icon-    folder.gif   Conference Reports for NATAP  
  17th CROI
Conference on Retroviruses
and Opportunistic Infections
San Francisco CA
February 16-19, 2010
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Bone Disease: Risk Factors
  Reported by Jules Levin
CROI 2010 Feb 16-19 SF
High Prevalence of Reduced Bone Mineral Density (BMD) in Primary HIV-infected Men: Reduced BMD was prevalent in PHI-men. 11/26 men (42%) had osteopenia and 2/26 (8%) had osteoporosis. As expected it was associated with BMI and age, but possibly also with the degree of HIV replication
Marlous Grijsen*1, S Vrouenraets1,2, R Steingrover1,2, P Lips3, J Lange1,2, P Reiss1,2, F Wit1,2, and J Prins1 1Academic Med Ctr, Amsterdam, The Netherlands; 2Ctr for Poverty-related Communicable Diseases, Amsterdam, The Netherlands; and 3VU Med Ctr, Amsterdam, The Netherlands
_ - Reduced BMD was prevalent in men with PHI: half of the men had osteopenia or osteoporosis.
_ - As expected reduced BMD was associated with lower BMI, increased age and thyroid stimulating hormone levels, but possibly also with a higher degree of HIV-1 replication.
_ - Additional studies involving men without HIV-1 infection are needed to improve our understanding whether these findings relate to the presence of HIV-1 or other risk factors for reduced BMD
Background: HIV-infected persons have an increased prevalence of reduced BMD, the pathogenesis of which is multifactorial. Besides traditional risk factors, HIV infection itself and HAART might contribute. To assess the effect of HIV infection, we studied the prevalence of osteopenia and osteoporosis in men with primary HIV infection (PHI).
Methods: All 26 men with PHI presenting at the Academic Medical Centre between February 1st 2008 and February 28th 2009 and enrolled in the ongoing Dutch Primo-SHM cohort, were included. BMD was measured at baseline by DEXA of the lumbar spine, femoral neck and total hip. Clinical data, parameters of HIV infection and biochemical markers of bone metabolism were evaluated. One patient had been on HAART for 9 days, others were therapy-naïve. The WHO criteria were used to define osteopenia and osteoporosis as T-scores between -1 and -2.5, and ≤-2.5, respectively. Multivariate linear regression models for lumbar spine, femoral neck and total hip T-scores were constructed using a stepwise selection procedure (P<0.1). All models were adjusted for age and BMI.
Results: Mean age was 38 (SD 9.3) years and mean BMI 23.4 (SD 3.5) kg/m2. In the study, 20 men (77%) were Caucasian, 19 (73%) had a negative or indeterminate Western blot, and 22 (85%) had symptoms of an acute retroviral syndrome. Mean CD4 count was 559 (SD 250) cells/mm3 and mean plasma HIV RNA 5.2 (SD 1.1) log10 copies/mL. Mean lumbar spine T (-0.8, SD 1.4, P =0.007) and Z-scores (-0.7, SD 1.4, P =0.02) and femoral neck T-scores (-0.5, SD 1.0, P =0.02) were significantly lower among the 26 PHI-men compared to the reference population. Of the participants, 11/26 men (42%) had osteopenia and 2/26 (8%) had osteoporosis. Markers of bone metabolism did not differ between patients with or without osteopenia/osteoporosis. In the multivariate analysis we investigated race, smoking, alcohol consumption, physical activity, CD4 count, plasma HIV RNA, and bone metabolism markers. Age and BMI were strongly associated with lumbar spine, femoral neck, and total hip T-scores. The bone formation marker P1NP was associated with femoral neck T-scores. Log10 HIV RNA was associated with total hip T-scores (see Table).
Conclusions: Reduced BMD was prevalent in PHI-men. As expected it was associated with BMI and age, but possibly also with the degree of HIV replication, which merits further study.


Longitudinal Analysis of Bone Mineral Density in Aging Men With or at Risk for HIV Infection, Heroin & Bone Loss: 41.6% had osteopenia, and 12.4% had osteoporosis at ≥1 site, HIV+ men had lower BMD....compared with HIV- men.....Of men initially with osteopenia, 12% (n = 19 of 158) progressed to osteoporosis....significant interaction between heroin use (within 5 yrs) and AIDS diagnosis, such that the greatest rate of bone loss was seen in persons with both AIDS and heroin use....hepatitis C virus seropositivity was associated with femoral neck bone loss
Anjali Sharma*1, P Flom1, J Weedon1, and R Klein2 1State Univ of New York Downstate Med Ctr, Brooklyn, US and 2Mt Sinai Sch of Med, New York, NY, US
Background: Longitudinal studies of bone mineral density (BMD) in aging HIV+ men, especially drug users, are lacking.
Methods: Men ≥49 years old at-risk for HIV infection underwent standardized semiannual interviews. HIV serology, CD4+ count, HIV viral load, and testosterone levels were measured. BMD was assessed by dual x-ray absorptiometry on study entry and ≥18 months later. Multivariate linear regression analysis assessed factors independently associated with change in BMD at the femoral neck, hip, and lumbar spine (LS).
Results: Of 389 participants, 230 (59%) were HIV+; 88% reported lifetime use of cocaine or opioids, 64% current smoking, and 49% had serum testosterone levels <300 ng/dL at baseline. Mean age was 55.6 years, mean BMI was 26.6; 58% were Black, 22% Hispanic, and 14% White. Initially, 46.1% had normal BMD at all 3 sites, 41.6% had osteopenia, and 12.4% had osteoporosis at ≥1 site. HIV+ men had lower BMD (in g/cm2) at the femoral neck, (0.98 vs 1.02, P =0.02), hip (1.01 vs 1.06, P <0.01) and LS (1.15 vs 1.19, P =0.03) compared with HIV- men. Of men initially with normal BMD at all sites, 13.7% progressed to osteopenia (n = 24 of 175). Osteopenia incidence for HIV- men was 2.6 per 100 person-years at risk [PYAR]) and for HIV+ men 7.2 per 100 person-years (P =0.02). Of men initially with osteopenia, 12% (n = 19 of 158) progressed to osteoporosis. For both HIV- and HIV+ men osteoporosis incidence was 2.2 per 100 person-years. In multivariate analysis of BMD change at the femoral neck, we found a significant interaction between heroin use (within 5 yrs) and AIDS diagnosis, such that the greatest rate of bone loss was seen in persons with both AIDS and heroin use, after adjusting for age, race/ethnicity, BMI, baseline BMD, corticosteroid use, family history of vertebral fracture, and current methadone use. In this model, hepatitis C virus seropositivity was associated with femoral neck bone loss (P =0.04). At the hip, the association of BMD loss with the interaction between AIDS and heroin use remained significant in the multivariable model, as was current methadone use (P <0.01). In multivariate analysis of factors associated with greatest decline in BMD at any of the 3 sites, the interaction between AIDS and heroin use was associated with greater bone loss (P =0.04) while current methadone use was borderline (P =0.06).
Conclusions: These findings suggest a combined effect of heroin use and AIDS upon bone metabolism. Heroin users with AIDS may be at particular risk for bone loss.

Changes in Bone Mineral Density: 2-year Follow-up of the ANRS CO3 Aquitaine Cohort, over 2 years patients with normal BMD progressed to osteopenia; 11% with osteopenia progressed to osteoporosis: The main laboratory abnormality was a deficiency in vitamin D (76.0%)
C Cazanave1, S Lawson-Ayayi1,2,3, N Barthe1, B Uwamaliya-Nziyumvira1,3, A Kpozehouen3, N Mehsen1, P Mercié1,2,3, P Morlat1,2,3, Michel Dupon*1,2, F Dabis1,2,3, and GECSA 1Univ Hosp Bordeaux, France; 2COREVIH-Aquitaine, France; and 3INSERM U897, ISPED, Univ Victor Segalen Bordeaux, France
Background: Early osteoporosis has been reported in HIV-infected patients, and found to be of multifactorial origin. Longitudinal studies measuring bone mineral density (BMD) are needed to better understand temporal changes of bone abnormalities. We examined the 2-year progression of BMD in a cohort of HIV-infected patients and estimated the incidence of pathological bone loss.
Methods: In a previous study we consecutively screened 492 patients for BMD from November 2004 to May 2005 and found that the prevalence of osteoporosis was 26.8%. We repeated the BMD assessment 2 years later in a sample of patients who had no bone abnormality or osteopenia diagnosis at baseline according to WHO criteria. BMD of lumbar spine, femoral neck, and whole body was measured by dual energy X-ray absorptiometry. Bone loss was calculated for each patient and each site by the difference of the 2 BMD measurements; only significant variations, larger than the scanner variation coefficient, were considered. All patients were evaluated by 2 different methods which allowed for the determination of a pathological bone loss either by an annual relative change in bone mass superior to physiological data or by a negative difference in Z-scores, between M24 and M0. Blood and urine tests were also performed to investigate the origin of these deleterious evolutions.
Results: For this study, 255 patients were recruited, 72 with no bone abnormality and 183 with osteopenia at baseline. Median age at baseline was 43 years; 67.5% were male; 20.8% patients had reached AIDS stage and all were treated with HAART: 77.3% had a plasma viral load <50 copies/mL and the median CD4 cell count was 569/µL. The median BMI was 23.1 kg/m2. Osteoporosis was diagnosed in 29 patients (11.4%) after 2 years (all of them had osteopenia at baseline); 20 patients with normal BMD progressed to the osteopenia stage. One-hundred-twenty-six patients had a pathological bone loss (results were the same with the 2 definitions), an incidence of 49.4% (Confidence interval: 43.1% to 55.7%). The main laboratory abnormality was a deficiency in vitamin D (76.0%); 41.0% of the patients had increased bone resorption markers. Nine cases of moderate phosphate diabetes and 19 of osteomalacia were diagnosed.
Conclusions: Using accurate follow-up BMD data, we can conclude that bone metabolism is rapidly evolving in 2 years among HIV-infected patients. This longitudinal study confirms the importance of pathological bone loss and the importance of vitamin D deficiency.

Bone Turnover, and In Particular Osteoclast Activity, is Increased in Patients with Confirmed Proximal Renal Tubulopathy Within the Swiss HIV Cohort Study
Christoph Fux*1, B Hasse2, M Opravil3, M Cavassini4, A Calmy5, V Gurtner-delaFuente6, P Schmid7, M Stoeckle8, M Flepp9, H Furrer1, and Swiss HIV Cohort Study 1Univ Hosp Bern and Univ of Bern, Switzerland; 2Univ Hosp Zurich, Switzerland; 3Hirslanden Klinik Aarau, Switzerland; 4Ctr Hosp Univ Vaudois, Lausanne, Switzerland; 5Univ Hosp Geneva, Switzerland; 6Ospedale Civico di Lugano, Switzerland; 7Cantonal Hosp, St Gallen, Switzerland; 8Univ Hosp Basel, Switzerland; and 9Klinik im Park, Zurich, Switzerland
Background: Tenofovir (TDF) use has been associated with losses in bone mineral density and proximal renal tubulopathy (PRT). The link between these pathologies is unclear. We have shown that PRT, and in particular tubular proteinuria and hyperphosphaturia, are significantly associated with TDF and PI use.
Methods: Among patients with confirmed tubular pathology, we quantified bone metabolism in 66 individuals with PRT (i.e. ≥3 of 4 pathologic parameters including proteinuria, phosphaturia, uricosuria and glucosuria) and 100 with isolated hyperphosphaturia. Patients were 88% male at a median age of 48 (IQR 45 to 55) years, 13 (7 to 17) years since HIV-diagnosis and 10 (6 to 11) years, since cART initiation.
Results: Osteoblast activation (ie, elevated serum osteocalcin and/or alkaline phosphatase in the absence of viral hepatitis) was documented in 10% of patients. Increased bone resorption (ie, elevated serum type I collagen C telopeptide and/or urine deoxypyridinoline (DPD)) was seen in 51%. Vitamin D deficiency and hyperparathyroidism occurred in 30% and 14%, respectively. Osteocalcin, telopeptide, and DPD levels were higher and more frequently pathologic in PRT compared to patients with exclusive hyperphosphaturia. A pathological cystatin C:creatinine ratio, but also micro-albuminuria were significantly associated with pathological osteocalcin and telopeptide values, while a protein/creatinine ratio >10 mg/mmol and a pathological a1-microglobulin/creatinine ratio only showed borderline associations with osteocalcin. IDU, lower BMI, lower eGFR, and hyperparathyroidism showed a significant, PRT and vitamin D deficiency, a borderline correlation with osteocalcin. None of these predictors remained significant in multivariable analysis. Similarly, IDU, PRT, vitamin D deficiency, and hyperparathyroidism correlated with osteoclast activation in univariate, but not multivariable analyses. Lower eGFR correlated with telopeptide; lower CD4 count, female sex, as well as the time since HIV diagnosis and cART initiation with DPD levels.
Conclusions: Increased bone turnover was frequent in patients with renal tubulopathy. The higher proportion of patients with osteoclast compared to osteoblast activation suggests net bone loss. The absence of significant predictors in multivariable analyses underlines the multifactorial etiology of osteopenia in HIV+ patients. Increased bone turnover could be related to low eGFR, PRT, vitamin D deficiency, and hyperparathyroidism.

Renal Phosphate Wasting and Increased Bone Turnover in Tenofovir-Treated Patients are not Mediated by Low 25(OH) Vitamin D or Hyperparathyroidism
S Wirz1,2, S Rubeli1,2, A Christen1,2, A Popp1, C Largiadèr1, N Mueller3, A Calmy4, H Furrer1,2, and Christoph Fux*1,2 1Univ Hosp Bern, Switzerland; 2Univ of Bern, Switzerland; 3Univ Hosp Zurich, Switzerland; and 4Univ Hosp Geneva, Switzerland
Background: Tenofovir (TDF)-use has been associated with proximal renal tubulopathy, in particular renal phosphate wasting, as well as increased bone turnover and a reduction in bone mineral density. It is unknown whether these renal and bone pathologies are linked.
Methods: Cross-sectional quantification of renal phosphate reabsorption (with TmPO4/GFR calculated from the Walton–Bijvoet normogram <0.8 defined as pathological), 25(OH) vitamin D and parathyroid hormone (PTH) levels in 251 HIV-positive patients.
Results: In the study, 25% of patients showed a pathologically reduced reabsorption of phosphate, 5% hyperparathyroidism >65ng/L and 40% 25(OH) vitamin D deficiency <30nmol/L. While 25(OH) vitamin D deficiency correlated with significantly lower renal phosphate losses, PTH showed no correlation (Figure 1a/b). Multivariable regression analyses correlated 25(OH) vitamin D with Caucasian ethnicity (coefficient 9.0; 95%CI 0.1 to 17.8), IDU (-10.4; -19.7 to -1.0), PTH (-1.1; -2.0 to -0.1) and protease inhibitors vs non-nucleoside reverse transcriptase inhibitor-use (11.8; 5.1 to 18.4), but not with TDF. PTH correlated with IDU (19.7; 8.2 to 31.2), 25(OH) vitamin D (-1.7; -3.1 to -0.2), glomerular filtration rates <60 mL/min (26.0; 8.1 to 43.8) and previous AIDS (9.6; 1.2 to 18.0), but not with TDF.
Conclusions: The TDF-associated increase in bone turnover is not mediated by 25(OH) vitamin D deficiency or hyperparathyroidism. However, TDF-use is associated with a significant increase in 1,25(OH)2 vitamin D. Phosphate deficiency has been shown to directly - and independently of PTH - stimulate 1a-hydroxylation of 25(OH) vitamin D, which in turn stimulates compensatory intestinal phosphate absorption and bone metabolism. Given an adequate supply of 25(OH) vitamin D, this autoregulatory increase in 1,25(OH)2 vitamin D may be sufficient to maintain phosphate and thus bone homeostasis in patients with TDF-related proximal renal tubulopathy. Consequently, vitamin D deficiency should be corrected in TDF-treated patients.