JAIDS Journal of Acquired Immune Deficiency Syndromes:
Functional Impairment Is Associated With Low Bone and Muscle Mass Among Persons Aging With HIV Infection
Erlandson, Kristine M. MD; Allshouse, Amanda A. MS; Jankowski, Catherine M. PhD; MaWhinney, Samantha ScD; Kohrt, Wendy M. PhD; Campbell, Thomas B. MD
Division of Infectious Diseases, Department of Medicine, Anschutz Medical Campus, University of Colorado, Aurora, CO.
Correspondence to: Kristine M. Erlandson, MD, Division of Infectious Diseases, Department of Medicine, Anschutz Medical Campus, University of Colorado, 12700 E 19th Avenue, Mail Stop B168; Aurora, CO 80045 (e-mail: email@example.com).
Supported by the National Institutes of Health (5UL1TR000154, P30 DK048520, and T32 AI007447-1), the Hartford Foundation Center of Excellence in Geriatric Medicine, and GlaxoSmithKline HIV Collaborative Investigator Research Award. Contents are the authors’ sole responsibility and do not necessarily represent official National Institutes of Health views.
The authors have no conflicts of interest to disclose.
Received November 20, 2012
Accepted January 24, 2013
Background: Disability and frailty are associated with osteoporosis, obesity, and sarcopenia. HIV-infected persons have early functional impairment, but the association between body composition and functional impairment is unknown.
Methods: HIV-1–infected participants on combination antiretroviral therapy with virologic suppression, aged 45–65 years, had standardized physical function measures. In a nested analysis, 30 low- and 48 high-functioning cases and controls were matched by age, gender, and time since HIV diagnosis. Bone mineral density, fat mass, and lean body mass were assessed by dual-energy x-ray absorptiometry. Odds ratios (ORs) with 95% confidence intervals were obtained from conditional logistic regression.
Results: Mean age was 53 years, mean CD4+ lymphocytes 598 cells per microliter, and 96% had plasma HIV-1 RNA <50 copies per milliliter. Low- and high-function subjects had similar CD4+ lymphocyte count and duration and type of antiretroviral therapy. Lower T scores at the hip [OR: 3.8 (1.1 to 12.5)] and lumbar spine [OR: 2.3 (1.1 to 4.5)] and lower lean body mass [OR: 1.1 (1.0 to 1.2)] were associated with significantly greater odds of low function (P ≤ 0.03). Lower insulin-like growth hormone [IGF-1; OR: 5.0 (1.4 to 20.0)] and IGF-1 binding protein-3 [OR: 3.3 (1.7 to 9.9)] increased the odds of low functional status (P ≤ 0.02). Fat mass and lower 25-OH vitamin D did not increase the odds of low functional status (P > 0.05).
Conclusions: Functional impairment in HIV-1–infected persons on successful antiretroviral therapy is associated with low muscle mass, low bone mineral density, and low IGF-1 and IGF-1 binding protein-3. These characteristics may be a manifestation of early “somatopause” in middle-aged HIV-infected adults.
Persons with HIV-1 infection are thought to undergo premature or accelerated aging, accompanied by an early occurrence of many comorbidities of aging.1,2 One such manifestation of premature aging in HIV-1 infection may be the early occurrence of the “somatopause.” The somatopause is an age-associated reduction in hypothalamic secretion of growth hormone (GH)–releasing hormone, resulting in decreased GH synthesis and, subsequently, lower hepatic production of insulin-like growth factor (IGF)-1, the key mediator of GH action on bone, muscle, fat, and multiple other tissues.3–5 Among persons without HIV-1 infection, this normal process of aging corresponds to increased visceral and subcutaneous fat (obesity), loss of muscle mass and strength (sarcopenia), and a loss of bone mineral density (BMD, osteopenia). Obesity, sarcopenia, osteopenia, and decreased IGF-1 are independently, and synergistically, associated with disability and frailty among elderly persons.6–9 Similarly, weight loss and muscle strength interventions lead to improved physical function and reduced frailty among aging persons.10
Changes in body composition resulting from HIV-1 infection and complications of antiretroviral therapy (ART) mimic those of normal aging, with common findings of low lean body mass, accumulation of visceral adipose tissue, and loss of BMD.4,11–13 Impairments in physical function and frailty are notable even among middle-aged HIV-infected persons,14,15 but little is known about the contributions of body composition changes to physical function and frailty in persons aging with HIV-1. If persons with HIV-1 infection truly undergo early somatopause, body composition changes could lead to premature functional impairment. The goal of the present study was to assess the relationships of body fat, muscle mass, and BMD with functional capacity among middle-aged persons with HIV-1 infection.
All individuals receiving care for HIV infection in the Infectious Diseases Group Practice Clinic at the University of Colorado Hospital were evaluated for potential participation. Individuals meeting the following criteria were eligible to participate: (1) 45–65 years of age, (2) able to consent and participate in study procedures, and (3) taking effective combination ART (2 or more) for at least 6 months with 1 undetectable plasma HIV-1 RNA (<48 copies/mL) and no plasma HIV-1 RNA >200 copies per milliliter in the prior 6 months. Individuals taking oral corticosteroids within 4 weeks of the visit and individuals weighing more than 300 pounds (limit of the dual-energy x-ray absorptiometry machine) were excluded. Approval was obtained from the Colorado Multiple Institutional Review Board and informed consent was obtained from all participants.
All enrolled study participants completed a standardized interview and available medical records were reviewed. Alcohol use was defined by self-reported history of current or prior abuse or currently consuming >7 drinks per week. Height and weight were measured and body mass index (BMI) calculated and categorized as obese (BMI ≥ 30 kg/m2), underweight (<18.5 kg/m2), or nonobese (BMI < 30 and ≥18.5 kg/m2). Physical activity was assessed by 2-week recall from the Minnesota Leisure-Time Physical Activity Questionnaire.16 Lipoatrophy was defined as self-reported loss of facial or extremity fat and confirmed by clinical diagnosis. A fall was defined as unintentionally coming to rest on the ground or lower level, not as a result of a major intrinsic event or external hazard.17 Cardiovascular disease included coronary artery, carotid artery, or peripheral vascular disease. Viral hepatitis was defined by a positive hepatitis B surface antigen or hepatitis C antibody. Chronic pain was defined as responding “moderately,” “quite a bit,” or “extremely” to the SF-36 question “During the past 4 weeks, how much did pain interfere with your normal work (including both work outside the home and housework)?” Fracture risk assessment (FRAX) tool scores were calculated under the assumption of a negative parent fracture history (data not collected).18 The Veterans Aging Cohort Study index was calculated using CD4 count, viral load, age, aspartate aminotransferase, alanine aminotransferase, platelets, hemoglobin, hepatitis C, and estimated glomerular filtration rate. Of a possible 164 points, higher values indicate greater mortality risk, and scores of ≤34 are associated with the lowest mortality.19
Physical function was assessed using 3 evaluation tools: Fried’s frailty phenotype, the short physical performance battery (SPPB), and the 400-m walk. For Fried’s frailty phenotype, shrinking was defined as unintentional weight loss of ≥10 pounds or decrease of ≥5% of body weight in the last year (self-reported and verified by records when available).20 Exhaustion was defined by 3–4 times per week of feeling “everything I do is an effort” or “sometimes I just cannot get going.” Low activity was defined as self-report of being “limited a lot” in vigorous physical activities from the SF-36.21,22 Weakness was assessed by the average of 3 maximal dominant hand grip strength measurements using a single Lafayette dynamometer, applying previously defined gender and BMI cutoffs.20 Slowness was defined by 4.5-m walk time adjusted for height: men ≤173 cm and women ≤159 cm in height requiring ≥7 seconds and taller men and women requiring ≥6 seconds.20 One point was given for each of the frailty indicators above. The SPPB comprised the tandem stand, time to complete a 4-m walk at usual pace, and time to complete 5 sit-to-stand repetitions without use of the arms.23 On each SPPB task, 0 points indicated inability to complete, 2 or less was considered “difficulty,” and 3 or 4 points were performance within the expected range, with a maximum attainable score of 12.24 A 400-m walk time was measured in a designated corridor; participants were instructed to walk the distance as quickly as possible.25
High function was defined as the ability to complete the 400-m walk and no deficits on Fried’s frailty phenotype or the SPPB (score of 0 or 12, respectively). Low function was defined as a score of ≥3 on Fried’s frailty phenotype or <9 on the SPPB and at least 1 deficit on the opposing test. All low-function persons were matched to 1 or 2 high-function persons (for a goal of 80 subjects) by age ±2 years, gender, and time since HIV infection (diagnosed before or after January 1, 1996), and all were asked to return for body composition measures and a blood draw. Two male-to-female transgendered subjects were enrolled (1 low and 1 high function) and considered as female for subsequent analyses.
Body and Bone Composition
Body composition and BMD were measured by dual-energy x-ray absorptiometry with a Hologic Discovery W instrument. Whole body lean mass was the bone-free, fat-free tissue mass. Appendicular skeletal muscle index (ASMI) was calculated as the sum of lean mass in the arms and legs, normalized to height (kg/m2). Low muscle mass was defined as ASMI <5.45 kg/m2 for women and <7.26 kg/m2 for men.26 The fat index was calculated as fat mass normalized to height (kg/m2). High relative body fat was defined as greater than the gender-specific median of 33% for women and 23% for men. Fat mass ratio using the ratio of % trunk/% lower extremity fat mass was dichotomized using a cutoff of >1.961 for men and >1.329 for women, as previously described.27 Low relative fat was defined as less than the gender-specific median for the cohort. Osteoporosis was defined by World Health Organization criteria as the lowest T score at hip or spine of ≤−2.5 and osteopenia as T score <−1 but >−2.5.28
Serum IGF-1 and insulin-like growth factor binding protein (IGFBP)-3 were measured by enzyme-linked immunosorbent assays using the manufacturer protocol (Diagnostic Systems Laboratory, Webster, TX). Low IGF-1 and IGFBP-3 were defined as at or above the gender-specific median (130 and 3.3 for women and 110 and 2.9 µg/mL for men). Serum 25-(OH) vitamin D was measured by chemiluminescence (Diasorin Liaison, Stillwater, MN). Vitamin D deficiency was defined as ≤20 ng/mL, vitamin D insufficiency >20 ng/mL but <30 ng/mL, and vitamin D sufficiency as ≥30 ng/mL.29 Low vitamin D was defined as either vitamin D deficiency or insufficiency. Serum testosterone was measured by immunoassay (Beckman Coulter, Brea, CA). HIV-1 RNA, CD4+ lymphocyte count, albumin, and hemoglobin were the most recent values in the medical record.
Data were collected and managed with Research Electronic Data Capture tools hosted at the University of Colorado.30 Demographic characteristics were summarized with mean and standard error for continuous measures, with log transformation and geometric mean and 95% confidence intervals (CIs) reported for skewed measures and frequency with percentage for categorical variables. Differences were tested using unequal variance 2-sample t test of χ2 test. Conditional logistic regression was used in the primary analysis of body composition in the case–control data, with odds ratios (ORs) and 95% CIs, and the P value of the Wald χ2 statistic reported. Each component was adjusted for 2–4 potential confounders as supported by the literature. Fat comparisons were adjusted for CD4+ lymphocyte count <350 cells per microliter, current protease inhibitor, any use of zidovudine, didanosine, or stavudine.11,31 Lean body mass was adjusted for CD4+ lymphocyte count <350 cells per microliter and any use of zidovudine, didanosine, or stavudine.31,32 BMD and T scores were adjusted for nadir CD4+ lymphocyte count, BMI, current tenofovir, and tobacco use33; FRAX estimates were adjusted for nadir CD4+ lymphocyte count and current tenofovir. IGF-1, IGFBP-3, and 25-OH vitamin D were adjusted for CD4+ lymphocyte count <350 cells per microliter, fat mass ratio, and BMI.4 Logistic regression was used to assess the associations of age, race, ethnicity, current, or prior ART class, hepatitis B and/or C, current tobacco or alcohol use, use of a statin, BMI, and lipoatrophy with relative fat, low muscle mass, osteopenia/osteoporosis, low IGF-1 and IGFBP-3, and vitamin D insufficiency/deficiency across the entire cohort. The entire cohort comparisons were adjusted for functional status, age (except for the age comparison), gender, and time since HIV diagnosis. Analyses were performed in SAS v9.2 (SAS Institute Inc, Cary, NC). No adjustments were made for multiple comparisons.
Between February and November 2010, 542 patients with HIV-1 infection seen in the Infectious Disease Group Practice Clinic fulfilled the inclusion criteria and were asked to participate. Of these, 369 consented to study participation and 359 completed the study assessment. Thirty-three (9%) were identified as low, 186 (52%) as moderate, and 140 (39%) as high function (Table 1). Thirty low-function persons returned for additional evaluation and were matched by age, gender, and time since HIV diagnosis to 48 high-function controls. Groups were similar by baseline demographic and clinical characteristics with the exception of more smokers, less physical function, and lower CD4+ lymphocyte nadir in the low-function group (Table 2). Among the biological women, all had reached menopause. Low-function women had a significantly longer time since menopause (12.66 ± 2.0 vs 5.39 ± 1.96 years, P = 0.008). Two low-function subjects had prior bilateral hip replacements and 1 high-function subject had a lumbar fusion. BMD data for the respective locations were excluded for those 3 subjects. No subjects were taking corticosteroids.
Association of Fat With Physical Function
Six low-function (20%) and 6 high-function (13%) subjects were obese based on BMI, and 4 low-function (13%) but no high-function subjects were underweight. BMI was not significantly different between low-function (geometric mean 25.5 kg/m2, 95% CI: 24.0 to 27.1 kg/m2) and high-function groups (24.2 kg/m2, 95% CI: 22.4 to 26.0 kg/m2, P = 0.25). Relative body fat was slightly higher among low-function (28.2% ± 1.6%) than high-function persons (25.0% ± 1.4%), but this was not significant after adjusting for CD4, current protease inhibitor use, or any use of zidovudine, didanosine, or stavudine (P = 0.14). Fat mass, fat index, fat distribution, and the fat mass ratio were not associated with greater odds of being low function (Table 3). In general and as expected, women had higher median percentage of body fat than men (33% vs 23%). When considering all subjects and adjusting for functional status, age, gender, and time since HIV diagnosis, demographics, smoking or alcohol use, or class of ART were not significantly associated with increased odds of higher relative body fat (all P ≥ 0.11).
Association of Muscle With Physical Function
Total lean body mass, appendicular lean mass, and ASMI were lower (all P < 0.05) among low-function subjects compared with high-function controls (Table 3). Using ASMI cut points,26 27 (35%) of all subjects met criteria for low muscle mass and 15 (50%) of the low-function subjects were classified as sarcopenic. We found a greater odds of low muscle mass among subjects with low function (OR: 2.5, 95% CI: 1.0 to 6.1, P = 0.04). When considering all subjects and adjusting for functional status, age, gender, and time since HIV diagnosis, lower BMI (OR: 1.7, 95% CI: 1.2 to 2.2, P < 0.001), but not demographics, smoking or alcohol use, or ART class, were associated with increased odds of low muscle mass (all P ≥ 0.11). Serum albumin (OR: 0.8, 95% CI: 0.2 to 2.6, P = 0.68), hemoglobin (OR: 0.96, 95% CI: 0.7 to 1.3, P = 0.81), and testosterone (OR: 1.0, 95% CI: 0.9 to 1.1, P = 0.95) were not associated with an increased odds of low muscle mass.
Association of Bone With Physical Function
Overall, 11 subjects (14%) had osteoporosis at the lumbar spine and 3 subjects (4%) had osteoporosis at the hip. Osteopenia or osteoporosis was more common among low-function subjects: 20 low-function group (67%) had osteopenia or osteoporosis at the lumbar spine compared with 18 (38%) in the high-function group (P = 0.02); 19 low-function persons (68%) had osteopenia or osteoporosis at the hip compared with 16 (33%) in the high-function group (P = 0.01). Low BMD and T scores at both the hip and lumbar spine were associated with greater odds of being low function. The predictive values of low BMD and T score at the lumbar spine and total hip were robust to adjustments for BMI, nadir CD4+ T-cell count, current tenofovir use, and smoking status (Table 3). By the FRAX tool, each 1% increase in the 10-year probability of a major osteoporotic fracture of a hip fracture was associated with a nonsignificant 1.2 (95% CI: 0.9 to 1.5, P = 0.11) and 1.9 (95% CI: 0.9 to 4.4, P = 0.25) greater odds, respectively, of low function. When considering factors related to osteopenia/osteoporosis among all subjects and adjusting for functional status, age, gender, and time since HIV diagnosis, white race (OR: 6.0, 95% CI: 1.4 to 26.0, P = 0.02) was associated with greater odds of osteopenia or osteoporosis. A trend toward greater odds of osteopenia or osteoporosis was seen with incrementally higher age (OR: 1.1, 95% CI: 0.99 to 1.3, P = 0.08). An incremental decrease in BMI was associated with an increased odds of osteopenia or osteoporosis (OR: 1.3, 95% CI: 1.1 to 1.5, P = 0.002). No significant associations were detected with ethnicity, tobacco or alcohol use, or class of ART (all P ≥ 0.25).
Association of Hormonal Alteration With Physical Function
Lower IGF-1 and IGFBP-3 were associated with significantly greater odds of being low function (Table 3). Among all subjects and adjusting for functional status, age, gender, and duration of HIV diagnosis, hepatitis B or C was associated with greater odds of having low IGF-1 or IGFBP-3 (OR: 3.5, 95% CI: 1.2 to 10.2, P = 0.03; OR: 6.6, 95% CI: 2.0 to 22.0, P = 0.002) and alcohol use was associated with greater odds of low IGFBP-3 (OR: 15.7, 95% CI: 2.8 to 88.5, P = 0.002).
Nine (30%) low-function and 13 (27%) high-function subjects were found to have vitamin D deficiency; 13 (43%) low-function and 12 (25%) high-function subjects had vitamin D insufficiency. Serum 25-OH vitamin D was not a significant predictor of functional group (Table 3; P = 0.11). Among all subjects and adjusting for functional status, age, gender, and duration of HIV diagnosis, no significant associations were seen with demographic characteristics, ART class, or BMI (all P ≥ 0.24).
The roles of adiposity, sarcopenia, and osteopenia/osteoporosis in functional impairment and frailty are well described among multiple elderly cohorts.7,8,10 Little is known, however, about the relationships of these normal aging processes to physical function in HIV-infected persons who are at increased risk for premature body and bone composition changes due to HIV-1, ART, and/or chronic inflammation.2,11,13,33 In the current study, we provided the first quantitative comparison of fat, muscle, and bone in HIV-infected persons with low or high function.
The frequency of low muscle mass was particularly surprising given the relatively young age (mean: 52 years) of the cohort and similar to what is commonly reported among persons 10–25 years older than the participants in our study.34,35 The implications of this finding are concerning because low muscle mass and sarcopenia are associated with functional dependence and increased mortality among both HIV-infected and HIV-uninfected adults.12,26,36
BMD and T scores in our entire middle-aged HIV-infected population, and the low-function cohort in particular, were also similar to those of older persons without HIV infection.13,37,38 A decrease in BMD of 1 SD among older women is associated with a 37–49% increased risk of fracture.39 The difference between groups in our cohort was slightly less, but nonetheless indicates a significant increase in fracture risk among low-function persons. Functional impairment is a consistently strong predictor of increased fall risk in HIV-infected and -uninfected elderly.40–42 The combination of increased fall risk and lower BMD highlights the importance of evaluating, monitoring, and modifying risks for both falls and bone fragility to prevent fractures among persons aging with HIV.40,43 In addition, persons with impaired physical function are less likely to engage in regular physical activity, and a resultant decline in muscle mass from physical inactivity may amplify the decline in BMD with age (Fig. 1). Although low-function subjects had a slightly greater frequency of vitamin D deficiency or insufficiency compared with high-function subjects, we were unable to detect significant differences in serum vitamin D concentrations possibly due to the fact that nearly 30% of low-function subjects were receiving vitamin D replacement therapy.
Low functional status was associated with low serum IGF-1 and IGFBP-3 concentrations in our cohort. Indeed, levels of IGF-1 in our low-function group (99 ± 8 ng/mL) were comparable with those reported in healthy men 70–80 years of age (125 ± SD of 48 ng/mL)44 and frail women 70–79 years of age (104 ± SD of 2 ng/mL).45 An age-related decline in the GH/IGF-1-axis has been well described,46,47 but the unexpectedly low levels of IGF-1 in our cohort, even after adjusting for potential confounders, may represent early somatopause as a manifestation of premature aging in HIV-1 infection. Whether low IGF-1 in our physically impaired group is due to an age-related decrease in GH–releasing hormone, impaired pituitary release of GH, impaired IGF-1 production, or related to hypothalamic infiltration of HIV or side effects of ART is not known.48–51
In our cohort, BMI and measures of fat were not significantly different between low- and high-functioning groups. This finding contrasts to findings from a cohort of “frail” (defined by at least 2 deficits in physical performance test, peak oxygen uptake, activities of daily living, or instrumental activities of daily living), HIV-infected subjects in the Rochester, New York area that demonstrated higher BMI, waist circumference, fat mass, and trunk fat than HIV-infected nonfrail controls.52 The discordance between studies may reflect the lower prevalence of obesity in Colorado compared with New York. In county-specific data collected by the Centers for Disease Control, 30.3% of adults in Monroe County, New York are obese compared with less than 20% of adults in counties of the Denver metropolitan area.53 Indeed, the average BMI of our cohort was 25 kg/m2 compared with 29 kg/m2 in the Rochester cohort.52
Our study had several limitations. First, we did not include an HIV-uninfected cohort. We used trunk fat as a measure of central adiposity but did not include visceral fat. Visceral fat accumulates with ART,54 is more proinflammatory and insulin-resistant than subcutaneous fat,55 and, thus, could contribute to low lean mass and osteopenia. The relatively low BMI in our cohort may make our results less applicable to more obese patient populations in the United States. Additionally, our cohort was intentionally limited to HIV-infected persons on successful ART. This focus allowed us to study the relationship of body composition and physical function in persons aging during successful HIV-1 treatment as opposed to persons with complications of untreated HIV-1 infection. Body composition can vary considerably by age, genetics, and gender. We attempted to reduce potential confounding by these factors by matching our low- and high-function cases by age and gender. Last, we demonstrated an association between physical function, body composition, and somatotropic hormones at a single time point. This cross-sectional design precludes conclusions regarding the direction and causality of the relationship of functional capacity to body composition.
Our findings indicate that functional impairment in middle-aged adults with HIV-1 infection is associated with low muscle mass, BMD, IGF-1, and IGFBP-3. These characteristics may be a manifestation of early “somatopause” in middle-aged HIV-infected adults (pathway postulated in Fig. 1).6–9,56,57 Longitudinal studies are needed to elucidate the complex interactions among bone, muscle, fat, GH/IGF-1, and physical function in HIV-infected adults during ART. Further studies should investigate the impact of interventions to increase bone, muscle, or IGF-1 on functional capacity among persons aging with HIV infection.
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frailty; HIV; sarcopenia; osteoporosis; growth hormone; vitamin D
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