Risk of Fracture in Women With Sarcopenia, Low Bone Mass, or Both

Rebekah Harris, PT, DPT; Yuefang Chang, PhD; Kristen Beavers, PhD, MPH, MS; Deepika Laddu-Patel, PhD; Jennifer Bea, PhD; Karen Johnson, MD, MPH; Meryl LeBoff, MD; Catherine Womack, MD; Robert Wallace, MD, MSc; Wenjun Li, PhD; Carolyn Crandall, MD, MS; Jane Cauley, DrPH

J Am Geriatr Soc. 2017;65(12):2673-2678. 

Abstract and Introduction

Abstract

Objectives To determine whether women with sarcopenia and low bone mineral density (BMD) are at greater risk of clinical fractures than those with sarcopenia or low BMD alone.

Design Women's Health Initiative (WHI) Observational and Clinical trials.

Setting Three U.S. clinical centers (Pittsburgh, PA; Birmingham, AL; Phoenix/Tucson, AZ).

Participants Women (mean age 63.3 ± 0.07) with BMD measurements (N = 10,937).

Measurements Sarcopenia was defined as appendicular lean mass values corrected for height and fat mass. Low BMD was defined as a femoral neck T-score less than −1.0 based on the Third National Health and Nutrition Examination Survey reference database for white women. Cox proportional hazards analysis was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). We followed women for incident fractures over a median of 15.9 years.

Results Participants were classified into mutually exclusive groups based on BMD and sarcopenia status: normal BMD and no sarcopenia (n = 3,857, 35%), sarcopenia alone (n = 774, 7%), low BMD alone (n = 4,907, 45%), and low BMD and sarcopenia (n = 1,399, 13%). Women with low BMD, with (HR = 1.72, 95% CI = 1.44–2.06) or without sarcopenia (HR = 1.58, 95% CI = 1.37–1.83), had greater risk of fracture than women with normal BMD; the difference remained statistically significant after adjustment for important covariates. Women with low BMD, with (HR = 2.78, 95% CI = 1.78–4.30 and without (HR = 2.42, 95% CI = 1.63–3.59) sarcopenia had higher risk of hip fractures. Women with sarcopenia alone had similar HRs to women with normal BMD.

Conclusion Compared to women with normal BMD.

Introduction

Osteoporotic fractures result in morbidity and mortality and increase healthcare costs.[1] By 2040, the world population aged 65 and older will have doubled from 506 million to 1.3 billion.[2] Fracture events occur disproportionately in older adults, due in part to age-associated declines in bone mineral density (BMD).[3–5] Declines in muscle mass have been associated with mobility disability and fractures.[6,7] The loss of bone and alterations in the structure of the bone, coupled with greater risk of falling, contribute to age-related increases in fractures.

Sarcopenia, which can be defined as loss of muscle mass, in addition to the loss of strength and physical performance, has been associated with fractures.[8] Aging is associated with loss in lean mass and strength, which predicts incident fracture independent of BMD,[9] by influencing functional ability and fall risk.[10–13]

The associations between the combination of sarcopenia and BMD and fracture risk have not been well examined in women. The condition "sarco-osteopenia" may indicate a higher fracture risk than of osteoporosis or sarcopenia alone.[14] A recent study in women after hip fracture showed that those with sarcopenia were more likely to have osteoporosis or low BMD at the lumbar spine and femoral neck.[15] The prevalence of sarco-osteopenia in this population was high (45%), probably because all the women had had a previous hip fracture. Other studies have reported a lower prevalence of this phenotype of closer to 10%. Assessing the role of sarco-osteopenia as a risk factor for fracture in women may improve the risk assessment. In men, it has been reported that a combination of low BMD and sarcopenia resulted in a risk of fracture that was almost four times as great as in men without sarcopenia and low BMD,[8] although women with sarcopenia and low BMD had a risk of fracture similar to that of women with low BMD alone.[8] The addition of sarcopenia did not increase the risk in women, although this study had a much smaller sample of women than men and perhaps less statistical power.[8]

To further explore the combined effect of sarcopenia and low BMD in women, we used data from the Women's Health Initiative (WHI). Better understanding of the relative contributions of each body compartment on fracture risk is needed to optimize therapeutic strategies to reduce fracture risk in older adults. We tested the hypothesis that women with both low BMD and sarcopenia would have greater risk of fracture than women with sarcopenia or low BMD alone and women without either condition.

Methods

Study Population

The WHI included 161,808 women aged 50 to 79 at baseline with predicted survival of 3 years or more who were postmenopausal.[16] Recruitment has been described elsewhere. Briefly, women were enrolled at 40 U.S. clinical centers[16] into one or more randomized clinical trials assessing the interventions of low-fat diets, hormone therapy, and calcium and vitamin D supplementation.[16] Women who were ineligible or not interested in the clinical trials were enrolled in the Observational Study. BMD was measured in women enrolled in WHI at three clinic sites (Pittsburgh, PA; Birmingham, AL; Phoenix/Tucson, AZ) who form the analytical sample for this report. All women with a baseline dual-energy x-ray absorptiometry (DXA) scan were examined for this report. Of the women with BMD measurements (N = 11,350), we excluded women taking bisphosphonates at baseline, leaving a final analytical sample of 10,937 women. When WHI ended on March 30, 2005, women provided consent to participate in an extension study; 77% of surviving women agreed to participate in the first extension (2005–10).

Sarcopenia and BMD

Femoral neck and total body BMD were measured. Details of this measurement and densitometry procedures have been previously published.[17] Briefly, all trained technicians used QDR 2000, 2000+, or 4500 machines (Hologic, Bedford, MA). A standardized procedure for participant positioning and scan analysis was used at all centers.[17,18] Phantom scans, scans with specific problems, and a random sampling of scans were reviewed in the WHI quality assurance program to monitor machine and technician performance. Low BMD was defined as a femoral neck T-score less than −1.0 based on the Third National Health and Nutrition Examination Survey reference database for white women. This is the reference database that the International Society for Clinical Densitometry recommends.[19] Lean mass was measured using whole-body scans (QDR 2000, 2000+, or 4500, Hologic). Appendicular lean mass (ALM) was derived from the sum of lean mass in the upper and lower extremities with bone mineral content removed.[20]

The definition of sarcopenia was based on ALM values following a previously developed approach.[21] To correct ALM for fat mass and height, linear regression was performed to model the association between ALM on height (meters) and fat mass (kg). The 20th percentile of the distribution of residuals from this model was used as the cut point for sarcopenia. The residuals method was chosen because it has been shown to be a stronger predictor of mobility and disability limitations in the Health, Aging and Body Composition (Health ABC) and Framingham studies than other definitions of sarcopenia.[21]

Participants were classified into four mutually exclusive groups based on BMD and sarcopenia status: normal BMD and no sarcopenia (n = 3,857, 35%), normal BMD and sarcopenia (n = 774, 7%), low BMD and no sarcopenia (n = 4,907, 45%), and low BMD and sarcopenia (n = 1,399, 13%). In additional analyses, we calculated sarcopenia based on the Baumgartner method (ALM/height[2]),[22] the Health ABC cutoff for sarcopenia (1.73 kg/m2),[21] and the osteoporosis cutoff for BMD (T score ≤−2.5).

Other Measurements

Information on covariates was obtained from self-report questionnaires, clinic interviews, and physical measurements at baseline.[16] Covariates include age, race and ethnicity, clinic site, history of fracture, fall history, smoking status, alcohol consumption, hormone use, corticosteroid use, physical activity, body mass index (BMI), total vitamin D and calcium intake, and rheumatoid arthritis. Smoking status was categorized as current smoker or not and alcohol consumption was measured as the average number of alcoholic drinks per week. BMI was calculated from height and weight measurements using calibrated scales and stadiometers. Fall history was quantified dichotomously as having a fall or not in the past 12 months. Recreational physical activity was from self-report and measured as metabolic equivalent task hours per week, which were derived from the literature and validated standardized questionnaires for this population.[23] The RAND-36 score was used as a measure of physical function, with a score of 90 or less indicating poor physical function (range 0–100).[24,25] Corticosteroid use was based on self-report. Vitamin D and calcium intake were calculated from self-report on the Food Frequency Questionnaire.

Fractures

Information on incident fractures was obtained prospectively—annually in women enrolled in the observational study and semiannually in women enrolled in the clinical trials. We included all self-reported clinical fractures except for fingers, toes, face, sternum, ribs, and skull. Pathological fractures were also excluded. Hip fractures were locally and centrally adjudicated;[26] all other fractures were self-reported. In WHI, although agreement between self-reported fractures and adjudicated fractures was 76%,[27] self-report of clinical spine fractures was poor. Therefore, we performed a sensitivity analysis excluding clinical spine fractures. We analyzed the risk of all fractures and hip fractures separately. Follow-up ranged from 1993 to 2009 (median 15.9 years).

Statistical Approach

Baseline characteristics were compared of the four groups using analysis of variance for continuous variables and chi-square tests for categorical variables. Multiple comparisons were calculated for baseline characteristics of participants. Incidence rates of total fracture were estimated using a Poisson model for each of the four groups, adjusted for age and race.

Using Cox proportional hazards models, the base and multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Base models were adjusted for age and race. The multivariable adjusted model was adjusted for established risk factors for fracture: age, race, clinic site, random clinical trial assignment, self-report fall history, fracture history, menopausal hormone therapy use over time, alcohol consumption, smoking status, vitamin D and calcium intake, and physical activity. Participants with normal BMD and no sarcopenia formed the reference group.

Results

Women with low BMD only and low BMD and sarcopenia tended to be older than the reference group (). Women with sarcopenia only, low BMD only, and low BMD and sarcopenia were more likely to be white than the reference group as well. Women who had normal BMD and no sarcopenia were less likely to be current smokers than those with sarcopenia and those with low BMD and sarcopenia. Physical activity was lowest in the groups with sarcopenia with and without low BMD. Lumbar spine and femoral neck BMD were lowest in both low BMD groups, with no difference according to sarcopenia status.

Table 1.  Baseline Characteristics according to Bone Mineral Density (BMD) and Body Composition

Baseline Characteristic Normal BMD, No Sarcopenia, n = 3,857 Sarcopenia, n = 774 Low BMD, n = 4,907 Low BMD, Sarcopenia, n = 1,399 P-Value
Age, mean ± SD 60.8 (7.0) 62.0 ± 7.2 65.0 ± 7.1 65.3 ± 7.0 a,b,c,d,f
White, n (%) 2,465 (64.1) 633 (82.0) 4,249 (87.0) 1,271 (91.1) a,b,c,d,e,f
Education, n (%) a
   <High school 421 (11.3) 78 (10.4) 405 (8.7) 125 (9.0)
   High school or vocational school 2,299 (59.6) 470 (60.7) 2,938 (59.9) 858 (61.5)
   ≥College 1,124 (29.1) 224 (28.9) 1,543 (31.4) 413 (29.5)
Total appendicular skeletal mass, kg, mean ± SD 16.6 ± 2.9 13.0 ± 1.9 14.4 ± 2.2 12.0 ± 1.6 a,b,c,d,e.f
Body mass index, kg/m2, mean ± SD 31.0 ± 6.3 29.2 ± 5.8 26.5 ± 4.9 26.2 ± 4.3 a,b,c,d,e,f
Baseline femoral neck BMD, g/cm2, mean ± SD 0.84 ± 0.09 0.82 ± 0.08 0.64 ± 0.07 0.64 ± 0.07 a,b,c,d,f
Current smoker, n (%) 314 (8.3) 49 (6.5) 399 (8.3) 104 (7.5) b,c,d
Alcohol use, servings/wk, n (%) 1.6 (4.0) 1.7 (4.1) 1.9 (4.3) 1.6 (3.8) a,e
Fall history >1 fall, n (%) 914 (29.3) 185 (27.7) 1264 (28.7) 421 (32.5) c,e,f
History of fracture, n (%) 1,038 (30.8) 191 (28.9) 1,831 (42.8) 543 (44.2) a,c,d,f
Use of hormones, n (%) 2,070 (53.9) 513 (66.5) 2,346 (48.0) 811 (58.1) a,b,c,d,e,f
Metabolic equivalent task h/wk, mean ± SD 10.9 ± 14.1 9.0 ± 11.4 12.9 ± 14.5 9.4 ± 11.9 a,b,c,d,e
RAND-36 score ≥90, n (%) 2,690 (69.7) 602 (31.8) 3,036 (68.2) 987 (68.2) a,b,c,d,e,f

Adjusted for multiple comparisons: anormal vs low BMD, bnormal vs sarcopenia, cnormal vs low BMD +sarcopenia, dlow BMD vs sarcopenia, elow BMD vs low BMD+sarcopenia, sarcopenia vs low BMD+sarcopenia.
SD = standard deviation.

One thousand six hundred forty-eight women experienced a fracture (n = 379 (10%) reference, 7.1 fractures per 1,000 person-years; n = 78 (11%) sarcopenia only, 6.6 fractures per 1,000 person-years; n = 903 (19%) low BMD only, 11.2 fractures per 1,000 person-years; n = 288 (20%) sarcopenia + low BMD, 12.9 fractures per 1,000 person-years). The log rank test was significant for difference in survival curves across all four groups, with adjustment for multiple comparisons (Figure 1).

Figure 1.

 

Survival curve in years according to bone mineral density (BMD) and body composition group. solid line = reference; small dash line = sarcopenia only; dotted line = low BMD only; large dash line = low BMD and sarcopenia.

Women with low BMD, with (HR = 1.76, 95% CI = 1.50–2.07) or without (HR = 1.57, 95% CI = 1.38–1.78) sarcopenia, had greater risk of fracture than those with normal BMD; the difference remained statistically significant after adjustment for important covariates (HR = 1.72, 95% CI = 1.44–2.06 and HR = 1.58, 95% CI = 1.37–1.83, respectively). The risk of hip fracture was the highest for those with low BMD and sarcopenia (HR = 2.78, 95% CI = 1.78–4.34) and low BMD alone (HR = 2.42, 95% CI = 1.63–3.59). HRs were highest in both groups with low BMD for all types of fracture (). Risk of fracture for women with sarcopenia alone was similar to that of normal women in both models. Additional analyses were performed with various definitions of sarcopenia and low BMD. The results remained consistent with our reported findings and can be found in Supplemental Tables S1 and S2.

Table 2.  Risk of Fracture According to Bone Mineral Density (BMD) and Body Composition Group

Group Any Fracture Models Hip Fracture Models
Basea Multivariableb Basea Multivariableb
Hazard Ratio (95% Confidence Interval)
Sarcopenia 0.92 (0.72–1.17) 0.85 (0.64–1.12) 0.84 (0.39–1.81) 0.58 (0.23–1.49)
Low BMD 1.57 (1.38–1.78) 1.59 (1.38–1.84) 2.71 (1.90–3.87) 2.42 (1.63–3.59)
Low BMD and sarcopenia 1.76 (1.50–2.07) 1.72 (1.44–2.06) 3.27 (2.18–4.91) 2.78 (1.78–4.34)

a Adjusted for age, clinic, and race.
b Adjusted for age, race, study assignment, physical function, history of fracture, history of self-report falls in past year, hormone use, physical activity, alcohol consumption, smoking status, corticosteroid use, body mass index, dietary calcium intake, dietary vitamin D intake.

Overall, there were 323 hip fracture events (n = 38 normal, n = 8 sarcopenia, n = 207 low BMD, n = 70 low BMD + sarcopenia). Women with low BMD and sarcopenia (HR = 2.78, 95% CI = 1.78–4.34) had a 20% greater risk of hip fracture than those with low BMD alone and (HR = 2.42, 95% CI = 1.63–3.59). The interaction between sarcopenia and low BMD was not statistically significant (P = .15).

Sensitivity analyses were performed excluding women with spinal fractures from the outcome assessment of fracture. Results from the sensitivity analysis demonstrate that the HRs remained highest in the women in the groups with low BMD. The results also continued to demonstrate that there is similar risk in women with sarcopenia alone and women without either condition (Supplemental Table S2).

Discussion

Women with low BMD, irrespective of their sarcopenia status, had a greater risk of fracture than women with normal BMD and normal ALM. Our results confirm that low BMD is a strong risk factor for fracture in women and show that sarcopenia does not increase this risk. Our results are similar to those of previous work that showed that the association between sarcopenia and low BMD was similar to the association between low BMD alone in women, although a previous study found that men with low BMD and sarcopenia had a risk of fracture that was four times as great as that of men without either.[8] This suggests that there is a sex difference in the relationship between sarcopenia and fracture risk. It could be that the decline of muscle strength and lean mass in women is not as swift as it is in men.[13] The decline in testosterone levels affects men more than women throughout aging, and testosterone levels have been associated with lean mass.[28] It may also be that the women in this cohort had not yet experienced a significant age-related decline in lean mass. The change in overall lean mass from baseline to Year 3 visit was a net increase of 0.12 kg. Adjusting for multiple comparisons, a difference was found in change in lean mass between women in the reference group and those with sarcopenia and low BMD (2.54 kg) and between women with low BMD and those with sarcopenia and low BMD (1.81 kg). These small differences in lean mass change did not influence the risk of fracture.

It has been proposed that sarcopenia may increase the risk of fracture that is generally associated with aging and improve fracture risk assessment.[14] Limiting fractures to those of the hip, we found that women with the combination of low BMD and sarcopenia had a higher risk of fracture than those in the other groups, but sarcopenia alone was not found to be an independent risk factor for fracture in women. In previous work, the consensus definitions of Sarcopenia did not improve the prediction of clinical outcomes, such as fracture.[29] The addition of sarcopenia to low BMD suggests greater risk of hip fracture in women. This combination may imply that there is communication between muscle and bone at this site, which is commonly associated with frailty.[30] This interaction may be influenced by mechanical stimuli, genetic factors, hormonal influences and body composition. Total bone mineral content has been shown to be associated more with lean tissue mass than fat tissue mass, and regional BMD has been more closely associated with changes in fat tissue mass.[31] Additionally, weight reduction, which can be attributed to both fat and lean tissue mass, can lead to accelerated rates of bone loss in post-menopausal women.[31]

In supplementary analyses, we explored differing cut-points for lean mass and BMD. We opted to define low BMD as a T-score of less than −1 to optimize our sample sizes in the four groups. Using a more-stringent cut point for low BMD, T-score less than −2.5, which is the cut off for osteoporosis, our results for all fractures yielded similar findings. Likewise, in comparison of definitions for sarcopenia, similar results were found in our analyses for all fractures. In comparing women currently using estrogen therapy with those who were not, the risk of fracture was similar across all groups.

Strengths of this analysis include use of a well-established cohort with validated measures of body composition and 15 years of follow-up. We adjusted for important covariates. The assessment of fracture risk based on bone and body composition in women is not completely understood, but there are several limitations. One key limitation is that the definition of sarcopenia is controversial. For example, the Foundation for the National Institutes of Health Sarcopenia Project proposes to define sarcopenia based not only on ALM, but also on muscle strength, but in WHI, we were unable to use this definition because we had only a small sample with measures of grip strength. Nevertheless, the residuals definition for sarcopenia has been proven to be a better indicator of low lean mass and to be predictive of disability and mortality, particularly in women.[21,32,33] Finally, the WHI cohort was relatively young and healthy, with those with sarcopenia accounting for only 5% of the population. Thus we had limited power to assess the association between sarcopenia alone and fracture risk. This current study adds to the existing literature examining this association in women and has found consistent results.[8] The risk of fracture is highest in women with low BMD. Previous work that examined this association had a small sample of women, with limited power, whereas we were able to examine more than 10,000 women over an extended period of follow-up in this analysis.

In conclusion, women with low BMD, with and without sarcopenia, had a higher risk of fracture than women with only sarcopenia and those considered normal. Results suggest that sarcopenia does not add additional risk for fracture in women.

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