Bisphosphonate Exposure

Bisphosphonates provide cumulative exposure effects, and only after consistent treatment for 6 to 12 months can sufficient osteoclast inhibition can be achieved. The 3- to 5-consecutive treatment years before drug holidays are based on results from the FLEX (ClinicalTrials.gov Identifier: NCT00398931) and HORIZON (ClinicalTrials.gov Identifier: NCT00049829) trials.

Some studies have reported that patients might begin drug holidays earlier than 5 years following oral bisphosphonate treatment, and that they may have a suboptimal adherence before a drug holiday; however, the association between increased risk for fracture and lower total bisphosphonate exposure during and before a drug holiday, respectively, is unknown. “Yet, based on the evidence to date, we would expect that shorter periods of therapy…or low adherence therapy, likely reduce the length of continued fracture protection during drug holiday,” the authors noted.

Bisphosphonate Use Before a Drug Holiday

Not all bisphosphonates have the same potency to inhibit osteoclast activity, and they do not result in the same affinity for hydroxyapatite, which can lead to variations in the length of drug holidays.

Currently, zoledronate has the highest affinity for hydroxyapatite, followed by alendronate, ibandronate, risedronate, and etidronate in decreasing affinities.

Results from the FLEX and HORIZON trials have suggested that alendronate and zoledronate suppress bone turnover markers for up to 5 years and 3 years after treatment discontinuation, respectively. Conversely, within 1 year after risedronate treatment was stopped, bone turnover marker levels returned to placebo levels.

Patients on a risedronate drug holiday may need to be more closely monitored for risk for fracture compared with patients discontinuing alendronate therapy. Authors of the review noted that the most appropriate drug holiday after risedronate therapy is 1 to 2 years.

Bone Mineral Density and Fall Risk

Changes in risk factors are one of the most important considerations when assessing appropriateness of a continued drug holiday. As fracture risk assessment tools have not been validated in patients on drug holiday, examination of certain fracture risk factors, including BMD and fall risk, is useful to determine the length of a drug holiday.

Medications such as chronic glucocorticoid therapy and aromatase inhibitors may affect BMD and fracture risk, and may justify ending a drug holiday. Other medications such as androgen deprivation therapy and some chemotherapeutic agents, thiazolidinediones, proton pump inhibitors, sodium-glucose cotransporter-2 inhibitors chronic heparin therapy, and thyroid hormone supplements may also affect BMD, but may not justify ending a drug holiday.

The authors added that a number of factors may increase fall risk and that there is no available evidence on the effects of new fall risk during a drug holiday.

Patient Sex and Body Weight

Authors of the review noted that sex and gender, as well as body weight, may have varying effects on length of drug holiday. Because bisphosphonates were developed when women were diagnosed with osteoporosis, there is a lack of understanding of osteoporosis diagnosis and treatment in men. As a result, there are no large empiric studies to assess the effects of long-term bisphosphonate therapy or drug holidays in men.

Bisphosphonates accumulate in areas of the body where there is a higher frequency of bone remodeling, and individuals with a larger body frames may not derive the same lasting antifracture effects as those with smaller body frames because of less remaining circulating bisphosphonate in proportion to bone size. To resolve the lack of knowledge surrounding these factors, the authors suggested that more studies should assess the differential fracture risk by using patient characteristics to determine whether drug holidays should be developed with sex or body weight in mind.

“Future research is needed to examine fracture risk by drug holiday length that considers how these factors modify fracture risk to form patient- and therapy-specific drug holiday timeframes,” the authors concluded.


Haynes KN, Winter EM, Cadarette SM, Burden AM. Duration of bisphosphonate drug holidays in osteoporosis patients: a narrative review of the evidence and considerations for decision-making. J Clin Med. 2021;(10):1140. doi:10.3390/jcm10051140