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J Clin Endocrinol Metab. Nov 2010; 95(11): E368–E372.
Published online Jul 28, 2010. doi:  10.1210/jc.2010-0780
PMCID: PMC2968723

Fat Infiltration of Muscle, Diabetes, and Clinical Fracture Risk in Older Adults

Abstract

Context: Older adults with type 2 diabetes are at higher risk for fracture compared with nondiabetic adults after adjustment for their higher bone mineral density. Infiltration of muscle by fat predicts increased risk of hip fracture.

Objective: We investigated whether fat infiltration of muscle, which is greater in diabetic adults, is associated with all clinical fracture and whether it accounts for the increased fracture risk in those with diabetes.

Design, Setting, and Participants: Data were analyzed from the Health, Aging, and Body Composition Study, a cohort of community-dwelling adults aged 70–79 yr. Glucose metabolism status and x-ray attenuation of thigh muscle were determined at baseline for 2762 participants.

Main Outcome Measures: During a mean 8.2 ± 2.3 yr follow-up, 331 participants reported at least one clinical fracture.

Results: Fat infiltration of muscle was higher in those with diabetes or impaired glucose metabolism than in those with normal glucose metabolism (P < 0.001). Fat infiltration of muscle was independently associated with a 19% increased risk of incident clinical fracture (multivariate hazard ratio = 1.19; 95% confidence interval = 1.04–1.36); this association did not differ across glucose metabolism groups (P for interaction = 0.65). As previously reported, diabetes was associated with a greater fracture risk compared with normal glucose metabolism (hazard ratio = 1.42; 95% confidence interval = 1.07–1.89) after adjustment for bone mineral density, but further adjustment for fat infiltration of muscle did not attenuate this association.

Conclusions: Fat infiltration of muscle predicts clinical fracture in older adults. Although fat infiltration of muscle is higher among those with diabetes, it does not account for their increased fracture risk.

Older adults with type 2 diabetes are at higher risk for fracture than nondiabetic adults, after adjustment for their higher bone mineral density (BMD) (1,2,3). What accounts for that increased risk is unclear, and investigation is made challenging by the complex determinants of fracture risk as well as the complex features and complications of diabetes (4,5,6,7,8).

One potential determinant of interest is lipid accumulation in and around muscle, or myosteatosis. This measure, referred to here as fat infiltration of muscle, has been linked to insulin resistance and diabetes (9,10) and is associated with decreased strength and increased mobility loss in older adults (11,12). Recently, fat infiltration of thigh muscle was shown to predict increased risk of hip fracture (13,14). We hypothesized that fat infiltration of muscle increases risk of all clinical fracture, possibly through falling or through bone loss, and that the higher fat infiltration of muscle observed in those with diabetes explains, at least in part, their higher fracture risk.

This study examined the association between fat infiltration of muscle and all incident clinical fracture and investigated whether that association differs by glucose metabolism status. We then explored whether fat infiltration of muscle accounts for any of the increased fracture risk in those with diabetes.

Participants and Methods

Study population

Data were analyzed from the Health, Aging, and Body Composition (Health ABC) study, an observational cohort of White and Black, community-dwelling adults aged 70–79 yr upon enrollment in 1997–1998. Participants were recruited from a random sample of White Medicare beneficiaries and all age-eligible Black residents in Pittsburgh, PA, and Memphis, TN. Eligibility requirements have been published previously and included no self-reported difficulty walking a quarter mile, climbing 10 steps, or performing activities of daily living (15). Informed consent was obtained, and the institutional review boards of the involved institutions approved the study.

Of the 3075 participants enrolled in the Health ABC study, this analysis includes the 2762 with complete baseline data for glucose metabolism characterization, total hip BMD, and the covariates included in our final adjusted model of the effect of fat infiltration of muscle on fracture risk.

Glucose metabolism status

At baseline, glucose metabolism status was classified as diabetes, impaired glucose metabolism, or normal glucose metabolism. Diabetes was defined by self-report of a diabetes diagnosis, use of antidiabetes medication, fasting glucose of 126 mg/dl or higher, or 2-h glucose of 200 mg/dl or higher after a 75-g oral glucose tolerance test. Impaired glucose metabolism, encompassing impaired fasting glucose and impaired glucose tolerance, was defined by fasting glucose of at least 100 mg/dl but less than 126 mg/dl and/or 2-h oral glucose tolerance test of at least 140 mg/dl but less than 200 mg/dl. Others were classified as having normal glucose metabolism.

Fat infiltration of muscle

Computed tomography (CT) scans of the thigh were obtained at baseline (in Pittsburgh, 9800 Advantage from General Electric, Milwaukee, WI; in Memphis, Somatom Plus 4 from Siemens, Erlangen, Germany, or PQ 2000S, Marconi Medical Systems, Cleveland, OH). A 10-mm-thick axial image (120 kVp, 200–250 mA) was obtained at midfemur. A line was drawn manually along the deep fascial plane surrounding the thigh muscles to distinguish muscle from surrounding sc adipose tissue, and the femur was segmented out of the muscle. Visible confluent adipose depots were identified and summed separately as intermusclar fat. Fat infiltration of muscle was assessed in Hounsfield units (HU, a measure of x-ray attenuation), with lower HU reflecting more fat infiltration (11). This measurement correlates with muscle triglyceride content determined by histological oil red O staining, and the mean test-retest coefficient of variation in a previous study was 0.51% (16). This analysis used right thigh measurements and excluded outliers with biologically improbable x-ray attenuation coefficients of less than 10 HU of muscle (n = 6).

Other covariates

At baseline, body mass index (BMI) was calculated as weight (kilograms)/height squared (square meters). Total hip areal BMD (grams per square centimeter) and whole-body percent fat were measured by dual-energy x-ray absorptiometry (Hologic QDR 4500A; Bedford, MA). Renal function was assessed by serum cystatin (17). Participants self-reported smoking, categorized as never, current, or former; alcohol use, categorized as zero, fewer than one, one to seven, or eight or more drinks weekly; and medications (18).

Fracture

During a mean ± sd 8.2 ± 2.3-yr follow-up, incident nonvertebral clinical fractures were ascertained by participant self-report every 6 months and then verified by radiographic report. Fractures were excluded if due to a pathological condition (e.g. cancer). High-trauma fractures were not excluded, because fractures of all trauma levels are associated with low BMD (19).

Statistical analysis

Differences in baseline characteristics by categories of glucose metabolism were assessed using χ2 and t tests. Cox proportional hazards models were used to determine the relationship between fat infiltration of muscle and subsequent clinical fracture risk. The measure of fat infiltration of muscle in HU was transformed so that a hazard ratio (HR) of more than 1 for the transformed predictor estimates the increase in fracture risk for each sd increase in fat infiltration. Potential confounders were added sequentially to the model. Medications known to be associated with both fat infiltration of muscle and fracture, thiazolidinediones (TZDs) and oral glucocorticoids, were included in the model as potential confounders. Finally, we assessed interactions of fat infiltration of muscle with glucose metabolism group, sex, and race.

Next, proportional hazards models were used to determine the relationship between diabetes and subsequent clinical fracture risk, adjusted for covariates including total hip BMD as described previously (3). Finally, fat infiltration of muscle was entered into the model and its role as a potential mediator assessed by change in the coefficient for diabetes. The process was repeated for impaired glucose metabolism and fracture risk.

Data were analyzed using Stata 10 software (StataCorp, College Station, TX).

Results

Baseline participant characteristics

At baseline, 24% (n = 658) of participants had diabetes, and 29% (n = 813) had impaired glucose metabolism (Table 11).). Those with diabetes were more likely than those with normal glucose metabolism to be male (55 vs. 47%, P < 0.01) and Black (52 vs. 37%, P < 0.01). Compared with those with normal glucose metabolism, those with impaired glucose metabolism or diabetes had higher BMI and BMD. As expected, those with impaired glucose metabolism or diabetes had more fat infiltration of muscle, reflected by a lower mean x-ray attenuation coefficient of muscle.

Table 1
Baseline participant characteristics, stratified by glucose metabolism status

As previously reported in this cohort (11), Black participants had more fat infiltration of muscle than White participants (34.5 vs. 36.1 HU, P < 0.01), and women had more fat infiltration than men (33.7 vs. 37.3 HU, P < 0.01). In the cohort as a whole, fat infiltration of muscle was positively correlated with whole-body percent fat (r = 0.50; P < 0.01) and BMI (r = 0.43; P < 0.01).

Fat infiltration of muscle and clinical fracture risk

During follow-up, 331 participants (12%) sustained one or more clinical fractures. The most common fracture sites were the hip (27%), radius and/or ulna (18%), ankle (10%), proximal humerus (10%), and foot (10%). In all participants, fat infiltration of muscle was associated with a 19% increased risk of clinical fracture [HR = 1.19; 95% confidence interval (CI), = 1.04–1.36 per sd increase in fat infiltration] after adjustment for age, race, sex, clinic site, BMI, whole-body percent fat, smoking, alcohol use, renal function, baseline use of TZD or oral glucocorticoid medication, and glucose metabolism status (diabetes, impaired glucose metabolism, or normal glucose metabolism). There was no evidence for a differential effect of fat infiltration of muscle on fracture risk across the glucose metabolism groups (P = 0.65 for interaction). There was also no evidence for an interaction between fat infiltration of muscle and sex (P = 0.82) or race (P = 0.76) and fracture risk. Sensitivity analyses excluding those with TZD or glucocorticoid use during follow-up yielded similar results. Results were still statistically significant after exclusion of high-trauma fractures.

Diabetes, impaired glucose metabolism, and clinical fracture risk

As reported previously for this cohort (3), diabetic participants had a higher risk of clinical fracture than participants with normal glucose metabolism, after adjustment for age, race, sex, clinic site, and total hip BMD (HR = 1.42; 95% CI = 1.07–1.89). The addition of fat infiltration of muscle to the primary model did not meaningfully change the estimated effect of diabetes on fracture risk (HR = 1.40; 95% CI = 1.06–1.87). With further adjustment for a more comprehensive list of covariates, there was still no difference in the effect of diabetes on fracture risk before and after the addition of fat infiltration of muscle to the model (Table 22).). As reported previously (3), there was no difference in risk of fracture between those with impaired glucose metabolism and those with normal glucose metabolism (multivariate HR = 0.98; 95% CI = 0.75–1.28).

Table 2
Diabetes and fracture risk: adjusted HR for clinical fracture among participants with diabetes, compared with those with normal glucose metabolism

Discussion

The observation that a diabetic adult with similar BMD to a given nondiabetic adult is more likely to sustain a fracture has generated interest in identifying the culprit mechanism (1,2,3). Factors studied include falls due to impaired vision, peripheral neuropathy, hypoglycemia, and effects of TZDs; to date, none has proved an adequate explanation. Because insulin resistance is strongly associated with increased fat infiltration of muscle (9,10), and fat infiltration of muscle was recently shown to predict hip fracture in older adults (14), we hypothesized that fat infiltration of muscle may account for some of the increased fracture risk. We found it does not. Continued investigation is needed to identify factors that do explain diabetic adults’ increased fracture risk, because targeted fracture prevention efforts may benefit this group already burdened by disability.

Higher fat infiltration of muscle did predict subsequent clinical fracture in the overall cohort, substantiating recently published findings from this cohort that higher fat infiltration of muscle predicted hip fracture (14). This was true despite adjustment for BMI and percent body fat, suggesting that among participants with equivalent overall adiposity, higher thigh muscle fattiness imparted a greater fracture risk. The underlying mechanism requires elucidation: on the one hand, fat infiltration of muscle is associated with decreased strength and increased mobility loss in older adults (11,12), so falling may be the pathway. On the other hand, fat infiltration of muscle could bring more rapid bone loss, due either to decreased skeletal loading from weaker muscle or to a common cause of fat infiltration of muscle and bone loss.

The underlying cellular processes also require elucidation. Lipid may be stored within myocytes when fatty acid uptake and oxidation are imbalanced. Additionally, preclinical investigation suggests skeletal muscle satellite cells possess mesenchymal plasticity with the capacity to commit to an adipogenic instead of a myogenic program (20). A limitation of the use of the CT-measured x-ray attenuation coefficient of muscle is that, although visible marbling adipose is excluded from the image before the measurement is made, CT does not differentiate between intramyocellular lipid and adipocytes lying between myocytes as muscle biopsy or magnetic resonance spectroscopy can. However, the x-ray attenuation coefficient of muscle is valuable as a noninvasive method of assessing large cohorts when alternate methods are not feasible. Also, our CT measurement assessed fat infiltration of muscle at a single site, and more global assessments may be useful.

Although those with impaired glucose metabolism or diabetes had more fat infiltration of muscle than those with normal glucose metabolism, we did not find statistical evidence that the effect of fat infiltration of muscle on fracture risk differed across glucose metabolism groups. One limitation of this study is that we assigned participants to glucose metabolism groups at baseline, yet some participants’ status may have changed during follow-up. However, a sensitivity analysis excluding those developing incident diabetes yielded similar results. In addition, the narrow age range of the participants may limit the generalizability of our findings to other age groups.

In conclusion, we demonstrated that fat infiltration of muscle is associated with a modest increase in incident clinical fracture but does not explain the increased fracture risk in older adults with diabetes compared with those with normal glucose metabolism. This finding suggests that targeted interventions to decrease fat infiltration of muscle may have value for older adults regardless of diabetes status, and it underscores the interaction of muscle, fat, and bone as a rich area for investigation.

Footnotes

This work was supported by the National Institute on Aging under contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. This research was supported in part by the Intramural Research Program of the National Institutes of Health National Institute on Aging.

Disclosure Summary: A.L.S., E.V., D.E.S., T.B.H., A.M.K., E.S.S., S.R.C., F.A.T., A.L.S., and A.V.S. have nothing to disclose. T.F.L. has received grant support from Merck. P.M.C. consults for Merck and Amgen.

First Published Online July 28, 2010

Abbreviations: BMD, Bone mineral density; BMI, body mass index; CI, confidence interval; CT, computed tomography; HR, hazard ratio; HU, Hounsfield unit; TZD, thiazolidinedione.

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