Zoledronic Acid Ups BMD in Seniors Without Cutting Fractures

Diana Swift

April 15, 2015

A single 5-mg infusion of the bisphosphonate zoledronic acid can improve bone mineral density (BMD) over the course of 2 years in frail institutionalized elderly women with osteoporosis, according to a study published online April 13 in JAMA Internal Medicine.

However, this improvement does not translate to better outcomes, reports the randomized, double-blind, placebo-controlled trial. The study found a slight fracture increase and higher mortality in the zoledronic acid group. "The clinical importance of nonsignificant increases in fracture and mortality rates in the treatment group needs further study," Susan L. Greenspan, MD, from the University of Pittsburgh's Division of Geriatric Medicine in Pennsylvania, and colleagues write.

Conducted from December 2007 to March 2012, the study included 181 frail women aged 65 years or older with osteoporosis and a range of impairments living in the nursing home or assisted living setting. These patients are usually excluded from large osteoporosis trials. The two groups were similar at baseline in terms of mean age (85.4 years), BMD, and cognitive and functional status, but after randomization, the intervention group had more patients with frailty (as per the Fried Frailty Index), a history of falls, diabetes, and anticonvulsant drug use.

Both groups took a daily calcium and vitamin D supplement and underwent hip and spine BMD assessment at 12 and 24 months, with a primary outcome measure of percentage change in BMD of the total hip and spine at 12 months. Other indices included adverse events (including falls), bone turnover markers, and BMD changes over the course of 24 months at other skeletal sites.

Mean (standard error) total hip BMD increased more in the treatment group than in the placebo group at both 12-month and 24-month follow-up: 2.8% (0.5%) vs −0.5% (0.4%) (P < .001) and 2.6% (0.6%) vs − 1.5% (0.7%) (P < .001), respectively. The adjusted mean (standard error) difference was 3.9 (0.7) percentage points at 24 months (P < .001). Comparable differences were observed in the femoral neck.

Similarly, mean (standard error) spine BMD also increased more in the intervention group, both at 12 months (3.0% [0.5%] vs 1.1% [0.5%]; P = .01) and at 24 months (4.5% [0.8%] vs 0.7% [0.5%]; P < .001), with an adjusted difference of 3.6 (0.7) percentage points at 24 months (P < .001).

At 24 months, the improvement seen with zoledronic acid was 4.8 (1.1) percentage points greater (P < .001) at the lateral spine and 1.2 (0.6) percentage points greater (P = .04) in the distal third of the radius.

As assessed by serum C–telopeptide cross-links type I collagen, bone resorption fell in the treatment group at 12 and 24 months by 0.095 and 0.087 nmol/L, respectively (P = .01) and rose in the placebo group at 12 and 24 months by 0.068 and 0.070 nmol/L, respectively (P < .05). At 24 months, the adjusted mean (standard error) between-group difference was 0.135 (0.035) nmol/L bone collagen equivalent (P < .001).

Bone formation, as measured by serum intact N-terminal propeptide type I procollagen, decreased in the treatment group at 12 and 24 months by 21.9 and 20.4 μg/L, respectively (P < .01). At 24 months, the mean (standard error) adjusted between-group difference was 16.95 (3.15) μg/L at 24 months (P < .001).

During the study period, 97% of patients experienced an adverse event and 64% had a serious one, but no group differences were found. There were no significant differences between the two groups in the number of deaths, fractures, or cardiac disorders, including atrial fibrillation. The treatment and placebo groups' fracture rates were 20% and 16%, respectively (odds ratio [OR], 1.30; 95% confidence interval [CI], 0.61 - 2.78; P = .50).

Mortality rates were 16% and 13% in the treatment and placebo groups, respectively (OR, 1.24; 95% CI, 0.54 - 2.86; P = .61). The proportion of single fallers was similar in both groups, at 28% vs 24% (OR, 1.24; 95% CI 0.64 - 2.42; P = .52). More participants in the treatment group, however, had multiple falls (49% vs 35%; OR, 1.83; 95% CI, 1.01 - 3.33; P = 0.047), a difference that was insignificant after adjustment for baseline frailty.

The failure of measurable BMD improvements in the zoledronic acid group to translate to fracture reduction may be a result of an attenuation in frail seniors of the link between BMD and bone strength. "Once sufficient bone mass is lost, structural integrity of the remaining bone may be compromised due to impaired trabecular connectivity, poor skeletal microstructure, and unhealed stress fractures," the authors write. "Treatment that adds mass to the remaining nonconnected 'bone stubs' may add little if any bone strength."

Although the single zoledronic acid infusion did improve BMD and bone turnover at 2 years in this cognitively challenged, less mobile osteoporotic group, it would be premature to recommend it for this population as a whole. "Since it is not known whether such therapy reduces the risk of fracture in this cohort, any change in nursing home practice must await results of larger trials powered to assess fracture rates," Dr Greenspan and associates write.

In an accompanying editorial, Robert Lindsay, MB, ChB, PhD, from the Department of Medicine, Columbia University, New York City, notes that previous research with risedronate has shown that a high prevalence of frailty can negate the fracture benefit of a bone-active agent. "This study confirms the clinical impression that to effectively reduce fractures in an older frail population, clinicians must address the nonskeletal components of risk that will not be modified by bone-active drugs," he notes.

Agreeing that it is too soon for the broad prescription of bone density treatment for the frail elderly in assisted living, he adds, "Perhaps methods should be considered to identify persons with fracture in the community so that they can be evaluated and possibly treated (both physically and pharmacologically) before they enter the nursing home."

In addition to potent drugs, full fracture management of the frail elderly might involve behavior modification interventions designed to increase physical activity and improve balance, a challenging task in frail elderly persons with sarcopenia. "For these practice changes to be effected, broad and bold educational initiatives will be required," Dr Lindsay writes, pointing to the need for large, controlled trials to determine whether combining fall-prevention strategies with bone-active drugs might reduce fractures in high-risk populations.

This study was supported by the National Institutes of Health, the Pittsburgh Older Americans Independence Center, the Pharmaceutical Outcomes Research Program in Aging, and the Clinical & Translational Science Institute. Study medication and placebo were provided free of charge by Novartis Pharmaceuticals. Dr Greenspan reports receipt of grants to her institution from Amgen and Eli Lilly. One coauthor reports receipt of grants to his institution from Merck, Ortho Biotech, and Eli Lilly. Another coauthor reports receipt of grants to his institution from Sanofi. The other authors and the editorialist have disclosed no relevant financial relationships.

JAMA Intern Med. Published online April 13, 2015. Article abstract, Editorial extract

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