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An increased rate of fracture occurs a decade earlier in HIV+ compared with HIV− men

Gonciulea, Andaa; Wang, Ruibinb; Althoff, Keri N.b; Palella, Frank J.c; Lake, Jordand; Kingsley, Lawrence A.e; Brown, Todd T.a

doi: 10.1097/QAD.0000000000001493
CLINICAL SCIENCE
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SDC

Objectives: To determine the incidence of fracture among aging HIV-infected (HIV+) and uninfected men (HIV−). To evaluate factors independently associated with fracture risk.

Design: Prospective, multicenter cohort study of men with or at risk for HIV.

Methods: Outcome measures: all fractures (excluding skull, face and digits) and fragility fractures (vertebral column, femur, wrist and humerus) were collected semiannually in 1221 HIV+ and 1408 HIV− men aged at least 40. Adjusted incident rate ratios (aIRR) with an interaction term for age (40–49, 50–59 and ≥60 years) and HIV serostatus were estimated with Poisson regression models accounting for additional risk factors.

Results: Fracture incidence increased with age among both HIV+ and HIV− men. Although there was no significant difference in fracture incidence by HIV serostatus among men aged 40–49 years, the HIV+ men aged 50–59 years had a significantly higher incidence of all fractures [aIRR: 2.06 (1.49, 2.84)] and fragility fractures [aIRR: 2.06 (1.21, 3.50)] compared with HIV− participants of similar age. HIV modified the effect of age on all fractures (P = 0.002) but did not significantly modify the effect for fragility fractures (P = 0.135). Hypertension increased the rate of all fractures by 32% after adjustment for covariates [aIRR: 1.32 (1.04, 1.69)].

Conclusion: Fracture incidence increased with age among HIV+ and HIV− men but was higher among HIV+ men. A significant increase in fracture incidence was found among 50–59-year-old HIV+ men, highlighting the importance of osteoporosis screening for HIV-infected men above the age of 50.

Supplemental Digital Content is available in the text

aJohns Hopkins University School of Medicine

bJohns Hopkins Bloomberg School of Public Health, Baltimore, Maryland

cNorthwestern University Feinberg School of Medicine, Chicago, Illinois

dUniversity of California Los Angeles, Los Angeles, California

eUniversity of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA.

Correspondence to Todd T. Brown, MD, PhD, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, MD 21287, USA. Tel: +1 410 502 2327; fax: +1 410 367 4114; e-mail: tbrown27@jhmi.edu

Received 5 December, 2016

Revised 10 March, 2017

Accepted 26 March, 2017

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

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Introduction

Osteopenia and osteoporosis are more prevalent in HIV-infected (HIV+) men and women compared with HIV-uninfected (HIV−) controls [1], and young HIV+ individuals are also at higher risk of bone loss [2–4]. Low bone mineral density (BMD) translates into a higher risk of fracture [5,6] that is higher in HIV+ individuals. Triant et al.[7] reported higher prevalence of vertebral, hip and wrist fractures in HIV+ men and higher prevalence of vertebral and wrist fractures in HIV+ women compared with HIV− controls. Higher rates of fracture in young HIV+ men have been previously reported [3,7], whereas studies in young HIV+ women have shown conflicting results [8,9]. Among HIV+ patients, several risk factors have been associated with bone loss and higher incidence of fracture, including traditional risk factors such as age, sex, race, BMI, smoking, alcohol and drug use [10,11], HIV-specific factors [3,12–15] and specific antiretroviral therapy (ART) agents, especially protease inhibitors and tenofovir disoproxil fumarate (TDF) containing combinations [15–18]. Coinfection with hepatitis C virus (HCV) increased fracture risk in several reports [3], whereas others found no association [9].

Early screening for fracture risk in HIV+ individuals has been recommended [19,20], but the exact age when screening should start remains controversial. There is still extensive variation in the approach to screening for osteoporosis in HIV+, not only in the United States of America but also worldwide [21].

In this study, we aimed to compare the incidence of fracture in HIV+ with HIV− men who participated in the Multicenter AIDS Cohort Study (MACS) and to determine the predictors of fracture. Our a-priori hypothesis was that HIV modified the effect of age on fractures.

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Methods

Study population

The MACS is an ongoing, prospective multicenter cohort study of the natural and treated history of HIV infection in men. As of March 2015, 3898 HIV+ and 3439 HIV− MSM had been enrolled [1984–1985 (N = 4954); 1987–1991 (N = 668); 2001–2003 (N = 1350) and 2010+ (N = 365)] at four centers in the United States of America (Baltimore, Maryland/Washington, DC; Chicago, Illinois; Los Angeles, California and Pittsburgh, Pennsylvania). MACS design and methods have been described previously [22–24]. In brief, at each semiannual study visit, participants complete a standardized questionnaire soliciting information about their medical history, HIV treatment, behaviors, depression and daily activities; undergo physical examinations and have blood and urine specimens collected for laboratory testing and storage [25]. Study questionnaires are available at http://aidscohortstudy.org/. Informed consent was obtained from all participants. Study protocols were approved by the Institutional Review Boards at each study site.

Self-reported fracture data were extracted from the MACS database using The International Classification of Diseases, Ninth Revision, Clinical Modification codes. At visit 36 (in 2001) and all subsequent visits, participants were asked if they had any bone-related diagnoses, including any new broken or fractured bones since the last visit. In addition, in 2010 (visit 53 and 54), participants were asked retrospectively about personal history of fractures. A total of 2283 men responded to the historical questions at visit 53 and 54; 1935 men who were 40 years or older and had at least one follow-up visit were included. For men who did not respond to the historical questions, bone outcomes were ascertained in 1141 participants at and after visit 36. Of these, 865 men who were 40 years or older and had one additional visit were considered eligible for this study. The first MACS visit at which an individual came under observation for fracture outcomes was designated the index visit. HIV+ participants who never received ART before they were last seen in the MACS by March 2015 were excluded. The final study population included 2629 men.

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Outcome: incident fracture

In this study, we considered two self-reported fracture outcomes that occurred among men of 40 years and over: all fractures except for those occurring at the face, skull or digits and fragility fractures, defined as fractures at vertebral column, femur, wrist and humerus [26].

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Exposure of interest: age and HIV

Self-reported date of birth was obtained at enrollment into the MACS. HIV seropositivity was determined using an ELISA confirmed by western blot. Standardized tests were used for measuring CD4+ T-lymphocyte counts (cells/μl) (CD4+) and plasma HIV-1 RNA concentrations.

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Confounders

Race was obtained at enrollment into the MACS. Self-reported cigarette smoking and alcohol use, BMI, comorbidities, T-lymphocyte counts (cells/μl) (CD4+) and plasma HIV-1 RNA concentrations were assessed at each semiannual visit. Estimated glomerular filtration rate (eGFR) in ml/min per 1.73 m2 was calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. HCV was determined by reactive HCV antibody or detectable plasma HCV RNA levels. Diabetes mellitus was defined as a fasting glucose at least 126 mg/dl or a self-reported diabetes diagnosis with the use of glucose-lowering medications. High blood pressure (BP) was defined as SBP at least 140 mmHg, DBP at least 90 mmHg or self-reported diagnosis with use of antihypertensive medication. Viremia copy-years (VCY) were calculated as the area under the viral load curve from the index visit or the first available viral load after seroconversion, whichever occurred later, by applying the trapezoidal rule [27]. Other HIV-specific factors that were considered include the history of AIDS diagnosis, any ART use and cumulative use of TDF and protease inhibitor per 5 years.

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Statistical analyses

Demographic and clinical characteristics at the index visit were compared by HIV serostatus using Wilcoxon rank-sum test for continuous variables and Fisher's exact test for categorical variables. Incident fracture was defined as the first self-reported fracture after age 40 while under observation for bone outcomes in the MACS. Individuals contributed person-time from the index visit to the time of incident fracture or the last time they were seen in MACS before 31 March 2015. Incidence rates were calculated as the number of new fractures (or fragility fractures) that occurred per 1000 person-years. Crude incidence rate ratio (IRR) and adjusted IRR (aIRR) and 95% confidence intervals ([,]) were estimated with Poisson regression models. To test the a-priori hypothesis, a nested models approach with a likelihood ratio tests to determine the better fit (the model with or without the interaction term) was used. The final model included a test for interaction between HIV serostatus and age and adjustment for confounders: race, BMI, hypertension, diabetes, HCV, eGFR, smoking and alcohol use. We also explored the associations between fractures and HIV-related factors including CD4+ T-cell count and plasma HIV-1 RNA level at index visit, VCY, ART use (time updated), AIDS diagnosis prior to index visit, and cumulative use of TDF and protease inhibitors among the HIV-infected men. Missing predictor data were handled by multiple imputation using the Markov Chain Monte Carlo methods. Ten imputations were carried out for the entire study population and after stratification by HIV serostatus. A P value less than 0.05 guided statistical interpretation. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina, USA). Plots were produced using R statistical software.

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Results

Participant characteristics at index visit

The study population included 1221 HIV+ and 1408 HIV− men (Table 1). The two groups were similar with respect to age, BMI, eGFR and moderate/heavy alcohol consumption. The presence of comorbidities such as diabetes and hypertension was similar by HIV serostatus. A greater proportion of HIV+ than HIV− participants were nonwhite, HCV-infected as well as current smokers.

Table 1

Table 1

Among the HIV+ men at index visit, the median CD4+ cell count was 490 cells/μl, median HIV-1 RNA level was 342 copies/ml, and 10% had a clinical AIDS diagnosis prior to the index visit. At the last follow-up visit, 798 (61%) HIV-infected men were using TDF, and the median [interquartile range (IQR)] cumulative TDF use at last follow-up visit was 3.4 (0.3–7.2) years. The proportion of men using protease inhibitor at the last follow-up visit was 44% (N = 581); median cumulative protease inhibitor use was 4.5 (IQR 0.3–9.4) years.

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Incidence of all fractures

New fractures occurred in 379 patients during 33 957 person-years with an incidence rate of 11.2 (10.1, 12.4) per 1000 person-years. Of those, 182 fractures occurred in HIV+ [incidence rate 12.8 (11.1, 14.8) per 1000 person-years] and 197 in the HIV− [incidence rate 10.0 (8.7, 11.5) per 1000 person-years]. The incidence rates of all fractures were similar among HIV− men aged 40–49 and 50–59 with an increase among those aged at least 60 years. Among HIV+, the increase in incidence rates was seen among men aged 50–59 and at least 60 years [Fig. 1 and Table 1 (Supplementary, http://links.lww.com/QAD/B83)].

Fig. 1

Fig. 1

Figure 2 and Table 2 (Supplementary, http://links.lww.com/QAD/B83) are showing risk factors associated with increased fracture risk. Only hypertension remained significantly associated with increased risk of all fractures after multiple adjustments [aIRR: 1.32 (1.04, 1.69)] [Fig. 2 and Table 3 (Supplementary, http://links.lww.com/QAD/B83)].

Fig. 2

Fig. 2

The test of interaction showed evidence that HIV modified the effect of age on fracture risk (P = 0.002). There was a significant increase in the incidence of all fractures in the HIV− aged at least 60 [aIRR: 1.51 (1.06, 2.16)] and in the HIV+ aged 50–59 [aIRR: 1.92 (1.41, 2.61)] as compared with the HIV− aged 40–49 years. Neither the HIV− aged 50–59 years nor the HIV+ aged 40–49 years had a significantly different fracture risk compared with the reference group (HIV− aged 40–49 years). A higher incidence of all fractures was seen in the HIV+ aged at least 60 years although with only marginal significance [aIRR: 1.56 (0.98, 2.49)].

Comparisons by HIV serostatus within each age group revealed a higher incidence of all fractures in the HIV+ aged 50–59 years compared with HIV− of similar age [aIRR: 2.06 (1.49, 2.84)]. We found no significant difference in the incidence of all fractures by HIV serostatus among men aged 40–49 years [aIRR: 0.92 (0.65, 1.29)] or at least 60 years [aIRR: 1.03 (0.65, 1.65)]. Sensitivity analysis restricted to the group aged at least 60 revealed no significant difference in the incidence of all fractures by HIV serostatus among men aged 60–69 [aIRR: 1.19 (0.72, 1.97)] or at least 70 years [aIRR: 0.45 (0.10, 2.01)].

In analyses restricted to HIV+, there was a significantly higher rate of fractures in men aged 50–59 compared with 40–49 years [aIRR: 1.66 (1.18, 2.34)]. Receipt of ART was associated with an increased risk of fracture [aIRR: 2.11 (1.22, 3.63)], whereas having BMI at least 25 kg/m2 was protective (Table 2). When current HIV-1 RNA more than 400 copies/ml was replaced by VCY in the multivariable model, higher VCY was associated with all fractures [IRR: 1.14 per log10 increase in VCY (1.01, 1.30); P = 0.042] (Table 4 Supplementary, http://links.lww.com/QAD/B83). Neither cumulative TDF use, nor cumulative protease inhibitor use was associated with a higher rate of all fractures (Table 2).

Table 2

Table 2

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Incidence of fragility fractures

A total of 140 fragility fractures occurred during 36 050 person-years [incidence rate 3.9 (3.3, 4.6) per 1000 person-years]. Of those, 70 fractures occurred in HIV+ [incidence rate 4.6 (3.6, 5.8) per 1000 person-years] and 70 in the HIV− [incidence rate 3.4 (2.7, 4.3) per 1000 person-years]. When stratified by age categories and HIV serostatus, the incidence rates of fragility fracture in HIV− were 2.9/1000 person-years in both the 40–49 and 50–59 year old groups and 5.1/1000 person-years in the group aged at least 60 years. Within HIV+ the incidence rate of fragility fracture increased from 2.6 to 6.3 and 7.6 per 1000 person-years in those aged 40–49, 50–59 and at least 60 years, respectively [Table 2 (Supplementary, http://links.lww.com/QAD/B83) and Fig. 1]. There was no evidence of an interaction between HIV and age on fragility fracture (P = 0.135).

The unadjusted risk of fragility fracture is shown in Table 3 (Supplementary, http://links.lww.com/QAD/B83) and Fig. 2. In the multivariate analysis, compared with HIV− aged 40–49 years, a higher rate of fracture was only seen in the HIV+ aged 50–59 [aIRR: 2.1 (1.24, 3.55)] and at least 60 years [aIRR: 2.51 (1.26, 5.01)]. Comparisons by HIV-serostatus within each age group revealed a higher incidence of fragility fracture in HIV+ aged 50–59 years compared with HIV− of similar age [aIRR: 2.06 (1.21, 3.50)]. We found no significant difference in fragility fracture incidence by HIV serostatus within the groups aged 40–49 [aIRR: 0.92 (0.51–1.66)] or at least 60 years [aIRR: 1.46 (0.74, 2.87)]. In sensitivity analysis restricted to the older group aged at least 60 years, although the rate of fracture was two-fold higher in HIV+ versus HIV− men aged 60–69 years, the difference was not statistically significant [aIRR: 2.01 (0.94, 4.31)].

In analyses of fragility fractures restricted to HIV+, there was a higher rate of fracture with increasing age [aIRR: 1.85 (1.04, 3.28) for the 50–59-year old and 2.08 (0.97, 4.48) for the at least 60-year old group, respectively] when compared with the 40–49-year old group. Current ART used was associated with a higher risk of fracture, although this was marginally significant [aIRR: 2.54 (0.97, 6.61)] (Table 2). Neither HIV-1 RNA more than 400 copies/ml nor VCY were associated with higher incidence of fragility fractures [Table 2 and Table 4 (Supplementary, http://links.lww.com/QAD/B83)]. Cumulative protease inhibitor use and cumulative TDF use were not associated with incident fragility fracture.

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Discussion

In this cohort of MSM, we found that the fracture incidence increased with older age among both the HIV+ and HIV− participants; however, the fracture rate was higher in HIV+ aged 50–59 years compared with HIV− men of the same age. Our findings support the Infectious Diseases Society of America [19] and the European AIDS Clinical Society guidelines, reinforcing the importance of baseline bone densitometry dual-energy X-ray absorptiometry (DXA) screening for osteoporosis in HIV-infected men aged 50 years and above.

Fracture rates are higher among HIV+ compared with HIV− persons and increase proportionally with advancing age [28]. Among HIV+ persons in the HIV Outpatient Study, age more than 47 years was associated with increased fracture risk even after adjusting for multiple factors (HR 1.43 per 10 years for fragility fractures) [3]. In a population-based retrospective cohort study conducted in Spain, age stratified analyses demonstrated significant associations between HIV infection and fractures only in the HIV+ participants aged 59 years and above [29]. In the Veterans Aging Cohort Study Virtual Cohort (VACS-VC), there was a significant increase in the risk of fragility fracture with advancing age (HR 1.52 per 10 year increments) even after adjustment for multiple factors [11]. In our analysis, we found an increase in the incidence of all fractures and fragility fractures among HIV+ men starting at age 50. The fracture incidence rates we observed in MACS are somewhat different from those reported by others. In the Danish population, Hansen et al. reported a fracture incidence of 21 per 1000 person-years in the HIV+ and 13.5 per 1000 person-years in the HIV−. The incidence of fragility fracture among male veterans from VACS-VC was slightly lower, with 2.5 per 1000 person-years for HIV+ and 1.9 per 1000 person-years for HIV− persons. It is possible that our study population is unique in several aspects. In addition, the HIV− comparison group in the MACS is drawn from a population of MSM with very similar underlying risk factors to the HIV+ men, which is a major strength of our study.

Amongst several risk factors investigated, we found that hypertension was an independent predictor of all fractures with similar trends for the outcome of fragility fracture. Although data are sparse, there is some clinical evidence, mainly from observational studies, supporting an increased fracture risk in hypertensive people. Although some studies found only an increased risk of vertebral fractures in hypertensive patients [30], others demonstrated a higher risk of any fracture [31]. An observational cohort study of Australians aged 50 years and above, found hypertension to be associated with an increased risk of fragility fractures in women but not in men [32]. Although the exact underlying mechanism remains uncertain, several potential explanations for the effect of hypertension on fracture risk exist. High BP has been associated with increased urinary calcium loss, secondary hyperparathyroidism and loss of calcium from bone [33]. In addition, hypertensive patients tend to be older and more prone to falls [34]. Furthermore, antihypertensive medications, apart from increasing the risk of fall injuries by causing or worsening orthostatic hypotension [35], may also exert direct effects on bone [36]. Data on falls, frailty and markers of calcium metabolism were not available for the entire period covered by this analysis; therefore, we could not assess potential mechanisms for the observed hypertension/fracture association.

Low eGFR has been associated with increased fracture risk [37]. In our study, eGFR was no longer associated with fractures after adjusting for age, BMI and hypertension. This finding suggests that the association of eGFR and fracture may be because of other confounders or that the lack of an association was due to the small number of participants with moderate and severe kidney impairment in our study population. Several studies evaluating the association between CKD and fractures have reported increased fracture risk only with moderate to severe CKD [38].

We found no associations between the incidence of fractures and other factors like BMI, race, current smoking, moderate-heavy or binge alcohol consumption, diabetes or HCV. Several studies have reported significantly higher rates of fractures in patients with HIV and HCV coinfection compared with those with HIV mono-infection [3,39], whereas others have not reproduced this finding [9]. HCV has been shown to be a marker of intravenous drug use [40], and the higher risk of fracture in HIV–HCV coinfected patients has thus been attributed to direct consequences of drug use such as higher risk of trauma, falls and nutritional deficiencies [17]. The small percentage of MACS participants reporting use of intravenous drugs (2%) might explain why no association was detected in our analysis.

The role of HIV-specific factors in fracture risk remains uncertain. Although no association with ART exposure has been reported in several studies [3,9], others found higher rates of fractures associated with ART exposure [11,17]. Using data from the ACTG Longitudinal-Linked Randomized Trial, Yin et al.[41] found a significantly higher fracture rate in the first 2 years after ART initiation that declined in subsequent years. We found that current ART use was associated with an increased risk of fracture. These findings are consistent with results from the Strategies for Management of Antiretroviral Therapy substudy in which continuous administration of ART results in losses in BMD, whereas ART interruption was associated with BMD stabilization or increases [16]. Taken together, these findings suggest that ART treatment, regardless of the ART regimens used, has detrimental effects on bone health.

Specific ART medications, including TDF and protease inhibitors, have been associated with loss of BMD and increased fracture risk in some [11,18,42], but not all studies [9]. In our multivariate analysis, neither cumulative protease inhibitor use, nor TDF was associated with increased incidence of all or fragility fractures, although our study was not specifically designed to assess effects of specific medications, in that the relatively small number of events may have limited the statistical power to detect associations.

We found no associations between CD4+ T-cell count and history of AIDS with fracture risk. Although some studies have reported increased fracture rates in individuals with low CD4+ T-cell count [3] and a history of AIDS-defining illness, others have not [17,42]. We did, however, find an association between cumulative viremia and fracture independent of receiving ART. This finding suggests that the legacy of poorly controlled HIV infection in the past may have important future clinical consequences with respect to fracture risk and that patients who have a long history of uncontrolled viremia may benefit from more aggressive osteoporosis screening and treatment.

Our study has several strengths including a relatively large sample size, incidence of all fractures and fragility fractures as main outcomes and data on several fracture risk factors. In addition, the MACS includes HIV− men with similar risk behaviors as the HIV+, and regardless of HIV serostatus, men were followed semiannually and completed the same fracture questionnaires. We performed risk analyses stratified by age and HIV serostatus allowing us to demonstrate age strata specific increases in fracture rates. Furthermore, data on HIV-specific risk factors were collected at semiannual visits.

We also recognize several limitations. Fractures were self-reported without confirmation by medical chart review or radiographic evaluation although fractures are adverse events that patients tend to remember and reliably self-report [43]. We were not able to determine specifically whether fractures occurred in the setting of major trauma, which might have resulted in the overestimation of fragility fractures. In addition, as histories of fractures were retrospectively collected through questionnaires, recollection bias might be an important limitation. Furthermore, we have no data on calcium and vitamin D supplementation, and we did not account for drugs that may have an impact on bone health, such as the proton pump inhibitors. Specific information on testosterone and glucocorticoid use was introduced in the MACS questionnaire only recently. Missing data were an issue particularly for variables only later routinely collected in the MACS, but we addressed this limitation by using multiple imputation analysis to fill in missing covariates data.

In conclusion, we found that HIV+ MACS participants had higher incidence of all fractures and fragility fractures compared with the HIV− controls and that the rate of fracture was higher among the HIV+ men aged 50–59 years compared with HIV− participants of similar age. Our findings support the current available guidelines recommending baseline DXA screening for HIV+ men starting at age 50. Hypertension remained consistently associated with higher incidence of all fractures even after adjustment for additional fracture risks. To our knowledge, this is the first report in which an association between hypertension and increased fracture incidence among HIV+ persons has been noted. The exact mechanism underlying the association between BMD, fracture, hypertension and antihypertensive agents remains largely unknown and warrants further exploration.

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Acknowledgements

Sources of funding: J.E.L. has received funding from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (K23 AI110532). T.T.B. has received funding from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (K24 AI120834 and R01AI093520). A.G. received support from the Clinical Research and Epidemiology in Diabetes and Endocrinology Training Grant T32DK062707. K.N.A. has received funding from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (K01AI093197).

Data in this article were collected by the Multicenter AIDS Cohort Study (MACS). MACS (Principal Investigators): Johns Hopkins University Bloomberg School of Public Health (Joseph Margolick), U01-AI35042; Northwestern University (Steven Wolinsky), U01-AI35039; University of California, Los Angeles (Roger Detels), U01-AI35040; University of Pittsburgh (Charles Rinaldo), U01-AI35041; the Center for Analysis and Management of MACS, Johns Hopkins University Bloomberg School of Public Health (Lisa Jacobson), UM1-AI35043. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional cofunding from the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by UL1-TR001079 (JHU ICTR) from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The research was also supported by the HIV Prevention Trials Network (HPTN) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the Office of AIDS Research, of the National Institutes of Health (NIH), Dept. of Health and Human Services (DHHS) (UM1 AI068613).

The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH), Johns Hopkins ICTR, or NCATS. The MACS website is located at http://aidscohortstudy.org/.

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Conflicts of interest

J.E.L. has served as a consultant for Gilead Sciences and G.S.K. T.T.B. has served as a consultant to Gilead Sciences, Merck, Theratechnologies, EMD-Serono, and Bristol Myers Squibb. F.J.P. has served as a consultant and on the Speakers Bureau for Gilead Sciences Janssen Pharmaceuticals, Merck and Co and Bristol Meyers Squibb. K.N.A. has served as a consultant for Gilead Sciences, Inc.

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Keywords:

antiretroviral therapy; fracture; fragility fracture; HIV; osteoporosis

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