Patients on HIV therapy have an increased risk of stress and fragility fractures; no link to specific drug

Patients taking antiretroviral therapy have an increased risk of fractures typically associated with low bone mineral density, Danish investigators report in the online edition of AIDS.

However, the most important risk factors were the presence of other chronic illnesses and smoking. Treatment with tenofovir (Viread, also in the combination pills Truvada and Atripla) did not increase the risk of fractures, nor did CD4 cell count.

“We found an association between HAART [highly active antiretroviral therapy]-exposure and increased risk of low-energy fractures but cannot determine whether this increased risk is induced by alterations in BMD [bone mineral density] observed after HAART initiation or by differences between HAART-treated and HAART-naïve patients,” write the investigators.

It is now well established that HIV-positive patients have an increased risk of developing low bone mineral density. The inflammation caused by HIV, and the low body weight seen in many patients with HIV, are known risk factors for this condition.

However, low bone mineral density has also been seen in patients treated with antiretroviral drugs and has been especially associated with tenofovir.

The clinical consequences of this reduction in bone density are unclear.

Studies examining the incidence of fractures in HIV-positive patients in the modern treatment era have produced conflicting results. Moreover, the research has been limited by small sample sizes, and the failure to take into account some factors that can increase the risk of fractures, such as injecting drug use and co-infection with hepatitis C virus.

To establish a clearer understanding of this important aspect of HIV medicine, Danish investigators therefore checked the records of over 5000 HIV-positive patients who received HIV care between 1995 and 2009. Each patient was matched with five HIV-negative controls of the same sex and a similar age.

Information was obtained on the overall incidence of fractures.

These were categorised as low- or high-energy fractures.

Low energy fractures were typically stress or fragility fractures and were therefore consistent with the presence of low bone mineral density. In contrast, high-energy fractures were unlikely to be due to problems with bone mineral density and were of a sort associated with traumatic injury.

The patients had a median age of 37 years. Three-quarters were men, 11% had a history of injecting drug use and 16% were co-infected with hepatitis C. The majority of patients (62%) were diagnosed after 1995 and 78% received therapy with antiretroviral drugs.

Overall incidence of any fracture among the HIV-positive patients was 21 per 1000 person years. This compared to an incidence of 13.5 per 1000 person years among the HIV-negative controls.

The investigators calculated that HIV-positive individuals were 50% more likely to experience a fracture than age- and sex-matched controls. This risk of facture was 40% higher for patients who were antiretroviral naïve and 60% higher for those with experience of HIV therapy.

Incidence of fractures consistent with low bone mineral density was 17.7 per 1000 person years among patients co-infected with HIV and hepatitis C. This compared to an incidence of only 7.4 per 1000 person years for HIV-mono-infected patients.

However, these mono-infected individuals were still 60% more likely to experience a fragility or stress fracture than matched controls.

Rates of high-energy fracture were comparable between the HIV-mono-infected patients and the HIV-negative controls (9.5 vs. 8.7 per 1000 person years). Among co-infected patients the incidence was 22.7 per 1000 person years.

The investigators suggest that this higher incidence “may be associated with the consequences of intravenous drug use or increased alcohol use including increased fall or trauma risk.”

Because of the association of co-infection with the increased risk of traumatic fractures, the investigators limited their analysis of the risk factors associated with low-impact fractures to HIV-mono-infected patients.

Patients who had not taken HIV therapy had the same risk of a low impact fracture as the HIV-negative controls.

In contrast, antiretroviral-experienced patients were approximately 80% more likely to have a fragility or stress fracture than the controls (IRR = 1.8; 95% CI, 1.5-2.1). This risk fell when the researchers controlled for the presence of other chronic illnesses (IRR = 1.6; 95% CI, 1.36-1.87).

Incidence of low-energy fractures among mono-infected patients increased from 3.5 per 1000 person years in the period before HIV therapy became available to 8.3 per 1000 person years between 1997 and 2003, and then remained relatively stable at 7.5 per 1000 person years in the period up to 2009.

“The risk of low-energy fracture associated with HAART exposure was moderate and did not increase over time,” comment the investigators.

The investigators then attempted to establish the specific risk factors for low-energy fractures among treatment-experienced patients. Smoking was strongly associated with the risk of such fractures (IRR = 2.0).

However, the use of tenofovir did not increase the risk of such fractures (IRR = 1.2; 95% CI, 0.8-1.7).

“HIV-infected patients without HCV-coinfection had increased risk of low-energy fractures,” conclude the researchers. “Future research should explore mechanisms behind the HAART-associated initial BMD loss and investigate possible interventions in patients at high risk of osteoporosis.”