This article is more than 5 years old. Information may no longer be current.
Bisphosphonates produce varying results during drug holidays
Click Here to Manage Email Alerts
Postmenopausal women assigned alendronate therapy are more likely to experience a loss of bone mineral density or an increase in bone turnover markers during a 3-year drug holiday than women assigned zoledronic acid, according to a post hoc analysis of two large trials published in the Journal of Bone and Mineral Research.
“After stopping therapy, former alendronate users had greater BMD loss and increases in bone turnover compared to former zoledronic acid users,” Tiffany Y. Kim, MD, an advanced fellow in women’s health with the San Francisco VA Health Care System and the University of California, San Francisco, told Endocrine Today. “This suggests the effects of alendronate may wear off faster than zoledronic acid.”
Kim and colleagues analyzed data from postmenopausal women participating in the placebo extension arms of two randomized controlled trials assessing bisphosphonate therapy, the FLEX trial (mean age, 74 years; 34.3% with vertebral fracture prevalence) and the HORIZON-PFT E1 trial (mean age, 76 years; 63.2% with vertebral fracture prevalence). In the FLEX trial, 1,099 women originally assigned to the alendronate arm who received at least 3 years of treatment were eligible for the randomized extension of continued alendronate or placebo, with 437 women assigned to placebo arm. In the HORIZON-PFT extension study, 1,233 women originally assigned to the zoledronic acid arm were eligible for the randomized extension phase, with 617 women assigned to placebo for 3 years.
In FLEX, women underwent hip BMD measurements annually and spine BMD measurements at 3 and 5 years. In the HORPZON-PFT extension, women underwent total hip and femoral neck BMD measurements at 1.5 and 3 years. Researchers calculated BMD change from baseline to 3 years in the extension phase of both trials. Least significant change for BMD was defined as at least 4% loss at the total hip and at least 5% loss at the lumbar spine. Researchers measured the serum bone formation marker N-terminal propeptide of type I collagen, or PINP, in 239 women in FLEX and in all women participating in the HORIZON-PFT extension trial.
The researchers examined 3-year changes in BMD and bone formation marker levels that exceed least significant change or threshold values, as there are no formal definitions for the offset of drug effect.
BMD values
Researchers found that total hip BMD in the HORIZON-PFT group was stable at 1.5 years and reduced by 1.2% after 3 years of placebo. In the FLEX trial, researchers observed a progressive BMD decline at the total hip during the first year and a 2.3% reduction by year 3. Researchers observed a femoral neck BMD decline for women in both extension trials at 3 years, with a trend toward greater femoral neck BMD loss in the FLEX trial (P = .07).
“When 3-year BMD change was categorized by BMD loss greater than least significant change, 25.2% of the FLEX placebo group met that criterion, compared to 18.7% of the HORIZON-PFT E1 placebo group (P = .02),” the researchers wrote. “There were similar trends with femoral neck BMD loss: 28.4% in FLEX versus 19.8% in HORIZON-PFT E1 (P < .01).”
PINP changes
Compared with pretreatment, baseline values, the researchers observed that PINP levels at the beginning of the placebo extension trials were in the lower range for menopausal women. During 3 years of placebo, researchers found that increases in PINP were higher in the FLEX trial vs. the HORIZON-PFT trial (mean, 11.6 ng/mL vs. 6.7 ng/mL; P < .01). In both trials, the majority of women experienced changes in PINP that exceeded least significant change (66% in FLEX and 56.5% in HORIZON-PFT). Mean values remained in the lower range for premenopausal women and did not return to pretreatment levels, according to researchers. At 3 years, nearly twice as many women in the FLEX extension trial had PINP levels above the median for premenopausal women, defined as 36 ng/mL, compared with those in the HORIZON-PFT trial (42% vs. 24.6%).
“Bisphosphonates act differently during a drug holiday,” Kim said. “Some clinicians may consider using zoledronic acid in the initial treatment of osteoporosis, given higher rates of compliance with IV therapy and less offset of drug effect after stopping therapy.”
Kim added that long-term fracture studies are needed to provide evidence-based recommendations on managing drug holidays. – by Regina Schaffer
For more information:
Tiffany Y. Kim, MD, can be reached at the University of California, San Francisco, and the San Francisco VA Health System, 1700 Owens St., Room 349, San Francisco, CA 94158; email: tiffany.kim@ucsf.edu.
Disclosures: Merck funded the FLEX trial. Novartis funded the HORIZON-PFT E1 trial. Kim reports no relevant financial disclosures. Please see the study for all authors’ relevant financial disclosures.
Click Here to Manage Email Alerts