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Fracture Risk Highest in First 2 Years of ART--and Maybe in First 12 Weeks
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18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
Mark Mascolini
Overall fracture incidence is higher in the first 2 years of antiretroviral therapy (ART) than afterwards, according to results of a 3413-person longitudinal cohort analysis [1]. But overall fracture incidence in this US HIV population proved no higher than incidence in the general population, and some evidence suggested that ART--and specifically nucleosides--may protect people from fracture. A separate study appeared to explain the mechanism behind swift bone loss in people who have just begun ART [2].
Because bone mineral density drops by 2% to 6% within the first 2 years of ART, then seems to stabilize, AIDS Clinical Trials Group (ACTG) investigators analyzed data from the ACTG Longitudinal Randomized Trial (ALLRT) to assess fracture incidence and risk factors in the first years of therapy. Standard data are collected on ALLRT cohort members every 16 weeks. This analysis focused on 3413 people from 24 ACTG studies who had any fracture except facial or finger fractures. Most fractures could not be categorized as fragility (low trauma) fractures or nonfragility fractures.
Of the 3413 cohort members, 67 (2%) had a fracture. Overall fracture incidence--0.31 per 100 person-years--was similar to that in the general population. Among antiretroviral-naive people, fracture incidence was higher in the first 2 years of antiretroviral therapy (0.36 per 100 person-years) than after 2 years (0.21 per 100 person-years). Median time to fracture was 120 weeks (interquartile range 73 to 194). The most prevalent fractures involved the ankle or leg (35%), the foot (20%), and the wrist or arm (20%).
Age averaged 42 in the fracture group and 40 in the no-fracture group. The groups did not differ substantially in proportion of men (83% overall), proportion of smokers (59%), proportion of injection drug user (10%), glucocorticoid use (2%), thyroid disease prevalence (1%), diabetes prevalence (4%), HCV or HBV positivity or diagnosis (10% and 37%), estimated glomerular filtration rate below 60 (3%), lowest-ever CD4 count (219), or baseline CD4 count (287).
A lower proportion in the fracture group was antiretroviral-naive at baseline (49% versus 64%), antiretroviral duration was marginally shorter in the fracture group (4.9 versus 5.2 years), and a higher proportion of women with fractures were postmenopausal (30% of 10 versus 19% of 555). Racial and ethnic proportions were 58% white, 34% black, and 7% Hispanic in the fracture group, and 50% white, 28% black, and 20% Hispanic in the no-fracture group.
Among all study participants, regardless of antiretroviral use, HCV positivity or diagnosis tripled the fracture risk (hazard ratio [HR] 3.233, 95% confidence interval [CI] 1.603 to 6.520, P = 0.001), while Hispanic ethnicity lowered the risk about 80% (HR 0.221, 95% CI 0.053 to 0.917, P = 0.0376). Any zidovudine use versus none lowered the risk of fracture about 70% (HR 0.292, 95% CI 0.115 to 0.742, P = 0.0097).
Among antiretroviral-naive people, HCV also tripled the risk of breaking a bone (OR 3.258, 95% CI 1.167 to 9.099, P = 0.0242). Any nucleoside use versus none lowered the risk about 70% (OR 0.310, 95% CI 0.124 to 0.777, P = 0.0124).
Among men with or without antiretroviral experience, thyroid disease raised the fracture risk 13 times (OR 12.986, 95% CI 1.464 to 115.191, P = 0.0213), and HCV again tripled the risk (OR 2.939, 95% CI 1.380 to 6.258, P = 0.0052). Any versus no zidovudine use lowered the risk about 70% (OR 0.337, 95% CI 0.129 to 0.879, P = 0.0261).
The ALLRT investigators proposed that the higher fracture incidence in the first 2 years of antiretroviral therapy suggests "acute bone loss with ART initiation may translate into immediate fracture risk." Another conference study in 20 people starting lopinavir/ritonavir plus tenofovir/emtricitabine documented a surge in bone resorption (breakdown) beginning at 2 weeks, peaking at 12 weeks, and persisting at 24 weeks [2]. CD4 counts climbed by an average 123 cells in these people, who also had significant elevations in receptor activator of NF-kappaB (RANKL). Previous work showed that activated T cells cause bone loss by secreting RANKL.
The Emory University investigators modeled these events by reconstituting T cells in mice lacking T cells. Bone resorption surged in these mice as RANKL rose 12.5-fold. These researchers suggested their findings may identify "a window where pre-emptive antiresorptive therapy could be applied to block skeletal decline" just after ART begins.
References
1. Yin M, Kendall M, Wu X, et al. Incidence and predictors of fracture in HIV-infected individuals: ALLRT. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 830.
2. Ofotokun I, Weitzmann N, Vunnava A, et al. HAART-induced immune reconstitution: a driving force behind bone resorption in HIV/AIDS. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 78.
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