In our cohort of predominantly premenopausal women, we did not find a statistically significant increase in incident fractures in HIV-infected women, even though the HIV-infected women were on average 4 years older than the HIV-uninfected women. Our findings are consistent with a prior analysis in a subset of pre-menopausal WIHS women, which found little difference in rates of bone loss or self-reported incident fracture over 2 years [10
]. Furthermore, rates of fracture observed at the hip and wrist in our HIV-infected women over a median of 5.4 years (0.2/100 and 0.3/100 person-years, respectively) are consistent with large epidemiological studies of healthy premenopausal women in the United Kingdom, where rates of hip and wrist fracture were 0.3/100 [26
] and 0.1/100 person-years [27
], respectively. Finally, we demonstrated that traditional risk factors including older age, white race, and renal insufficiency were statistically significant predictors of fracture, as was HCV infection. Among HIV-infected women, history of an ADI was also an independent predictor of fracture.
Our fracture incidence rates are somewhat higher than those reported in two other studies of HIV-infected patients of comparable age. A French cohort of 1281 ART-treated, mainly HIV-infected men with a median age of 36 years and follow-up of 7.1 years reported an incidence density rate of 0.33/100 person-years [17
]. This study also found that the observed rates within their HIV-infected cohort were similar to that observed in the general population [17
]. In the HIV Outpatient Study (HOPS), Dao et al.
] reported a fracture incidence rate of approximately 0.8/100 person-years in HIV-infected patients (median age of 37, 81% men, 56% white), which was higher than rates from the National Hospital Discharge Survey. Estimates from our study (1.8/100 person-years for all fractures, 0.6/100 person-years for fragility fractures) are likely higher than previous studies because of more complete ascertainment resulting from use of a dedicated fracture questionnaire at semiannual visits, and possibly because all participants were women. Another critical difference between our study and the aforementioned studies is that our HIV-uninfected controls were prospectively enrolled and evaluated with the same questionnaire as our HIV-infected participants. The French study also defined fracture as having a fracture leading to severe or complete limitation of activity [17
Two studies have also examined fracture rates in older HIV-infected men. In a study of 559 men 49 years of age or older, rates of self-reported incident fractures were similar for HIV-infected and uninfected groups (3.1/100 versus 2.6/100 person-years, P
= 0.69) during a 2-year follow-up [16
]. In contrast, the much larger Veterans Aging Cohort Study observed that HIV-infected veterans have higher rates of fragility fracture at the spine, hip, and wrist than uninfected veterans after the age of 50 [18
]. There are no published data on fracture risk in HIV-infected postmenopausal women.
We found that in addition to white race and renal insufficiency, HCV infection but not HIV infection was associated with fracture. Several studies in HIV-uninfected individuals have described the association between noncirrhotic HCV infection and low bone mass [28
] or increased fracture [29
]. Putative mechanisms are likely multifactorial and may be associated with increased alcohol use in patients infected with HCV, alterations in calciotropic and gonadotropic hormone levels, weight loss, and increased fall risk [28
]. In the setting of HIV infection, Lo Re et al.
] found that HIV/HCV-coinfected women had lower BMD than HIV-monoinfected women, but did not observe a similar difference in men. Collin et al.
] found an association of HCV coinfection and higher alcohol consumption with increased fracture risk. In our cohort, HIV/HCV-coinfected and HIV monoinfected women were similar in age, weight, and alcohol consumption; we were unable to assess for group differences in calciotropic or gonadotropic hormones.
Among HIV-infected women in our cohort, history of ADI was associated with incidence of new fracture. This may reflect more advanced HIV disease stage, or the impact of hormonal, nutritional or neurological alterations associated with AIDS, opportunistic infections or their treatment on fracture risk. AIDS wasting syndrome has also been associated with lower BMD [32
] and loss of muscle mass and functional status [33
] that may lead to increased falls. Interestingly, we found an association of cumulative exposure to NNRTIs with decreased fracture risk in multivariate analyses. It is unclear if these results represent a direct effect of NNRTI on fracture risk. First, there was only a weak, nonsignificant association in the unadjusted models; therefore, this may be a spurious finding. Second, women on NNRTI-based regimens may be less sick than those on protease inhibitor-based regimens; protease inhibitors may more likely be used in those with advanced disease. Studies comparing bone loss with initiation of protease inhibitor versus NNRTI-based regimens have yielded inconclusive results [34
]. Moreover, a prior analysis in a subset of WIHS women suggested that BMD may be slightly higher in those on an NNRTI-based regimen [14
], but no statistically significant difference in change in BMD occurred over 2 years between ART groups [10
]. We found no association between tenofovir use at index and new fractures.
There are several strengths to our study. WIHS is one of the only cohorts that has collected detailed data semiannually regarding fractures in HIV-infected women and a well matched comparison group of HIV-uninfected women. Traditional risk factors for fracture have also been collected at regular intervals, and participant retention is excellent. Limitations include the lack of characterization of fracture sites other than spine, hip, and wrist and of radiographic confirmation of fractures. We also did not assess muscle strength or fall risk, which are other potential determinants of fracture. As the majority of women in WIHS are African-American and overweight, our results may not be generalizable to all HIV-infected women (although our enrolled cohort is representative of the HIV epidemic among US women). Finally, our sample size may be insufficient for comparisons of fracture rates by ART exposure.
In conclusion, after 5.4 years of median follow-up in predominantly premenopausal women of color, fracture rates were not significantly increased in HIV-infected as compared to uninfected women. Traditional risk factors were important predictors of fracture, whereas HIV status was not. Among HIV-infected women, history of ADI was more predictive of fracture than ART exposure. Our data provide some reassurance that fracture risk is modest in predominantly premenopausal HIV-infected women. However, further research is necessary to assess fracture risk as these women transition through menopause and to clarify whether fracture risk differs among antiretroviral regimens.