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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1660
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 12 4522-4528
Copyright © 2007 by The Endocrine Society

CLINICAL REVIEW

Low Body Weight Mediates the Relationship between HIV Infection and Low Bone Mineral Density: A Meta-Analysis

Mark J. Bolland, Andrew B. Grey, Greg D. Gamble and Ian R. Reid

Department of Medicine, University of Auckland, Auckland, New Zealand

Address all correspondence and requests for reprints to: Mark Bolland, Osteoporosis Research Group, Department of Medicine, University of Auckland, Private Bag 92 019, Auckland, New Zealand. E-mail: m.bolland{at}auckland.ac.nz.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Context: HIV infection has been associated with low bone mineral density (BMD) in many cross-sectional studies, although longitudinal studies have not demonstrated accelerated bone loss. The cross-sectional studies may have been confounded by the failure to control for low body weight in HIV-infected patients.

Objective: Our objective was to determine whether low body weight might explain the association of HIV infection with low BMD.

Data Sources: MEDLINE and EMBASE were searched for English language studies published from 1966 to March 2007, and conference abstracts prior to 2007 were hand-searched.

Study Selection: All studies reporting BMD and weight or body mass index in adult patients with HIV and a healthy age- and sex-comparable control group were included. Nine of 40 identified studies and one of 68 identified abstracts were eligible.

Data Synthesis: We adjusted for the between-groups weight differences using regression coefficients from published cohorts of healthy men and women. On average, HIV-infected patients were 5.1 kg [95% confidence interval (CI), –6.8, –3.4; P < 0.001] lighter than controls. At all skeletal sites, unadjusted BMD was lower by 4.4–7.0% in the HIV-infected groups than the controls (P < 0.01). After adjustment for body weight, residual between-groups differences in BMD were small (2.2–4.7%) [lumbar spine, –0.02 (95% CI, –0.05, 0.01) g/cm2; P = 0.12; total hip, –0.02 (95% CI, –0.04, 0.00) g/cm2; P = 0.031; femoral neck, –0.04 (95% CI, –0.07, –0.01) g/cm2; P = 0.013; and total body, –0.03 (95% CI, –0.07, 0.01) g/cm2, P = 0.11].

Conclusion: HIV-infected patients are lighter than controls and low body weight may largely account for the high prevalence of low BMD reported in HIV-infected patients. However, in the setting of current treatment practice, HIV infection per se is not a risk factor for low BMD.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
RECENTLY, HIV INFECTION has been associated with low bone mineral density (BMD) in at least 30 cross-sectional studies (1, 2). A meta-analysis of studies published before December 2005 reported an increased odds ratio of 6.4 for reduced BMD and 3.7 for osteoporosis in HIV-infected patients compared with uninfected controls (3). Subsequently, we reported that a group of HIV-infected Caucasian men were 6.3 kg lighter than age-matched healthy controls and that there were no differences in BMD between the groups after adjusting for this weight difference (4). Body weight is an important determinant of BMD. Significant correlations between body weight and BMD are seen in men and women, in adults and children, and at all skeletal sites (5). Therefore, we hypothesized that differences in body weight between HIV-infected patients and controls may have confounded the analysis of previous cross-sectional studies of BMD in HIV disease, especially because prospective longitudinal studies of HIV-infected patients do not suggest that accelerated bone loss occurs (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). Therefore, we have meta-analyzed all the published studies that report body weight and BMD in patients with HIV infection and in age- and sex-comparable healthy uninfected controls. We adjusted the reported BMD results for the differences in body weights between the groups and therefore were able to compare weight-adjusted BMD for HIV-infected patients and controls.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We followed the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines for meta-analysis of observational studies (17).

Study selection

We carried out a literature search using MEDLINE and EMBASE on all published English language studies from 1966 to March 2007 using the terms "HIV" or "AIDS" and "bone mineral density" or "osteopenia" or "osteoporosis". We also used NLM Gateway to search for abstracts published before 2007 using the same criteria and searched for abstracts from the annual scientific meeting of the American Society for Bone and Mineral Research, and the annual Conference on Retroviruses and Opportunistic Infections. We also hand-searched references of obtained studies and published reviews.

To be eligible for consideration, a study must have been published in English, reported data from adult (>18 yr) participants, had a control group without HIV infection, presented data on BMD, and presented data on body weight or body mass index (BMI) for both groups. Where studies that were otherwise eligible did not present body weight or BMI data, we contacted the authors by letter and e-mail requesting additional data. Where studies presented BMD T scores only, these were converted to absolute BMD using manufacturer-supplied reference data. Specific exclusion criteria were groups not comparable for mean age (within 5 yr) or gender (male:female ratio within 15%); groups matched for weight, BMI, or other variables likely to be related to or impact upon body weight; and differential application of weight- or BMI-based inclusion or exclusion criteria to the HIV-infected and control groups. Where the same cohort was described in more than one publication, only the largest study conforming to the inclusion and exclusion criteria was included. Each of the studies and abstracts identified was independently assessed by two of the authors (M.J.B. and A.B.G.), and a consensus was reached regarding the suitability of each study without knowledge of the body weight data.

Statistics

Pearson correlation analysis was used to test for significant linear correlations between variables. Weight adjustment was performed using regression coefficients for BMD and body weight from published cohorts (18, 19, 20, 21). Where only correlation coefficients were published, regression coefficients were calculated from the equation: regression coefficient = correlation coefficient * SD (BMD)/ SD (weight). Because the relationship between BMD and body weight might vary between men and women and when BMD is measured by densitometers from different manufacturers, we applied different regression coefficients for these groups (Table 1Go). For each study, the pooled mean weight of the HIV-infected patients and the controls was calculated, and the difference between this pooled weight and the mean weight of the HIV-infected group or the control group was used to calculate a weight-adjusted BMD. Where studies only presented BMI data, these were converted to predicted mean weights using age-matched height data from the NHANES 1999–2002 study (22). For all analyses, BMD and weight-adjusted BMD values obtained from GE Lunar densitometers were converted to Hologic equivalent values using published equations (23, 24, 25).


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  		TABLE 1. Regression coefficients between BMD and body weight

 
Weighted mean differences in body weight, BMD, and weight-adjusted BMD were calculated for all eligible studies using a fixed effects model. In the presence of significant heterogeneity (P < 0.10), a random effects model was also run in an attempt to incorporate the differences between studies into the analysis. Funnel plots for each model were inspected, and no evidence of publication bias was evident (data not shown).

Finally, we plotted mean Hologic equivalent values for BMD for each skeletal site against mean body weight for each of the cohorts in the studies in the meta-analysis and used linear regression to obtain the regression coefficients for BMD and body weight. We used these coefficients to calculate weight-adjusted BMD and repeated the weighted mean difference analyses.

All tests were two-tailed; a P value < 0.05 was considered statistically significant, and 95% confidence intervals (CI) are presented. All analyses were carried out using the SAS software package (SAS Institute, Cary, NC; version 9.1).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Forty studies and 68 abstracts were identified in the initial searches. Of the 40 studies, 20 were not included because they had no control group; five studies (11, 26, 27, 28, 29) were excluded because, although they were potentially eligible, there were missing data that we were not able to obtain from the authors; two studies because of a control group matched for BMI (30, 31); one study because of a control group that was not age-matched (32); one study because it was a duplicate publication (33); and two studies because they had weight-related inclusion and exclusion criteria that were applied only to the HIV-infected group and not the control group (15, 34). Of the 68 abstracts, 41 were not included because they had no control group, 21 were excluded because they were duplicate publications, one was excluded because of a control group matched for BMI, and four were excluded because, although they were potentially eligible, there were missing data that we were not able to obtain from the authors. Thus, nine published studies (4, 35, 36, 37, 38, 39, 40, 41, 42) and one published abstract (43) [recently published in full (44)] were eligible for inclusion in the review that collectively reported on 1371 HIV-infected patients and 1644 uninfected controls (Table 2Go).


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  		TABLE 2. Studies of HIV-infected patients and uninfected controls presenting data on BMD and body weight or BMI

 
HIV-infected patients were on average 5.1 kg (95% CI, –6.8 to –3.4; P < 0.001) lighter than controls (Fig. 1Go). In all 10 studies, the HIV-infected group had lower mean body weight than the control group, and this reached statistical significance in seven of the 10 studies.


Figure 1
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  		FIG. 1. Weighted mean difference in body weight in studies of HIV-infected patients (n = 1371) and uninfected controls (n = 1644). Data are mean [95% CI].

 
BMD data from the included studies are shown in Table 2Go. Lumbar spine BMD was reported in nine studies. Unadjusted BMD was on average 0.05 g/cm2 or 4.7% lower (95% CI, –0.07 to –0.02 g/cm2; P < 0.001) in the HIV-infected groups than in the controls (Fig. 2Go). However, Fig. 2Go shows that there was no statistically significant difference in weight-adjusted BMD between the groups (0.02 g/cm2 or 2.2% lower in HIV-infected groups; 95% CI, –0.05 to 0.01 g/cm2; P = 0.12). Total hip BMD data were reported in four studies. Unadjusted BMD was on average 0.04 g/cm2 or 4.4% lower (95% CI, –0.06 to –0.02 g/cm2; P < 0.001) in the HIV-infected groups than in the controls. Weight-adjusted BMD was on average 0.02 g/cm2 or 2.4% lower (95% CI, –0.04 to 0.00 g/cm2; P = 0.031) in the HIV-infected groups than in the controls (Fig. 3Go). Femoral neck BMD data were reported in eight studies. Unadjusted BMD was on average 0.06 g/cm2 or 7.0% lower (95% CI, –0.09 to –0.03 g/cm2; P < 0.001) in the HIV-infected groups than in the controls. Weight-adjusted BMD was on average 0.04 g/cm2 or 4.7% lower (95% CI, –0.07 to –0.01 g/cm2; P = 0.013) in the HIV-infected groups than in the controls (Fig. 4Go). Total body BMD data were reported in three studies. Unadjusted BMD was on average 0.07 g/cm2 or 5.5% lower (95% CI, –0.11 to –0.02 g/cm2; P = 0.006) in the HIV-infected groups than in the controls, but Fig. 5Go shows that there was no statistically significant difference in weight-adjusted BMD between the groups (0.03 g/cm2 or 2.8% lower in HIV-infected groups; 95% CI, –0.07 to 0.01 g/cm2; P = 0.11).


Figure 2
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  		FIG. 2. Weighted mean difference in lumbar spine BMD and lumbar spine BMD adjusted for the between-groups differences in body weight in studies of HIV-infected patients (n = 1209) and uninfected controls (n = 1403). Data are mean [95% CI], expressed in Hologic-equivalent values (g/cm2).

 

Figure 3
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  		FIG. 3. Weighted mean difference in total hip BMD adjusted for the between-groups differences in body weight in studies of HIV-infected patients (n = 279) and uninfected controls (n = 728). Data are mean [95% CI], expressed in Hologic-equivalent values (g/cm2).

 

Figure 4
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  		FIG. 4. Weighted mean difference in femoral neck BMD adjusted for the between-groups differences in body weight in studies of HIV-infected patients (n = 1178) and uninfected controls (n = 1217). Data are mean [95% CI], expressed in Hologic-equivalent values (g/cm2).

 

Figure 5
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  		FIG. 5. Weighted mean difference in total body BMD adjusted for the between-groups differences in body weight in studies of HIV-infected patients (n = 332) and uninfected controls (n = 390). Data are mean [95% CI], expressed in Hologic-equivalent values (g/cm2).

 
The between-groups difference in weight-adjusted BMD was at least twice as large at the femoral neck as at other sites. Figure 4Go shows that much of this difference was due to one outlying study. This study by Knobel et al. (35) had a between-groups difference in BMD approximately twice that of any other study and contributed more than 40% of the weighted mean difference in BMD, despite contributing only 8% of the sample size. Therefore, we repeated the analyses in two ways. First, we excluded this study and found a smaller between-groups difference in weight-adjusted BMD of 0.02 g/cm2 or 3.0% (P = 0.06). Second, we included all studies but weighted them proportionately to the sample size (fixed effects model) and found a similar between-groups difference of 0.02 g/cm2 or 2.3%.

The above analyses used individual data from other studies to determine the relationship between body weight and BMD and to generate correction factors for the weight difference. An alternative approach is to regress the mean values for weight and BMD from the actual studies in the meta-analysis. This approach generated the following coefficients: 0.009 g/cm2·kg for lumbar spine, 0.010 g/cm2·kg for total hip, 0.004 g/cm2·kg for femoral neck, and 0.007 g/cm2·kg for total body. We used these coefficients to calculate weight-adjusted BMD and repeated the previous analyses. There were no between-groups differences in BMD at the lumbar spine (0.00 g/cm2; P = 0.7), total hip (0.00 g/cm2; P = 0.7), or the total body (0.01 g/cm2; P = 0.5), but a small 0.04 g/cm2 (P = 0.01) difference was present at the femoral neck.

Three studies reported data on women only, four studies on men only, and three studies on at least 70% men. When we grouped the studies by gender (women; men/predominantly men), there were only sufficient studies to separately analyze the data on lumbar spine BMD. The results for each gender separately were similar to those for the entire cohort.

There appeared to be temporal changes in the results of the studies, such that more recent studies found smaller differences in BMD. Thus, there was a significant between-groups difference in unadjusted lumbar spine BMD in only one of five individual studies published between 2005 and 2007, whereas significant differences were reported at the same site in three of four studies published between 2001 and 2005 (Fig. 2Go). At the femoral neck, three of four studies published before 2005 reported a significant between-groups difference in weight-adjusted BMD, whereas none of the four studies published subsequently found a significant difference (Fig. 4Go). Six studies reported the duration of highly active antiretroviral therapy (HAART) (Table 2Go). There was a trend toward a positive correlation between the duration of HAART and the year of publication (r = 0.7; P = 0.10).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We found that HIV-infected patients are on average 5.1 kg lighter than controls and that unadjusted BMD was 4.4 to 7.0% lower in HIV-infected patients than controls. However, after taking into account this weight difference, the between-groups differences in BMD ranged from 2.2 to 2.8% at the lumbar spine, total hip, and total body. At the femoral neck, the differences were greater, in part due to an outlying study, and after we excluded this study or reduced its weighting in the analyses, the between-groups differences were also 2–3%. These between-groups differences in BMD were statistically significant at the femoral neck, but of borderline statistical significance at the total hip, and not significant at the lumbar spine or total body. We and others have previously reported that changes in body weight are associated with greater changes in BMD at the spine, radius, and total body than at the femoral neck (45, 46). This may in part explain why, when we adjusted for the weight differences between the groups, the greatest persisting differences in BMD were at the femoral neck. However, any persisting differences at all sites were small, and given the findings of stable or increasing BMD in longitudinal studies of BMD in HAART-treated, HIV-infected patients (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16), they are unlikely to be of clinical importance. For example, differences in BMD of this magnitude (approximately 0.25 SD values) would be predicted to confer a 1.1- to 1.2-fold increased risk of osteoporotic fracture, which is considerably smaller than other recognized risk factors such as smoking, low body weight, family history, previous fracture or glucocorticoid treatment (all > 1.5-fold increased risk) (47). Consistent with these results, Arnsten et al. (42) reported that HIV infection was not an independent risk factor for incident fractures in men, and Prior et al. (44) reported that HIV infection was not an independent risk factor for lifetime fragility fractures in women, after adjusting for possible confounders.

The failure to adjust for body weight differences between groups in many of the published studies may also explain a discrepancy between the findings of cross-sectional and longitudinal studies of BMD in HIV-infected patients taking HAART. At least 30 cross-sectional studies have reported a higher than expected rate of low BMD in HIV-infected subjects (1, 2), whereas 11 longitudinal studies have reported stable or increasing BMD over time (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). Weight loss occurs with advancing untreated HIV infection, but there is steady regain of this lost weight after the commencement of HAART. Weight is a major determinant of BMD, and changes in weight are positively correlated with changes in BMD in various populations (5, 45, 46). Therefore, it would be predicted that BMD would decrease with advancing untreated HIV infection and increase after the commencement of HAART, although there may be time lags between initiation of HAART, regain of body weight, and regain of BMD (16). If this was the case, cross-sectional studies performed shortly after the commencement of HAART would report higher than expected rates of low BMD because of low body weight. However, because of HAART-related weight gain, longitudinal studies would report stable or increasing BMD, and cross-sectional studies performed after a longer time interval after the commencement of HAART would not report increased rates of low BMD. Consistent with this hypothesis, we found that the year of publication of the individual studies was positively correlated with the duration of HAART, and that the greatest between-groups differences in BMD occurred in the earliest published studies. In addition, there is only one published study with a HIV-infected group and a comparable weight-matched control group (30), and this study reported no between-groups difference in BMD.

The cause of the weight differences between the HIV-infected groups and the control groups is likely to be multifactorial. It may be due in part to the loss of body weight that occurs with chronic illness and advancing HIV infection; in part to the higher prevalence of smoking in the HIV-infected groups, because smoking exposure is inversely related to body weight (48); and in part to the predominance of homosexual men in the HIV-infected groups. Homosexual men have been reported to have lower body weight (49), be more concerned with body shape and appearance (50), and have higher rates of smoking (51) than heterosexual men.

The regression coefficient used to adjust BMD data for the weight differences between the groups determines the magnitude of the weight adjustment. We used coefficients generated by two different methods but obtained similar results using either. First, we used gender-specific and densitometer manufacturer-specific coefficients derived from regression of individual data from published cohorts of healthy men and women. Second, we used the mean data for BMD and weight from the studies in the meta-analysis to calculate coefficients specific to these data. The coefficients obtained in this way were similar to the published coefficients for the femoral neck but higher elsewhere, although the 95% CI for both sets of coefficients overlapped. In our previous study of HIV-infected men, the regression coefficients were also in the similar range (lumbar spine, 0.005 g/cm2·kg; total hip and femoral neck, 0.004 g/cm2·kg; and total body, 0.003 g/cm2·kg) (4), and other studies of HIV-infected participants have reported similar values (40, 41, 42, 52).

There are several limitations to our analyses. There were only 10 studies that met the criteria for inclusion in our review. Although we followed established methods for identification of eligible studies, it is possible that we overlooked some. Publication bias may have also influenced our findings. If such a bias was present, it is likely to favor publication of studies reporting significant reductions in BMD in HIV-infected populations, and therefore to accentuate rather than diminish the between-groups differences in the meta-analysis. Because individual-level data for weight and BMD were not available from the studies in our meta-analysis, we used summary data from other healthy cohorts and from the studies in our meta-analysis to adjust for body weight. If the individual-level data were available, we would expect to obtain similar results although the exact magnitude of the weight-adjustment may be different from those obtained using the summary data (53).

In summary, we found that HIV-infected patients in studies that report BMD data are lighter than controls. Most studies reported lower BMD in HIV-infected patients than controls, but after adjusting for the body weight differences between the groups, we found only small residual differences in BMD that were unlikely to be of clinical importance. We conclude that low body weight in HIV-infected patients can largely account for the reported high occurrence of low BMD in HIV-infected patients, and that HIV infection in the absence of low body weight is not a risk factor for low BMD. The stability of BMD in longitudinal studies of HIV-infected cohorts lends support to this conclusion. Therefore, routine assessment of skeletal status is not justified in HAART-treated HIV-infected patients, and decisions around the need to investigate and treat low bone mass in such patients should be made using guidelines available for the general population (54, 55).


   Footnotes
 
This study was funded by the Health Research Council (HRC) of New Zealand.

Disclosure Statement: The authors have nothing to disclose.

First Published Online October 9, 2007

Abbreviations: BMD, Bone mineral density; BMI, body mass index; CI, confidence interval(s); HAART, highly active antiretroviral therapy.

Received July 25, 2007.

Accepted September 28, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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