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Conflicting Data on Bone Fracture Link to HIV Meds

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Overall, use of antiretroviral therapy (ART) appears to be associated with a decreased likelihood of bone fractures among people with HIV, but whether specific drugs such as tenofovir increase the risk, reduce the risk, or have a variable effect over time remains unclear based on conflicting data reported in the February 1, 2012, advance online edition of AIDS.

Numerous studies over the course of the epidemic have found that HIV positive people are more likely to have low bone mineral density (BMD) and bone loss (osteopenia, or the more severe osteoporosis) compared with the general population. It is not clear whether this is related to HIV itself, inflammatory or metabolic changes associated with chronic viral infection, effects of antiretroviral therapy, or some combination of factors -- nor is it certain whether low bone density actually leads to greater incidence of fractures.

ART Reduces Risk

In the first analysis, Linda Mundy from GlaxoSmithKline and colleagues assessed the risk for fractures associated with time-dependent exposure to different antiretroviral drugs.

This retrospective nested case-control study looked at a cohort of 59,594 insured HIV patients enrolled in medical care between January 1997 and March 2008, identified in the Ingenix Impact National Benchmark Database. A majority were men and the average age was about 40 years.

A total of 2411 case patients who had sustained fractures were each matched 4-to-1 with 9144 HIV positive control subjects without fractures. The researchers then analyzed differences in antiretroviral drug use between the case and control groups.

Results

  • Exposure to antiretroviral therapy overall was associated with significantly reduced risk of bone fractures (odds ratio [OR] 0.64).
  • Use of nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) drug classes was associated with reduced fracture risk.
  • Exposure to protease inhibitors (PIs) was associated with a "null effect" that became slightly reduced among people with the longest duration of exposure (> 18 months).
  • Use of darunavir (Prezista), delavirdine (Rescriptor), and saquinavir (Invirase or Fortovase) were associated with increased fracture risk over time.
  • Efavirenz (Sustiva), emtricitabine (Emtriva), lamivudine (3TC; Epivir), tenofovir (Viread), and zidovudine (AZT; Retrovir) were associated with reduced fracture risk.
  • Abacavir (Ziagen), didanosine (ddI; Videx), nelfinavir (Viracept), ritonavir (Norvir), and stavudine (d4T; Zerit) were initially associated with increased risk, but this became null with longer duration of use.
  • Nevirapine (Viramune) was initially associated with a null risk that became reduced risk with longer use.
  • Amprenavir (Agenerase), atazanavir (Reyataz), enfuvirtide (T-20; Fuzeon), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Norvir), tipranavir (Aptivus), and zalcitabine (ddC; Hivid) were all associated with null or uncertain fracture risk.
  • Other significant fracture risk factors included history of prior fractures, heavy alcohol use, low physical activity, and low body weight.

"Our findings suggest an overall reduced risk for facture in persons treated versus not treated with antiretroviral drugs for HIV infection," the study authors concluded.

"For darunavir, although the number of fracture events were low, the estimate of risk was substantial...and further assessment of this PI in other study populations seems justified," they added in their discussion (adjusted OR 1.93, or about twice the risk).

With regards to tenofovir -- the drug most frequently linked to bone loss among people with HIV -- they wrote, "our time-censored subset analysis of abacavir versus tenofovir exposures revealed null risk in adjusted models for known risk variables and other antiretroviral drug exposures." Prior studies have seen larger reductions in bone density with tenofovir compared to abacavir, they noted, but have not found significant difference in the risk of non-traumatic fractures (breaks not due to traumatic injury).

As to why ART might reduce fracture risk, the authors explained that as BMD decreases with age, "the mechanisms of bone modeling are not unidirectional and untreated HIV infection has been associated with uncoupled bone formation and bone resorption that seems attributed to both viral and inflammatory effects."

Some Drugs Raise Risk

The second study in the same issue, however, contradicted some of Mundy's findings.

In this retrospective analysis, Roger Bedimo from the VA North Texas Health Care System and colleagues looked at the link between osteoporotic fractures of the wrist, vertebrae, or hip -- that is, breaks due to bone fragility rather than trauma -- among 56,660 HIV positive participants in the Veterans Affairs Clinical Case Registry between 1988 and 2009.

The researchers used 2 multivariate models: Model MV1 controlled for race, age, tobacco use, diabetes, body mass index, and hepatitis C status, while model MV2 controlled for the same variables plus antiretroviral drug exposure.

Results

  • Here, tenofovir exposure was associated with a small but significant increase in fracture risk in a univariate analysis (hazard ratio [HR] 1.08; P < 0.001), falling to 1.06 in both multivariate models.
  • Among  32, 439 patients who entered the cohort during the highly active antiretroviral therapy (HAART) era starting in the mid-1990s, tenofovir was associated with a yearly hazard ratio of 1.16 in a univariate analysis (P < 0.001), 1.13 in model MV1 (P  =  0.001), and 1.12 in model MV2 (P =  0.011).
  • Boosted protease inhibitor exposure was also associated with a small increase in fracture risk: HR 1.11 (P  =  0.001) in a univariate analysis, 1.08 (P  =  0.026) in model MV1, and 1.05 (non-significant) in model MV2.
  • Within this class, lopinavir/ritonavir had an HR of 1.09, which was borderline significant (P = 0.051) in model MV2.
  • Osteoporotic fractures were also independently associated with older age, non-black race, low body mass index, and smoking.

Based on these findings, the researchers concluded, "Cumulative exposure to [tenofovir] and, among PIs, [lopinavir/ritonavir] were independently predictive of increased risk of osteoporotic fracture in the HAART era."

"Using a cohort of 56,660 HIV-infected patients followed for a mean of 5.4 patient-years, we found for the first time that exposure to [tenofovir]and [ritonavir-boosted protease inhibitors] were associated with a modestly increased osteoporotic fracturerisk," they wrote in their discussion. "After controlling for traditional osteoporotic fracturerisk factors, these associations were no longer statistically significant."

However, they continued, "stronger associations between either [tenofovir]or [ritonavir-boosted protease inhibitors] with osteoporotic fracture were found when analysis was limited to patients who entered the cohort in the HAART era...[Tenofovir] remained independently predictive of osteoporotic fracture risk (12% higher risk per year of exposure) after controlling for traditional osteoporotic fracture risk factors and concomitant [antiretrovirals] used."

Furthermore, they noted, "we found evidence of an interaction between [tenofovir] and [ritonavir-boosted protease inhibitors]...Concomitant exposure to both [tenofovir] and [ritonavir-boosted protease inhibitors] [was] associated with a greater osteoporotic fracturerisk than exposure to either [tenofovir] without [ritonavir-boosted protease inhibitors], or [ritonavir-boosted protease inhibitors] without [tenofovir]."

"These findings, if confirmed, might warrant consideration of osteoporotic fracturerisk in decisions [about] ART initiation among HIV-infected patients," they suggested, but emphasized that traditional -- and in some cases controllable -- risk factors such as low body weight and smoking are "much more important in predicting fracture risk among HIV-infected patients than antiretroviral exposure."

Further studies are needed to resolve contradictory findings about the impact of ART on bone health, and -- perhaps more important -- whether lifestyle changes or therapies such as vitamin D or biphosphonates drugs might help prevent bone loss and fractures among people with HIV.

2/7/12

References

LM Mundy, AO Youk, G McComsey, and SJ Bowlin. Overall benefit of antiretroviral treatment on the risk of fracture in HIV: nested casecontrol analysis in a health-insured population. AIDS. February 1, 2012 (Epub ahead of print).

R Bedimo, NM Maalouf, S Zhang, H Drechsler, and P Tebas. Osteoporoticfracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS. February 1, 2012 (Epub ahead of print).