HAART has led to dramatic declines in morbidity and mortality for HIV-infected persons. However, this improved lifespan has been accompanied by greater recognition of long-term complications of the disease and its therapies, including adverse bone health effects . Low bone mineral density (BMD) is common in HIV-infected adults [2,3]. A recent meta-analysis demonstrated a 15% prevalence of osteoporosis and a 52% prevalence of osteopenia in HIV-infected adults . For children with perinatal HIV infection (HIV+), adverse bone health effects can be magnified by the life-long exposure to both HIV infection and its treatment. These effects may be particularly important during puberty when children experience the most rapid growth and bone mineral accrual . Perinatally infected adolescents (particularly boys) have lower BMD at the end of puberty than do their HIV-uninfected and unexposed peers , which may lead to lower adult peak bone mass and subsequently contribute to increased fracture rates [7,8].
Low BMD in HIV-infected individuals may be the result of chronic inflammation and promotion of osteoblast apoptosis and osteoclast proliferation by the HIV envelope glycoprotein, gp120 [9,10]. Other purported factors include HIV-associated complications such as wasting, corticosteroid use, hypogonadism, renal disease, and adverse effects of antiretroviral therapy (ART) . Finally, traditional risk factors for osteoporosis, such as older age, female sex, low BMI, diabetes, decreased physical activity, vitamin D deficiency, smoking, and alcohol use may also play similar roles in HIV-infected individuals as they do in uninfected individuals.
We measured BMD in children with perinatal HIV infection and children who were perinatally HIV-exposed but uninfected (HEU) to examine the prevalence of low total body and/or lumbar spine BMD in the current HAART era. We hypothesized that HIV+ children would have lower BMD than expected when compared to both age-matched and sex-matched normative data and to their HEU peers. We sought to determine which factors, including lifestyle, disease and treatment characteristics, were associated with BMD outcomes in the HIV+ children.
Children 7–15 years of age born of HIV+ mothers were enrolled into the Adolescent Master Protocol (AMP) of the NIH-supported Pediatric HIV/AIDS Cohort Study (PHACS). AMP is an ongoing prospective cohort study examining specific outcomes of HIV infection and ART in HIV+ preadolescents and adolescents. HEU children were enrolled as a comparison group. Enrollment occurred between March 2007 and December 2009 at 15 sites in the United States. Study visits occurred semi-annually through July 2010 and annually thereafter. Institutional Review Boards at all clinical sites and the Harvard School of Public Health approved the protocol. Informed consent from the parent(s) or guardian(s) and assent from the participants were obtained.
Sociodemographic and clinical history
Sociodemographic characteristics were collected at entry. Clinical data were abstracted from medical records and obtained from prior study databases. Weights and heights were measured and BMI's were calculated [weight (kg)/height (m2)] and expressed as Z-scores based on Centers for Disease Control (CDC) growth data  as previously described . Trained examiners performed Tanner pubertal staging for breasts (in girls), genitalia, and pubic hair. For HIV+ children, ART start and stop dates, quantitative plasma HIV-1 RNA (copies/ml) (viral load), absolute CD4+ lymphocyte (CD4) count (cells/μl) and CD4%, and CDC pediatric HIV clinical classification  were obtained at each visit from the clinical charts.
Dual-energy X-ray absorptiometry scans
Total body (including head) BMD and lumbar spine BMD were measured for HIV+ and HEU using Lunar (General Electric Healthcare, UK) or Hologic (Hologic Inc., Bedford, Massachusetts, USA) DXA scanners according to standard methods. Sites were standardized using circulated phantoms. Scans were sent to the Body Composition Analysis Center at Tufts University School of Medicine for central analysis and standardization. Hologic scans were analyzed using Hologic QDR version 12.3 and APEX version 3.3. Lunar scans were analyzed using Prodigy Advance enCORE 2005 version 9 and enCORE 2011 version 13.6. All scans were analyzed by a single technician blinded to the participants’ HIV status. For this analysis, we used the first dual-energy X-ray absorptiometry scans (DXA) obtained on study for every participant who had a DXA performed. At the time of the DXA, children who had not yet reached Tanner 5 pubertal status had a left hand and wrist radiograph performed to determine bone age . Normative BMD data from Baylor University  were used to generate chronologic age-adjusted and sex-adjusted BMD Z-scores for total body and lumbar spine BMD. In addition, a second set of bone age-adjusted BMD Z-scores was calculated for these two outcomes based on the following algorithm. For children at Tanner stage 1–4, the bone age was used instead of the chronological age if the child's chronological age was more than 1 SD from bone age; otherwise the chronological age was used. For children at Tanner 5, the chronological age was used. We excluded children at Tanner 1–4 from all analyses if their bone age was missing. The prevalences of BMD Z-scores below less than −1, −1.5, and −2 (not mutually exclusive) were calculated for each chronological age-adjusted and bone age-adjusted BMD outcome.
Dietary recall and physical activity
Dietary intake and physical activity were assessed by recall using the Block Dietary Questionnaire and the Physical Activity Screener for children and adolescents from Block Dietary Data Systems (Nutriquest, Berkeley, California, USA). The recommended dietary allowance (RDA) for calcium and vitamin D were based on the Dietary Reference Intakes (Dietary Reference Intakes: The Essential Reference for Dietary Planning and Assessment. 2006 Food and Nutrition Board, Institute of Medicine). The calculated minutes of vigorous physical activity were dichotomized into above or below the 75th percentile, based on the distribution of all HIV+ and HEU.
The analysis dataset consisted of children with complete data on total body and/or lumbar spine BMD, a bone age if required, and a Tanner stage measurement near the time of DXA. Children's characteristics and prevalence of low BMD by HIV status were compared via Fisher's exact test for categorical variables and Wilcoxon test for continuous variables. Multivariate linear regression models were fit to determine differences by HIV status in bone age-adjusted total body and lumbar spine BMD Z-scores. We used bone age-adjusted values to reduce the effect of variation in bone maturity on outcomes. Sex, race/ethnicity, and Tanner stage were included in all models. Other potential confounders were included in the model if they were significant at P < 0.1. The potential confounders included Z-scores for height, weight, any supplement use, vitamin D intake less than recommended dietary allowance (RDA), and vigorous activity more than the 75th percentile. When the F-test overall P value was less than 0.05 for any multilevel categorical variable, pairwise differences were tested by the Wald test and shown when P ≤ 0.05. Interaction between HIV status and Tanner stage and HIV and sex were tested for each outcome. Among HIV+ children, basic models were fit using linear regression for each variable on each bone age-adjusted BMD outcome, adjusted for the basic covariates including sex, race/ethnicity, and Tanner stage. The following variables were examined: ART class and individual ART medications, as well as nadir and current CD4% (<15%, 15–24%, >25%), peak and current viral load, CDC disease classification at the time of DXA, Z-scores for height and weight, any supplement use, vitamin D intake less than RDA, and vigorous activity more than the 75th percentile. Variables associated with the outcomes at P < 0.2 in these basic models were tested in multivariate linear regression models to determine independent predictors of bone age-adjusted BMD Z-scores in predictive models. Sex, race/ethnicity, and Tanner stage were included in all final models and any of the above other covariates significant at P < 0.1.
Characteristics of HIV+ and HIV-exposed but uninfected children
Of 451 HIV+ children and 227 HEU children enrolled in AMP, 510 (350 HIV+ and 160 HEU) had total body and/or lumbar spine BMD and a bone age available by January 1, 2011 (Table 1). There were no significant differences between those included and those excluded because of a missing bone age by chronological age, sex, race/ethnicity, or Tanner stage. HIV+ children were older than HEU children. The two groups had a similar sex distribution, but the HIV+ children were more likely to be non-Hispanic black. As expected, because of their older age, HIV+ had more advanced sexual maturation than HEU and slightly older bone age. HIV+ had lower height, weight, and BMI Z-scores. HEU children were more likely than HIV+ to have advanced bone age compared with HIV+ (34 vs. 16%).
Data on vitamin D and calcium consumption were available from 457 participants (320 HIV+ and 137 HEU) (Table 1). Intake from dietary sources was similar between the groups, but HIV+ children were more likely to report use of dietary supplements. HIV+ were less likely than HEU to be below the dietary reference intake for vitamin D (52 vs. 59%), but not calcium (73 vs. 67%). HIV+ and HEU reported similar levels of vigorous physical activity.
HIV disease severity and antiretroviral therapy
Table 2 shows HIV-specific disease characteristics of HIV+ children at the time of DXA. Twenty-five percent were CDC clinical category C and their median CD4 count and nadir CD4% at the time of DXA were 725 cells/μl and 33%, respectively. Fifty-five percent had viral load less than 400 copies/ml. Eighty-seven percent were receiving HAART, with protease inhibitor-based regimens being most common (70%); 55% of the HIV+ children were receiving a ritonavir-boosted protease inhibitor and an additional 9% had previously received a boosted protease inhibitor. The median lifetime duration of HAART was 9.5 (interquartile range: 7.1, 11.3) years. The most common nucleoside reverse transcriptase inhibitors (NRTIs) ever used (previously and/or at the time of DXA) were lamivudine (3TC) (90%), zidovudine (ZDV) (85%), and stavudine (76%). Tenofovir disoproxil fumarate (TDF) was used at the time of the DXA by 21%, with an additional 4% having received it previously. Thirty-five percent of children had ever used efavirenz and 35% nevirapine.
Unadjusted prevalence of low BMD in HIV+ and HIV-exposed but uninfected based on different cut-offs for chronological age-adjusted and bone age-adjusted BMD Z-scores
Table 3 shows the percentage of HIV+ and HEU children with total body and lumbar spine BMD Z-scores less than −1.0, −1.5, and −2.0 SD (categories not mutually exclusive). The results on the left show chronological age-adjusted BMD Z-scores and those on the right show bone age-adjusted BMD Z-scores, as specified in the methods. For total body BMD, the difference in proportion between HIV+ and HEU for each cut-off ranged from 5–6% higher in HIV+ for the chronological age-adjusted and 3–6% higher for the bone age -adjusted Z-scores. As compared to HEU, HIV+ had a greater proportion of children with chronological age-adjusted or bone age-adjusted total body Z-score less than −2.0 (P = 0.019 and P = 0.008, respectively). For lumbar spine BMD, the difference in proportion between HIV+ and HEU at each cutoff ranged from 3 to 7% higher in HIV+ for chronological age-adjusted and 3–5% higher for bone age-adjusted Z-scores compared with HEU. The differences were not statistically significant at P < 0.05 for any cutoff of lumbar spine, but the trends suggest a greater proportion of HIV+ than HEU were below all cut-offs for the chronological age-adjusted lumbar spine Z-scores and at the less than −2.0 cutoff for bone age-adjusted lumbar spine Z-score.
Comparison of total body and spine bone mineral density Z-scores between HIV+ and HIV-exposed but uninfected children
The mean (SD) total body Z-scores in HIV+ and HEU were −0.06 (1.3) vs. 0.40 (1.4) for chronological age-adjusted total body and −0.13 (1.2) vs. 0.03 (1.2) for bone age-adjusted total body. Mean (SD) lumbar spine Z-scores for HIV+ and HEU were 0.06 (1.3) vs. 0.53 (1.5) for chronological age-adjusted lumbar spine and −0.03 (1.2) vs. 0.16 (1.3) for bone age-adjusted lumbar spine.
Table 4 shows the univariate (unadjusted) and multivariate models of linear regression analyses on bone age-adjusted BMD outcomes. The unadjusted difference between HIV+ and HEU was −0.16 for total body and −0.19 for lumbar spine. With adjustment for sex, race/ethnicity, and Tanner stage (not shown), the difference between the two groups was −0.33 (P = 0.004) for total body and −0.30 (P = 0.01) for lumbar spine. However, with further adjustment for height and weight as shown in the multivariate models in Table 4, these differences between HIV+ and HEU were attenuated for both total body (−0.03, P = 0.81) and lumbar spine (0.03, P = 0.78). In the multivariate models, total body and lumbar spine Z-scores were associated with race/ethnicity, Tanner stage, height, and weight, but not sex. There was no interaction of sex or Tanner by HIV status on total body or lumbar spine BMD. Weight was a better predictor of outcomes than was BMI.
Correlates of spine and total body bone mineral density in HIV+ children
In HIV+ children, each antiretroviral drug was regressed individually on bone age-adjusted total body and lumbar spine BMD Z-scores, adjusted for sex, race/ethnicity, and Tanner stage. The results are described for ‘ever use’ of the antiretroviral drugs with a P value < 0.2 as well as for years on HAART. In univariate analyses, bone age-adjusted total body BMD was associated with ever use of protease inhibitor (−0.25, P = 0.16); boosted protease inhibitor (−0.27, P = 0.03), 3TC (−0.73, P < 0.001); indinavir (−0.40, P = 0.10); and TDF (−0.24, P = 0.17). Bone age-adjusted lumbar spine BMD was associated with ever use of NNRTI (0.21, P = 0.09); protease inhibitor (−0.23, P = 0.20); boosted protease inhibitor (−0.32, P = 0.009); ZDV (−0.55, P = 0.006); indinavir (−0.36, P = 0.13.); TDF (−0.26, P = 0.13); and years on HAART (−0.03 per year, P = 0.14).
The multivariate results among HIV+ children are shown in Table 5. Bone age-adjusted total body BMD Z-scores were higher in non-Hispanic blacks, Tanner 4 and 5 vs. Tanner 1, and with greater height and weight Z-scores. They were lower with CD4% at least 25% and with ever use of 3TC. They did not differ by sex. Bone age-adjusted lumbar spine BMD Z-scores were higher with greater weight Z-score and more minutes of vigorous physical activity. They were lower with CD4% greater than 15%, peak viral load more than 10 000 copies/ml, greater duration of HAART, and indinavir use. Lumbar spine did not differ by sex, race/ethnicity, Tanner stage, or height. No other antiretroviral drugs were significant in the multivariate models for either outcome.
In this large cross-sectional study, we found lower total body and lumbar spine BMD Z-scores in HIV+ compared with HEU children. Some, but not all, of the decrease in BMD was explained by differences in bone maturation between HIV+ and HEU children, as adjustment for bone age attenuated, but did not eliminate, the differences. Whether chronological age-adjusted or bone age-adjusted, there were relatively few HIV+ children with low BMD (Z-score < −2); however, we observed still more than double the expected rates based on normal population distributions. We found that the differences in BMD between the HIV+ and HEU groups, both at the total body and lumbar spine, persisted after adjusting for sex, race, and pubertal maturity, but were greatly attenuated and no longer significant after adjustment for height, weight, or BMI Z-score.
Some of the differences between cohorts may have been due to artifactual effects of bone size on areal BMD measures, as our HIV+ children were shorter and, therefore, likely had lower areal BMD by DXA. As areal BMD (g/cm2) is a two-dimensional measurement derived by dividing bone mineral content (g) by the apparent area (cm2) of the analyzed bone, it provides a two-dimensional estimate of a three-dimensional structure, which is dependent on the size of the bone. Some of the difference may also have been due to lighter children having lower muscle mass exerting force on bone, resulting in lower bone mass, as the difference was also mediated by weight . Differences in body weight in HIV+ adults largely explain differences in their BMDs . Unlike a prior study, which reported greater differences in BMD between HIV+ and uninfected children with increasing Tanner stage, we did not find any difference in BMD between HIV+ and HEU across Tanner stages . This may be because our population was younger or because our controls were HEU, whereas the other study's controls were HIV-unexposed.
It is possible that we underestimated our rates of low BMD for age and sex due to differences between the racial composition of our cohort and that of the Baylor normative data set used to determine Z-scores in our cohort . Blacks have higher BMD than do whites . Sixty-six percent of our HIV+ and 53% of our HEU population were black, non-Hispanic compared with less than one-third of the participants in the Baylor normative data. However, when we repeated our analyses using Hologic reference data (which account for race, in addition to sex and age ) in the subset of participants (166 HIV+ and 90 HEU) with DXA by Hologic scanners, the findings for the overall prevalence of low BMD Z-scores by HIV status were similar, and BMD differences between HIV+ and HEU were still attenuated after adjustment for height Z-score.
Without fracture data in this HIV+ cohort, we are unable to evaluate whether low BMD scores are associated with bone fractures or fragility (osteoporosis) . Several reports suggest higher fracture rates in HIV+ adults [8,21–23] and some have speculated that HIV+ children may be at higher risk of fracture than their uninfected peers, but the presence, magnitude, and timing of this increased risk are not certain . Although we assessed vitamin D intake, we also did not have blood measures of 25-hydroxy vitamin D status.
For the HIV+ children, specific antiretroviral drugs and measures of disease severity were associated with BMD. For example, ever use of boosted protease inhibitor or 3TC and higher CD4% were associated with a lower total body BMD, while longer duration of HAART, ever use of indinavir, higher CD4%, and higher peak viral load were associated with a lower lumbar spine BMD. The associations of greater height and/or weight Z-scores with total body and lumbar spine Z-scores within the HIV+ cohort could be expected to be an indicator of differences in past degree of disease severity, although there were no differences by CDC stage and nadir CD4, which also reflect past disease severity.
Data from studies examining the effects of ART on bone in HIV+ individuals are conflicting, but, in general, suggest that initiation of HAART is associated with early bone loss. HAART-treated HIV-infected adults have a 2.4-fold increased risk of osteoporosis vs. those who are HIV-infected, but HAART-naive . In addition, adults randomized to continuous HAART were at risk of greater BMD loss and possibly of fracture than were adults randomized to intermittent, CD4-guided HAART . In our study, 87% of HIV+ children were receiving HAART, mostly protease inhibitor-based. Although interpretation of these effects in children is confounded by their relatively wide range of age and pubertal status, the observed negative effects of boosted protease inhibitor, 3TC, and indinavir use on BMD are consistent with findings in other published studies. Previous reports suggest that boosted protease inhibitor is associated with lower bone mineral content and TB BMD . Others have found adverse bone effects associated with regimens containing 3TC and ZDV [25,26]. Indinavir is known to increase osteoclast activity . The positive effect of vigorous physical activity on spine BMD is consistent with findings in other pediatric studies  and is of import, as physical activity is a modifiable risk factor.
We had expected to see lower BMD with TDF use, but did not. Pediatric and adult studies of TDF-containing HAART treatment have shown BMD decreases, but the effect of chronic TDF-containing therapy, especially in adolescents, is still unclear . Only 96 (23%) HIV+ children in the current study had ever used TDF and only ∼ 1/3 had more than 1 year of TDF exposure before the age of 12 years. The children who had ever used TDF did not differ by race or sex from nonusers, but were, on average, 2.1 years older than those who had never received TDF. This pattern of use is not surprising, because many children in this relatively young cohort had not reached the age at which guidelines routinely recommend TDF .
Evidence that HIV infection itself contributes to bone loss includes data from an HIV-1 transgenic rat model that demonstrates increased osteoclastic bone resorption leading to BMD loss . These findings are supported by data demonstrating high levels of bone turnover markers in postmenopausal HIV-infected women . Lower nadir CD4 counts have also been associated with increased fracture risk . Limited pediatric data suggest that low bone formation (as assessed by serum osteocalcin) may be an initial sign of poor bone status in children with HIV infection .
There were relatively low overall rates of reduced BMD for age and sex in our HIV+ cohort, and the differences between HIV+ and HEU were largely attributable to differences in their body size. However, the majority of these children had not yet entered their pubertal growth spurt. Bone deficits may be magnified during the pubertal years, resulting in a failure to reach optimal peak bone mass leading to a trajectory favoring a higher adulthood risk of osteoporosis and increased fractures. This is important given that fracture rates in adults, including adults with HIV infection, are greater with increasing age . This concern about bone health is analogous to concerns about other aspects of long-term health for HIV+ children (e.g. cardiovascular events, renal failure, and premature cognitive decline) in which clinical problems with roots in childhood may not become manifest until adulthood. Longitudinal studies of bone accrual in a pediatric cohort are critical in order to clarify risk factors and periods of greatest risk for poor bone accrual. It is essential to monitor long-term bone health in this population.
We thank the children and families for their participation in PHACS, and the individuals and institutions involved in the conduct of PHACS.
Author contributions: R.B.V., D.L.J., M.E.G., and T.L.M. were the primary authors who conceived of and designed the study. L.A.D. and D.L.J. led the writing of the article. L.A.D., J.W., D.L.J., G.K.S., T.L.M., R.H., and R.B.V. were primarily responsible for analysis and interpretation of the data. K.P., R.A.F., L.D. and Y.G. assisted with data interpretation in their individual areas of expertise. W.B. and J.S.C. were involved in the conduct of the trial and provided key feedback on the M.S. content. All authors were involved in the design and conduct of the PHACS protocol, interpretation of results, and revised the article critically.
Funding: The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with cofunding from the National Institute of Allergy and Infectious Diseases, National Institute on Drug Abuse, the National Institute of Mental Health, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Neurological Disorders and Stroke, the National Institute of Dental and Craniofacial Research, and the Office of AIDS Research through cooperative agreements with the Harvard University School of Public Health (HD052102, 3 U01 HD052102–05S1, 3 U01 HD052102–06S3) (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104, 3U01HD052104–06S1) (Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc. (PI: Julie Davidson).
The following institutions, clinical site investigators, and staff participated in conducting PHACS AMP in 2010, in alphabetical order: Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Mahboobullah Baig, Anna Cintron; Children's Diagnostic & Treatment Center: Ana Puga, Sandra Navarro, Doyle Patton, Deyana Leon; Children's Hospital, Boston: Sandra Burchett, Nancy Karthas, Betsy Kammerer; Children's Memorial Hospital: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter; Jacobi Medical Center: Andrew Wiznia, Marlene Burey, Molly Nozyce; St. Christopher's Hospital for Children: Janet Chen, Latreca Ivey, Maria Garcia Bulkley, Mitzie Grant; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Heida Rios, Vivian Olivera; Tulane University Health Sciences Center: Margarita Silio, Medea Jones, Patricia Sirois; University of California, San Diego: Stephen Spector, Kim Norris, Sharon Nichols; University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Emily Barr, Robin McEvoy; University of Maryland, Baltimore: Douglas Watson, Nicole Messenger, Rose Belanger; University of Medicine and Dentistry of New Jersey: Arry Dieudonne, Linda Bettica, Susan Adubato; University of Miami: Gwendolyn Scott, Patricia Bryan, Elizabeth Willen. Body Composition Analysis Center at Tufts University: Andrea Desilets, Justin Wheeler.
Disclaimer: The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or US Department of Health and Human Services.
Conflicts of interest
All authors declare no conflict of interest.
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