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Increasing Clarity on Bone Loss Associated With Antiretroviral Initiation - editorial
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The Journal of Infectious Diseases June 15 2011;203:1791-801
Michael T. Yin1 and E. Turner Overton2
1Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York; and 2Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
(See the article by McComsey et al, on pages 1791-801.)
If the doors of perception were cleansed everything would appear to man as it is, infinite.
William Blake,The Marriage of Heaven and Hell
The field of HIV medicine is rapidly evolving to the point at which studies evaluating potential long-term complications of HIV infection and combination antiretroviral therapy (cART) are as informative as viral efficacy studies. With effective cART, HIV-infected individuals have a life expectancy approaching that of the general population; therefore, recent research has focused on understanding the long-term consequences of chronic viral infection, inflammation, and cART. As opposed to other end-organ comorbidities, such as cardiovascular and renal disease, which appear to improve with therapy, initiation of cART is associated with a decrease in bone mineral density (BMD), as measured by dual energy X-ray absorptiometry (DXA), of 2%-6% at both the spine and hip. This has been observed with initiation of different cART regimens in several randomized clinical trials [1-6], with most of the change occurring within the first 6 months, followed by stabilization and increase in BMD-first at the lumbar spine, then hip-within 1-2 years after ART initiation. In this issue of the Journal, McComsey et al [7] report additional insight into this metabolic co-morbidity that was first recognized by Tebas et al [8] over a decade ago.
A5224s is a substudy of A5202 that compares changes in BMD after initiation of abacavir-lamivudine (ABC-3TC) or tenofovir-emtricitabine (TDF-FTC), combined with efavirenz or atazanavir-ritonavir (ATV/r). These results confirm previous findings and extend our knowledge in several important ways. First, this study had, to our knowledge, the longest follow-up of participants after initiation of cART. Most studies have BMD data up to 96 or 144 weeks after cART initiation, but A5224s included BMD data up to 192 weeks in a subgroup, confirming that BMD stabilizes after an initial decrease. This finding is reassuring because the SMART study demonstrated that BMD continued to decrease over 4 years of follow-up in the continuous cART arm, compared with the intermittent cART arm [9]. Data from SMART are not exactly comparable, because only 6% of the participants in BMD substudy were cART naive at baseline; in addition, the sample size was extremely small for the later time points [9].
Second, A5224s confirmed that certain antiretroviral drugs are associated with greater decreases in BMD. Decrease in spine and hip BMD at 96 weeks was 1.4%-2.0% greater with TDF-FTC than with ABC-3TC, especially when TDF-FTC was given in combination with ATV/r. These results are consistent with other cART-initiation studies demonstrating that BMD decreased more with regimens containing TDF than with D4T or ABC [3, 5]. When used as part of a nucleoside reverse-transcription substitution study in virologically suppressed HIV-infected individuals, TDF-FTC was also associated with greater short-term decreases in BMD, compared with ABC-3TC [10]. Of interest, recent data from pre-exposure prophylaxis studies in high-risk HIV-uninfected individuals showed that initiation of TDF or TDF-FTC is also associated with a 0.7%-1.0% decrease in BMD that occurs predominantly within the first year [11, 12]. These results confirm that TDF has effects on bone metabolism that are independent of HIV infection or other antiretroviral drugs. A5224s also found that ATV/r was associated with greater BMD loss at the spine at 96 weeks.
Third, the authors identified other key variables at baseline that are associated with decrease in BMD in a multivariable analysis. Lower BMI was independently associated with lower hip BMD. High viral loads and low CD4 cell counts, markers of more advanced disease, were independently associated with lower BMD at the lumbar spine. This latter finding informs the decision regarding when to start cART, suggesting that earlier initiation may have another potential benefit.
Although the present study further clarifies the relationship between cART initiation and BMD, several questions still remain unanswered. What is the mechanism of this acute decrease in BMD with initiation of ART? Are there differences in the way that certain antiretroviral drugs induce bone loss? What are the short and long-term clinical impacts of 2%-6% decrease in BMD that appear to stabilize and improve after the first 1-2 years after cART initiation? Finally, are there prevention measures that providers can initiate to preserve BMD and limit the subsequent burden of fragility fractures?
Several in vitro models suggest that specific antiretroviral drugs can affect osteoclast or osteoblast activity [13-15], tipping the balance in favor of bone osteoclast resorption over osteoblast formation. Bone loss may be more profound in patients with advanced HIV infection who initiate cART because their bone cells are primed by high levels of proinflammatory and proresorptive cytokines, such as TNF-α, IL-6, and receptor activator of NFΚB ligand. A decrease in BMD by DXA may reflect decrease in bone volume and changes in bone microarchitecture, characteristic features of osteoporosis, or it could represent inadequate bone mineralization or subclinical osteomalacia. TDF use is associated with proximal renal tubular dysfunction, which may result in excessive renal phosphate wasting, hypophosphatemia, and decreased bone mineralization. Significant loss of renal tubular cells may also result in decreased renal production of 1,25 hydroxyvitamin D, the active form of vitamin D. TDF exposure in simian immunodeficiency virus-infected Rhesus monkeys inhibits mineralization of cortical bone [16], and several cases of severe osteomalacia have been reported in HIV-infected patients receiving TDF. In addition, efavirenz and protease inhibitors are associated with abnormal vitamin D metabolism [17, 18], which may also result in inadequate bone mineralization.
It is uncertain whether the decrease in BMD associated with TDF is attributable to inadequate bone mineralization, decreased bone volume and structure, or both. Availability of calciotropic hormone levels, serum and urine levels of phosphate, and bone turnover markers before and during initiation of cART in this study may have helped to clarify mechanisms; however, definitive results may still require serial bone biopsies.
McComsey et al indicate that the magnitude of decrease in BMD with cART initiation is similar or greater than that seen in the menopausal transition. It is also similar to the magnitude of the 2%-10% decrease in lumbar spine BMD associated with initiation of oral glucocorticoids. However, initiation of oral glucocorticoids is also associated with incident vertebral fracture in 8%-17% of patients within the first year [19]. Fracture risk increases sharply within the first 3-6 months after initiation and then decreases after stopping glucocorticoids, although it is uncertain whether risks returns to baseline [19]. In the study by McComsey et al, initiation of cART was associated with fracture in 15 participants (5.6%); all fractures were associated with trauma. This was similar to the fracture rate reported in the parent study, which translates to an incidence rate of 1.4-1.9 cases/100 person-years. Short-term risk of fracture with cART initiation is certainly lower than that associated with initiation of oral glucocorticoids; however, the fracture incidence appears to be higher than the 0.3 cases/100 person-year rate for HIV-infected individuals with long-term follow-up after initiation of cART [20]. In addition, the median age of participants in A5224s was only 38 years. In older HIV-infected individuals, especially those with additional risk factors for fragility fracture, the acute decrease in BMD may translate to significant increases in short-term or longer-term fractures.
There are no published studies on interventions to reduce the bone loss associated with cART initiation. Calcium and vitamin D supplementation and bisphosphonates have been studied for prevention of bone loss associated with glucocorticoids. Well-designed randomized trials of established and novel interventions for prevention of cART-induced bone loss may help to fill gaps in our knowledge of both mechanism and clinical impact.
The present study [8] highlights significant advances in our understanding of HIV infection and bone health. Initiation of cART is associated with a decrease in BMD that stabilizes after 1-2 years, but more studies are needed to elucidate the precise mechanism and clinical impact of this acute decrease in BMD. Although more data are required to establish evidence-based approaches toward optimization of bone health in HIV-infected individuals, expert recommendations have recently been published [21, 22]. Nevertheless, our understanding of the myriad aspects of HIV disease has been made clearer by well-designed studies, such as the present one.
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