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Bone Loss in HIV
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From Jules Levin
Abstracts presented at the 7th International Workshop on
Adverse Drug Reactions and Lipodystrophy in HIV
13-16 November 2005, Dublin, Ireland
Antiretroviral therapy and the prevalence of osteopaenia and osteoporosis: a meta-analysis
TT Brown1 and RB Qaqish2
1Johns Hopkins University, Baltimore, MD, USA; 2Abbott Laboratories, Abbott Park, IL, USA
ABSTRACT 87
Antiviral Therapy 2005; 10:L52
Introduction: Prevalence estimates of osteopaenia and osteoporosis (reduced bone mineral density) in HIVinfected patients compared to HIV-seronegative subjects vary in the literature. In addition, reports of the role of antiretroviral therapy (ART) and, specifically, protease inhibitor (PI) exposure, have been inconsistent.
Methods: We conducted a systematic review and six meta-analyses of cross-sectional studies published in English to determine the pooled odds ratios (ORs) of reduced BMD and osteoporosis in the following groups: 1) HIV+ vs HIV-; 2) ART-treated vs ART-naive; 3) PI-treated vs PIuntreated. We searched MEDLINE, PubMed and EMBASE databases for eligible references from January
1995-May 2005. Random effects models were used to generate pooled OR estimates and confidence intervals (CIs). Heterogeneity was examined using meta-regression and sensitivity analyses.
Results: Of the 29 articles identified, 23 met our inclusion criteria. In 19 studies, data were available for quantitative summary. Twelve studies were included to determine the pooled OR of reduced BMD and osteoporosis in HIV-infected
patients compared with HIV-seronegative controls.
Of the 884 HIV-infected patients, 67% had reduced BMD of whom 15% had osteoporosis, yielding a pooled OR of 6.4 (95% CI: 3.7, 11.3) and 3.7 (95% CI: 2.3, 5.9), respectively, compared to HIV-seronegative controls (n=654).
Compared to ART-naive patients (n=189 from eight studies), ART-treated individuals (n=807) had a 2.7-fold increased odds of prevalent reduced BMD (95% CI: 1.9, 4.1). The risk of prevalent osteoporosis (derived from
five studies) was similar (OR 2.6; 95% CI: 1.2, 5.4).
Compared to HIV-patients not treated with PIs (n=402 from 13 studies), PI-treated patients (n=768) had increased odds of reduced BMD (OR 1.5; 95% CI: 1.1, 1.6) and osteoporosis (OR 1.6 95% CI: 1.08, 2.5, from 11 studies). Few studies adjusted for important covariates such as HIV-disease severity or treatment duration.
Conclusions: The prevalence of osteoporosis in HIV-infected subjects is more than three times greater compared to HIV-seronegative controls. ART-exposed and PI-exposed subjects have a higher prevalence of reduced BMD and osteoporosis compared to their respective controls. The influence of other disease and treatment variables on these estimates could not be determined.
Incidence and natural history of osteonecrosis in HIV-infected adults
CG Morse1, JM Mican2, EC Jones2, GO Joe1, E Formentini2 and JA Kovacs1
1Clinical Center, National Institutes of Health, Bethesda, MD, USA; 2National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
ABSTRACT 86
Antiviral Therapy 2005; 10:L52
Background: Osteonecrosis is increasingly recognized as a debilitating complication of HIV infection. We have previously documented a high prevalence (4.4%) of MRIdocumented osteonecrosis of the hip in a cohort of 339 asymptomatic HIV-infected patients. The current study was designed to determine the incidence of newly diagnosed osteonecrosis in this cohort and to describe the natural history of osteonecrosis in HIV-infected patients.
Methods: Participants without evidence of osteonecrosis on the initial screening MRI were invited to undergo a second MRI 12-24 months following the first study. Patients with MRI-documented osteonecrosis, diagnosed either as part of this study or outside the context of this study, were eligible to participate in a natural history study, which included serial MRI scanning and physiotherapy and orthopaedic follow-up.
Results: Of 320 eligible patients, 235 underwent a second MRI scan a median of 23 months after the initial scan. Three patients (1.3%) were diagnosed with osteonecrosis of the femoral head (all bilateral), an incidence rate of
0.7 cases/100 patient-years. An additional patient, with normal screening and follow-up MRI scans, was diagnosed with symptomatic left hip osteonecrosis 3 years following his second MRI. Two of these four patients subsequently underwent total hip replacement (THR), one remained asymptomatic and one was lost to follow-up.
Among the 15 patients with osteonecrosis diagnosed on the initial screening MRI, six had bilateral and nine had unilateral disease. At a median follow-up of 5.8 years, five patients remained asymptomatic, four reported mild pain
symptoms, one underwent bilateral THR, three patients died and one was lost-to-follow-up. Among 19 additional symptomatic patients referred to the study following diagnosis of osteonecrosis, 15 had bilateral involvement of the
femoral heads, and seven had osteonecrosis involving other bones. Nine of the 19 required surgical intervention for pain control, with six patients undergoing THR.
Conclusions: Results from this prospectively studied cohort provide further evidence that HIV-infected patients are at increased risk for developing osteonecrosis. Longitudinal observations suggest that slower disease progression may occur in asymptomatic compared to symptomatic patients. Follow-up studies are needed to further evaluate risk factors and to assess preventive and treatment strategies.
Protease inhibitors selectively induce chemokine expression in human osteoblasts
A Patricelli, PP Doran and WG Powderly
Genome Resource Unit, School of Medicine and Medical Sciences, University College Dublin, Mater Misericordiae University Hospital, Dublin, Ireland
ABSTRACT 85
Antiviral Therapy 2005; 10:L51
Aims: Retroviral protease inhibitors (PIs), including nelfivavir (NFV), ritonavir (RTV), saquinavir (SQV) and indinavir (IDV), have become key components of conventional HAART therapy for HIV infection. Recent evidence has emerged implicating HAART as a contributor to decreased bone density seen in treated HIV patients. In this study we have assessed the relative contribution of PIs to alterations in osteoblast phentoype. Whilst the exact molecular mechanisms
underpinning decreased bone density remain to be elucidated, inflammation has been postulated to be an important pathogenomic mechanism. In particular, the
inflammatory chemokines, monocyte chemoattractant protein 1 (MCP1) and interleukin 8 (IL-8) have been proposed as mediators of locally induced inflammation contributing to overall alterations in osteoblast biology.
Methods: Primary human osteoblast cultures were exposed to pharmacological concentrations (5mM) of the PIs RTV, SQV, NFV or IDV for 24 h. The cell proliferation and the apoptosis index were evaluated by MTS assay and apoptosis detection kit. MCP1 and IL-8 protein secretion from treated
cells were analysed using quantitative real-time PCR.
Results: Pharmacological doses of the PIs did not induce significant alterations in osteoblast apoptosis or proliferation. MCP1 protein secretion was significantly enhanced in the NFV and RTV treated cells (P<0.05, P<0.01). This protein level increase was correlated with enhanced MCP1 mRNA expression in the NFV-treated cells (DDCt 2.58 P<0.01), demonstrating that the NFV-associated
proinflammatory chemokine induction is associated with de novo gene expression. Furthermore, IL-8 protein levels were enhanced in response to NFV (P<0.01) exposure, an effect that was mirrored by enhanced mRNA levels of this
gene (DDCt 4.0 P<0.01).
Conclusions: Herein we have demonstrated that osteoblasts, key cellular players in active bone formation, release the pro-inflammatory cytokines MCP1 and IL-8 following exposure to pharmacological concentration of NFV.
This enhanced protein expression was due to de novo gene expression induction as demonstrated by real-time PCR. These data suggest that induction of local inflammatory cascades may contribute to the development of decreased bone mineral density in HAART-treated HIV patients.
Acknowledgement: AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH. USA.
Four weeks of indinavir does not affect bone turnover in healthy HIV-negative subjects
SS Shankar and HO Steinberg
Indiana University School of Medicine, Indianapolis, IN, USA
ABSTRACT 88
Antiviral Therapy 2005; 10:L53
Introduction and objectives: HIV-1 protease inhibitors have been reported to increase bone resorption in HIV-infected patients. However, it is unclear if this is a direct effect of the drug on bone, or due to an interaction between drug and underlying disease. In order to assess the effect of drug alone on bone turnover, we studied the effect of a single protease inhibitor, indinavir, on markers of bone turnover.
Methods: We studied eight healthy HIV-negative subjects with normal bone density as determined by dual X-ray absorptiometry. We measured markers of bone turnover in our subjects at baseline, and after four weeks of daily oral indinavir at 800mg three times a day. Results were compared before and after indinavir, using a paired t-test, and expressed as mean ±SEM.
Results: We studied six male and two female subjects with a mean age of 37 ±2 years, with a mean BMI of 29.2 ±1.0 kg/m2. All subjects had normal serum calcium, phosphorus, alkaline phosphatase, as well as urinary N-telopeptide levels prior to initiation of the study. There was no change in BMI after indinavir. Urinary N-telopeptide levels normalized to urinary creatinine were comparable
before and after four weeks of indinavir (29.6 ±7.3 pre-indinavir vs 25.6 ±2.9 nmBCE (bone collagen equivalent)/ mmol creatinine, post-indinavir; P=NS). Urinary calcium and phophorus remained unchanged as well.
Conclusions: Indinavir does not alter markers of bone turnover in healthy HIV-negative subjects. This indicates that the HIV-1 protease inhibitor indinavir does not appear to have a direct effect on bone resorption.
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