Efficacy and Safety of Single-Dose Zoledronic Acid for Osteoporosis in Frail Elderly Women

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SCIENCE
Efficacy and Safety of Single-Dose Zoledronic Acid for Osteoporosis in Frail Elderly Women
Key Take-Away: 
  • The use of a single infusion of zoledronic acid to benefit skeletal health for at least 2 years and extended benefit also reported in younger patients.
  • This study is able to capture serious adverse events in a timely matter through use of an electronic record system rather than relying on patient recall.

Eighty-five percent of elderly Americans individuals have osteoporosis, and their bone fracture rates are 8-9 times higher than those observed among less impaired elderly persons. The impact of an associated hip fracture is dire: decreased mobility and independence, frequent hospitalizations and a 6-month mortality rate of upto 36%. In frail elderly persons, the link between bone mineral density (BMD) and bone strength may be attenuated.

ABSTRACT: 
Background: 

Eighty-five percent of elderly Americans individuals have osteoporosis, and their bone fracture rates are 8-9 times higher than those observed among less impaired elderly persons. The impact of an associated hip fracture is dire: decreased mobility and independence, frequent hospitalizations and a 6-month mortality rate of upto 36%. In frail elderly persons, the link between bone mineral density (BMD) and bone strength may be attenuated.

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. Treatment that adds mass to the remaining non connected "bone stubs" may add little if any bone strength. Thus, effectiveness of anti osteoporosis therapy is unclear in frail elderly persons. Because of the rapid global growth of older, more physically impaired group, multiple organizations—including the National Institutes of Health—have for decades reiterated the critical need for osteoporosis research and treatment for these individuals. Obstacles to such studies are substantial, especially if the goal is to demonstrate fracture reduction. However, virtually every trial that has demonstrated fracture reduction by a potent bisphosphonate has also demonstrated an increase in BMD. Although this does not prove that such an increase is required, it suggests that fracture reduction would be unlikely in the absence of an impact on BMD. Thus, a stepwise approach is used in this study.

Rationale behind research

  • Few osteoporosis trials have focused on frail elderly individuals and none has evaluated the efficacy or safety of a bisphosphonate in this group
  • The effectiveness of anti osteoporosis therapy in frail elderly persons is unclear

Objective: To determine the efficacy and safety of zoledronic acid to treat osteoporosis in frail elderly women in long-term care facilities

Methods: 

 

Study outcomes

  • Primary outcome: Percentage change in BMD of total hip & spine at 12 months
  • Secondary outcomes: Adverse events and bone turnover markers
  • Other outcomes: Change in BMD through 24 months at other skeletal sites, physical and cognitive function, co morbidity, survival and an exploratory assessment of fragility fractures at 12 and 24 months.

Time-points

  • Efficacy: Baseline, 6,12, and 24 months
Results: 

 

Baseline: There were no baseline differences in mean (SE) age (85.4 [0.6] years), BMD, or functional or cognitive status, but the treatment group included more participants with frailty, falls history, diabetes, and anticonvulsant medication use.

  • Primary outcome:
  • Mean (SE) total hip BMD increased more in the treatment group than in the placebo group, both at 12 months (2.8% [0.5%] vs −0.5%[0.4%]; P < .001) and 24 months (2.6%[0.6%] vs −1.5%[0.7%]; P < .001).
  • Mean (SE) spine BMD also increased more in the treatment group than in the placebo group at 12 months (3.0%[0.5%] vs 1.1% [0.5%]; P = .01) and 24 months (4.5% [0.8%] vs 0.7% [0.5%]; P < .001),
  • Secondary outcomes:
  • Ninety seven percent of the participants had an adverse event and 64% had serious adverse event, but there were no group differences.
  • Born turn over markers assessed by serum C–telopeptide cross-links type I collagen, bone resorption decreased in the treatment group at 12 and 24 months (by 0.095 and 0.087 nmol/L, respectively) (P = .01) and increased in the placebo group at 12 and 24 months (by 0.068 and 0.070 nmol/L, respectively) (P < .05); the adjusted mean(SE) between-group difference was 0.135 (0.035) nmol/L bone collagen equivalent at 24 months (P < .001)
  • Other outcomes:
  • Both cognitive and physical function declined significantly in both groups over time, but differences between the 2 groups were not significant
  • The treatment and placebo groups fracture rates were 20% and 16%, respectively (or 1.30; 95%CI, 0.61-2.78); mortality rates were 16% and 13% (or 1.24; 95% CI, 0.54-2.86). Groups did not differ in the proportion of single fallers (28% vs 24%; or 1.24; 95% CI, 0.64-2.42; P = .52), but more participants in the treatment group had multiple falls (49% vs 35%; or 1.83; 95% CI, 1.01-3.33; P = .047); however, this difference was no longer significant when adjusted for baseline frailty.
Conclusion: 

In this group of frail elderly women with osteoporosis, 1 dose of zoledronic acid improved BMD over 2 years. The clinical importance of non significant increases in fracture and mortality rates in the treatment group needs further study. 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.

Our study was neither designed nor powered to examine absolute fracture reduction, but our point estimates contrast with findings from the pivotal zoledronic acid study, which reported a 60% reduction in vertebral fractures after 1 year and a 30% reduction in clinical fractures after 2 years. Our treatment group experienced more non injurious falls than the control group.
However, the treatment group also included more participants at baseline who met criteria for frailty, had a history of falls and diabetes, and took anticonvulsant medications. Moreover, there were no differences in serious falls or fractures and, after adjusting for baseline frailty, the difference in falls was no longer significant.

JAMA Intern Med. 2015 Jun; 175(6):913-21
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