PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
AIDS. Author manuscript; available in PMC Jul 31, 2010.
Published in final edited form as:
PMCID: PMC2748675
NIHMSID: NIHMS121757
Continuous antiretroviral therapy decreases bone mineral density
Birgit Grund,a Grace Peng,a Cynthia L. Gibert,b Jennifer F. Hoy,c Rachel L. Isaksson,a Judith C. Shlay,d Esteban Martinez,e Peter Reiss,f Fehmida Visnegarwala,g and Andrew D. Carrh, for the INSIGHT SMART Body Composition substudy group
a University of Minnesota, Minneapolis
b George Washington University Medical Center and Veterans Affairs Medical Center, Washington, District of Columbia, USA
c Alfred Hospital and Monash University, Melbourne, Australia
d Denver Public Health, Denver, USA
e Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
f Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
g Absolute Care Medical Center and Morehouse School of Medicine, Atlanta, Georgia, USA
h St Vincent’s Hospital and University of New South Wales, Sydney, Australia
Correspondence to Birgit Grund, PhD, Coordinating Center for Biometric Research, University of Minnesota, 2221 University Avenue, Suite 200, Minneapolis, MN 55414, USA. Tel: +1 612 626 8622; fax: +1 612 624 2819; birgit/at/ccbr.umn.edu
Objectives
To assess the effects of antiretroviral therapy (ART) on bone mineral density (BMD)
Design
Randomized comparison of continuous ART (viral suppression group; VS) with intermittent ART (drug conservation group; DC)
Setting
Outpatient clinics in the United States, Australia, and Spain.
Participants
Participants in the Strategies for Management of Antiretroviral Therapy Body Composition substudy.
Main outcome measures
Annual hip and spine BMD by dual-energy radiographic absorptiometry (DXA) and spine BMD by quantitative computed tomography (qCT).
Methods
Comparisons were by intention-to-treat analysis, using longitudinal models for change in BMD. Risk factors for BMD loss were evaluated.
Results
The 214 participants (median 44 years, 19% female participants, 73% on ART; median T-scores −0.5 total hip, −0.7 spine DXA, −0.9 spine qCT; 98 randomized to VS and 116 to DC) were followed for a mean 2.4 years. With continuous ART, BMD declined per year by 0.8% (hip), 0.4% (spine DXA), and 2.4% (spine qCT). BMD declined significantly less with intermittent ART. Estimated DC minus VS group differences in mean BMD change through follow-up were 1.4% [hip; 95% confidence interval (CI) 0.6–2.3; P=0.002], 1.3% (spine DXA; 95% CI 0.1–2.4, P=0.03), and 3.0% (spine qCT; 95% CI 0.8–5.2, P=0.007). No consistent drug-specific association with BMD decline was found. In the parent study, 10 of 2753 participants in the VS group and two of 2720 in the DC group reported serious fractures (hazard ratio 4.9; 95% CI 1.1–22.5; P=0.04).
Conclusion
Continuous ART is associated with decline in BMD and possibly more fractures relative to intermittent, CD4 cell count-guided ART.
Keywords: antiretroviral therapy, bone mineral density, fracture, HIV, osteoporosis
HIV-infected adults have a higher prevalence of low bone mineral density (BMD; 40–83%) than the general population [110] and perhaps a higher prevalence of fracture [11]. A systematic review of cross-sectional studies of adults with HIV infection found a 6.4-fold increased odds ratio of reduced BMD (T-score <−1.0) and a 3.7-fold increased odds ratio of osteoporosis (T-score <−2.5) [6]. Use of antiretroviral therapy (ART) was associated with low BMD in HIV-infected adults in several studies [any ART, thymidine analogue-nucleoside reverse transcriptase inhibitor (TA-NRTI) or protease inhibitor therapy], as were traditional risk factors (older age, female sex, menopause, corticosteroid therapy, low BMI, low serum testosterone level) and HIV-related factors (HIV duration, elevated plasma HIV viral load) [110,1217]. Not all studies, however, evaluated all risk factors, and associations of individual ART drugs or drug classes with low BMD were not consistent.
Four prospective studies [1821] have reported stable, decreasing, or increasing BMD with protease inhibitor therapy. In a randomized trial, BMD declined with both tenofovir and stavudine, but more with tenofovir [22].
No prospective, randomized trial has compared ART with no ART with respect to BMD. The INSIGHT Strategies for Management of Antiretroviral Therapy (SMART) study [23] was an international, randomized trial comparing intermittent, CD4 lymphocyte count-guided ART with continuous ART. We compared the randomized groups for BMD changes at the hip and spine in 214 participants in the SMART Body Composition substudy over a mean follow-up of 2.4 years. We hypothesized that BMD loss would be less with intermittent ART.
Participants
Eligibility criteria for participation in SMART were documented HIV-1 infection, age greater than 13 years, CD4 cell count above 350cells/μl, and no pregnancy or breastfeeding.
SMART participants at 32 clinical sites in the United States, Australia, and Spain were offered coenrolment in the Body Composition substudy; persons for whom valid scan data could not be obtained (e.g., weight above 160kg) were excluded. Sites were selected based on access to study-certified imaging equipment. The substudy was approved by the institutional review board at each site. Each participant gave written, informed consent.
Study design
Design and data collection of the SMART study have been published [23,24]. Participants were randomized to two groups: intermittent, CD4 cell count-guided ART [drug conservation (DC) group], in which ART was stopped or deferred at study entry, restarted when the CD4 cell count declined below 250cells/μl, and stopped again at CD4 cell counts above 350cells/μl; and continuous ART [viral suppression (VS) group]. ART drugs were not protocol-specified. The Body Composition substudy planned to enrol 300 participants and follow them for 5 years. The substudy was powered for adipose endpoints [25].
Enrolment into SMART was terminated early on 11 January 2006, and all participants were advised to receive continuous ART because of increased risks for death, opportunistic disease, and serious non-AIDS diseases in the DC group, identified at an interim review by the independent Data and Safety Monitoring Board [23]. The Body Composition substudy closed to follow-up on 30 June 2006.
Research questions and methodology
Research questions and methodology are as follows:
  • Does ART contribute to BMD decline? We compared changes in BMD between the VS and DC groups from baseline through follow-up, and through the first year. The first-year comparison is closest to comparing continuous ART to no ART because, by study design, the between-group difference in ART use was greatest during the first year.
  • What is the effect of specific drugs or drug classes on BMD? We performed two analyses: first, we evaluated associations of cumulative drug use with decline in BMD in the VS group. We restricted the analysis to the VS cohort because the duration of ART use in the DC group depended on factors that also may have influenced BMD; for example, participants who were healthier at study entry tended to use less ART during follow-up [26]. Second, among participants who were receiving ART at baseline, we compared the first-year DC–VS group difference between two subgroups: those participants whose baseline ART regimen did and did not include the target drugs. We hypothesized that stopping/continuing drugs associated with decline in BMD would result in larger DC–VS group differences than stopping/continuing other ART regimens.
The treatment group comparisons were prespecified in the protocol, but not the VS cohort analysis.
Bone mineral density outcome measures
For each participant, BMD was assessed at baseline and annually by dual-energy radiographic absorptiometry (DXA) of the total hip; DXA of the lumbar spine (L1–L4); and quantitative computed tomography (qCT) of the spine (L2–L4). Spine qCT evaluated volumetric density of the trabecular bone. In contrast, DXA measures areal BMD and includes both cortical and trabecular bone.
For each scan, BMD, T-scores, and Z-scores were reported. T-scores compare the BMD to the mean of a healthy, young (20–30 years) reference population, matched by sex and race, and are expressed as number of standard deviations above or below the reference mean. For Z-scores, the reference population is also matched by age. T-scores and Z-scores were used as provided by the radiographic equipment manufacturer. BMD measurements were corrected by the central reading center for longitudinal and cross-sectional consistency based on scans of phantoms (see below).
We defined osteoporosis as the lower of the two DXA T-scores (spine and total hip) being less than −2.5, as recommended by the National Osteoporosis Foundation [27]. Low BMD (osteopenia or osteoporosis) was defined as at least one of the DXA T-scores being less than −1. WHO guidelines use similar T-scores, but concentrate on hip DXA [2830].
Imaging procedures
The 10 radiographic imaging sites used standardized scanning protocols. Each patient had all scans performed by the same imaging site. Scans were centrally analyzed (Bio-Imaging Technologies, Inc., Newtown, Pennsylvania, USA) to ensure longitudinal consistency. Radiology equipment and personnel were certified by Bio-Imaging before protocol initiation. For women of childbearing potential, a negative serum or urine pregnancy test result was required within 14 days before each scan.
Dual-energy radiographic absorptiometry
DXA was performed according to the manufacturer’s (GE Lunar or Hologic Inc., Bedford, Massachusetts, USA) specifications. Instruments were standardized and crosscalibrated using Bio-Imaging’s Bona Fide Phantom; instrument quality control included regular scans of manufacturer-specified spine phantoms.
Quantitative computed tomography
For lumbar spine qCT, participants lay supine on a K2HPO4 CT calibration phantom; 40–45 slices were scanned, from the lower endplate of L1 to the upper endplate of L5. Instrument quality assurance included daily scans of a quality assurance phantom. Images were analyzed centrally using Mindways QCT PRO software (Mindways Software, Inc., Austin, Texas, USA).
Other data collection
In addition to the demographic, HIV, ART, and clinical data collected for all SMART participants [23], we recorded risk factors for low BMD (smoking status, history of alcohol abuse, but not menopausal status), body composition (clinician-assessed lipoatrophy or abnormal generalized fat accumulation), BMI, and drug treatment for osteoporosis.
Fractures were identified from grade 4 adverse event reports using the International Statistical Classification of Diseases and Related Health Problems-9 (ICD-9) codes, for all SMART participants through study completion in July 2007. Consequently, we identified only those fractures that met the definition of grade 4 events: potentially life-threatening, symptomatic events requiring medical intervention.
Statistical methods
All follow-up data were censored on the date of the participant’s last BMD scan. Median time to first ART initiation in the DC arm was estimated from the Kaplan–Meier curve.
Randomized comparisons
Comparisons between the treatment groups were by intent-to-treat analysis. Changes in BMD were expressed as percentage of baseline BMD. The DC and VS groups were compared for changes in BMD from baseline through follow-up using longitudinal, mixed models, and for changes from baseline to a given visit using linear regression. Estimated DC–VS treatment differences with 95% confidence intervals (CIs) and P values for the differences were cited. As sensitivity analyses, treatment groups were also compared after adjusting for race, sex, and the race-by-sex interaction, because by chance more women were randomized to the VS group and the race distribution differed by sex; and after censoring follow-up at the start of osteoporosis treatment.
Treatment groups were compared for changes in BMD within predefined subgroups of participants by fitting separate models (longitudinal or regression) for each subgroup. Homogeneity across subgroups was assessed by testing for interaction between the subgroup factor and the treatment group indicator in a joint model.
Cox regression was used to compare treatment groups for incidence of osteoporosis in the substudy (through June 2006) and for incidence of fractures in the main SMART study (through July 2007).
Viral suppression cohort analyses
The rate of BMD decline in the VS group was estimated by the slope of the BMD change over time, using repeated measures models with zero intercept. Time-updated cumulative years of exposure to specific antiretroviral drugs were calculated from study entry to each annual scan date. The association of change in BMD with duration of ART since study entry was assessed by fitting two longitudinal mixed models. In the first model, time-updated covariates for cumulative use of TA-NRTIs, tenofovir, and protease inhibitors were included, because these drugs were associated with loss of BMD in previous studies. The second model included cumulative use of specific drugs that were used by 10 or more participants (15 for NRTIs). Both models included follow-up time as covariate, along with race, sex, their interaction, age, smoking, BMI, history of alcohol abuse, and baseline BMD.
Analyses used SAS version 9.1 (SAS Institute, Cary, North Carolina, USA). All P values are two-sided.
Baseline characteristics
From May 2002 to January 2006, the SMART Body Composition substudy coenrolled 275 patients at 32 sites in the United States, Australia, and Spain. The present analysis includes 214 participants (98 in the VS and 116 in the DC group) with at least one follow-up DXA or qCT; of 61 participants without follow-up scans, 57 (93%) had none because the study was terminated early (Fig. 1 Fig. 1).
Fig. 1
Fig. 1
Study design and patient disposition. ART, antiretroviral therapy; BMD, bone mineral density; DC, drug conservation; VS, viral suppression. gr1
Baseline median age was 44 years, 19% were female participants, 28% were black, and 55% white (Table 1 Table 1). The proportion of women was higher in the VS group. Among women, the proportion of blacks (66%) was higher than that among men (18%). More participants in the DC group had HIV-RNA of 400copies/ml or less. Otherwise, treatment groups were well balanced, including for BMD. BMD measurements were slightly lower than in the general population of similar age, sex, and race, with median Z-scores of −0.2, −0.6, and −0.1 for the total hip DXA, spine DXA, and spine qCT BMD, respectively. Eight of 214 participants (4%) had osteoporosis. None was receiving osteoporosis therapy. Only 6% of participants were ART-naive and 27% were not receiving ART at baseline.
Table 1
Table 1
Baseline characteristics
Compared with the parent SMART study, the proportion of women, of participants receiving ART at baseline, and of those with HIV-RNA of 400copies/ml or less was lower in our cohort.
Treatment through follow-up
Participants were followed for a mean 2.4 years (range 0.9–4.1). Figure 2a Figure 2 shows the percentage of participants receiving ART by treatment group. VS group participants received ART for 93% of their follow-up time (2.3 of 2.5 years), compared with 41% (0.9 of 2.3 years) in the DC group. In the DC group, median time to first ART initiation after study entry was 1.2 years.
Fig. 2
Fig. 2
Antiretroviral therapy use and mean change in bone mineral density by treatment group. gr2
Four participants in the DC group and eight in the VS group started osteoporosis treatment.
Changes in bone mineral density
By all three measures, changes in BMD favored the intermittent treatment arm (Fig. 2b–d). In the VS group, hip BMD declined on average by 0.8% per year (P<0.001), spine DXA by 0.4% per year (P=0.04), and spine qCT by 2.4% per year (P<0.001). In the DC group, BMD remained stable or increased at year 1. After year 1, BMD appeared to decline at similar rates in both treatment groups. Estimated treatment differences (DC–VS) through follow-up were 1.4% for change in hip BMD (95% CI 0.6–2.3, P=0.002), 1.3% for spine DXA (95% CI 0.1–2.4, P=0.03), and 3.0% for change in trabecular BMD by spine qCT (95% CI 0.8–5.2, P=0.007). Results were similar after adjustment for race, sex, and the race-by-sex interaction (data not shown). After censoring follow-up at the start of osteoporosis treatment, estimated treatment differences were 1.3% (P=0.004), 1.0% (P=0.08), and 2.8% (P=0.01) for hip, spine DXA, and spine qCT BMD, respectively.
The DC–VS group difference in spine BMD through follow-up was larger among participants who were on ART at baseline (spine DXA: P=0.02 for the interaction between ART status and treatment group; qCT: P=0.05). Otherwise, the treatment effect did not vary by sex, race, age, or other baseline factors, including smoking, history of alcohol abuse, baseline and nadir CD4 lymphocyte counts, HIV-RNA of 400copies/ml or less, prior AIDS, BMI, and baseline BMD (P>0.05 for all interactions between factors and treatment groups; data not shown).
Risk factors associated with decline in bone mineral density in viral suppression group
Associations between the cumulative use of specific ART drugs with change in BMD in the VS group are summarized in Table 2 Table 2.
Table 2
Table 2
Association of cumulative use of ART with loss of bone mineral density in the VS group (continuous ART)
In the first model, TA-NRTIs, tenofovir, other NRTIs, protease inhibitors, and nonnucleoside reverse transcriptase inhibitors (NNRTIs) were assessed. Per year of use of a TA-NRTI after study entry, spine BMD by qCT declined by 2.3% (P=0.02); TA-NRTI use was borderline associated with loss of spine BMD by DXA (P=0.09), but not with change in hip BMD. The second model included those drugs used most often in each drug class. Among NRTIs, both stavudine and zidovudine were at least borderline associated with spine BMD loss. Among protease inhibitors, lopinavir/r was associated with decline in spine BMD by qCT (P=0.006), but not DXA, and borderline with loss of hip BMD (P=0.06). For all other drugs, trends for association with BMD change (P≤0.10) were present for at most one of the three BMD outcomes.
Models 1 and 2 also included additional covariates (see Table 2 footnote) that may be risk factors for low BMD; none of these covariates was associated with change in BMD in our analyses, except for a positive association of BMI change with hip BMD change. As sensitivity analysis, both models were also fitted without any of the additional covariates; results were similar (data not shown).
Subgroup analyses comparing stopping versus continuing antiretroviral regimens
Table 3 Table 3 summarizes first-year DC minus VS treatment differences in BMD outcomes within subgroups defined by use of various ART regimens at study entry. In all subgroups, and for all three BMD outcomes, continuing ART led to less favorable changes than intermittent ART, and the treatment difference was statistically significant in most subgroups. However, when comparing the treatment effects across the subgroup pairs, there was no evidence that stopping regimens that included a TA-NRTI, tenofovir, a protease inhibitor, or lopinavir/r, respectively, was more favorable than stopping other ART regimens. Subgroup analyses that included the entire follow-up provided similar results (data not shown).
Table 3
Table 3
Change in BMD in the first year among those on ART at study entry, within subgroups by type of ART at baseline
Osteoporosis and fractures
There was no difference between the DC and VS groups in incidence of osteoporosis (P=0.80 by Cox regression). In years 1–3, 4.3, 4.2, and 5.0% of participants had a DXA hip or spine T-score below −2.5 (osteoporosis); of those, 25% were receiving osteoporosis therapy 1 year later.
In the main SMART study, fractures were reported as grade 4 adverse events for 10 of 2753 participants in the VS group and two of 2720 in the DC group, at a rate of 0.13 and 0.03 per 100 person-years of follow-up, respectively [hazard ratio (VS/DC) 4.9, 95% CI 1.1–22.5, P=0.04; about 7500 person-years of follow-up per treatment group]. Most of these fractures were associated with some degree of trauma.
In this SMART substudy of 214 participants with mean follow-up of 2.4 years, BMD steadily declined in the group receiving continuous ART, whereas BMD remained stable or increased in the first year of intermittent, CD4 cell count-guided ART. For all three BMD measures, the between-group differences were statistically significant at year 1 and persisted through follow-up. Continuous ART may also have been associated with higher risk of fracture than intermittent ART. The unfavorable effect of continuous ART on BMD is in contrast to clinical outcomes, including progression to AIDS, myocardial infarction, and end-stage liver or renal disease, all of which were more common with intermittent ART [23,24,31].
The randomized comparisons between the DC and VS groups provide evidence that ART causes BMD loss. Moreover, the pattern of BMD change is consistent with the increasing percentage of DC participants receiving ART after the first year (Fig. 2a); BMD declined in both treatment groups during this period (Fig. 2b–d). We found no evidence that uncontrolled HIV replication reduced BMD, as was previously suggested [6,32,33]; on the contrary, BMD remained stable in the intermittent ART group during the first year, when most participants were not receiving ART.
The treatment difference and the rate of BMD decline appeared largest for spine qCT. This is consistent with studies in the general population, in which the age-related BMD decline varies by scan location and technique, and spine BMD measured by qCT declines faster than BMD by DXA of the spine or hip [34,35]. Trabecular bone turns over more rapidly and, therefore, tends to show greater effects of bone-active agents.
In the VS cohort, the annual BMD decline by DXA (total hip 0.8%, spine 0.4% per year) was steeper than in healthy white men from age 35 to 55 years (hip 0.2%, spine 0.2%); BMD loss at the hip was similar to that in postmenopausal white women from 55 to 75 years (hip 0.8%, spine 0.8%) [36,37]. Also, BMD declined throughout follow-up (Fig. 2b–c), whereas in a study comparing tenofovir with stavudine in 600 participants over 144 weeks, BMD stabilized after the first year. Their rate of BMD loss averaged through week 144 was similar to our study, however, at 1.0% per year at the hip and 0.6% spine [22].
We could not determine which antiretroviral drugs or drug classes were most responsible for the BMD declines we observed. In the analysis of the VS cohort, associations of cumulative use of specific drugs with BMD decline varied by bone site, and statistical evidence was weak. No association was confirmed in the randomized comparisons across subgroups by baseline ART regimen.
In the VS cohort, cumulative use of stavudine and zidovudine were each associated with loss in spine BMD, consistent with other studies [22,38,39]. Cumulative use of lopinavir/r was associated with BMD loss at the spine (by qCT) and total hip. Association of lopinavir/r with BMD loss has been reported previously [21,40]. Results of the cohort analysis are by design hypothesis-generating, not conclusive evidence.
The weak associations of specific drugs with BMD decline in the presence of a clear BMD difference between intermittent and continuous ART may be due to several factors. These factors are as follows:
  • Sample size and follow-up time were moderate.
  • Several drugs may contribute to BMD decline, and the effects of individual drugs may have been too weak to be identified in the presence of other BMD-active ART.
  • In the VS cohort, 93% of follow-up time was spent on ART and follow-up time was included as covariate in the regression. Therefore, P values for individual drugs assess only the added contribution beyond the average ART effect. Such analysis tends to give weaker statistical evidence for the effect of drugs that are taken by many participants.
Traditional risk factors for low BMD such as age, sex, race, smoking, or alcohol abuse at baseline were not associated with change in BMD. It is possible that the effect of these factors on BMD is evident only with longer follow-up.
The fracture data from the parent SMART trial suggest, but certainly do not prove, that continuous ART may increase the risk of fracture as compared with intermittent ART. Fracture events were not systematically collected, but identified from grade 4 adverse event reports.
The main strengths of our study are the randomized comparisons of intermittent versus continuous ART and the standardized assessment of BMD. The study has the following limitations:
  • Mean follow-up was only 2.4 years and many participants had only 1 year of follow-up due to the early termination of the substudy. The subgroup analyses in particular were underpowered.
  • Fractures were only passively collected.
  • The study was conducted between 2002 and 2006; some antiretroviral drugs such as TA-NRTIs and first-generation protease inhibitors are less common today in industrialized countries.
Our study did not address management of low BMD in patients receiving continuous ART. Current US Department of Health and Human Services (DHHS) guidelines suggest to consider BMD assessments in adults receiving ART [41]. In clinical trials, the use of bone turnover markers in addition to BMD improved estimates of fracture risk in postmenopausal osteoporotic women; their diagnostic value in clinical practice is still unclear [42]. In small, randomized trials, bisphosphonates improved BMD in HIV-infected adults [43,44]; other potential agents such as parathyroid hormone have not been evaluated.
Given the current trend to initiate ART earlier in the course of HIV infection and the importance of maintaining continuous ART, our data suggest that low BMD may become more prevalent as more patients use ART for decades, possibly resulting in higher fracture rates. Studies are needed to better predict osteoporosis risk in HIV-infected persons in order to guide individualized recommendations for diagnosis and treatment of low BMD.
Acknowledgments
The authors gratefully acknowledge the study participants, investigators, study coordinators, and the staff at imaging centers and BioImaging, Inc., without whom this study could not have been completed. We particularly thank Avis Thomas, protocol manager, for her tireless work, and Dr Kris Ensrud for helpful comments. The study was funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U01AI042170 and U01AI46362. Clinical Trials.gov identifier: NCT00027352.
The following authors have received research funding, consultancy fees, lecture sponsorships from, or have served on advisory boards for companies listed in parentheses: A.C. (Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Roche, and Tibotec); E.M. (Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, and Tibotec); J.H. (Janssen-Cilag, Boehringer Ingelheim, Roche, and Merck Sharp & Dohme); P.R. (Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Science, GlaxoSmithKline, Hoffmann, LaRoche, Merck, Pfizer, Theratechnologies, and Tibotec).
Footnotes
The primary article was written by B.G. and A.C. Statistical analyses were performed by B.G., G.P., and R.I. The substudy protocol was conceived by F.V. and A.C. C.G., J.H., J.S., E.M., F.V., and A.C. recruited and followed up participants and oversaw the study conduct. All authors contributed to design of the analyses and successive drafts of the article.
Additional members of the INSIGHT SMART Body Composition study team: Fraser Drummond (National Center in HIV Epidemiology and Clinical Research, University of NSW, Sydney, Australia), Kenneth Ellis (Baylor College of Medicine, Houston, Texas, USA), Wafaa El-Sadr (Harlem Hospital and Columbia University, New York, New York, USA)
Clinical site investigators for the INSIGHT SMART Body Composition substudy (numbers of enrolled participants are in parentheses):
Houston AIDS Research Team, Houston, Texas (n=94): Estela A. Acosta LVN, Roberto C. Arduino, MD, Jorge Darcourt Riso-Patron MD, Carmen Machado, Pablo C. Okhuysen, MD, Maria C. Rodriguez-Barradas, MD, Maria Tadea Insignares MD, A. Clinton White, MD.
The Research & Education Group, Portland, Oregon (n=56): Diana Antoniskis, MD, Doug Beers, MD, David Gilbert, MD, Joel Godbey, MD, Gordon Johnson, MD, Todd Korthuis, MD, James Leggett, MD, Michael McVeigh, MD, Melinda Mueller, MD, Mary O’Hearn, MD, James Sampson, MD
Australia Site Coordinating Center, Sydney, Australia (n=50): Jonathan Anderson, Kathy Barnes, Alison Cain, David Cooper, Beng Eu, Martyn French, Jennifer Hoy, Nic Medland, Richard Moore, Sally Price, Norm Roth, Jega Sarangapany, Don Smith, Bak Kiem Tee.
Harlem AIDS Treatment Group, New York, New York (n=39): Susan Caras, MS, Rosetta Contreras, RN, John Corser, MD, Livette Johnson, MD, Subha Raghavan, PhD, Helen May Seedhom, RN.
Spain Site Coordinating Center, Barcelona, Spain (n=13): Maria Larrousse, Sergi Vidal.
Richmond AIDS Consortium, Richmond, Virginia (n=11): Robert Brennan, MD, Vivian Bruzzese, MD, Anne Chiang, MD, Clarence Childress, MD, Carol Clark, RN, BSN, Patricia Dodson, RN, BSN, CCRC, Kathleen Genther, RN, BSN, CCRC, Robert Higginson, PAC, Jane Kaatz, RN, ANP, Johanna McKee, RN, CCRC, Daniel Nixon, DO, PhD, Jane Settle, RN, ANP, Vicky Watson, RN, Joy Zeh, RN, FNP.
University of North Texas Health Science Center, Fort Worth, Texas (n=10): Isabel Vecino, MD, Stephen E. Weis, DO.
Louisiana Community AIDS Research Program, New Orleans, Louisiana (n=2): Suzanne L. Adams, RN, BSN, Sr. Sue Pabolvich, RN, MPH, C-FNP, Connie Z. Scott, RN, BSN, ACRN, Janice Y. Walker, RN, NP, MN, CCRC.
B.G., C.G., R.I., G.P., J.S., and F.V. report no conflicts of interest.
1. Amiel C, Ostertag A, Slama L, Baudoin C, N’Guyen T, Lajeunie E, et al. BMD is reduced in HIV-infected men irrespective of treatment. J Bone Mineral Res. 2004;19:402–409. [PubMed]
2. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review [see comment] AIDS. 2006;20:2165–2174. [PubMed]
3. Brown TT, Ruppe MD, Kassner R, Kumar P, Kehoe T, Dobs AS, Timpone J. Reduced bone mineral density in human immunodeficiency virus-infected patients and its association with increased central adiposity and postload hyperglycemia. Journal of Clinical Endocrinology & Metabolism. 2004;89:1200–1206. [PubMed]
4. Bruera D, Luna N, David DO, Bergoglio LM, Zamudio J. Decreased bone mineral density in HIV-infected patients is independent of antiretroviral therapy. AIDS. 2003;17:1917–1923. [PubMed]
5. Dolan SE, Huang JS, Killilea KM, Sullivan MP, Aliabadi N, Grinspoon S. Reduced bone density in HIV-infected women. AIDS. 2004;18:475–483. [PubMed]
6. Fausto A, Bongiovanni M, Cicconi P, Menicagli L, Ligabo EV, Melzi S, et al. Potential predictive factors of osteoporosis in HIV-positive subjects. Bone. 2006;38:893–897. [PubMed]
7. Jones S, Restrepo D, Kasowitz A, Korenstein D, Wallenstein S, Schneider A, et al. Risk factors for decreased bone density and effects of HIV on bone in the elderly. Osteoporos Int. 2007 [Epub ahead of print] [PubMed]
8. Knobel H, Guelar A, Montero M, Carmona A, Luque S, Berenguer N, Gonzalez A. Risk of side effects associated with the use of nevirapine in treatment-naive patients, with respect to gender and CD4 cell count. HIV Medicine. 2008;9:14–18. [PubMed]
9. Moore AL, Vashisht A, Sabin CA, Mocroft A, Madge S, Phillips AN, et al. Reduced bone mineral density in HIV-positive individuals. AIDS. 2001;15:1731–1733. [PubMed]
10. Yin M, Dobkin J, Brudney K, Becker C, Zadel JL, Manandhar M, et al. Bone mass and mineral metabolism in HIV+ postmenopausal women. Osteoporosis International. 2005;16:1345–1352. [PMC free article] [PubMed]
11. Triant V, Brown T, Lee H, Grinspoon SK. Fracture prevalence among HIV-infected versus non HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab. 2008 [Epub ahead of print] [PubMed]
12. 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. AIDS. 2007;21:617–623. [PMC free article] [PubMed]
13. Bolland MJ, Grey AB, Horne AM, Briggs SE, Thomas MG, Ellis-Pegler RB, et al. Bone mineral density is not reduced in HIV-infected Caucasian men treated with highly active antiretroviral therapy. Clinical Endocrinology. 2006;65:191–197. [PubMed]
14. Carr A, Miller J, Eisman JA, Cooper DA. Osteopenia in HIV-infected men: association with asymptomatic lactic acidemia and lower weight pre-antiretroviral therapy. AIDS. 2001;15:703–709. [PubMed]
15. Cazanave C, Dupon M, Lavignolle-Aurillac V, Barthe N, Lawson-Ayayi S, Mehsen N, et al. Reduced bone mineral density in HIV-infected patients: prevalence and associated factors. AIDS. 2008;22:395–402. [PubMed]
16. Dolan SE, Carpenter S, Grinspoon S. Effects of weight, body composition, and testosterone on bone mineral density in HIV-infected women. Journal of Acquired Immune Deficiency Syndromes: JAIDS. 2007;45:161–167. [PubMed]
17. Fernandez-Rivera J, Garcia R, Lozano F, Macias J, Garcia-Garcia JA, Mira JA, et al. Relationship between low bone mineral density and highly active antiretroviral therapy including protease inhibitors in HIV-infected patients. HIV Clinical Trials. 2003;4:337–346. [PubMed]
18. Dolan SE, Kanter JR, Grinspoon S. Longitudinal Analysis of Bone Density in Human Immunodeficiency Virus-Infected Women. Journal of Clinical Endocrinology & Metabolism. 2006;91:2938–2945. [PMC free article] [PubMed]
19. Duvivier C, Kolta S, Assoumou L, Ghosn J, Rozenberg S, Murphy R, et al. First line PI-containing regimens cause a greater decrease in bone mineral density compared to NNRTI-containing regimens in HIV-1 infected patients: a substudy of HIPPOCAMPE-ANRS 121 trial. 15th Conference on Retrovirus and Opportunistic Infections (CROI); Boston, MA. February 3–6 2008.
20. Nolan D, Upton R, McKinnon E, John M, James I, Adler B, et al. Stable or increasing bone mineral density in HIV-infected patients treated with nelfinavir or indinavir. AIDS. 2001;15:1275–1280. [PubMed]
21. Rivas P, Gorgolas M, Garcia-Delgado R, Diaz-Curiel M, Goyenechea A, Fernandez-Guerrero ML. Evolution of bone mineral density in AIDS patients on treatment with zidovudine/lamivudine plus abacavir or lopinavir/ritonavir. HIV Medicine. 2008;9:89–95. [PubMed]
22. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JMAH, Miller MD, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial [see comment] JAMA. 2004;292:191–201. [PubMed]
23. The SMART Study Group. CD4+ guided antiretroviral treatment interruption: Primary results of the SMART study. New England Journal of Medicine. 2006;355:2283–2296. [PubMed]
24. The SMART Study Group. Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in HIV patients previously receiving episodic therapy: a randomized trial. Annals of Internal Medicine. 2008;149:289–299. [PubMed]
25. Visnegarwala F, Grund B, Thomas A, Ellis K, Gibert C, Shlay J, et al. The effects of intermittant, CD4-guided antiretroviral therapy on peripheral limb fat and metabolic parameters: The SMART Body Composition Substudy. Poster 803. In: AIDS; Toronto, Canada. 2007.
26. The SMART Study Group. Inferior clinical outcome of the CD4+ cell count guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ cell counts and HIV RNA levels during follow-up. J Infect Dis. 2008;197:1145–1155. [PubMed]
27. National Osteoporosis Foundation. National Osteoporosis Foundation (NOF) 2008. Clinician’s guide to Prevention and Treatment of Osteoporosis.
28. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk [see comment] Lancet. 2002;359:1929–1936. [PubMed]
29. WHO Scientific Group on the Assessment of Osteoporosis at the Primary Health Care Level. Summary Meeting Report; Brussels, Belgium. 5–7 May 2004; 2004.
30. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Technical Report Series. 1994;843 [PubMed]
31. Phillips AN, Carr A, Neuhaus J, Visnegarwala F, Prineas R, Burman WJ, et al. Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial. Antiviral Therapy. 2008;13:177–187. [PubMed]
32. Aukrust P, Haug CJ, Ueland T, Lien E, Muller F, Espevik T, et al. Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. Journal of Clinical Endocrinology & Metabolism. 1999;84:145–150. [PubMed]
33. Gibellini D, Borderi M, De Crignis E, Cicola R, Vescini F, Caudarella R, et al. RANKL/OPG/TRAIL plasma levels and bone mass loss evaluation in antiretroviral naive HIV-1-positive men. Journal of Medical Virology. 2007;79:1446–1454. [PubMed]
34. Blake GM, Fogelman I. The role of DXA bone density scans in the diagnosis and treatment of osteoporosis. Prostgrad Med J. 2007;83:509–517. [PMC free article] [PubMed]
35. Grampp S, Genant HK, Mathur A, Lang P, Jergas M, Takada M, et al. Comparisons of noninvasive bone mineral measurements in assessing age-related loss, fracture discrimination, and diagnostic classification [see comment] Journal of Bone & Mineral Research. 1997;12:697–711. [PubMed]
36. Bonnick SL. Bone densitometry in clinical practice. Application and interpretation. 2. Totowa, NJ: Humana Press; 2004. Appendix XI. Hologic DXA reference data; pp. 383–391.
37. Looker AC, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP, et al. Updated data on proximal femur bone mineral levels of US adults. Osteoporosis International. 1998;8:468–489. [PubMed]
38. McComsey GA, Re VL, 3rd, O’Riordan M, Walker UA, Lebrecht D, Baron E, et al. Effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in HIV-infected subjects: a randomized, controlled study [see comment] Clinical Infectious Diseases. 2008;46:1290–1296. [PMC free article] [PubMed]
39. Pan G, Wu X, McKenna MA, Feng X, Nagy TR, McDonald JM. AZT enhances osteoclastogenesis and bone loss. AIDS Research & Human Retroviruses. 2004;20:608–620. [PubMed]
40. Anastos K, Lu D, Shi O, Mulligan K, Tien PC, Freeman R, et al. The association of bone mineral density with HIV infection and antiretroviral treatment in women. Antiviral Therapy. 2007;12:1049–1058. [PubMed]
41. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008; 101–102, table 13. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed January 29, 2009. In.
42. Civitelli R, Armamento-Villareal R, Napoli N. Bone turnover markers: understanding their value in clinical trials and clinical practice. Osteoporosis International. 2009 E-pub ahead of print. [PubMed]
43. Bolland MJ, Grey AB, Horne AM, Briggs SE, Thomas MG, Ellis-Pegler RB, et al. Bone mineral density remains stable in HAART-treated HIV-infected men over 2 years. Clinical Endocrinology. 2007;67:270–275. [PubMed]
44. McComsey GA, Kendall MA, Tebas P, Swindells S, Hogg E, Alston-Smith B, et al. Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS. 2007;21:2473–2482. [PubMed]