DXA indicates dual energy x-ray absorptiometry.
Error bars represent standard error.
aPaired t test for change from baseline.
bLinear mixed models for comparison of zoledronic acid (active treatment arm) with placebo.
Error bars represent standard error; BCE, bone collagen equivalent; CTX, serum C–telopeptide cross-links type I collagen; P1NP, serum intact N-terminal propeptide type I procollagen.
Greenspan SL, Perera S, Ferchak MA, Nace DA, Resnick NM. Efficacy and Safety of Single-Dose Zoledronic Acid for Osteoporosis in Frail Elderly WomenA Randomized Clinical Trial. JAMA Intern Med. 2015;175(6):913-921. doi:10.1001/jamainternmed.2015.0747
Copyright 2015 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
Eighty-five percent of institutionalized elderly people have osteoporosis and bone fracture rates 8 to 9 times higher than rates observed among community-dwelling elderly people. Nevertheless, most of these persons are left untreated and are excluded from pivotal osteoporosis trials.
To determine the efficacy and safety of zoledronic acid to treat osteoporosis in frail elderly women in long-term care facilities.
Design, Setting, and Participants
We conducted a 2-year, randomized, placebo-controlled, double-blinded study from December 2007 through March 2012. Included were 181 women 65 or older with osteoporosis, including those with cognitive impairment, immobility, and multimorbidity, who were living in nursing homes and assisted-living facilities.
One 5-mg dose of zoledronic acid or placebo intravenously and daily calcium and vitamin D supplementation.
Main Outcomes and Measures
Hip and spine bone mineral density (BMD) at 12 and 24 months and adverse events.
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. Values for BMD were available for 87% of participants at 12 months and 73% at 24 months. Mean (SE) BMD changes were greater in the treatment group: 3.2 (0.7) and 3.9 (0.7) percentage-point differences in the total hip at 12 and 24 months, respectively (P < .01 for both comparisons), and 1.8 (0.7) and 3.6 (0.7) percentage-point differences at the spine (P < .01); adjusted analyses were similar. 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.
Conclusions and Relevance
In this group of frail elderly women with osteoporosis, 1 dose of zoledronic acid improved BMD over 2 years. The clinical importance of nonsignificant 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.
clinicaltrials.gov Identifier: NCT00558012
Nearly 2 million frail elderly Americans reside in long-term care (LTC) facilities, and another 4 to 6 million similarly frail elderly people live in the community.1 Eighty-five percent of such individuals have osteoporosis, 2- 4 and their bone fracture rates are 8 to 9 times higher than those observed among less impaired elderly persons.5 Moreover, the impact of an associated hip fracture is dire6,7: decreased mobility and independence, frequent hospitalizations, and a 6-month mortality rate of up to 36%.8 Yet osteoporosis therapy remains vastly underprescribed to such individuals.9,10
Few osteoporosis trials have focused on frail elderly individuals, and to our knowledge, none has evaluated the efficacy or safety of a bisphosphonate in this group. Although post hoc analyses of the pivotal osteoporosis trials suggest that therapy is efficacious for healthy, community-dwelling participants older than 75 years,11- 13 these trials excluded functionally impaired individuals, and so the findings might not apply to them. 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.14- 16 Treatment that adds mass to the remaining nonconnected “bone stubs” may add little if any bone strength. The odds of this phenomenon occurring in frail LTC residents are likely substantial because they are 10 to 15 years older than those included in the pivotal trials, with that many more years of bone loss as well as greater comorbidity, more frequent illnesses, a more sedentary lifestyle, and greater renal impairment, all of which tend to accelerate bone loss. Support for this concern is heightened by results of the risedronate hip fracture trial,17 which, despite having adequate power, demonstrated a reduction in hip fractures for community-based women younger than 80 years but not for those older than 80 years (although evaluation of the older group did not include BMD).17 Thus, it is unclear whether antiosteoporosis therapy is effective in frail elderly persons. Because of the rapid global growth of this 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.18- 21
Obstacles to such studies are substantial,22 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.23,24 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, we used a stepwise approach in the present study. Our objective was to determine the impact of a bisphosphonate on BMD and safety for 2 years in frail women residents of LTC facilities. Although frail elderly women are more likely to live outside of institutions, we enrolled an institutionalized group to ensure that we could deliver therapy and closely monitor its impact and adverse effects. We chose zoledronic acid because it can be given as a single intravenous dose, the effect of which may last for 2 years25,26; this eliminates difficulties inherent in administering an oral bisphosphonate on a regular basis in this setting.
The present report describes findings of the ZEST study (Zoledronic acid in frail Elders to STrengthen bone), 22 a 2-year, double-blind, placebo-controlled, randomized clinical trial based in the Pittsburgh, Pennsylvania area. Participants were enrolled and treated from December 2007 through March 2012 (ClinicalTrials.gov identifier: NCT00558012). The ZEST study protocol is available in the Supplement.
We included frail women 65 years or older who resided in a nursing home or assisted-living facility,22 who were not receiving a bisphosphonate, and who had either a history of vertebral or hip fracture or a measured BMD below the treatment cutoff for osteoporosis (based on 2003 National Osteoporosis Foundation guidelines27: lower than −2.0 SD at the spine, hip, or radius [ie, more than 2 standard deviations below the bone density of a healthy 30-year-old]).28 All women whose 25-hydroxyvitamin D levels were lower than 20 ng/dL29 received vitamin D supplements (50 000 IU/wk for 2 months) and were rescreened. All participants received a daily divided dose of vitamin D (800 IU/d) and 1200 mg/d of elemental calcium (supplement plus diet30).
We included women who had cognitive and functional impairment, immobility, multiple medical conditions, and who were prescribed multiple medications (including glucocorticoids and antiseizure medications). We excluded those with a projected life expectancy of less than 2 years or an estimated glomerular filtration rate below 30 mL/min.
The study was approved by the University of Pittsburgh institutional review board and the Pennsylvania Department of Health. Informed consent was obtained for all participants. Those with cognitive impairment provided assent, and the resident’s responsible party provided written consent.
The study biostatistician randomized participants in a 1:1 ratio using random block sizes of 2 and 4. The research pharmacist provided identical-appearing active drug or placebo. Investigators, study personnel, providers, and participants were blind to treatment assignment.
Study visits were conducted at each participant’s facility. All BMD assessments took place in a mobile unit that included a motorized platform to facilitate access for participants with restricted mobility. Baseline blood tests and BMD values were obtained, and 10-year fracture risk (FRAX31) was calculated.
After completing the baseline assessment, participants were randomized to infusion with either 5 mg of intravenous zoledronic acid or placebo. Patients were assessed for immediate adverse reactions for 3 days after infusion.32 Subsequent follow-up visits occurred at 6, 12, and 24 months.
The primary outcome was percentage change in BMD of the total hip and spine at 12 months. Secondary outcomes included adverse events and bone turnover markers. Additional outcomes included change in BMD through 24 months at other skeletal sites, bone turnover markers, physical and cognitive function, comorbidity, survival, and an exploratory assessment of fragility fractures at 12 and 24 months.
Measured sites included the hip (total hip, femoral neck), spine (posterior-anterior and lateral projection), and distal one-third of the radius. Dual energy x-ray absorptiometry was performed using a Discovery densitometer (Hologic Inc); the precision ranged from 1.2% to 1.9% at these skeletal sites.33
Fractures of T6-L4 were detected by vertebral fracture assessment performed by dual energy x-ray absorptiometry (DXA) at baseline and at 12 and 24 months and were classified by the Genant criteria as mild, moderate, or severe.34 We included new fractures and fracture grade progression. Compared with conventional radiography, the sensitivity and specificity of DXA vertebral fracture assessment are 100% and 95%, respectively,35 with a κ statistic of 0.92.35
In addition to medical record review, we asked participants every 6 months about clinical fragility fractures (defined as a fracture following a fall from standing or sitting height). Fractures were confirmed by radiology reports.
Bone resorption was assessed by serum C–telopeptide cross-links type I collagen (CTX; Crosslaps, Osteometer Biotech). Bone formation was assessed by serum intact N-terminal propeptide type I procollagen (P1NP; Orion Diagnostica). Serum 25-hydroxyvitamin D level was assessed by liquid chromatography–mass spectrometry.
Function was assessed using the Katz Activities of Daily Living scale,36 Instrumental Activities of Daily Living scale,37 gait speed,38,39 Short Portable Mental Status Questionnaire,40 Comorbidity Index,41 Patient Health Questionnaire (PHQ-9) depression scale,42 modified Fried Frailty Index (categorized as frail, prefrail, or robust),43 and the Physical Performance Test.44
We collected information on adverse events from patients and medical records at scheduled visits. To improve reporting of serious adverse events, we created an electronic database alert system.22
A priori assumptions, statistical power, and sample size justification have been published elsewhere.22 Briefly, assumptions were based on available data from younger, postmenopausal women in whom zoledronic acid increased mean (SE) BMD at 12 months by 4.5% (3.6%) at the spine and 3.0% (2.9%) at the femoral neck.45,46 We assumed 25% less improvement in our cohort, no change in our placebo group, and 30% attrition over a year. This suggested that randomizing 180 women would yield 126 completers at 1 year and provide 95% power to detect an absolute difference in BMD between groups of 2.4 percentage points at the spine and 86% power to detect a 1.6 percentage-point difference at the femoral neck (2-tailed test; α = .05).
To compare baseline characteristics in the treatment and placebo groups, we used independent sample t, Wilcoxon rank sum, χ2, and Fisher exact tests. For the main analysis, we fitted a series of linear mixed models, using percentage change between baseline and follow-up assessment in each of the BMD and biomarker measures as the dependent variable; treatment arm (active or placebo), follow-up assessment (6, 12, and 24 months), and their interaction as fixed effects of interest; baseline value of the measure as a fixed effect covariate; and a participant random effect to account for multiple measurements from the same participant over time and the resulting nonindependence of observations. We used appropriately constructed contrasts to compare treatment arms at each of the 6-, 12-, and 24-month assessments. To assess robustness of the main results, we conducted sensitivity analyses using raw change in measurements instead of percentage change from baseline; last value carried forward and a multiple imputation approach for missing database data on multivariate normality and the Markov Chain Monte Carlo method; additional covariate adjustments for participant characteristics that differed significantly at baseline (frailty, falls risk, diabetes, and anticonvulsant use); and log transformations of markers of bone turnover.47,48 Finally, we used χ2 and Fisher exact tests to compare the proportions of participants in each group who experienced each and any type of adverse event. We fitted logistic regression models for events of specific interest (deaths, falls, fractures) with covariate adjustments for frailty, falls risk, and diabetes. We used SAS software, version 9.3 (SAS Institute Inc), with MIXED and LOGISTIC procedures for the main analyses.
We contacted 733 women; 252 consented to screening, and 181 received the infusion (Figure 1). At baseline (Table 1), both groups had substantial impairment: 95% of participants were categorized as frail or prefrail; 74% were dependent in at least 1 basic activity of daily living (and 31% in at least 3); 93% had at least 1 deficit measured in the Instrumental Activities of Daily Living37 (and 70% in at least 3); 85% had a gait speed characteristic of frailty (<0.8 m/s), and most participants were cognitively impaired. There were no group differences in age, body mass index, or calcium or vitamin D intake. However, compared with the placebo group, more women in the treatment group were categorized as frail by the modified Fried Frailty Index,43 more tended to be fallers in the year prior to the study, more had a diagnosis of diabetes mellitus, and more were taking anticonvulsant medications. Baseline safety laboratory values were similar between the 2 groups, as were markers of bone turnover, BMD, the number of women with vertebral fractures, and the 10-year calculated risk of osteoporotic fractures. Seventy-six percent of patients (n = 138) completed 24 months of follow-up.
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); the adjusted mean (SE) difference was 3.9 (0.7) percentage points at 24 months (P < .001) (Figure 2). Similar differences were observed in the femoral neck, with an adjusted difference of 2.7 (1.0) percentage points at 24 months (P = .01).
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), with an adjusted difference of 3.6 (0.7) percentage points at 24 months (P < .001) (Figure 2). At 24 months, the improvement from 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) at the distal one-third of the radius. When BMD was stratified by diabetes, trends were similar, as were trends when group differences were assessed for missing data by the last value carried forward and multiple imputation methods.
Results were nearly identical when adjusted for the baseline imbalance in frailty, diabetes, and anticonvulsant use: the adjusted mean (SE) difference for spine BMD was 2.0 (0.7) percentage points at 12 months and 3.8 (0.7) at 24 months (P < .001); for total hip BMD, it was 3.2 (0.7) percentage points at 12 months and 3.8 (0.7) at 24 months (P < .001 for each); and for femoral neck BMD, it was 3.7 (0.9) percentage points at 12 months (P < .001) and 2.9 (1.0) at 24 months (P = .004).
As 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) (Figure 3). As expected, P1NP, the marker of bone formation, decreased in the treatment group at 12 and 24 months by 21.9 and 20.4 μg/L, respectively (P < .01); the mean (SE) adjusted between-group difference was 16.95 (3.15) μg/L at 24 months (P < .001).
Both cognitive and physical function declined significantly in both groups over time, but differences between the 2 groups were not significant.
Ninety-seven percent of participants had an adverse event, and 64% had a serious adverse event, but there were no group differences (Table 2). As expected, in the 3 days following the infusion, the treatment group experienced more acute symptoms, but there were no group differences in the laboratory safety parameters other than a small drop in serum calcium level on day 2 in the zoledronic acid group (0.52 mg/dL less than control; P < .001) that was not significantly different at 6 months. Overall, there were no significant differences in number of deaths, fractures, or cardiac disorders, including atrial fibrillation (Table 2). Specifically, 14 participants in the treatment group (16%) and 12 in the placebo group (13%) died during the study period (odds ratio [OR], 1.24; 95% CI, 0.54-2.86; P = .61). Eighteen women in the treatment group (20%) and 15 in the placebo group (16%) experienced any fracture (OR, 1.30; 95% CI, 0.61-2.78; P = .50), 6 of them vertebral in the treatment group (7%) and 8 vertebral in the placebo group (9%) (OR, 0.76; 95% CI, 0.25-2.28) (P = .62). Patients who experienced fractures were neither unmasked nor treated.
Although there were no differences in serious falls, there were more fallers in the treatment group than in the placebo group over the 2-year study. There was no significant difference between groups in the number 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). When adjusted for baseline frailty, however, the difference in the proportion of multiple fallers was no longer significant (OR, 1.60; 95% CI, 0.85-2.99; P = .14). When incident falls were stratified by diabetes, there were more falls in the treatment group than in the placebo group (87% [n = 20] vs 33% [n = 4]; OR, 13.3; 95% CI, 2.42-73.5; P < .001) but numbers were small, and confidence intervals wide. Results did not differ appreciably in any of the sensitivity analyses.
To our knowledge, this is the first randomized trial of a potent antiresorptive therapy administered to a group of frail elderly women. We found that, compared with calcium and vitamin D alone, adding a single dose of intravenous zoledronic acid significantly improved BMD of the hip and spine over 2 years. Improvements were similar to those found in healthy younger women in the pivotal zoledronic acid trial.32 Changes in bone turnover suggest that zoledronic acid had a continued effect for 2 years after a single dose. There were no significant differences in serious adverse events through 24 months, although fracture and mortality rates were descriptively higher in the zoledronic acid group.
Our cohort was more impaired than the one previously investigated from assisted-living communities.49 Those participants were 8 years younger than these, and all were cognitively intact, mobile, able to self-administer a daily medication, and able to attend a centralized study site for assessments. Nonetheless, bone mass response to a single dose of zoledronic acid in the current group was similar to that seen in the less impaired group, who took an oral bisphosphonate (alendronate) daily for 2 years.
Despite the robust increase in BMD at the hip and spine, we did not observe a reduction in total or vertebral fractures. 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.32 It is possible that the significantly greater frailty of our treatment group masked beneficial differences in fracture rates. It is also possible that, despite the improvement in bone density, such frail individuals may not benefit from therapy because skeletal integrity may be so compromised that poor connectivity, impaired microstructure, altered microgeometry, unhealed stress fractures, restricted mobility (less weight bearing), reduced life expectancy, or other factors may prevent fracture reduction.15,16 However, neither the limited statistical power of this study nor the point estimates observed can be used to infer that fracture reduction would or would not be seen in a larger study50; strong computational evidence suggests that only a fracture-reduction study will suffice. Based on our data demonstrating a positive impact on both BMD and bone turnover, we believe that such a study is now justified and essential. The need for such a trial is also timely, since many payers use bisphosphonate treatment as a quality-assessment measure in this population despite the lack of safety and fracture-reduction data.
Approximately 30% of community-dwelling elderly people fall annually, as do at least half of LTC residents.51,52 Our treatment group experienced more noninjurious 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. We do not know of other studies that reported an increase in falls as a potential adverse effect of zoledronic acid or other bisphosphonates; this finding is likely owing to poorer baseline status of participants in the treatment arm in our study or simply owing to chance.
In addition to its randomized design, a strength of our study was the use of a single infusion of zoledronic acid to benefit skeletal health for at least 2 years. Extended benefit has also been reported in younger patients.25,26 Another strength was inclusion of residents with immobility and cognitive impairment as well as those taking glucocorticoids and anti-seizure medications; such patients are generally excluded from pivotal trials. Third, we were able to capture serious adverse events in a timely matter through use of an electronic record system rather than relying on patient recall. Finally, as in all LTC facilities, falls were well captured owing to regulation.
Our study also had limitations. First, despite randomization, the treatment group contained more participants with frailty, falls, diabetes, and anticonvulsant use. Despite the baseline differences, however, the adjusted analyses were similar, confirming the robustness of the findings. Second, our study was neither designed nor powered to examine fracture reduction, although we did gather fracture data from adverse events and vertebral fracture assessment examinations. Instead, this was a proof-of-concept study. It was designed to assess the impact of therapy on the surrogate markers of BMD and bone turnover and thereby to determine whether a larger trial of fracture reduction would be justified in a frail elderly population. If we had found that these patients were too frail or too sick to achieve differences in BMD or bone turnover, a fracture study would not be worthwhile. Finally, and not surprisingly in such a debilitated population, there were a number of dropouts by 24 months. However, the use of 2 different approaches to account for their missing data did not change the findings.
In summary, we found that a single infusion of zoledronic acid in frail, cognitively challenged, less mobile elderly women improved bone density and reduced bone turnover for 2 years. This suggests that even a very frail cohort may benefit. However, prior to changing practice, larger trials are needed to determine whether improvement in these surrogate measures will translate into fracture reduction for vulnerable elderly persons.
Accepted for Publication: October 6, 2014.
Corresponding Author: Susan L. Greenspan, MD, Department of Medicine, University of Pittsburgh, 3471 Fifth Ave, 1110 Kaufmann Bldg, Pittsburgh, PA 15213 (firstname.lastname@example.org).
Published Online: April 13, 2015. doi:10.1001/jamainternmed.2015.0747.
Author Contributions: Dr Greenspan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Greenspan, Nace, Resnick.
Acquisition, analysis, or interpretation of data: Greenspan, Perera, Ferchak, Nace, Resnick.
Drafting of the manuscript: Greenspan, Perera, Ferchak, Resnick.
Critical revision of the manuscript for important intellectual content: Greenspan, Perera, Nace, Resnick.
Statistical analysis: Perera, Resnick.
Obtained funding: Greenspan, Nace.
Administrative, technical, or material support: Ferchak, Nace, Resnick.
Study supervision: Greenspan, Nace, Resnick.
Conflict of Interest Disclosures: Dr Greenspan reports receipt of grants to her institution from Amgen and Eli Lilly. Dr Perera reports receipt of grants to his institution from Merck, Ortho Biotech, and Eli Lilly. Dr Nace reports receipt of grants to his institution from Sanofi. No other disclosures are reported.
Funding/Support: Support for this project was provided by National Institutes of Health (NIH)/National Institute on Aging (NIA) grant R01 AG028068 (Dr Greenspan), NIH/The National Institute of Diabetes and Digestive and Kidney Diseases grant K24DK062895 (Dr Greenspan), Pittsburgh Older Americans Independence Center NIA grant P30 AG024827, Pharmaceutical Outcomes Research Program in Aging award K07 AG033174, and Clinical Translational Science Institute NIH/National Center for Research Resources grant Ul1 RR024153. Study medication and matching placebo were provided free of charge by Novartis Pharmaceuticals, East Hanover, NJ.
Role of the Funder/Sponsor: The supporting institutions, including Novartis, had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Previous Presentations: Preliminary results of this research were presented at the American Society of Bone Mineral Research Annual Meeting; October 5, 2013; Baltimore, Maryland. The research was also presented at the American Geriatrics Society Annual Meeting; May 15, 2014; Orlando, Florida.