Osteoporosis is defined as a ‘systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and fracture’ . Bone mineral density (BMD) can be measured through imaging modalities, such as dual X-ray absorptiometry (DXA), with the goal of preventing fractures with early intervention. The World Health Organization has grouped reduced BMD into two categories. Osteoporosis is defined as a bone density less than 2.5 standard deviations of the mean BMD of a sex-matched, young healthy population, i.e. a T-score less than −2.5. Osteopenia is an intermediate category of bone loss defined as a T-score between −1 and −2.5. Although these categories were created to classify postmenopausal women, they are often applied to other adult populations.
Among HIV-infected patients receiving antiretroviral therapy (ART), reduced BMD has been reported with increasing frequency. Because of the relatively small size of these studies, investigators have generally grouped osteopenia and osteoporosis together, and have not been able to assess accurately the prevalence of osteoporosis per se and its relative risk in HIV-infected patients compared with HIV-uninfected controls.
Other aspects of reduced BMD also require clarification. Initially, reduced BMD was considered to be a complication of ART , which has also been implicated in the development of insulin resistance, dyslipidemia, fat atrophy, and fat hypertrophy in HIV-infected patients. The use of protease inhibitors (PI), for example, has been associated with reduced BMD in some studies [2,3]. Nucleoside analogs have also been implicated . However, other factors, such as the effects on chronic immune activation , appear to be important in the pathogenesis of reduced BMD in HIV, and other studies have failed to show an association with ART in general or PI, specifically.
With these issues in mind, we undertook a systematic review of the published literature to answer the following questions: (i) What is the prevalence of reduced BMD, and more specifically osteoporosis in HIV-infected patients, and what is the risk of these disorders compared with HIV-uninfected control subjects? (ii) What is the risk of reduced BMD and osteoporosis in HIV-infected patients receiving ART compared with ART-naive patients? (iii) What is the risk of reduced BMD and osteoporosis in HIV-infected patients receiving PI compared with those who are not PI treated?
We conducted a systematic review and six meta-analyses of cross-sectional studies published in English to determine the pooled odds ratios (OR) of reduced BMD and osteoporosis in the following groups: HIV-positive versus HIV-negative; ART-treated versus ART-naive; and PI-treated versus PI-untreated individuals. We followed the Meta-Analysis of Observational Studies in Epidemiology guidelines for meta-analysis of observational studies .
Studies included in the analysis were identified by searching MEDLINE (January 1966–November 2005) and EMBASE (1980–November 2005), using four medical subject headings terms: ‘HIV’, ‘bone’, ‘osteoporosis’ and ‘bone density’, the merging of two medical subject headings terms: ‘HIV and osteoporosis’, and ‘HIV and bone density’. The results of the above two search strategies were combined to yield a pool of preliminary studies. A Science Citation Index search, using the authors of the studies identified for the final analysis as key words, was also performed. The references of identified articles and review papers regarding bone and HIV were also reviewed for other potential references.
Articles included in the meta-analysis reported on trials that were cross-sectional, had at least two adult groups (> 18 years) for comparison (e.g. HIV-positive versus HIV-negative), used DXA scan to measure BMD and were published in English. Articles were excluded if the outcomes of interest were not reported (i.e. Z-score, BMD).
Each abstract was reviewed independently by two investigators who applied the inclusion and exclusion criteria. Any differences in the resulting pool of articles were resolved by discussion. Data from the articles identified as appropriate were abstracted and recorded on a standardized abstraction form.
The data extracted from each publication included demographic information, an assessment of the study's quality, and outcomes of interest. The outcomes evaluated were reduced BMD (osteopenia and osteoporosis) and osteoporosis. We used the World Health Organization (WHO) criteria to define osteopenia (T-score between −1 and −2.5) and osteoporosis (T-score ≤ −2.5) at any of the following sites: lumbar spine, total hip, femoral neck, distal radius or total body. We then determined the proportion of patients with reduced BMD or osteoporosis.
The following rules were employed when abstracting and compiling the data: When only reduced BMD data were presented (i.e. combined prevalence of osteopenia and osteoporosis), authors were contacted and asked to provide the proportion of participants with osteopenia or osteoporosis. If reduced BMD or osteoporosis was presented separately for different sites (e.g. lumbar spine and total hip), we asked the authors to provide data regarding reduced BMD or osteoporosis at any of the sites measured. In some cases, it could be determined that groups of interest (e.g. ART-treated versus ART-naive) were included in a study, but were not fully presented in the article. We contacted the authors to provide reduced BMD and osteoporosis data in the format described above. We also asked for demographic information regarding the groups of interest. If an inexplicit or incomplete comparison was made between PI-treated and PI-untreated patients, we asked authors to group their subjects as PI-treated and PI-naive.
The pooled analysis was performed using the studies that met the inclusion and exclusion criteria, in order to estimate an overall effect for each of the outcomes. Heterogeneity was examined using meta-regression and sensitivity analyses. STATA 8.0 (College Station, Texas, USA) was used for all analyses. Random effects models were used to generate pooled OR estimates and confidence intervals (CI) and used an inverse variance method to weight the studies. χ2 Tests were used to assess for heterogeneity. Forest plots were generated for each of the outcome variables studied, which present the individual and pooled effect estimates and their 95% CI. The potential for influential studies was examined for each of the outcome variables using the ‘metainf’ command to perform sensitivity analyses. A funnel plot was used for each of the outcome variables to investigate for the potential of publication bias, in addition to the Begg's test. A two-sided P value of 0.05 or less was considered significant.
Using our search strategy, 340 citations were retrieved, of which 303 did not meet the inclusion criteria. The remaining 37 articles were reviewed in their full text format. Twenty of these met the inclusion and exclusion criteria and had data available for at least one quantitative summary. Of the 17 articles excluded, five lacked a relevant comparison group [7–11], 11 lacked relevant outcome data (WHO classification) [4,12–21], one presented duplicate data included in another article in the analysis .
HIV-infected patients versus HIV-uninfected controls
Eleven studies included data relevant to this analysis (Table 1). Three of the studies included only men [2,23,24], and three included only women [25–27]. The participants in the remainder of the studies were predominately men (63–89%). Age and body mass index (BMI) were generally well matched between the HIV-infected and HIV-uninfected subjects. In one study, HIV-infected participants were older , and in two studies BMI was lower in the HIV-infected participants [23,26]. Menstrual status was reported in all three studies that included exclusively women and was well matched by HIV status, with the exception of one study , in which amenorrhea was present in 14% of HIV-infected women compared with 0% in HIV-uninfected controls. Smoking status was reported in two studies, one of which  showed an increased prevalence of smoking in HIV-infected subjects (52 versus 33%). None of the bone density outcomes in any study were adjusted for the presence of imbalances between study groups.
Of the 884 HIV-infected patients in the 11 studies, 593 (67%) had reduced BMD, of whom 135 (15%) had osteoporosis. Compared with 654 HIV-uninfected controls, HIV-infected patients had a 6.4-fold increased odds of reduced BMD (95% CI 3.7, 11.3) and a 3.7-fold increased odds of osteoporosis (95% CI 2.3, 5.9; Fig. 1a).
Significant heterogeneity between the studies was observed for the reduced BMD analysis (Q statistic 38.8, P < 0.001). Meta-regression analysis showed that the prevalence of reduced BMD in the HIV-uninfected groups accounted for a significant portion of the between-study heterogeneity (τ = −4.86, P = 0.003; adjusted OR 3.3; 95% CI 2.2, 4.4). Sequential exclusion of each study did not appear to change the resulting OR, arguing against the influence of one study on the pooled OR. However, a sensitivity analysis that excluded the four studies with the largest OR yielded an OR of 3.7 (95% CI 2.4, 5.7), consistent with the above findings regarding the effect of the prevalence of reduced BMD in the control group. The sex composition of the study could not explain between-study heterogeneity (τ = −0.79, P = 0.44). For the analysis of the prevalence of osteoporosis, significant between-study heterogeneity was not observed (Q statistic 6.47, P = 0.77).
Publication bias was investigated by inspecting a funnel plot of the effect size versus the standard error of the effect size in conjunction with Begg's test. No evidence of publication bias was observed for either analysis (data not shown).
Antiretroviral-treated versus antiretroviral-naïve
Ten studies were used to compare the prevalence of reduced BMD in HIV-infected patients receiving ART and those who were ART-naive, and seven of these studies had data available for the osteoporosis analysis (Table 2). All of the studies had a majority of male participants. In the eight studies that characterized the ART-treated and ART-naive patients [23,28,31–36], the average age was 4.4 years (95% CI 1.7, 7.2) greater in the ART-treated group. BMI was similar between the groups in all studies, except one study in which ART-treated patients had a lower BMI (22.7 versus 24.1 kg/m2) . In the four studies that reported on the duration of HIV infection [23,28,34], ART-treated patients had known HIV infection for a longer period of time compared with ART-naive, with a weighted mean difference of 3.5 years (95% CI 2.0, 5.0). Lifestyle factors that may affect BMD were reported in two studies [31,34]; in one study, the groups were matched for smoking, alcohol use, activity level, and calcium intake, whereas another study showed an increased prevalence of alcohol use and a decreased prevalence of sedentary lifestyle in those who were ART-naive .
ART-treated subjects (n = 824) had a higher prevalence of reduced BMD compared with ART-naive subjects (n = 202; OR 2.5, 95% CI 1.8, 3.7). In addition, for the seven studies that included appropriate data (Fig. 1b), the odds of osteoporosis was increased 2.4 times (95% CI 1.2, 4.8) in ART-treated subjects compared with ART-naive subjects. None of the studies adjusted for potentially important confounding factors, such as age or the duration of HIV infection.
There was no significant heterogeneity between the studies in either the reduced BMD analysis or the osteoporosis analysis (Q = 8.7, P = 0.47; Q = 3.62, P = 0.73, respectively). Neither analysis showed evidence of publication bias.
Protease inhibitor-treated versus protease inhibitor-untreated
Fourteen studies were used to compare the prevalence of reduced BMD in HIV-infected patients receiving PI with those not receiving PI (Table 3). Twelve of these studies presented data that could be used to calculate the prevalence of osteoporosis in PI-treated versus PI-untreated patients. In 11 of the studies, information was provided as to whether the PI-untreated group had ever been exposed to PI; in nine of the 11 studies the PI-untreated group was truly PI-naive. In all 11 studies except for one  data were available regarding whether the PI-untreated group was receiving ART. In three of 11 studies [2,26,38], the PI-untreated group also included patients who were not receiving any ART. For those studies in which the PI-untreated group was receiving ART, the combinations of the ART used could not be reliably determined.
Four of the studies included only men [2,23,24,38]. Two of the studies included only women [25,26]. Other studies were mixed, but were predominately male. In three of those studies [28,33,36], there were notable sex imbalances between the PI-treated and PI-untreated groups. Overall, age and BMI were similar between the groups. In seven of the 11 studies in which data were available regarding the duration of ART [23,24,26,29,34,38,39], PI-treated subjects were treated for an average of 9.9 months (95% CI 1.5, 18.3) longer than the PI-untreated subjects.
PI-treated patients (n = 791) had a higher prevalence of reduced BMD compared with PI-untreated patients (n = 410; OR 1.5, 95% CI 1.1, 2.0). In the 12 studies with available data, the odds of osteoporosis in PI-treated patients (n = 666) was 1.6 greater (95% CI 1.1, 2.3) than those not treated with PI (n = 367; Fig. 1c). For the reduced BMD analysis, point estimates did not appreciably change when the analysis was limited to the eight studies in which the PI-untreated patients had never been previously exposed to a PI (OR 1.8, 95% CI 1.2, 2.6) or the 10 studies in which the PI-untreated individuals were exposed to ART in general (OR 1.5, 95% CI 1.1, 2.1).
Data to determine the extent to which the association between PI treatment and reduced BMD was confounded by other factors were limited. Two studies presented adjusted OR, both adjusted for factors that were significantly different between the PI-treated and PI-untreated groups (sex  and nadir CD4 cell count, history of AIDS ). In a third study , an OR adjusted for age, BMI, duration of ART, antiretroviral drugs, history of AIDS was calculated from the primary data. For those three studies, the crude and the adjusted OR for the reduced BMD analysis were similar (OR 2.8, 95% CI 1.5, 5.2 and OR 2.8, 95% CI 1.1, 7.2, respectively).
Both the reduced BMD and the osteoporosis analysis showed no evidence of significant heterogeneity between studies (Q = 16.0, P = 0.25; Q = 10.11, P = 0.52, respectively). Inspection of the funnel plot for the reduced BMD analysis showed some asymmetry, in that three of the studies with the largest point estimates were not matched by studies with opposing effects. The Begg's statistic, however, was not significant (P = 0.16). A sensitivity analysis that excluded those three studies yielded similar results to the full analysis (OR 1.4, 95% CI 1.1, 1.8). There was no evidence of publication bias for the osteoporosis analysis.
In this meta-analytical review of published cross-sectional studies, we found that the prevalence of osteoporosis was 15% in HIV-infected individuals, which is more than three times higher than that observed in HIV-uninfected controls. Although individual studies have documented a higher prevalence of reduced BMD in HIV-infected patients, few studies have been large enough to estimate accurately the risk of osteoporosis and to compare this prevalence estimate with that of HIV-uninfected controls. The designation of osteoporosis (T-score < −2.5) is more meaningful than reduced BMD (T-score < −1), because it represents more significant bone loss. Although this classification was created for postmenopausal women , it is often applied to other adult populations, although its use in men and premenopausal women is controversial [41–43]. In the absence of other methods to assess fracture risk, most consider the designation of osteoporosis by DXA criteria a trigger for further evaluation and treatment, including in HIV-infected patients .
Because only crude OR could be calculated, the comparison of the prevalence of osteoporosis in HIV-infected and HIV-uninfected individuals is only valid to the extent that these groups are similar with respect to other factors. Whereas the study groups were generally well matched for age and BMI, some studies showed notable differences between HIV-infected and HIV-uninfected subjects on factors that may affect BMD, including smoking status and menstrual history. It is unclear whether differences in these factors or other potentially important variables, such as calcium intake, physical activity level, or the use of osteotoxic medications (e.g. glucocorticoids) influenced the results.
The factors that underlie the increased prevalence of osteoporosis in HIV-infected patients have not been fully elucidated. Chronic inflammation caused by HIV infection has been associated with bone resorption , and HIV itself may have direct effects on osteoclast activity . The contribution of ART, however, remains controversial. Experimental evidence in vitro and in in-vivo animal models suggests that some antiretroviral medications can have a direct effect on bone metabolism. Among the nucleoside reverse transcriptase inhibitors (NRTI), zidovudine has been shown to increase osteoclast activity , and tenofovir can impair bone mineralization . In-vitro evidence suggests that individual PI can have heterogeneous effects on bone [45,48].
We posed two questions regarding the association between ART and reduced BMD in cross-sectional studies. First, we were interested in whether the prevalence of osteoporosis was different in HIV-infected patients who were treated with ART compared with those who were not. In an analysis of seven studies, we found that the prevalence of osteoporosis was more than two times greater in ART-treated compared with ART-naive patients (OR 2.4, 95% CI 1.2, 4.8). However, none of the studies adjusted for important differences between the groups such as age or the duration of HIV infection. Other potentially important differences, such as the severity of HIV disease, were not addressed.
The second question of interest was whether HIV-infected patients receiving PI have an increased prevalence of osteoporosis compared with those not receiving PI. We found that the odds of having osteoporosis was 1.6 times higher (95% CI 1.1, 2.3) in patients receiving PI compared with those who were not treated with PI. Although these results would suggest that PI therapy is associated with osteoporosis, few studies adjusted for potentially confounding factors, such as age, duration of disease, severity of disease, and duration of ART (which was an average of 10 months longer in the PI-treated group). In the three studies in which both adjusted and unadjusted OR were available, the crude estimate of OR and the adjusted OR were identical, suggesting minimal confounding and relative accuracy of the crude estimate. It should be kept in mind, however, that these three studies represented only a small subset of the studies and not all important factors were considered in the adjustment.
The issue of whether ART affects BMD is best addressed by longitudinal studies of HIV-infected patients either receiving or initiating therapy. The few numbers of studies and the heterogeneity in the designs and the outcomes reported precluded a quantitative synthesis. Using the same search criteria as above, we found six published studies that presented longitudinal DXA data in ART-treated HIV-infected patients (Table 4). In four of the studies [31,38,39,49], BMD was followed over time in ART-experienced patients and showed either increases or stable BMD over the study interval. In contrast, the two published studies of treatment-naive HIV-infected patients show decreases in BMD with ART initiation [4,9]. In a large randomized, double-blinded trial comparing the safety and efficacy of tenofovir to stavudine with a lamivudine and efavirenz backbone (n = 602) , significant BMD reductions in the spine and hip were observed in both treatment groups over the 144-week study interval. Interestingly, there was a greater decline in the tenofovir group at the spine (−2.2% tenofovir DF versus −1.0% stavudine, P = 0.001) and hip (−2.8% tenofovir DF versus −2.4% stavudine, P = 0.06). Mallon et al.  also noted significant decreases in T-scores with ART initiation. Taken together, the data from the longitudinal studies would suggest that BMD decreases with the initiation of ART, but then stabilizes or improves thereafter. In addition, these data confirm that individual medications within a given class can have heterogeneous effects on BMD.
These longitudinal data are compatible with our pooled analysis from the cross-sectional studies, in that HIV-infected patients receiving ART have a higher odds of osteoporosis compared with those who are ART naive. It is not clear, however, whether the decline in BMD observed with the initiation of ART can entirely account for the increased prevalence of osteoporosis in ART-treated patients. Other confounding factors may be contributing to the observed results. In addition, in these cross-sectional studies, it was not possible to determine the effect of individual antiretroviral medications on BMD. Further longitudinal studies of HIV patients beginning therapy will be needed to clarify the effect of ART initiation and also provide information on the effect of individual antiretroviral agents on bone density.
Our analysis had other limitations. Although we did not observe evidence of publication bias (with the exception of the PI/reduced BMD analysis), we acknowledge that we still could have failed to take into account studies that were not published in the medical literature that could have affected the pooled estimates. We elected not to include unpublished conference abstracts because these studies are minimally peer reviewed. In addition, we used DXA criteria as a surrogate measure for the diagnosis of osteoporosis. The more important question regarding whether the increased risk of osteoporosis by DXA criteria in HIV-infected patients is associated with an increased risk of fracture has not been addressed to date.
In conclusion, we found that the prevalence of osteoporosis in HIV-infected subjects is approximately 15%, which is more than three times greater than reported in HIV-uninfected controls. ART-exposed and PI-exposed HIV-infected individuals appeared to have a higher odds of reduced BMD and osteoporosis compared with their respective controls. However, the influence of other important factors on these OR estimates, such as disease severity and previous ARV treatment history, could not be determined. Further controlled, longitudinal studies are needed to clarify the impact of HIV infection, ART use, and PI treatment on reduced BMD and fracture risk.
Sponsorship: This work was partly supported by the National Institutes of Health grant no. 1K23AT002862-01 (T.T.B.).
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