Bisphosphonate Drug Holiday Not Associated With Increased Fracture or Mortality Risk

Doctor showing older woman spine x-ray
Female doctor showing to female senior patient an x-ray on the tablet
Fracture and mortality risk are not significantly different between periods of ongoing bisphosphonate treatment and bisphosphonate holidays.

Fracture and mortality risk are not significantly different between periods of ongoing bisphosphonate (BP) treatment and BP holidays, according to study results published in Bone.

To reduce the risk for adverse events in long-term BP treatment, a drug holiday with periodic reassessments may be considered. However, the risks and benefits associated with BP holidays need to be evaluated further.

In a prospective observational study of 1973 patients (96.60% women) with prior BP treatment, investigators aimed to compare the risk for fracture and mortality associated with BP holiday and ongoing BP use.

Patients included in the analysis had been treated with BPs for ≥4 years and for ≥80% of the preceding 4 years. Baseline fracture risk was determined from referring clinicians and follow-up information was obtained periodically over 24 months after recruitment.

Outcomes of interest included incident major osteoporotic fractures, any clinical osteoporotic fracture, clinical osteoporotic vertebral fractures, and death. Outcomes were analyzed either according to treatment status at 3 months or using time-dependent treatment variables. Temporal changes in fracture risk during BP holiday were evaluated by comparing 3 increasing levels of simple moving averages of BP treatment (BP-SMA) during the preceding 12 months (0%, >0% to <50%, and ≥50%). The 3 BP-SMA levels roughly corresponded to the time since the start of BP holiday (≤6 months, >6 to ≤12 months, and >12 months, respectively).

At the time of first interview (approximately 3 months after recruitment), 1250 participants reported ongoing BP use and 601 reported a BP holiday. Between the 6-month and final interviews, 884 patients reported a BP holiday ≥6 months long. The median length of the first BP holiday was 1.71 years (interquartile range, 1.03-2.02 years).

The risk for major osteoporotic fractures, any clinical osteoporotic fracture, and clinical vertebral fractures were lower but not significantly different between patients who underwent a BP holiday compared with ongoing BP use. A pattern of increasing fracture risk was observed across the 3 BP-SMA levels for major osteoporotic fractures and incident clinical vertebral fractures but the association was not significant.

An interaction was observed between prevalent vertebral fracture and BP-SMA level with regard to major osteoporotic fracture risk (P =.046). Within BP-SMA levels, fracture risk was higher in patients with a prevalent vertebral fracture than in those without. A similar but nonsignificant trend was observed with regard to any clinical osteoporotic fracture.

The mortality rate was lower but not significantly different in the BP holiday group compared with the ongoing BP group, even after adjusting for length of treatment.

Atypical femoral fracture and osteonecrosis of the jaw, which represent rare but serious adverse effects related to long-term BP treatment, occurred in 2 and 3 participants, respectively.

Related Articles

The researchers noted that the small size of the study represented a limitation and prevented the identification of statistically significant relationships. In addition, treatment and fracture status were assessed by interview rather than medical records, which may have resulted in missing confounding factors, such as initiation of menopausal hormone therapy.

“Fracture risk and mortality in patients with preceding BP treatment did not significantly differ between BP holidays and ongoing BP use for an observation period up to 25 months,” the study authors concluded. However, given the observation that fracture risk increased in patients with higher BP-SMA levels within the backdrop of a prevalent vertebral fracture, they noted that “[t]he presence of a [prevalent vertebral fracture] may increase the relative risk of [major osteoporotic fractures] associated with a longer BP holiday.”

Disclosures: Dr Pfeilschifter and Dr Steinebach report affiliations with the pharmaceutical industry. Please see the original reference for a full list of disclosures.

Follow @EndoAdvisor


Pfeilschifter J, Steinebach I, Trampisch HJ, Rudolf H. Bisphosphonate drug holidays: risk of fractures and mortality in a prospective cohort study [published online May 15, 2020]. Bone. doi:10.1016/j.bone.2020.115431