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Continued ART Does Not Raise Fracture Rate in 5-Year US Study

Author: Mark Mascolini


22 November 2012

Fracture incidence was higher in the first 2 years of antiretroviral therapy (ART) than in subsequent years, according to a 5-year study of a US AIDS Clinical Trials Group (ACTG) cohort. Fracture risk was related to smoking and glucocorticoid use, but not to specific antiretrovirals.

Bone mineral density decreases by 2% to 6% in the first 1 to 2 years of antiretroviral therapy. But the impact of this decline on long-term fracture risk was unknown until this analysis of the ACTG Longitudinal-Linked Randomized Trial study.

The analysis involved 4640 HIV-positive adults enrolled in 26 randomized ART trials. Follow-up lasted for a median of 5 years. Researchers recorded both fragility and nonfragility fractures every 6 months at scheduled study visits. They calculated incidence as fractures per total person-years.

Median age of the study group stood at 39 years (interquartile range [IQR] 33 to 45), and 83% were men. Median nadir CD4 count measured 187 cells/μL (IQR 65 to 308). Almost half of cohort members (48%) were white, 29% were black, 20% Hispanic, and 2% Asian. (Whites have a higher fracture risk than blacks.)

After excluding fractures of the face, skull, or fingers, the ACTG team recorded 116 fractures in 106 cohort members. Median time to first fracture during follow-up was 2.3 years. Fracture incidence stood at 0.40 per 100 person-years overall and 0.38 per 100 person-years among 3398 study participants who were antiretroviral-naive when follow-up began.

Fracture incidence measured 0.41 per 100 person-years in men and 0.33 per 100 person-years among women. Among antiretroviral-naive participants, fracture incidence was higher in the first 2 years after ART began than in later years (0.53 versus 0.30 per 100 person-years).

Multivariate analysis determined that current smoking almost doubled the risk of fracture (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.1 to 3.2, P = 0.03) and glucocorticoid use almost quadrupled fracture risk (HR 3.7, 95% CI 1.3 to 10.4, P = 0.01). Cumulative use of specific antiretrovirals or antiretroviral regimens was not associated with fracture risk.

When the analysis was limited to 2798 antiretroviral-naive men, current smoking (HR 1.8, 95% CI 1.01 to 3.2, P = 0.04) and glucocorticoid use (HR 4.8, 95% CI 1.7 to 13.5, P = 0.003) remained independent predictors of fracture. When the analysis was limited to 614 antiretroviral-naive women, two factors independently raised fracture risk: perimenopausal or postmenopausal status (HR 5.8, 95% CI 1.4 to 23.2, P = 0.01) and history of hysterectomy (HR 4.2, 95% CI 1.2 to 15.4, P = 0.03).

The ACTG team believes their findings “suggest that fracture risk is increased during the first few years after ART initiation, even in relatively young individuals.” They note that “the increase in fracture incidence is temporally aligned with the acute 2–6% decline in bone mineral density that has been reported in multiple studies within the first 2 years after ART initiation.”

The researchers suggest their findings “provide assurance that continuation of ART is not associated with increased fractures in younger HIV-infected individuals.” They suggest that “adequate calcium and vitamin D intake, participation in regular weight-bearing and muscle-strengthening exercise, avoidance of tobacco, identification and treatment of alcoholism, and modification of fall risk may be especially beneficial” during the first few years of antiretroviral therapy.

Source: Michael T. Yin, Michelle A. Kendall, Xingye Wu, Katherine Tassiopoulos, Marc Hochberg, Jeannie S. Huang, Marshall J. Glesby, Hector Bolivar, Grace A. McComsey. Fractures after antiretroviral initiation. AIDS. 2012; 26: 2175-2184.

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