Bisphosphonate Drug Holiday Doesn't Increase Fracture Risk

Nancy A. Melville

September 14, 2014

HOUSTON — Women who take a drug holiday from bisphosphonate treatment for a year or longer after 3 or more years of exposure show no greater risk for osteoporosis-related fragility fractures or hip fractures than those who remained on the drugs without interruption, according to new research presented here at the American Society for Bone and Mineral Research (ASBMR) 2014 annual meeting.

"It is reassuring that the women who went on to have a drug holiday did not appear to be at increased risk for any osteoporosis-related fractures or for hip fractures, specifically," first author Annette Adams, PhD, MPH, a research scientist with Kaiser Permanente Southern California, in Pasadena, California, told Medscape Medical News.

"Drug holidays may be a reasonable approach to managing bisphosphonate risk among women with at least 3 years of prior treatment — especially if a corresponding decrease in rare adverse events can also be demonstrated."

Concerns about those rare but serious adverse events — specifically, atypical femur fractures and osteonecrosis of the jaw — that have been associated with long-term bisphosphonate use are the primary reasons that some are motivated to consider bisphosphonate drug holidays, but a looming question has been whether the interruption in treatment will compromise the drug's effects.

Angela M. Cheung, MD, PhD, director of the Osteoporosis Program and the Centre of Excellence in Skeletal Health Assessment with the University Health Network and Toronto Rehabilitation Institute, Ontario, who comoderated the session, agreed that the study is a valuable addition to the evidence on bisphosphonate holidays. "This is an important study looking at whether drug holidays for patients on more than 3 years of bisphosphonates increase fracture risk," she told Medscape Medical News.

"There have been previous studies related to drug holidays and fracture risk, but they were much smaller," said Dr. Cheung. "This current study involves 28,620 women age over 45, and the analysis adjusted for some cofounders, making their results more [robust]."

Findings Key in Helping to Make Decisions About Osteoporosis Therapy

In exploring the issue, Dr. Adams and her colleagues evaluated electronic medical record data on 28,620 women in 4 regions of the Kaiser Permanente system who had initiated bisphosphonate use between 1998 and 2009 and had more than 3 years of exposure to the drugs. The majority of patients were taking alendronate.

The women were followed until they experienced a fracture, were no longer enrolled in the health plan, died, or the study's end on December 12, 2012.

Of the subjects, 17,123 (59.8%) were persistent bisphosphonate users, defined as having at least 50% adherence to the drugs throughout the study, and 11,497 (40.2%) took drug holidays of 12 months or longer.

A total of 3571 osteoporosis-related fractures were reported, with women who had taken a drug holiday showing improvements in various areas, including fewer comorbidities, higher baseline T-scores, and reduced fracture and fall risk scores.

In terms of osteoporosis-related fractures, the women in the drug-holiday group showed a reduced risk, with an unadjusted rate ratio (RR) of 0.87, with the exception of hip fractures, in which there was no difference compared with those who did not have a drug holiday (RR, 1.0).

After adjustment for factors including the baseline fall and fracture risk, comorbidities, and the use of other bone-active medications, time-varying models showed no significant differences in the general risk for fracture (hazard ratio [HR], 0.90; 95% CI, 0.80–1.00) or hip fracture (HR, 0.84; 95% CI, 0.68–1.03) between those who did and did not take a drug holiday.

Limitations of the study included the fact that data on patients' functional status or frailty was not available, nor was information on the reason for taking a drug holiday.

The findings nevertheless add to important evidence that could be key in decision-making for the management of osteoporosis patients, Dr. Adams said.

"Some patients are concerned about losing protection, as hip fractures are life-changing and can be life-ending," she observed.

"This [provides] an opportunity for patients and their clinicians to have an informed conversation and assess the risk/benefit for each individual. Factors such as age, sex, race, and duration of prior or current treatment all need to be taken into consideration in making patient-by-patient decisions about drug holidays."

But Randomized Trial Design Would Provide Better Information

Speaking with Medscape Medical News, Dr. Cheung said a main factor that likely prevents the worsening of symptoms during a drug holiday is the extended drug life of bisphosphonates. This class of agents has "long half-lives and may have residual beneficial effects after 1 year of stopping," she noted.

However, she added that an important limitation of the study is its retrospective nature, which, despite the statistical adjustment, still leaves some residual confounding.

"A better design would be to randomize patients to either have drug holidays or to continue therapy and follow them prospectively for fracture outcomes," she suggested.

In addition, the findings leave open the important question of high-risk patients.

"It would be helpful to see whether these results are the same in further analyses of subgroups of low-, moderate-, and high-fracture-risk patients,"Dr. Cheung noted.

And analysis of risks according to the duration of drug use would also be valuable, she added.

"Currently, the study presents general results for a drug holiday of more than 12 months, but to answer the question of when to restart bisphosphonates, an adjusted analysis of fracture outcomes breaking down duration of drug holiday would be helpful."

Dr. Adams received research funding from Amgen. Dr. Cheung has reported no relevant financial relationships.

American Society for Bone and Mineral Research 2014 Annual Meeting; September 13, 2014; Houston, Texas. Abstract 1045.

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