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PrEP demonstration project: Modest bone density loss observed among young men

, by Liz Highleyman

human radiography scan with glowing bonesMost young men participating in a pre-exposure prophylaxis (PrEP) demonstration project saw a small but significant amount of bone loss after starting Truvada, researchers reported at the 15th European AIDS Conference last week in Barcelona. Men who had the most highly protective levels of tenofovir in their blood, consistent with at least four doses per week, saw the largest decreases in bone density.

“Although the BMD losses were generally modest [in this study], their occurrence before attainment of peak bone mass in young men who already have low bone mass may increase their risk of fragility in adulthood,” the researchers said.

Tenofovir—one of the two drugs in the Truvada combination pill—was approved in 2001 and is one of the most widely used antiretrovirals for HIV treatment. Tenofovir is generally safe and well-tolerated.

Bone loss has been previously observed among HIV-positive adults who include tenofovir in their antiretroviral regimen, among infants whose mothers took tenofovir during pregnancy, and among HIV-negative men and transgender women taking tenofovir as part of PrEP. But this study is unique because it investigated tenofovir-related bone loss over time in HIV-negative adolescents and young adults—the age at which most people reach peak bone density.

Kathleen Mulligan, MD, from UCSF and her team looked at bone density changes among participants in ATN 110, a demonstration project investigating the safety and feasibility of PrEP for young gay men. Results from the main study were presented this summer at the International AIDS Society Conference in Vancouver.

Bone mass generally peaks during early adulthood, typically around age 20, after which it begins to gradually decline, Mulligan explained. Peak bone mass is an important predictor of bone fracture risk later in life.

ATN 110 enrolled 200 at-risk HIV-negative young men who have sex with men, ages 18 to 22, in 12 U.S. cities. Nearly half were African-American and about a quarter were Latino. All study participants were offered PrEP using once-daily Truvada for 48 weeks, along with a full package of HIV prevention services including risk reduction counseling, STI testing, and free condoms.

Tenofovir drug levels were measured throughout the study. Dosing frequency was estimated based on drug concentrations in dried blood spots. The bone sub-study performed dual X-ray absorptiometry or DXA scans of the hip, spine, and whole body at the start of the study and again at weeks 24 and 48.

At the beginning of the study, bone mineral density (BMD) levels were below norms for age and race/ethnicity. The percentage of people who had spine, hip and whole body BMD below international thresholds for low bone mass was 8.1%, 6.1% and 3.7%, respectively. Mulligan noted that, though  BMD levels were lower than expected among the men in the study, low bone mass has also previously been reported in other studies of HIV-negative gay men.

After 24 days of using Truvada, bone density decreased on average in the spine (by about -0.2%), hip (by about -0.4%), and whole body (by about -0.8%). The hip and whole body changes were statistically significant, meaning they were unlikely to occur by chance.

After this point, hip BMD continued to decrease steeply (falling to -1.0% by week 48) and whole body BMD further decreased by a small amount, but spine BMD started to increase, and in fact rose above the starting level.

After the conference, Mulligan stated that about 75% of participants in the study experience some hip, spine or whole-body bone loss.

The researchers then looked at the relationship between bone loss and tenofovir drug concentrations in dried blood spots.

More than half of participants had drug levels known to be highly protective against HIV for the first 12 weeks, indicating that they took Truvada at least four times a week. But adherence among about a third of participants declined over time to dosing consistent with less than four doses per week, allowing researchers to compare bone density changes between men who had highly protective tenofovir levels and those with lower levels.

Young men with highly protective tenofovir levels showed spine bone loss of about -1.5% at week 48, while those with undetectable drug levels saw their bone density increase by about the same amount. Hip bone density decreased by about -1.5% in men with high drug levels but remained unchanged in those with undetectable drug levels. Normally, bone mass would still be rising in people this age.

Looking at bone fractures, about a quarter of participants reported that they had fractures prior to the study. During the study period five men experienced eight fractures. All were due to physical trauma, including slamming fingers in a door, a vehicle accident, a fall, and a fight. There was no evidence of so-called fragility fractures, which can happen even without physical trauma when the bones are weak.

It is still not clear what the bone loss seen in this study might mean for young men considering PrEP.

Studies of tenofovir-related bone loss in older adults have generally found that while bone density decreases may be statistically significant, they are not clinically significant—meaning they probably won’t lead to problems such as fractures. Some studies have found that bone loss stops after being on tenofovir for several months, but others have seen ongoing decreases.

Unlike HIV-positive people who take tenofovir for years or decades as part of a treatment regimen, experts expect that most people will take PrEP daily during periods of time in their life when they are at the most risk—what San Francisco AIDS Foundation chief medical officer Robert Grant, MD, calls “seasons of risk.”

In this study there were no major differences in bone loss between men who took Truvada seven days a week and those who took it four days a week, Mulligan said, so it is not clear whether taking PrEP less often—such as taking it “on demand” before and after sex, as was done in the Ipergay study—would protect against bone loss. In the U.S., daily use is the only regimen approved for use by the Federal Drug Administration.

Mulligan explained that young men in the 18 to 22 age range would normally still be gaining bone mass. So not only did the men with protective PrEP levels lose a bit of bone, they also failed to gain the bone mass that might have been expected otherwise. Again, it is not yet known whether this could lead to problems later on.

The ATN 110 study will continue to follow participants for a year to determine whether bone loss is reversible after stopping Truvada.

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