Determinants of Hip, Femoral-neck, and Spine Z-Scores
shows the relationship between demographic and clinical covariates and site-specific Z-scores. Lower BMI and controlled HIV replication (HIV RNA < 400 copies/mL) were associated with lower Z-scores at all three sites in multivariable models. At the total hip, smoking (ever vs. never) was marginally associated with lower Z-scores in the univariate model (−0.32 ±0.17, p=0.07), but this trend was no longer observed after multivariable adjustment. At the femoral neck, smoking history, nadir CD4 cell count, and the lowest ALT tertile (vs. highest, p=0.09) were marginally associated with lower Z-scores in univariate models, but not after multivariable adjustment. At the lumbar spine, longer cumulative HAART (p=0.002), current EFV use (p=0.08), and ever AZT use (p=0.08) were associated with higher Z-score in univariable models. There was no association between HCV therapy or injection drug use with BMD at any site. After adjustment for age, sex, BMI, HIV RNA, and cumulative HAART exposure, current EFV use (0.79±0.28; p=0.005), but not AZT use (0.24±0.32; p=0.44), was also associated with higher spine Z-score. Alcohol abuse, hepatic fibrosis, cumulative or current exposure to protease inhibitors (PI), d4T, or tenofovir (TDF) were not associated with Z-scores at the any of the 3 sites (data not shown).
Correlates of bone mineral density Z-scores at the total hip, femoral neck, and lumbar spine. Coefficients represent the difference in mean Z-score in relation to the reference group.
In this study of a predominately African-American, HIV/HCV co-infected population in Baltimore, we found a very high prevalence of osteoporosis and low BMD, particularly at the lumbar spine. Contrary to our initial hypothesis, there was no relation between the severity of liver disease, by stage of fibrosis or necroinflammatory activity and the degree of bone loss at the spine or the hip. However, controlled HIV infection (< 400 copies/mL) was consistently associated with lower Z-scores, but no association was seen with any specific antiretroviral drug.
The 28% prevalence of osteoporosis (T-score ≤ −2.5 at the lumbar spine, total hip, or femoral neck) observed in our study was considerably higher than the 10-15% prevalence of osteoporosis observed in many cross-sectional studies of HIV-infected persons [23
]. Similarly, the 26% prevalence of low BMD ( Z-score ≤ −2 at any of the 3 sites) was higher than the 16% prevalence of low BMD in a large cohort of HIV/HCV co-infected patients from Modena Italy [24
] . The explanation for the very high prevalence of low BMD in our cohort deserves further investigation. Although our cohort was similar to the Modena Cohort with respect to HIV/HCV co-infection, smoking, alcohol use, and illicit drug use, the extent to which the two cohorts differed by nutritional, behavioral, and other health-related factors that affect BMD is unclear.
One major difference between the two cohorts was the racial composition. Unlike the Modena Cohort, which was nearly exclusively Caucasian, 85% of our cohort was of African descent. In population-based studies in the US, BMD in African-Americans is 2-18% higher in the hip and spine compared to Caucasians [25
], which likely accounts for the lower fracture rates among African-Americans, compared to other races [31
]. The BMD of the men in our study was approximately 4-8% lower than a community-based cohort in Boston of a similar racial composition [25
], and total hip and femoral neck BMD in women was approximately 3-8% lower in our cohort compared to NHANES III data [32
]. Interestingly, the prevalence of osteoporosis in this cohort was similar to a separate cohort of participants in inner-city Baltimore, who shared many of the same demographic characteristics and risk factors [33
]. Whether this unexpectedly low BMD in both cohorts translates into a higher than expected fracture rate is an important area for further inquiry.
Over 88% of the cases of osteoporosis in our cohort were attributable to osteoporosis at the spine. The lumbar spine is more metabolically active as it consists mainly of trabecular bone and may be affected earlier in disease than cortical bone. Findings of lower lumbar spine BMD have been similarly reported in several studies of cirrhotic patients [34
], and have been associated with low IGF-1 and low 25OH Vitamin D levels. While not measured in the current study, these factors will be an important target for future investigations in this cohort.
Although 26% had histologic evidence of cirrhosis in our sample, we found no association between liver disease severity and BMD at any site. Several studies in patients with liver disease have found a relation between bone loss and the degree of liver disease [35
], but this finding has been inconsistent [34
]. These studies have primarily relied on clinical classification of disease severity, comparing patients in Child-Pugh Class B or C to Class A [34
]. In contrast to these studies, we used liver histology to categorize liver disease severity and none of our patients had decompensated liver disease. It is possible that the mechanisms inducing bone loss in patients with liver disease are triggered as a response to liver disease decompensation (eg hypogonadism) or as a result failure of synthetic activity (egs, decreased production of IGF-1 or 25OH Vitamin D). Our findings stand in contrast to a small German study of HBV or HCV monoinfected patients which found an association with liver fibrosis stage and BMD [13
]. The explanation for the differences between the studies is not clear. In addition to HIV infection and antiretroviral therapy, the cohorts also differed by other important characteristics including race, socioeconomic factors, and likely HCV genotype.
Despite the well-established link between systemic inflammation and bone loss in the general population [38
] and in patients with rheumatoid arthritis or inflammatory bowel disease [39
], our data do not support the hypothesis that liver inflammation associated with HIV/HCV co-infection is related to loss of bone mineral density. Our analysis was limited by the lack of markers of systemic inflammation or cellular immune activation which would be useful to further evaluate the relationship between inflammation, liver disease, and bone mineral density.
One of the most consistent correlates with lower BMD in our study was controlled HIV replication, likely indicative of effective antiretroviral therapy. Although untreated HIV may be associated with increased osteoclast activity and decreased osteoblast activity, initiation of antiretroviral therapy is associated with a rapid increase in bone turnover [41
] and a 2-6% decrease in BMD over 48-96 weeks [3
]. Conversely, interruption of antiretroviral therapy in the SMART study was associated with an attenuation of bone loss compared with continuous viral suppression [6
]. The mechanisms underlying this seemingly counter-intuitive association between controlled HIV viral replication and lower BMD deserve further investigation. It is possible that uncontrolled HIV and the resulting systemic inflammation impair osteoblast function, thereby slowing down bone turnover and protecting against BMD loss. Studies investigating bone turnover with antiretroviral interruption and re-initiation may be particularly useful in understanding the potential mechanisms.
Although we observed a consistent relationship between lower BMD and controlled viral replication, we did not observe a similar relationship between BMD and HAART use, per se. This was likely due to the fact that persons receiving HAART may not be compliant with therapy or may have drug-resistant virus. Alternatively, because HIV RNA was assessed within 6 months of the DXA and the medication database is updated every 6-12 months, the laboratory value may provide a more accurate assessment of effective HAART.
In studies investigating the effect of ART initiation on BMD, pre-treatment CD4 cell count has been an important predictor of subsequent bone loss with ART initiation [3
] and consistent with this finding, we found that nadir CD4 cell count tended to be associated with lower BMD at the femoral neck. Earlier ART initiation may be useful to attenuate the bone loss observed with ART initiation, but this hypothesis has not yet been tested.
Certain antiretroviral medications may contribute to bone loss among HIV-infected patients. Although tenofovir has been consistently associated with a larger decrease in bone density with ART initiation [5
], we did not find any association between TDF use and lower BMD. Tenofovir use, however, was not widespread in our cohort, such that power may have been limited to detect an effect. Similarly, although PIs have also been implicated in the pathogenesis of bone loss among HIV-infected patients [4
], we did not find an association with PIs and lower Z-score. We did however find that those receiving efavirenz had a higher spine Z-score compared to those not receiving efavirenz, although this effect was not observed at either the total hip or the femoral neck. This finding is consistent with ACTG 5224s, which showed that efavirenz was associated with a smaller decrease in BMD at the spine with ART initiation compared to atazanavir/ritonavir [7
]. However, at the total hip, BMD decreased similarly in both groups. The explanation for this differential effect of efavirenz on the spine and hip is unclear.
It is unknown if low BMD will translate to increased fracture risk in HIV/HCV men and women. A French group that studied an HIV-infected cohort treated with combination ART found that the 2-year incidence rate of bone fractures 3.6-fold higher in those with HCV co-infection than HIV mono-infected subjects [15
]. In that cohort, only fractures requiring hospitalization were reported, which could have underestimated fracture risk. Recently, data from HOPS cohort showed that HCV-co-infection was associated with a 60% increased risk of fragility fracture [16
]. Our finding of a lack of association between the severity of liver disease and lower BMD may suggest that the increased risk of fracture in HIV/HCV co-infected patients is not mediated by low BMD, but rather compromised bone quality, which is not measured by conventional DXA. Alternatively, HCV-infection may be a marker of other conditions (eg, nutritional factors, opiate exposure) which mediate the relationship between HCV and low BMD, but have not been captured in our study.
There are a few additional limitations to our study. First, our study was cross-sectional and our findings do not exclude the possibility that those with more advanced liver fibrosis may experience accelerated bone loss, or that progression of liver disease may be associated with decreasing BMD. Further longitudinal studies are required to address these issues. Second, our study did not include an otherwise similar HIV-monoinfected or HCV-monoinfected control groups to explore the independent contributions of these chronic infections on bone health. Next, HIV RNA was not always measured at the time that a DXA scan was performed, raising the possibility of misclassification; however, we specified that the HIV RNA assessment occur within 6 months of the DXA scan and the median difference between these two assessments was very short (approximately 1 week). Finally, although hepatic inflammation via liver biopsy was not found to be a determinant of low bone density, this assessment may have limitations when used as a measure of hepatic inflammation in that: 1) it was assessed at a single time point, 2) it is potentially subject to sampling error, and 3) it may not be reflective of systemic inflammation.
In conclusion, we found high prevalence of osteoporosis, particularly at the spine, in this middle-aged population of predominately African-American subjects with HIV/HCV co-infection, which was not related to the severity of liver fibrosis. In the general population, African-Americans are less likely to be screened for osteoporosis compared to Caucasians, perhaps because BMD is higher and fracture risk is comparatively lower [43
]. Our data would suggest that fracture risk may be higher than expected in African-American HIV/HCV co-infected persons and that more aggressive screening of persons with these risk factors who are 50 years or older may be warranted. In addition, further evaluation of the mechanisms underlying the high prevalence of osteoporosis and its clinical significance is warranted.