Trial Information

Bone Mineral Density in HIV+ Patients Recently Started on Antiretroviral Therapy (ART)

The life expectancy of persons infected with HIV has improved greatly since the institution
of combination antiretroviral therapy (cART). However, many metabolic derangements have
been discovered with long-term cART therapy, including lipodystrophy, insulin resistance,
and, more recently, abnormal bone metabolism. It is well documented that bone mineral
density (BMD) in HIV+ patients is lower when compared with the expected BMD in non-HIV
patients [1-10]. The underlying cause of lower BMD is unknown but it is felt to be a
multifactorial process [10-14]. Current guidelines recommend first line treatments consist
of a combination of protease inhibitor (PI) or non-nucleoside reverse transcriptase
inhibitor (NNRTI) in combination with two nucleoside reverse transcriptase inhibitors
(NRTIs). Despite the known change in BMD in HIV+ persons, less is known about the effect of
antiretroviral (ART) exposure and duration of treatment, ART type, and cumulative HIV
viremia on bone health. This is demonstrated by studies showing loss of BMD with use of
protease inhibitors compared to other regimen [15], other studies showing more detrimental
effect from NRTIs [6, 9, 16], and yet others that have shown that BMD improves with all ART
therapy [17]. Tenofovir (an NRTI), in particular, has been implicated as playing a role in
bone changes, possibly due to its effect at the proximal tubule leading to a Fanconi-like
syndrome with phosphate wasting [18]. Tenofovir led to significant reductions in BMD of
children and this loss reversed after tenofovir was stopped [9]; other studies have shown
similar deleterious effects [16]. A recent study evaluating the effect of continuous ART
therapy vs. intermittent use for viral suppression showed that patients receiving continuous
ART had greater loss of BMD, despite an increased risk of AIDS progression, myocardial
infarction, or renal- or liver-failure [19]. However, prior longitudinal studies with
longer follow-up have shown that the initial loss of BMD following ART is recovered and
longer-term BMD changes are similar to changes seen in HIV-negative persons [20-22]. There
is evidence that there is a positive correlation between HIV viremia and proinflammatory
cytokines and that up-regulated proinflammatory cytokines may play a role in both osteoclast
and osteoblast function. Prior studies have shown that during HIV infection osteoblast and
osteoclast function is uncoupled and following ART treatment, regulation of bone turnover
and formation ensues [23]. However, changes in cytokines have not been correlated with BMD
and changes in bone turnover during routine ART treatment, to our knowledge. Most studies
to date have been cross-sectional studies comparing HIV+ (with varying ART exposure
histories) and HIV- persons or small longitudinal studies with limited sample sizes and
short duration. It is not known if the decline of proinflammatory cytokines which occurs
concurrent with the fall in HIV viral loads leads to improved regulation of bone formation
and hence a lower rate of bone loss and lower risk of fracture.