Bone Mineral Density in HIV+ Patients

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.

Inclusion Criteria:

- All treatment naïve patients seen in the 1917 Clinic between January 1, 1999 and
December 31, 2010 will be identified.

- Of these patients, those who are currently under care at the time of the initiation
of the study (>1 clinic visit in the past 12 months) will be eligible (regardless of
current use of ART treatment).

Exclusion Criteria:

- Patients with a history of chronic renal failure (estimated GFR <30ml/min) will be
excluded from the study.

- In addition, patients with a known diagnosis of a metabolic bone disease (i.e.
osteoporosis, primary hyperparathyroidism, Paget Disease, Osteogenesis Imperfecta),
multiple myeloma, cancer, untreated thyroid disease, or inflammatory bowel disease,
or persons currently treated with or plans to begin an osteoporosis-specific
medication (including estrogen) will be excluded from participation.

- Patients treated with oral glucocorticoids and anticonvulsants will also be excluded.