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Do HIV Positive People Have a Higher Risk of Bone Fractures?

SUMMARY: Older people with HIV may be more likely to sustain bone fractures than HIV negative individuals of the same age, according to research presented last week at the 1st International Workshop on HIV and Aging in Baltimore. However, another recent study, published in the September 20, 2010, advance online issue of AIDS, did not see more bone breaks among HIV positive compared with at-risk HIV negative participants in the Women's Interagency HIV Study.

By Liz Highleyman

A growing body of research indicates that people with HIV are at higher risk for bone problems compared with the general population, including reduced bone density (osteopenia) and more advanced bone loss known as osteoporosis. It has not yet been established whether this is due to HIV infection itself, inflammation, antiretroviral therapy, or some combination of these and other factors.

As described at a new conference dedicated to concerns of HIV positive people as they age, L. Mundy and colleagues from GlaxoSmithKline (GSK) performed a retrospective cohort study to assess the incidence of fractures among adults with and without HIV infection.

Reduced bone mineral density (BMD) is a known risk factor for fractures. But while research supports an association between HIV and bone loss, there is little data about the link between HIV and fractures, the investigators noted as background.

This analysis included more than 200,000 participants age 18 and older enrolled in the Ingenix Impact National Benchmark Database for more than 12 months between January 1997 and March 2008. The researchers looked at incident (new) low-impact, non-traumatic fractures, that is, bone breaks not caused by trauma such as accidents.

The final cohort included 238,336 participants, of whom 59,584 (25%) were HIV positive. Each HIV positive patient was matched with 3 HIV negative individuals according to sex, date of enrollment, and duration of follow-up. A majority of participants (72%) were men. Notably, only about half were on antiretroviral therapy (ART).

Known fracture risk factors were uncommon overall. People in the HIV positive group were significantly more likely than those in the HIV negative group to report heavy alcohol consumption (3% vs 1%, respectively), excessive steroid use (6% vs 4%), low body weight (8% vs 2%), lipodystrophy (3% vs < 1%), and coinfection with hepatitis B (4% vs < 1%) or hepatitis C (7% vs < 1%). People in the HIV negative group were more likely to use bisphosphonate drugs to manage osteoporosis (2% vs 1%), and the groups were about equally likely to have had previous fractures (about 2%).


Overall, 9027 participants (3.8%) sustained fractures over 13,757 person-years of follow-up:
4.2% of HIV positive participants: hazard ratio (HR) 2.02;
3.7% of HIV negative participants: HR 1.77.
The fracture incidence rate ratio was 1.14, or 14% higher for HIV positive vs HIV negative patients.
In a multivariate analysis, the following factors were significant fracture risk factors overall:
Prior fractures: HR 4.49, or more than 4 times higher risk;
Low physical activity: HR 2.59, or more than 2 times higher risk;
Heavy alcohol use: HR 1.90, or nearly double the risk;
Bisphosphonate use: HR 1.49, or about 50% higher risk;
Low body weight: HR 1.32, or about 30% higher risk.
Risk factors varied significantly by age group when models were stratified by age categories (<30, 30-59, or > 59 years).
Among patients < 30 years, the only significant predictors were:
Prior fractures: HR 7.77;
Heavy alcohol use: HR 2.24.
In the 30-59 year group, the risk factors that were significant in the full model remained significant, along with some additional factors:
Prior fractures: HR 3.81;
Low physical activity: HR 2.24;
Heavy alcohol consumption: HR 1.86;
Bisphosphonate use: HR 1.36;
Low body weight: HR 1.30;
HIV infection without AIDS: HR 1.18;
HIV infection with AIDS: HR 1.15;
Vitamin D deficiency or use of vitamin D or calcium supplements: HR 0.72, or a slightly lower risk.
Among participants > 59 years, the only significant risk factors were:
Prior fractures: HR 2.79;
Low physical activity: HR 2.65.
Fracture risk increased significantly more with advancing age among HIV positive people with and without AIDS (CD4 count < 200 cells/mm3 or opportunistic infections) compared with HIV negative participants.

"Incidence of fracture was significantly higher among subjects with HIV infection compared to subjects without HIV infection," the investigators concluded. "Prior fracture was the strongest risk predictor in all age strata, with additional age-stratified differentiation of modifiable risks that have implications for clinical practice and preventive medicine."

Notably, this study did not report associations between fractures and ART use or specific antiretroviral drugs or drug classes.

WIHS Women

As described in the second report, Michael Yin, Phyllis Tien, and fellow investigators with the Women's Interagency HIV Study (WIHS) measured time to self-reported first new fractures at any body site among 2391 women in the cohort, of whom 1728 were HIV positive and 663 were HIV negative.

The clinical importance of the association between HIV infection and ART use with low BMD in pre-menopausal women is uncertain because bone density tends to stabilize on established ART and fracture data are limited, the researchers noted as background.

At baseline, the HIV positive women were significantly older (40 vs 36 years), more likely to be post-menopausal, and more like to have hepatitis C coinfection compared with the HIV negative group. A majority were back or Latina in both groups. Overall, about half were current cigarette smokers. Among the HIV positive women, the average CD4 cell count was 482 cells/mm3 and 66% were on ART. The median follow-up duration was 5.4 years.


148 HIV positive women (8.6%) and 47 HIV negative women (7.1%) sustained new fractures during follow-up.
Fracture incidence rates were 1.8 per 100 person-years among HIV positive women vs 1.4 per 100 person-years among HIV negative women.
The likelihood of new fractures did not differ significantly between the HIV positive and HIV negative groups in an unadjusted analysis or after adjusting for known risk factors.
In a multivariate model, significant predictors of new fractures were:
Older age;
White vs black race;
Hepatitis C coinfection;
Higher serum creatinine (a potential indicator of kidney impairment).
Among HIV positive women, significant fracture predictors were:
Older age;
White vs black race;
Hepatitis C coinfection;
History of AIDS-defining illnesses;
Current or past cigarette smoking;
History of opiate use.
HIV serostatus and CD4 cell count, however, were not statistically significant fracture risk factors.
There was also no observed link between fractures and use of any antiretroviral drug class or particular drug, including tenofovir (Viread, also in the Truvada and Atripla coformulations).

Based on these findings, the study authors concluded, "Among predominantly pre-menopausal women, there was little difference in fracture incidence rates by HIV status, rather traditional risk factors were important predictors."

Although fracture risk was "modest" overall in this mostly pre-menopausal group, they recommended that, "Further research is necessary to characterize fracture risk in HIV-infected women during and after the menopausal transition."

Investigator affiliations: Mundy study: GlaxoSmithKline, WW Epidemiology, Collegeville, PA; GlaxoSmithKline, WW Epidemiology, Research Triangle Park, NC; GlaxoSmithKline, WW Epidemiology, Boston, MA; GlaxoSmithKline and Medco Health Services Inc., WW Epidemiology and Research, Collegeville and Blue Bell, PA.

Yin study: Columbia University Medical Center, New York, NY; New York Medical College, Valhalla, New York, NY; Rutgers University, Piscataway, NJ; Montefiore Medical Center, Bronx, New York, NY; State University of New York, Downstate, Brooklyn, NY; Georgetown School of Medicine, Washington DC; Keck School of Medicine, University of Southern California, Los Angeles, CA; Departments of Medicine, Stroger Hospital and Rush University, Chicago, IL; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; San Francisco Veterans Affairs Medical Center, University of California at San Francisco, CA.



LM Mundy, H Li, S St. Laurent and S Bowlin. Age-stratified risk assessment for fracture among adults with and without HIV infection. 1st HIV and Aging workshop. Baltimore, October 4-5, 2010. Abstract O_07.

MT Yin, Q Shi, DR Hoover, PC Tien, and colleagues. Fracture incidence in HIV-infected women: results from the Women's Interagency HIV Study. AIDS (Abstract). September 20, 2010 (Epub ahead of print).



















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