Osteopenia and osteoporosis are more prevalent in HIV-infected (HIV+) men and women compared with HIV-uninfected (HIV−) controls , 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. 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 , whereas others found no association .
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 .
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.
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 . 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.
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 .
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.
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 . 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.
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.
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.
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.
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)].
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)].
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).
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.
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  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 . 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) . 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 . 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 . 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 , others demonstrated a higher risk of any fracture . 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 . 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 . In addition, hypertensive patients tend to be older and more prone to falls . Furthermore, antihypertensive medications, apart from increasing the risk of fall injuries by causing or worsening orthostatic hypotension , may also exert direct effects on bone . 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 . 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 .
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 . HCV has been shown to be a marker of intravenous drug use , 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 . 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. 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 . 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 . 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  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 . 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.
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/.
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.
1. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review
2. Mulligan K, Harris DR, Emmanuel P, Fielding RA, Worrell C, Kapogiannis BG, et al. Low bone mass in behaviorally HIV-infected young men on antiretroviral therapy: Adolescent Trials Network Study 021B
. Clin Infect Dis
3. Young B, Dao CN, Buchacz K, Baker R, Brooks JT. HIV
Outpatient Study (HOPS) Investigators. Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population, 2000–2006
. Clin Infect Dis
4. Battalora L, Buchacz K, Armon C, Overton ET, Hammer J, Patel P, et al. Low bone mineral density and risk of incident fracture in HIV-infected adults
. Antivir Ther
5. Arnsten JH, Freeman R, Howard AA, Floris-Moore M, Lo Y, Klein RS. Decreased bone mineral density and increased fracture risk in aging men with or at risk for HIV infection
6. McComsey GA, Huang JS, Woolley IJ, Young B, Sax PE, Gerber M, et al. Fragility fractures in HIV-infected patients: need for better understanding of diagnosis and management
. J Int Assoc Physicians AIDS Care (Chic Ill)
7. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system
. J Clin Endocrinol Metab
8. Yin MT, Shi Q, Hoover DR, Anastos K, Sharma A, Young M, et al. Fracture incidence in HIV-infected women: results from the Women's Interagency HIV Study
9. Sharma A, Shi Q, Hoover DR, Anastos K, Tien PC, Young MA, et al. Increased fracture incidence in middle-aged HIV-infected and HIV-uninfected women: updated results from the Women's Interagency HIV Study
. J Acquir Immune Defic Syndr
10. Brown TT, McComsey GA. Osteopenia and osteoporosis in patients with HIV: a review of current concepts
. Curr Infect Dis Rep
11. Womack JA, Goulet JL, Gibert C, Brandt C, Chang CC, Gulanski B, et al. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans
. PLoS One
12. Yong MK, Elliott JH, Woolley IJ, Hoy JF. Low CD4 count is associated with an increased risk of fragility fracture in HIV-infected patients
. J Acquir Immune Defic Syndr
13. Grijsen ML, Vrouenraets SM, Steingrover R, Lips P, Reiss P, Wit FW, et al. High prevalence of reduced bone mineral density in primary HIV-1-infected men
14. Cotter EJ, Malizia AP, Chew N, Powderly WG, Doran PP. HIV proteins regulate bone marker secretion and transcription factor activity in cultured human osteoblasts with consequent potential implications for osteoblast function and development
. AIDS Res Hum Retroviruses
15. Brown TT, McComsey GA, King MS, Qaqish RB, Bernstein BM, da Silva BA. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen
. J Acquir Immune Defic Syndr
16. Grund B, Peng G, Gibert CL, Hoy JF, Isaksson RL, Shlay JC, et al. Continuous antiretroviral therapy decreases bone mineral density
17. Hansen AB, Gerstoft J, Kronborg G, Larsen CS, Pedersen C, Pedersen G, et al. Incidence of low and high-energy fractures in persons with and without HIV infection: a Danish population-based cohort study
18. Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents
19. Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA, et al. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America
. Clin Infect Dis
20. McComsey GA, Tebas P, Shane E, Yin MT, Overton ET, Huang JS, et al. Bone disease in HIV infection: a practical review and recommendations for HIV care providers
. Clin Infect Dis
21. Alvarez E, Belloso WH, Boyd MA, Inkaya AC, Hsieh E, Kambugu A, et al. Which HIV patients should be screened for osteoporosis: an international perspective
. Curr Opin HIV AIDS
22. Detels R, Jacobson L, Margolick J, Martinez-Maza O, Munoz A, Phair J, et al. The Multicenter AIDS Cohort Study, 1983 to …
. Public Health
23. Dudley J, Jin S, Hoover D, Metz S, Thackeray R, Chmiel J. The Multicenter AIDS Cohort Study: retention after 9 1/2 years
. Am J Epidemiol
24. Kaslow RA, Ostrow DG, Detels R, Phair JP, Polk BF, Rinaldo CR Jr. The Multicenter AIDS Cohort Study: rationale, organization, and selected characteristics of the participants
. Am J Epidemiol
25. Jacobson LP, Phair JP, Yamashita TE. Update on the virologic and immunologic response to highly active antiretroviral therapy
. Curr Infect Dis Rep
26. Gazzola L, Comi L, Savoldi A, Tagliabue L, Del Sole A, Pietrogrande L, et al. Use of the FRAX equation as first-line screening of bone metabolism alteration in the HIV-infected population
. J Infect Dis
2010; 202:3301; author reply 331-2.
27. Mugavero MJ, Napravnik S, Cole SR, Eron JJ, Lau B, Crane HM, et al. Viremia copy-years predicts mortality among treatment-naive HIV-infected patients initiating antiretroviral therapy
. Clin Infect Dis
28. Shiau S, Broun EC, Arpadi SM, Yin MT. Incident fractures in HIV-infected individuals: a systematic review and meta-analysis
29. Guerri-Fernandez R, Vestergaard P, Carbonell C, Knobel H, Aviles FF, Castro AS, et al. HIV infection is strongly associated with hip fracture risk, independently of age, gender, and comorbidities: a population-based cohort study
. J Bone Miner Res
30. Wada H, Hirano F, Kuroda T, Shiraki M. Breast arterial calcification and hypertension associated with vertebral fracture
. Geriatr Gerontol Int
31. Vestergaard P, Rejnmark L, Mosekilde L. Hypertension is a risk factor for fractures
. Calcif Tissue Int
32. Yang S, Nguyen ND, Center JR, Eisman JA, Nguyen TV. Association between hypertension and fragility fracture: a longitudinal study
. Osteoporos Int
33. McCarron DA, Pingree PA, Rubin RJ, Gaucher SM, Molitch M, Krutzik S. Enhanced parathyroid function in essential hypertension: a homeostatic response to a urinary calcium leak
34. Bergland A, Jarnlo GB, Laake K. Predictors of falls in the elderly by location
. Aging Clin Exp Res
35. Tinetti ME, McAvay GJ, Fried TR, Allore HG, Salmon JC, Foody JM, et al. Health outcome priorities among competing cardiovascular, fall injury, and medication-related symptom outcomes
. J Am Geriatr Soc
36. Ghosh M, Majumdar SR. Antihypertensive medications, bone mineral density, and fractures: a review of old cardiac drugs that provides new insights into osteoporosis
37. Fried LF, Biggs ML, Shlipak MG, Seliger S, Kestenbaum B, Stehman-Breen C, et al. Association of kidney function with incident hip fracture in older adults
. J Am Soc Nephrol
38. Dooley AC, Weiss NS, Kestenbaum B. Increased risk of hip fracture among men with CKD
. Am J Kidney Dis
39. Dong HV, Cortes YI, Shiau S, Yin MT. Osteoporosis and fractures in HIV/hepatitis C virus coinfection: a systematic review and meta-analysis
40. Hansen AB, Lohse N, Gerstoft J, Kronborg G, Laursen A, Pedersen C, et al. Cause-specific excess mortality in siblings of patients co-infected with HIV and hepatitis C virus
. PLoS One
41. Yin MT, Kendall MA, Wu X, Tassiopoulos K, Hochberg M, Huang JS, et al. Fractures after antiretroviral initiation
42. Womack JA, Goulet JL, Gibert C, Brandt CA, Skanderson M, Gulanski B, et al. Physiologic frailty and fragility fracture in HIV-infected male veterans
. Clin Infect Dis
43. Yin MT, Shiau S, Rimland D, Gibert CL, Bedimo RJ, Rodriguez-Barradas MC, et al. Fracture prediction with modified-FRAX in older HIV-infected and uninfected men
. J Acquir Immune Defic Syndr