Doubt cast on link between tenofovir disoproxil and bone fractures

Study raises questions about the value of switching to more expensive tenofovir alafenamide

Treatment with tenofovir disoproxil fumarate (TDF) does not increase the risk of fractures, according to French research published in the online edition of the Journal of Acquired Immune Deficiency Syndromes. Findings of the case-controlled study showed there was no association between TDF and fractures in any of the statistical models designed by the authors.

This is the most thorough research to date assessing the relationship between TDF and fracture risk. The lack of any clear associations between the drug and fracture risk calls into question of value of prescribing patented tenofovir alafenamide (TAF) over TDF which is now available in much cheaper generic formulations.

TDF is a component of Truvada and Atripla and their generic equivalents, as well as Eviplera and Stribild. TAF is a component of Odefsey, Genvoya, Symtuza, Descovy and Biktarvy.



In relation to medicines, a drug manufactured and sold without a brand name, in situations where the original manufacturer’s patent has expired or is not enforced. Generic drugs contain the same active ingredients as branded drugs, and have comparable strength, safety, efficacy and quality.


In a case-control study, a process to make the cases and the controls comparable with respect to extraneous factors. For example, each case is matched individually with a control subject on variables such as age, sex and HIV status. 

bone mineral density (BMD)

The higher your bone mineral content, the denser your bones are. And the denser your bones, the stronger they are and the less likely they are to break. A bone density test uses X-rays to measure how many grams of calcium and other bone minerals are packed into a segment of bone. The bones that are most commonly tested are in the spine, hip and sometimes the forearm. 

protease inhibitor (PI)

Family of antiretrovirals which target the protease enzyme. Includes amprenavir, indinavir, lopinavir, ritonavir, saquinavir, nelfinavir, and atazanavir.


Lowest of a series of measurements. For example, an individual’s CD4 nadir is their lowest ever measured CD4 count.

Protease inhibitor (PI) therapy has also been associated with an increased risk of fracture but the authors were unable to establish a robust link between any antiretroviral, PIs included, and elevated fracture rates.

“We found no evidence of an excess risk of fracture after exposure to TDF and PIs,” comment the authors. “This has important implications for the debate concerning tenofovir alafenamide versus generic TDF.”

People with HIV have lower bone mineral density (BMD) and an increased risk of fractures compared to age- and sex-matched HIV-negative controls. BMD drops after starting antiretroviral therapy (ART), especially with TDF-containing regimens and treatment based on a PI.

Ten studies have examined the links between specific antiretroviral drugs and the risk of fracture. Their methodology differed considerably, including the definition of fracture. Moreover, few of the studies took into account the full range of traditional risk factors for low BMD and fractures.

Investigators used data from the French Hospital Database on HIV to design a study in order to more thoroughly examine the potential link between individual antiretroviral drugs and fracture risk.

Their study population consisted of 254 people who experienced a low-impact fracture between 2000 and 2010 who were enrolled in the database before starting antiretroviral treatment. These people were matched with 376 age- and sex-matched HIV-positive fracture-free controls who were likewise recruited while antiretroviral naïve.

The association between ART exposure and individual drugs was studied using various models that took into account any exposure and cumulative use.

The investigators considered a range of potential confounders. The following traditional risk factors were explored: region of geographical origin, body mass index (BMI), smoking, alcohol consumption, use of systemic glucocorticoids, and menopausal status for women. Numerous HIV-related factors were also included in the investigators’ modelling, including year of HIV diagnosis, HIV transmission group, year of ART initiation, AIDS status, nadir and current CD4 cell count, viral load and hepatitis C virus antibody status. Information was also gathered on kidney function, a possible pathway for the posited link between TDF therapy and increased fracture risk.

Median age was 49 years and 67% of participants were men. Almost three-quarters of the cases were diagnosed with HIV before 1997. Median and nadir CD4 cell counts for the cases were 436 cell/mm3 and 172 cells/mm3, respectively. Two-thirds of cases had an undetectable viral load.

All fractures were low impact and at sites potentially associated with osteoporosis. Over three-quarters of cases (79%) experienced only one fracture, 14% had two fractures, 4% had three fractures and 2% had four fractures. The most common fracture sites were the vertebrae, hip and wrist.

At the time of fracture diagnosis, 49% of cases had ever been treated with TDF and 82% with a PI. The median duration of exposure was 2.5 years for TDF and 4.3 years for PIs.

In both the univariate nor multivariate models, and regardless of how ART use was defined, no association was found between TDF use and risk of fracture. After adjustment for confounders, there was no association in the “ever-exposed” model (OR = 1.21; 95% CI, 0.61-2.39) or the cumulative exposure model (OR = 1.04; 95% CI, 0.86-1.27).

Therapy with the protease inhibitor atazanavir was associated with increased fracture risk in some models, but this finding was far from robust and ceased to be significant in a sensitivity analysis that took into account other risk factors. Nor did the investigators find any evidence of an interaction between TDF and atazanavir to increase fracture risk.

The authors were also unable to establish a clear and robust relationship between any other individual antiretroviral and an increased risk of fractures.

“We found no robust association between the risk of fracture in HIV-infected patients and exposure to ARV drugs including exposure to TDF and PIs,” comment the authors. “Some drugs, particularly efavirenz associated with a lower risk and atazanavir associated with a higher risk, were significantly associated with fracture risk in some models we constructed; however, sensitivity analyses showed that these associations were not robust.”

TAF is being presented as a safer alternative to TDF, with a lower risk of osteoporosis, fractures and kidney dysfunction. But the results of this research call into question the potential safety benefits of branded TAF over much cheaper generic TDF, in relation to fractures specifically. The investigators conclude: “these results have important implications for the use of tenofovir alafenamide versus generic TDF.”


Costagliola D et al. Impact of antiretroviral drugs on fracture risk in HIV-infected individuals: a case-control study nested within the French Hospital Database on HIV (FHDH-ANRS CO4). J Acquir Imme Defic Syndr, online edition, 2018.