Real-life risks and benefits of fracture-reducing drugs

Rethink therapy for 2 types of patients?

Recent reports, however, may cause us to rethink that approach, especially in 2 types of patients:

Stefanick et al reported on the 10,739 women aged 50–79 in the estrogen-only arm of the WHI, who received placebo or0.625 mg of conjugated equine estrogen. After a mean follow-up of 7.1 years, there were 104 cases of invasive breast cancer in this CEE group and 133 cases in the placebo group.

Stated another way, this represents a 20% reduction in breast cancer in women in the CEE group. Although this reduction was not statistically significant, it is in stark contrast with the increase in breast cancer seen in numerous studies of estrogen and progestogen together.

Statistically significant reductions in fracture, compared with placebo, in the WHI E2-only arm were:

wrist 42%

clinical vertebral 36%

hip 35%

total fractures 29%

Women in the WHI had all levels of fracture risk

Jackson et al also analyzed fracture incidence in the WHI E2-only arm, as assessed by semiannual questionnaires and verified by adjudication of radiology reports.

Women on CEE had statistically significant reductions in hip fracture (35%), clinical vertebral fracture (36%), wrist fracture (42%), and total fractures (29%), compared with placebo. This trend held across all levels of fracture, although the reductions were greatest in patients at highest risk.

This is notable, however, because the WHI was primarily studying the effect of CEE on coronary heart disease. Unlike virtually all osteoporosis studies, in which women with increased risk of fracture are studied, the women selected for the Women’s Health Initiative represent all levels of fracture risk—and this placebo-controlled, large, randomized study discovered that all fractures, across all levels of risk, were significantly reduced. And there was no increase in breast cancer.

This may well weigh in on many a clinician’s thought process about indications and real risks of estrogen therapy.

4 Risedronate: Not just for fracture prevention?

Buckland-Wright JC, Messent EA, Bingham CO III, et al. A 2 yr longitudinal radiographic study examining the effect of a bisphosphonate (risedronate) upon subchondral bone loss in osteoarthritic knee patients. Rheumatology (Oxford). 2006 Jul 11; [Epub ahead of print].

Bone formation in osteoarthritic knees reversed disease-related bone loss while maintaining structural integrity within the subchondral cancellous bone in patients treated with risedronate, in this 2-year study. Patients with progressive knee osteoarthritis were enrolled in this double-blinded, multicenter, randomized, placebo-controlled trial.

The treatment groups included placebo, risedronate 5 mg/day, 15 mg/day, and 50 mg/week. Patients receiving risedronate 15 mg/day retained vertical trabecular structure and those receiving 50 mg/week increased vertical trabecular number, thereby preserving the structural integrity of the subchondral bone.

This is important because weakening and loss of vertical trabecular support, when combined with the biomechanical weakening of the bone due to disease-related reduction in mineral content, are believed to contribute to collapse of the tibial compartment in late-stage osteoarthritis. It has been suggested that bisphosphonates are associated with decreased bone formation as an expected consequence of suppressing the coupled bone remodeling process. This did not appear to be the case in this study. In fact, the study tends to agree with experimental work that shows that high doses of bisphosphonates, as well as repeated administration, may enhance bone accretion.

The author serves on the advisory boards for Eli Lilly, Merck, Pfizer, Procter & Gamble, and GlaxoSmithKline.