TORONTO – Among postmenopausal women with osteoporosis, treatment with zoledronic acid had a similar effect on fracture reduction regardless of whether women had a low, intermediate, or high baseline fracture risk, based on a post-hoc analysis of nearly 3,900 women who received the agent in the drug’s pivotal trial for fracture prevention.
The analysis showed that rates of vertebral fractures and total clinical fractures fell by roughly similar amounts, regardless of the women’s baseline fracture risk, with annual injection of zoledronic acid during 3 years of treatment and follow-up.
The rate of hip fractures showed a greater reduction in women who entered the study in the lowest tertile for fracture risk relative to the placebo group than in women with intermediate or high risk, but this difference failed to reach statistical significance, Jane A. Cauley, Dr.P.H. said at the meeting.
The message is that postmenopausal women with osteoporosis should feel comfortable starting zoledronic acid treatment regardless of the severity of their fracture risk at baseline, said Dr. Cauley, professor of epidemiology at the University of Pittsburgh. It is not necessary to target treatment to women with an especially elevated fracture risk, such as those with a high FRAX (Fracture Risk Assessment Tool) score, she explained.
The results support a prior report with similar findings from the Women’s Health Initiative on the impact of estrogen or estrogen plus progesterone on fracture risk (JAMA 2003;290:1729-38). However, results from another prior study on the impact of clodronate on fracture risk suggested that osteoporotic women with the highest baseline fracture risk stood to gain the most from bisphosphonate treatment (Osteoporosis Int. 2009;20:811-17).
The current analysis used data collected in the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) pivotal fracture trial, which randomized 7,765 postmenopausal women to either an annual infusion with 5 mg zoledronic acid or placebo for 3 years (N. Engl. J. Med 2007;356:1809-22). Assessment of the study’s primary end point showed that annual treatment with zoledronic acid significantly cut the rate of vertebral and hip fractures as well as total clinical fractures.
To perform the post-hoc analysis, Dr. Cauley and her associates rated the baseline fracture risk of the 3,889 women randomized to receive zoledronic acid using a modification of the Fracture Index developed for the Study of Osteoporotic Fractures (SOF) (Osteoporosis Int. 2001;12:519-28). The modification calculated a woman’s baseline fracture risk using five of the seven variables of the SOF tool available in the HORIZON records: age, femoral neck bone mineral density T score, clinical fracture history, weight, and smoking status. The two SOF tool elements not available were maternal history of hip fracture and the use of arms to stand from a chair.
Analyses by Dr. Cauley and her associates using SOF data showed that calculating a fracture risk score with the five elements had a 98% correlation with the seven-item score, as well as a 64% correlation with women’s FRAX scores. To further confirm the validity of the modified SOF score, they calculated scores for the 3,876 women enrolled in the placebo arm of HORIZON. During 3 years of follow-up, the rate of total fractures per 1,000 person-years was 30, 35, and 45 respectively in the low-, intermediate-, and high-risk tertiles. Overall, for every 1-point rise in the modified SOF score, the risk of a fracture among the placebo women during follow-up rose by 11%, a statistically significant difference.
The researchers then assessed follow-up fracture rates among the low-, intermediate-, and high-risk women who received zoledronic acid. The rate of morphometric vertebral fractures compared with the placebo group fell by 80% in the low-risk tertile of women, by 69% in the intermediate-risk tertile, and by 68% in the high-risk women, differences that were not statistically significant.
The rate of all clinical fractures dropped by 35% in the low-risk women, 38% in the intermediate-risk women, and 30% in the high-risk women, also nonsignificant differences.
The rate of hip fractures with zoledronic acid treatment compared with placebo fell by 71% in the low-risk women, 41% in intermediate-risk women, and 22% in high-risk women. These between-group differences just missed being statistically significant (P = .06).
Additional analyses also showed that the zoledronic acid treatment consistently increased bone mineral density, and reduced two biomarkers of osteoporosis, procollagen type I N-propeptide and C-telopeptide cross-linked collagen, compared with the placebo group, regardless of baseline fracture risk, Dr. Cauley said.
HORIZON was supported by Novartis, the company that markets zoledronic acid (Reclast). Dr. Cauley said that she has received research funding from and has served as a consultant to Novartis.