Much of HIV Treatment-Related Bone Loss Occurs Early in Therapy and Is Related to Immune Recovery, Study Finds
March 29, 2011
The following is our transcript of a press conference that took place on March 1 at CROI 2011. In it, Ighovwerha Ofotokun, M.D., summarized the findings of a study he was presenting at the conference entitled, "HAART-Induced Immune Reconstitution: A Driving Force Behind Bone Resorption in HIV/AIDS." Much as the title suggests, the study's chief finding is that bone loss in people who begin antiretroviral therapy occurs primarily during the early phase of treatment, and is related to the treatment-induced recovery of an HIV-infected person's immune system.
Ighovwerha Ofotokun: What we have known for 10 years is that bone loss and osteoporosis are common complications of HIV. Before now it had not come to the forefront because people were dying from this epidemic. Now that we have successful therapy with health, and people are living longer, the issue of long-term complications has become important.
Recently, what we showed was that there is a great deal of integration between the immune and the skeletal system, and any disease condition that disrupts the immune system also affects the skeletal system. We were able to show, using our HIV transgenic rat model, that disruption of the immune system, cells of the immune system, induced by HIV-1 protein also leads to skeletal abnormalities.
One other thing that many of us that are interested in this field have grappled with is the fact that, even though treatment with HIV improves other HIV-related conditions, pathologies, HAART worsened bone complications of HIV. People who are on HAART actually have worsened bones rather than improved bones.
One of the things we were interested in, in our group at Emory [University], was understanding the pathogenesis driving this phenomenon. Why are there so many risk factors, osteoporosis risk factors, that might be at play? We wanted to investigate the role of immune reconstitution, and we also wanted to identify the timing of HAART-induced bone loss. When does it occur? Is this an early or a delayed event?
In our study that we reported during this conference, we looked at markers of bone resorption immediately following HAART initiation. What we observed was surprising to us: As early as two weeks of starting HAART, people began to lose bone, and this resorption peaked around 12 weeks, then plateaued, but remained elevated at 24 weeks. Because this increase in resorption corresponded to a time when immune reconstitution with HAART reaches a significant point during HAART therapy, we speculated that this process may be partly related to immune reconstitution.
To address this, we resorted to an animal model that was T cell deficient, the TCRb knockout mice. We performed purified adoptive CD3/T cell transfer in these mice, and then, as they reconstituted their immunity, we profiled their bone with microcytic markers of bone turnover, as well as DEXA scanning.
We observed a similarity to the effect of HAART in human immune reconstitution, and this HAART model also led to significant increase in bone resorption. All the markers and cytokines involved with bone resorption were also elevated following immune reconstitution with these mice.
The two things we took away from our study were that: One, the bone resorption following HAART probably begins much earlier than previously thought, and starts as early as 2 weeks and peaks at 12 weeks in our experience, continuing up to 24 weeks. And two, this process may be partly driven by the process of disease reversal that is induced by health.
I think the implication of this study is that, while there are so many factors that may contribute to bone loss in HIV infection, the timing of HAART contribution may be within an identifiable window that we can target for therapeutic intervention. Thank you.
Reporter: I realize your human study was very small, but was there any sign that the CD4 count that a person had when they started therapy made them any more or less likely to have a lot of bone resorption?
Ihgovwerha Ofotokun: We are still trying to sort through those data. What we have observed with those 20 patients is that those with higher markers of resorption; there's a good correlation between the levels of bone resorption and gain changes in CD4 cell count from baseline to week 24. That does not apply to everybody in the cohort, but because it was a small study, a proof-of-concept study, we're not able to present those papers yet.
Increased Rates of Bone Fracture Among HIV-Infected Persons in the HIV Outpatient Study (HOPS) Compared With the U.S. General Population, 2000-2006
This article was provided by TheBodyPRO.
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