Bisphosphonate treatment beyond 5 years?

Continuing bisphosphonate treatment beyond 5 years does not appear to bring benefit nor harm in terms of hip fracture risk compared with stopping treatment after 5 years, a study has shown.

While clinical evidence was strong for the first 3–5 years of treatment in reducing fracture risk, data on the optimal treatment duration beyond this initial period were scarce. Also, many of the studies were focused primarily on vertebral fracture risk.

For the current retrospective cohort study, 29,685 older women (median age 71 years) from the Kaiser Permanente Northern and Southern California healthcare delivery systems were followed on hip fracture incidence. All participants had completed 5 years of bisphosphonate treatment and were categorized into three groups according to the duration of bisphosphonate exposure: 5 years (for women who discontinued after study entry), 7 years (for those who continued for an additional 2 years), and 10 years (for those who remained on therapy for another 5 years). [JAMA Netw Open 2020;doi:10.1001/jamanetworkopen.2020.25190]

The researchers found that the cumulative incidence of hip fracture was similar regardless of whether women discontinued bisphosphonates after completing 5 years of treatment or remained on therapy for 5 additional years (5-year risk difference [RD], 3.8 per 1,000 individuals, 95 percent confidence interval [CI], -7.4 to 15.0).

“These findings were evident in analyses when defining discontinuation with or without a 6-month grace period,” the researchers noted. “If women continued treatment for 5 additional years, the risk of hip fracture was not significantly different than if they discontinued after the first 5 years.”

The findings for continuing bisphosphonates for 2 additional years (ie, total 7 years exposure) were, however, mixed — depending on inclusion of a 6-month grace period for treatment discontinuation, which according to the authors, allowed more women to be included in the analysis.

Compared with women exposed to bisphosphonates for 10 years in total, those with 7 years of exposure appeared to have lower interim risk of hip fracture: 3-year RD of 2.8 per 1,000 individuals (95 percent CI, 1.3–4.3) and 4-year RD of 9.3 per 1,000 individuals (95 percent CI, 6.3–12.3); but not if a 6-month grace period for discontinuation was excluded from the analysis.

In addition, the RD of hip fracture eventually became statistically insignificant at 5 years between the group with a total of 7 vs 10 years of bisphosphonate exposure (5-year RD, 6.0 per 1,000 individuals, 95 percent CI, -9.9 to 22.0).    

“Whether there is hip fracture benefit from continuing bisphosphonate treatment for only 2 additional years should be further studied [in randomized clinical trials,]” suggested the researchers. “Future investigation should also examine whether such findings apply to women at higher or lower fracture risk and to what degree other fracture outcomes might be affected.”

As the study specifically looked at hip fracture outcome, data on atypical femur fracture were not available, which constitutes a study limitation. The authors also noted that the incidence of atypical femur fracture, on the other hand, is typically very low compared with hip fracture.

“Taking bisphosphonates for more than 5 years may increase the risk of having an atypical femoral fracture. For many women, limiting the treatment period to 5 years or less maximizes the benefits of taking bisphosphonates in reducing the chance of having typical osteoporotic fractures while minimizing the risk of having an atypical femoral fracture,” informed Dr Kristine Ensrud from the University of Minnesota, Minneapolis, US, in a related JAMA patient column. [JAMA 2021;doi:10.1001/jama.2020.2923]