Oakland, CA—In the last 20 years, bisphosphonate drugs have been a first-line therapy for preventing osteoporotic fractures. That has been based on strong evidence that fracture risks are reduced during the first 3 to 5 years of treatment. But what about continuing therapy after that point?

With limited data on the optimal duration of bisphosphonate treatment to minimize fracture risk beyond the initial period, a cohort study in JAMA Network Open sought to determine what happened with nearly 30,000 women who completed 5 years of bisphosphonate treatment and then continued the therapy for an additional 5 years.

Kaiser Permanente Northern California–led authors determined that, despite the additional years of treatment, the risk of hip fracture was not significantly different than if they discontinued after the first 5 years. Researchers also found, however, that if women continued for 2 additional years and then discontinued, some difference in hip fracture outcome could be detected depending on the use of a grace period for discontinuation.

“In this study of women who completed 5 years of bisphosphonate treatment, completing an additional 5 years of treatment was not associated with a reduction in hip fracture risk; the potential hip fracture benefit for continuing 2 additional years but not for 5 additional years should be further studied,” the authors write.

Previously, a task force of the American Society for Bone and Mineral Research recommended that a drug holiday be considered following 5 years of oral bisphosphonate treatment in women who were not at high fracture risk, although it suggested that ongoing treatment probably would benefit women at high fracture risk. Those recommendations were based on collective evidence from clinical trials that each included fewer than 1,000 women who continued oral bisphosphonate treatment beyond 5 years. The FDA analyzed pooled data from the extension phases of major bisphosphonate clinical trials, concluding that the benefits of continued treatment beyond 3 to 5 years remained unclear.

Those studies, and other research, “emphasize the importance of distinguishing efficacy during the first 5 years of bisphosphonate treatment from efficacy beyond this period,” according to the study.

Included in the recent research were women who were members of Kaiser Permanente Northern and Southern California. Participants had initiated oral bisphosphonate and completed 5 years of treatment by January 1, 2002, to September 30, 2014. Data analysis was conducted from January 2018 to August 2020.

The authors explain that patients had discontinuation of bisphosphonate at study entry (within a 6-month grace period), discontinuation at 2 years (within a 6-month grace period), and continuation for 5 additional years. Defined as the primary outcome was hip fracture determined by principal hospital-discharge diagnoses.

The 29,685 women, mean age 71 years and 60% non-Hispanic white, had 507 incident hip fractures over the study period. Results indicate that, compared with bisphosphonate discontinuation at study entry, no differences in the cumulative incidence of hip fracture were documented between women who remained on therapy for 2 additional years (5-year risk difference [RD], −2.2 per 1,000 individuals; 95% CI, -20.3 to 15.9 per 1,000 individuals) or those who continued therapy for 5 additional years (5-year RD, 3.8 per 1,000 individuals; 95% CI, −7.4 to 15.0 per 1,000 individuals).

“While 5-year differences in hip fracture risk comparing continuation for 5 additional years with discontinuation at 2 additional years were not statistically significant (5-year RD, 6.0 per 1,000 individuals; 95% CI, -9.9 to 22.0 per 1,000 individuals), interim hip fracture risk appeared lower if women discontinued after 2 additional years (3-year RD, 2.8 per 1,000 individuals; 95% CI, 1.3 to 4.3 per 1,000 individuals; 4-year RD, 9.3 per 1,000 individuals; 95% CI, 6.3 to 12.3 per 1,000 individuals) but not without a 6-month grace period to define discontinuation,” according to the study.

In other words, the authors explain, “In this study of women treated with bisphosphonate for 5 years, hip fracture risk did not differ if they discontinued treatment compared with continuing treatment for 5 additional years. If women continued for 2 additional years and then discontinued, their risk appeared lower than continuing for 5 additional years. Discontinuation at other times and fracture rates during intervening years should be further studied.”

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