Abstract
BACKGROUND:
Coexistence of osteoporosis and sarcopenia (osteosarcopenia), is associated with increased risk for fractures, falls, and mortality. Although there are multiple medications for management of osteoporosis, there are no approved pharmacotherapy for sarcopenia.
OBJECTIVES:
We examined the effect of zoledronic acid on muscle mass indices including ALM (Appendicular Lean Mass) and ALM/Height2 in a cohort of older women with osteoporosis who were residents of Long-Term Care Communities (LTCCs).
DESIGN:
A secondary analysis of a 2-year double-blind, randomized, placebo-controlled clinical trial.
SETTING:
Residents of LTCCs.
PARTICIPANTS:
Sixty-two postmenopausal women with osteoporosis.
INTERVENTION:
Participants either received 5 mg infusion of zoledronic acid or placebo, once at the start of the study.
MEASUREMENTS:
Participant’s ALM/Height2, ALM, total hip BMD (Bone Mineral Density) and spine BMD were measured in 6, 12 and 24 months.
RESULTS:
On average, participants were 86.7 years old and had a BMI of 27.4 kg/m2. There was no significant difference in change from baseline (mean ± SE) between the treatment group and the placebo group in ALM/Height2: (−0.15 vs −0.02, p = 0.541) and (−0.17 vs 0.001, p = 0.315) and (−0.29 vs −0.19, p = 0.646) or ALM: (−0.38 vs −0.09, p = 0.455) and (−0.45 vs −0.005, p = 0.216) and (−0.70 vs −0.48, p = 0.553) at 6, 12, and 24 months respectively. In addition, after adjusting for a possible confounding, the ALM/Height2 or ALM did not have significant improvements from baseline at 6 months, 12 months, and 24 months either in the treatment group or in the placebo group. However, there were significant improvements in the BMD at the total hip and the spine in the treatment group compared with the placebo group at all three time points.
CONCLUSIONS:
Among older women residing in LTCCs, a single dose of zoledronic acid did not increase ALM/Height2 and ALM, despite improving the BMD at the total hip and the spine at the 2-year follow-up.
Keywords: Osteoporosis, sarcopenia, bone mineral density, appendicular lean mass, zoledronic acid, long-term care
Introduction
Osteosarcopenia is an under-recognized yet common geriatric musculoskeletal syndrome. This syndrome describes coexistence of osteoporosis and sarcopenia (1). The prevalence of osteoporosis and sarcopenia is much higher in older adults who are residents of long-term care communities (LTCCs) compared with the general population. Nearly 85% of older adults who live in LTCCs have osteoporosis and 10% had a hip fracture (2,3). Sarcopenia has been reported in 30% of older adults in LTCCs (4). Low bone mass and deteriorated skeletal micro-architecture in osteoporosis places individuals at high risk for fragility fractures. Low skeletal muscle mass, strength, and functional capacity as the result of sarcopenia significantly increases the risk for falls. Coexistence of osteoporosis and sarcopenia, or osteosarcopenia, is associated with significant functional impairment, increased mortality and a substantial increase in cost of care (5).
Sarcopenia, unlike osteoporosis, does not have broadly accepted diagnostic criteria. Despite differences in clinical definitions for sarcopenia, low muscle mass has been proposed as a confirmatory criterion for diagnosing sarcopenia in most consensus panels including the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) and the Foundations for the National Institutes of Health (FNIH) (6, 7). EWGSOP2, as the most widely used guideline, uses whole body dualenergy x-ray absorptiometry (DXA)-derived appendicular lean mass (ALM) normalized by squared height (ALM/Height2) as an index for lean mass (6). EWGSOP2 suggests ALM/Height2 less than two standard deviations below mean reference value of healthy young adults (<7.0 kg/m2 in men and <5.5 kg/m2 in women) as the cut point for low lean mass (6).
Several classes of medications are approved to treat osteoporosis, but not for sarcopenia. Due to emerging knowledge about cross-talk between bone and muscle through different biochemical and mechanical pathways, there is growing interest in examining the effect of osteoporosis medical treatment on sarcopenia (8-11). Bisphosphonates are generally the first line and the most widely used medications for treatment of osteoporosis (12). Due to their structural similarity to pyrophosphate, they attach to the hydroxyapatite molecules on the surface of the bone and interfere with the osteoclast bone resorption function (12, 14). Zoledronic acid is a nitrogen-containing, parenteral bisphosphonate that has the highest affinity for hydroxyapatite compared with other bisphosphonates (15). Multiple studies, in both community dwelling older adults and those who are residents of LTCCs, have shown once-yearly zoledronic acid improves bone mineral density and decreases risk for fractures at various skeletal sites including the total hip and the spine (16-19). Despite proven benefits of bisphosphonates on bone health, their effect on muscle health is still an area of investigation (20). In a study by Park et al. in 38 community-dwelling postmenopausal women in Korea with average age of 56 years old, combination of the bisphosphonate alendronate and calcitriol did not significantly improve ALM/Height2 (21). In vitro studies have shown bisphosphonates alendronate and zoledronic acid improve muscular function and even muscle mass by proliferation and differentiation of undifferentiated myogenic cells (22, 23).
In this sub-analysis of a randomized clinical trial in older women with osteoporosis who were residents of LTCCs and at the greatest risk for falls and fractures, we evaluated the effect of zoledronic acid on appendicular lean mass indices ALM/Height2 and ALM.
Methods
Study Design
This sub-analysis included data from ZEST (Zoledronic Acid for Osteoporosis in the Elderly; ClinicalTrials.gov identifier: NCT00558012) which was a double-blind, randomized, placebo-controlled osteoporosis clinical trial in postmenopausal women who were residents of LTCCs. The aim of ZEST trial was to assess the safety, efficacy and feasibility of a single dose of zoledronic acid in the maintenance of skeletal integrity in this specific population who are the highest risk for osteoporotic fractures. Following the baseline assessment, participants were randomized to infusion with either one dose of intravenous zoledronic acid 5 mg or placebo. Subsequent follow-up visits occurred at 6, 12, and 24 months. This study was reviewed and approved by the institutional review board (IRB).
Participants
Our study included women who were 70 years or older and were residents of LTCCs. This sub-analysis includes 62 participants who had the assessment of body composition by whole-body DXA scan. All participants had diagnosis of osteoporosis based on the Bone Health and Osteoporosis Foundation (BHOF) diagnostic criteria (24), had 25-hydroxy vitamin D level of 30 ng/ml or more at the time of randomization and received a total daily dose of 800 IU vitamin D3 and up to 1200 mg of elemental calcium. Participants with a projected life expectancy of less than 2 years or an estimated glomerular filtration rate below 30 mL/min or history of other osteoporosis medication use were excluded from the study.
Measures
We measured the bone mineral density (BMD) (g/cm2) of the total hip and PA spine with Discovery DXA bone densitometer (Hologic Inc., Bedford, Massachusetts, USA) at the baseline, 6, 12 and 24 months (17). We excluded vertebrae with >1 Standard Deviation (SD) T-score difference with adjacent vertebrae. This difference could have been due to a fracture or other etiologies. We used whole-body DXA (Hologic Inc., Bedford, Massachusetts), to measure ALM and ALM/Height2 at the baseline 6, 12 and 24 months. ALM was calculated by sum of the lean tissue in the upper and the lower extremities. Participant’s height was measured at the baseline.
Statistical Analysis
We used appropriate descriptive statistics to summarize participant characteristics, and independent samples t- and Fisher’s exact tests to compare the same between treatment groups at baseline. To elicit the main findings, we fitted a series of linear mixed models with baseline to follow-up change and percent change in each muscle and in bone outcome as the dependent variable; treatment group, follow-up time point and their interaction as fixed effects; baseline value of the outcome and BMI (to account for baseline imbalance and obesity-sarcopenia-osteoporosis connection in old age) as fixed effect covariates; and a participant random effect to account for multiple post-randomization assessments per participant (25, 26). We used means contrasts to estimate between-group adjusted differences at each of the follow-up time points, controlling for the covariates: baseline value of outcome and BMI. To examine cross-sectional (longitudinal) associations between ALM and BMD measures, we used (baseline-adjusted partial) Pearson correlation coefficients (r). SAS® version 9.4 (SAS Institute, Inc., Cary, North Carolina) was used for all statistical analyses.
Results
Participants included 62 older women who were residents of LTCCs with an age (mean ± standard deviation) of 86.7 ± 5.6 (range 72-100) years and a BMI of 27.4 ± 4.5 kg/m2. We collected their total hip BMD, PA spine BMD, whole-body DXA-derived ALM and ALM/Height2 at the baseline, and 6, 12 and 24 months. Table 1 provides a summary of baseline data.
Table 1.
Baseline Characteristics (mean ± standard deviation or N(%))
| Characteristic | Zoledronic Acid (n=21) | Placebo (n=41) | p-Value* |
|---|---|---|---|
| Age, year | 87.6 ± 6.2 | 86.3±5.4 | 0.412 |
| BMI, kg/m2 | 29.0 ± 4.7 | 26.6±4.2 | 0.040 |
| Race | |||
| White (%) | 21 (100.0) | 39 (95.1) | 0.545 |
| Black (%) | 0 (0.0) | 2 (4.9) | |
| History of cancer | 4 (19.1) | 12 (29.3) | 0.384 |
| Glucocorticoid/steroid use | 4 (19.1) | 7 (17.1) | 1.000 |
| Height, meter | 1.55 ± 0.05 | 1.57 ± 0.06 | 0.417 |
| Total Hip BMD, g/cm2 | 0.706 ± 0.108 | 0.697 ± 0.110 | 0.617 |
| Spine BMD, g/cm2 | 0.950 ± 0.172 | 0.954 ± 0.163 | 0.885 |
| ALM, kg | 16.0 ± 3.1 | 15.7 ± 2.5 | 0.524 |
| ALM/Height2, kg/m2 | 6.8 ± 1.1 | 6.6 ± 1.0 | 0.194 |
BMI = Body Mass Index, BMD = Bone Mineral Density, ALM = Appendicular Lean Mass, N = frequency
Obtained using independent samples t- and Fisher’s exact tests.
Following administration of zoledronic acid 5mg at the start of the study, percent improvement in the spine BMD was greater in the treatment group compared with the placebo group at 6 months (3.20 vs −0.01, p = 0.003), 12 months (3.92 vs 0.31, p=0. 002) and 24 months (5.99 vs −0.34, p <0.001). Percent improvement in the total hip BMD was also higher in the treatment group than the placebo group at 12 months (3.27 vs −1.12, p = <0.001) and 24 months (2.78 vs −2.18, p<0.001) (Table 2 and Figure 1).
Table 2.
Absolute and Relative Change in BMD
| Skeletal Site | Zoledronic Acid | Placebo | Zoledronic Acid vs Placebo | |||
|---|---|---|---|---|---|---|
| Mean Change from BL ± SD |
P-Value * | Mean Change from BL ± SD |
P-Value * | Adjusted Difference ± SE |
P-Value § | |
| Spine BMD Change (g/cm2) | ||||||
| 6 months | 0.030±0.044 | 0.005 | 0.000±0.027 | 0.968 | 0.026±0.009 | 0.004 |
| 12 months | 0.036±0.034 | 0.0001 | 0.004±0.029 | 0.395 | 0.028±0.009 | 0.003 |
| 24 months | 0.055±0.042 | <0.001 | −0.003±0.030 | 0.506 | 0.054±0.010 | <0.001 |
| Total Hip BMD Change (g/cm2) | ||||||
| 6 months | 0.011±0.019 | 0.011 | −0.004±0.021 | 0.235 | 0.013±0.007 | 0.069 |
| 12 months | 0.023±0.026 | <0.001 | −0.007±0.025 | 0.075 | 0.029±0.007 | <0.001 |
| 24 months | 0.020±0.021 | 0.001 | −0.015±0.036 | 0.023 | 0.032±0.008 | <0.001 |
| Spine BMD Percent Change | ||||||
| 6 months | 3.20 ± 4.46 | 0.004 | −0.01 ± 2.87 | 0.972 | 2.91±0.97 | 0.003 |
| 12 months | 3.92 ± 3.57 | < 0.001 | 0.31 ± 3.18 | 0.550 | 3.15±0.99 | 0.002 |
| 24 months | 5.99 ± 4.60 | < 0.001 | −0.34 ± 3.08 | 0.520 | 5.86±1.02 | <0.001 |
| Total Hip BMD Percent Change | ||||||
| 6 months | 1.59 ± 2.74 | 0.015 | −0.62 ± 3.32 | 0.233 | 1.93±1.08 | 0.077 |
| 12 months | 3.27 ± 3.46 | <0.001 | −1.12 ± 3.77 | 0.078 | 4.24±1.10 | <0.001 |
| 24 months | 2.78 ± 2.95 | 0.001 | −2.18 ± 5.44 | 0.026 | 4.69±1.15 | <0.001 |
BMD = Bone Mineral Density, BL = Baseline, SD = Standard Deviation, SE = Standard Error
Obtained using paired samples t-tests
Obtained using a linear mixed model.
Figure 1. Mean Percent Change in BMD in Spine (A) and Total Hip (B) from Baseline to 24 Months.
** p<0.05 change from baseline using paired t-test. ## p<0.05 for comparison between zoledronic acid (solid line) and placebo (dashed line) groups using linear mixed models; The error bars represent a one standard error of the mean computed as standard deviation/√(number of observations) using descriptive statistics.
There were no statistically significant differences in ALM/Height2 change in the treatment group compared with the placebo group at 6 months (−0.15 vs −0.02, p = 0. 541), 12 months (−0.17 vs 0.001, p = 0. 315) and 24 months (−0.29 vs −0.19, p = 0. 646) (Table 3). ALM change was also not statistically significant between the two groups at 6 months (−0.38 vs −0.09, p = 0. 455), 12 months (−0.45 vs −0.005, p = 0. 216) and 24 months (−0.70 vs −0.48, p = 0. 553) (Table 3 and Figure 2).
Table 3.
Absolute and Relative Change in Lean Mass Indices
| Lean Mass Index | Zoledronic Acid | Placebo | Zoledronic Acid vs Placebo | |||
|---|---|---|---|---|---|---|
| Mean Change from BL ± SD | P-Value * | Mean Change from BL ± SD | P-Value * | Adjusted Difference ± SE | P-Value § | |
| ALM/Height2 Change | ||||||
| 6 months | −0.15 ± 0.53 | 0.210 | −0.02 ± 0.37 | 0.689 | −0.09±0.15 | 0.541 |
| 12 months | −0.17 ± 0.71 | 0.313 | 0.001 ± 0.99 | 0.994 | −0.16±0.16 | 0.315 |
| 24 months | −0.29 ± 0.89 | 0.225 | −0.19 ± 0.51 | 0.067 | −0.08±0.17 | 0.646 |
| ALM Change | ||||||
| 6 months | −0.38 ± 1.34 | 0.219 | −0.09 ± 0.91 | 0.527 | −0.28±0.38 | 0.455 |
| 12 months | −0.45 ± 1.78 | 0.297 | −0.005 ± 1.03 | 0.980 | −0.49±0.39 | 0.216 |
| 24 months | −0.70 ± 2.21 | 0.237 | −0.48 ± 1.24 | 0.063 | −0.25±0.41 | 0.553 |
| ALM Percent Change | ||||||
| 6 months | −1.98±7.09 | 0.226 | −0.47±6.03 | 0.635 | −1.52±2.22 | 0.497 |
| 12 months | −2.26±9.95 | 0.348 | −0.02±6.54 | 0.986 | −2.45±2.31 | 0.292 |
| 24 months | −3.50±12.0 | 0.276 | −3.02±7.99 | 0.071 | −0.70±2.45 | 0.775 |
ALM = Appendicular Lean Mass, BL = Baseline, SD = Standard Deviation, SE = Standard Error
Obtained using paired samples t-tests
Obtained using a linear mixed model.
Figure 2. Mean Change in ALM/Height2 (A) and ALM (B) from Baseline to 24 Months.
There was no statistical significance at the alpha level of 0.05 in change from baseline or comparison between zoledronic acid (solid line) and placebo (dashed line) groups. Error bars represent standard error of the mean; The error bars represent a one standard error of the mean computed as standard deviation/√(number of observations) using descriptive statistics.
At baseline, measures of ALM and BMD were significantly correlated (r=0.26-0.32; all p<0.05). Over the 24-month follow-up, changes in ALM and BMD had positive partial correlations in both zoledronic acid (r=0.25-0.52) and placebo (r=0.49-0.54) groups.
Discussion
Osteoporosis and sarcopenia are common age-related disorders that often coexist due to the cross-talk between bone and muscle and their tightly integrated nature (1, 8-11). Abundant evidence exists that bisphosphonates, in particular zoledronic acid, improve bone density and reduce fractures, however, there is scarce knowledge about impact of these medications on sarcopenia and lean muscle mass (16,17,19). The objective of this sub-study of the ZEST clinical trial was to examine the effect of zoledronic acid on appendicular lean mass, as a confirmatory criterion for diagnosing sarcopenia in EWGSOP2, in older women who had diagnosis of osteoporosis and were residents of LTCCs. Results of our study, for the first time to our knowledge, demonstrate that in this specific population, zoledronic acid does not significantly alter ALM/Height2 and ALM despite increasing BMD at the PA spine and the total hip. Our findings are in contrast to a retrospective study by Haung et. al in 231 community dwelling older men and women, in which participants received zoledronic acid annually for three years and improvement in ALM/Height2 and ALM were observed in year four. However, the study by Haung et. al. was not a randomized clinical trial, participants were not residents of LTCCs and they received zoledronic acid annually for three doses over four years, whereas our study participants received one dose of zoledronic acid over two years (27). We also found that ALM and BMD were positively correlated. We speculate the underlying mechanism for these associations may be a combination of simply mechanical load or complex biochemical pathways.
Biochemical cross-talk between bone and muscle has been the focus of many studies in recent years (8-11, 28,29). In fact, the osteoporosis medication denosumab, by affecting one of the mediators of this cross-talk, the receptor-activator of nuclear factor kB ligand (RANKL), not only inhibits the osteoclasts in bones but also stimulates myogenic differentiation (30). In several clinical trials in community dwelling older adults, denosumab was associated with significant improvement in lean mass, muscle strength and decreased risk for falls (31,32). Nevertheless, the effects of bisphosphonates, including zoledronic acid, on lean mass, strength and function in patients with osteoporosis has been controversial. In a retrospective study by Bashi et al. in 115 older women and men with osteoporosis, zoledronic acid did not improve muscle strength or muscle performance (33). Unlike the study by Bashi et. al., in a longitudinal follow up study by Miedany et al. in 136 postmenopausal women, zoledronic acid was associated with improved muscle strength and performance (32). These studies did not examine the effect of zoledronic acid on lean mass. Impact of zoledronic acid on lean mass has been examined in animal studies such as the study by Essex et al., that found administration of zoledronic acid preserved muscle fiber size in cisplatin-treated mice by alleviating chemotherapy-induced muscle hypercatabolism; however, zoledronic acid did not improve lean mass in healthy animals (34). These finding have not been validated in human studies.
The positive correlation between BMD and ALM may generate speculation that they should behave similarly, yet we found an effect of zoledronic acid on BMD and not ALM which may be due to a combination of factors. First, the correlations are not that strong, explaining <30% (as approximated by squared correlation) of variability in one measure by the other. Second, it may be due to different underlying mechanisms. There is an emerging literature documenting the bone-muscle connection through biochemical pathways or simply mechanical forces of weight (8, 29). On the other hand, the known mechanism behind zoledronic acid’s action is through reduced bone resorption (15).
Our study has several strengths. This is the first double-blind, placebo-controlled clinical trial study where the effect of zoledronic acid on both bone mass and lean mass were investigated. Our study included residents of LTCCs, a cohort of older adults with frailty at the highest risk for falls and fractures. Moreover, all study participants had normal 25-hydroxy vitamin D level at the time of randomization and received a standard maintenance dose of vitamin D3 throughout the study period. Our study also had limitations. It was limited by its relatively small sample size. Lack of a significant difference between groups in ALM could be due to lack of statistical power rather than a true similarity. However, the magnitudes of the estimates favor the placebo group, rendering the possibility unlikely. Furthermore, our participants only received a single dose of zoledronic acid, and the medication may be needed on an annual basis for several years to see an impact on muscle. In addition, other criteria for sarcopenia including grip strength and muscle function were not evaluated in our study. Moreover, subjects may not represent the general population of LTCCs as participants were all women and were mostly white.
Since muscle mass and ALM are not equivalent, lack of improvement in ALM, necessarily does not equivalate to lack of improvement in muscle mass. Results from previous trials showing discordant effects of bisphosphonates on muscle strength and lean mass (21) and studies that examined correlation between muscle mass and strength indicate that DXA-derived ALM may not be an ideal surrogate of muscle mass (35-37).
In conclusion, this study demonstrates that in older women who were residents of LTCCs, a single dose of zoledronic acid 5mg infusion, despite increasing the BMD at the total hip and spine, did not improve lean mass indices such as ALM/Height2 and ALM at the 2-year follow-up. Further prospective studies are required to confirm these findings.
Funding:
This work was supported by following grants: National Institutes of Health National Institutes of Health (NIH)/National Institute on Aging (NIA) grant R01 AG028068, NIH/The National Institute of Diabetes and Digestive and Kidney Diseases grant K24 DK062895, 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.
Footnotes
Conflicts of interest: Dr. Safai Haeri reports no conflicts of interest in the subject matter or materials discussed in this manuscript. Dr. Perera is co-investigator on NIH-sponsored osteoporosis trials conducted at the institution where study medications are provided by Amgen. Dr. Greenspan reports receipt of grants to her institution from Amgen.
Ethical standards: This study was reviewed and approved by the University of Pittsburgh’s IRB
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