Immune recovery and T-cell restoration may play a key role in bone loss
that occurs very soon after starting antiretroviral therapy, according to a
small study presented on Tuesday at the
18th Conference on Retroviruses and Opportunistic
Infections (CROI), taking place this week in Boston.
A growing body of evidence shows
that bone loss commonly occurs after starting HIV treatment. This has been
linked to specific drugs, in particular tenofovir (Viread),
but also appears to be an
effect of antiretroviral therapy (ART) more generally. Most research has looked at bone loss
over time, however, and there are few data about changes immediately after
Ighovwerha Ofotokun, from Emory
University in Atlanta, and colleagues, performed human and
animal studies to evaluate when ART-related bone loss occurs and what might be
its underlying cause.
In many diseases inflammation and T-cell
activation contribute to bone loss by altering production of cytokines, or
chemical messengers that affect bone build-up and breakdown. A cytokine known
as RANKL stimulates osteoclasts, the cells that break down bone and promote
resorption (loss and reassimilation) of its minerals, whilst a protein called osteoprotegerin binds to
RANKL and protects against bone loss.
As considerable CD4 T-cell recovery occurs
during the first 12 weeks on ART, the researchers looked at bone changes during
this period. Most prior studies, in contrast, have looked at bone loss after
six months or more.
Their first analysis included 20 HIV-positive
individuals with an average age of 40 who started antiretroviral drugs for the
first time. The mean CD4 count at the beginning of treatment was quite low, at
Participants responded well to therapy, with all
but one achieving undetectable viral load by week 24. At baseline and at weeks
2, 12 and 24, the researchers measured blood biomarkers of bone
formation and resorption, namely RANKL, tumour necrosis factor alpha, osteocalcin (a
protein produced by bone-building cells called osteoblasts) and CTx (a
by-product of collagen breakdown).
The researchers noted
a dramatic and unexpected early surge in bone resorption immediately after
ART initiation. The large increase in bone loss markers was similar to changes
seen in women at the menopause, Ofotokun said.
Bone loss was clearly evident by week 2 and
peaked at week 12, but resorption markers remained significantly elevated at
week 24. Of note, however: there was also a compensatory increase in markers of
bone formation, explaining the absence of extreme bone loss.
To further explore the link between bone loss
and immune reconstitution, the investigators then looked at an animal model of
HIV disease reversal, using T-cell deficient mice that were given purified CD3
T-cells by adoptive transfer.
Here, too, they saw a surge in bone resorption,
with CTx levels rising by more than 100%. By week 12 the mice showed reduced
bone mineral density in the femur (thigh bone), tibia (shin bone) and lumbar
spine. Unlike the humans, however, bone formation decreased in concert with
The researchers concluded that ART-related bone
loss begins earlier than previously suspected after treatment initiation,
driven at least in part by T-cell activation and reconstitution.
Although the data are not yet fully analysed,
Ofotokun noted that there appears to be a correlation between the degree of
bone resorption and magnitude of CD4 cell gains.
Some study participants took tenofovir, and the
researchers are currently assessing the role of antiretroviral drug choice in
early bone loss.
Knowing that bone resorption occurs so soon
after starting treatment, Ofotokun suggested, may offer a window for
pre-emptive interventions to prevent bone loss at the time of ART initiation.