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Review of Bone Posters at CROI 2008
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Turner Overton, M.D.
Washington University School of Medicine
St Louis, MO
Bone health remains an important metabolic consideration for persons living with HIV, particularly in the current era with a growing proportion of persons over the age of 50. While the National Osteoporosis Foundation does not recommend bone mineral density screening on all patients with HIV, it explicitly states that post-menopausal women and men over 50 should be considered for evaluation if they have additional risk factors for osteoporosis, some of which may be more common in HIV-infected individuals. The data regarding bone health in HIV-infected persons presented at the 15th Conference on Retroviruses and Opportunistic Infections confirms that low bone mineral density (BMD) is a common metabolic complication of HIV infection. Of the data presented on bone health, three studies evaluated the prevalence of low BMD in various cohorts, two studies evaluated the impact of HAART initiation on BMD, and one study looked at serum alkaline phosphatase as a surrogate marker for bone turnover
Yin et al presented data from the WIHS cohort on bone health in premenopausal women from the Women's Interagency HIV Study (WIHS), including data on HIV-infected and uninfected women (1). Baseline parameters are outlined in the table below. Of note, baseline BMD at both the femoral neck and lumbar spine was significantly lower in the HIV-infected women but this was at least partially attributable to older age and thus the mean T scores were not different. However, osteopenia (T score < -1.0) was notably more common in HIV-infected women receiving a Protease Inhibitor based therapy (17%) than in uninfected women (7%).
By mutilvariate analysis, low BMD (T score < -1.0) at the femoral neck was associated with lower weight, current alcohol intake, osteocalcin levels, and serum RANKL levels. Low BMD (T score < -1.0) at the lumbar spine was associated with current alcohol use, osteocalcin levels, TNF-alpha levels, serum alkaline phosphatase levels, and HIV status.
Several bone markers were also evaluated in this cohort; osteocalcin, alkaline phosphatase, serum NTX, IL-6, TNF alpha, RANK-L, and intact PTH were the same between groups at baseline. Among HIV-infected women, alkaline phosphatase was higher in women receiving HAART. NTX, a marker of bone turnover, was higher among women on a PI-based HAART regimen. The change in BMD was similar in the groups over two years of follow-up and fracture risk was also similar between the groups (~3%). The premenopausal state of these women, combined with AA race and high BMI likely protected them from low BMD, despite very low vitamin D levels. While we do not routinely evaluate patients with serum measurements of markers of bone turnover, these markers appear to be relevant and additional research is warranted. (from Jules: being African-American is protective against low BMD, so since there was such a high percent of AAs in this study, 61% in HIV+ and 56% in HIV-negative, the rates of change in BMD could be higher in HIV+ women who are not AAs.)
Guillemi et al presented cross sectional data on bone health from their Vancouver clinic cohort of 285 HIV-infected persons who underwent BMD screening with DEXA scanning (from Jules: in Canada DEXAs are covered by insurance so you can perform a baseline test) and completed a questionnaire (2). Median age was 48 years and men comprised 89% of the cohort. Their data confirmed that low BMD is very prevalent with two thirds of subjects having low BMD: 54% with osteopenia (T score < -1.0 and > -2.5) and 13% with osteoporosis (T score < -2.5). By multivariate analysis, low BMD was associated with low BMI, being Caucasian, current alcohol use, lower CD4 cell counts, and cumulative tenofovir use. Unlike the data from the WIHS study, no association was identified with PI use. No bone markers were assessed in this study. Although it is difficult to determine the impact of various factors in a cross sectional study, the high prevalence confirms data presented previously in highly treated cohorts.
Cazanave et al reported on longitudinal data on bone health from the ANRS CO3 Aquitaine Cohort specifically to address the impact of co-infection with hepatitis B and C (3). From an initial cross sectional evaluation of 363 HIV-infected subjects with a high prevalence of low BMD (osteopenia in 53% of men and 51% of women; osteoporosis in 35% of men and 7% of women), 208 subjects were followed longitudinally with serial DEXA scanning. Median age of the latter cohort was 46 years with 73% having low BMD at baseline. While hepatitis co-infection was not noted to have a specific effect on BMD in the cohort, there was significant progression over the 2 years of follow up noted in patients with baseline osteopenia at the femoral neck. BMD declined over the time period but the changes were not statistically different than at baseline.
Duvivier et al evaluated the effect of PI-based, NNRTI-based, or PI/NNRTI combined HAART initiation on BMD in 71 naive patients, 16 (23%) of whom were female, 18 (25%) Black Africans, and 49 (69% were Caucasian (4). Median BMI was 23 kg/m2, median CD4 cell count was 219 cells/mm3. At baseline, 31% were osteopenic and 3% osteoporotic. At week 48, there was an overall median decrease in BMD that was significant at both the lumbar spine and the femoral neck (4.1% and 2.8%, respectively). Greater decrements were noted in the PI containing regimens than in the NNRTI/NRTI regimen. There was no mention of specific agents in the various regimen.
Brown et al presented data from the M03-613 sub-study evaluating the effect of HAART initiation on BMD (5). This study randomized 155 naive subjects to zidovudine/lamivudine with either lopinavir/ritonavir versus efavirenz. 106 subjects were included in the BMD analysis. The mean age was 41 years, 78% of the study population was male, 66% white, 64% current alcohol drinkers, and 39% current tobacco users.
At baseline, lower BMD was associated with lower weight, non-black race, and lower baseline HIV viral loads. Overall, there was a statistically significant decline in total BMD of -2.5% in the LPV/r group and -2.3% in the efavirenz group. There was no difference between the two groups. Persons who experienced >5% loss of BMD during the study had lower CD4 cell counts at baseline, had higher fasting glucose, and were more likely to be of non-black race.
The findings from these two studies are consistent with data that has previously been published and presented illustrating the loss of BMD that is seen with the initiation of HAART (6,7). The differences reported in the two studies on the impact of different regimens illustrate the need for additional research to evaluate the mechanism of bone loss seen in persons initiating HAART.
Fux et al presented data from the SWISS HIV Cohort Study evaluating the change in serum alkaline phosphatase levels (sALP) seen with the initiation of HAART, specifically tenofovir-based therapy (8). They included 971 patients initiating a new regimen. The initiation of a tenofovir containing regimen was associated with statistically higher elevations in sALP in both naive and treatment experienced patients. Of note, these increases did not correlate with changes in transaminases or with hepatitis C co-infection and the authors concluded that its origin was predominantly bone. The discontinuation of tenofovir was also consistently associated with significant decreases in sALP.
Tenofovir has been associated with renal tubular toxicity and subsequent renal phosphate wasting. The authors surmised that renal phosphate wasting leads to increased bone turnover and hence elevated increased alkaline phosphatase in the serum as a marker of regenerative osteoblast activity. The authors did not specifically measure bone alkaline phosphatase or other bone markers. Nor did they evaluate BMD in this cohort. Rather, they attempted to illuminate the process by which bone disease, specifically osteomalacia, may be induced by one of the agents commonly used in HIV care. Clearly, the work is provocative but requires more sophisticated evaluation of bone metabolism in HIV-infected populations.
During the symposium on aging, Dr. Bill Powderly discussed many of the key co-morbidities that older adults living with HIV and their care providers must address (9). Specifically, he focused on high prevalence of bone disease and the growing concern of the long-term ramifications, most notably the risk of fragility fractures and their significant morbidity. He also suggested that we need to explore the direct effects of HIV and antiretroviral therapy on bone health as well as develop effective strategies to better combat this growing clinical issue. Further research is needed to better understand the mechanism of bone loss, the long-term ramifications of low BMD (specifically fracture risk), and the interplay between aging and HIV on bone health in HIV-infected populations.
References
1. Yin M, Cremers S, Lu D, Shane E, Gao W, McMahon D, Anastos K. Short-term Bone Loss in HIV-infected Premenopausal Women. Proceedings of the 15th Conference on Retroviruses and Opportunistic Infections 2008. Boston, MA: Abstract 965.
2. Guillemi S, Ng F, Zhang W, et al. Risk Factors for Reduced Bone Mineral Density in HIV-infected Individuals in the Modern HAART Era. Proceedings of the 15th Conference on Retroviruses and Opportunistic Infections 2008. Boston, MA: Abstract 969.
3. Cazanave C, Dupon M, Lavignolle-Aurillac V,et al. Reduced Bone Mineral Density in HCV- or HBV-co-infected Patients: 2-year Follow-up, ANRS CO3 Aquitaine Cohort, France. Proceedings of the 15th Conference on Retroviruses and Opportunistic Infections 2008. Boston, MA: Abstract 970.
4. Duvivier C, Kolta S ,Assoumou L, Ghosn J, Rozenberg S, Murphy R, Katlama C, Costagliola D and the ANRS 121 study group. First-line PI-containing Regimens Enhance Decreased Bone Mineral Density Greater than NNRTI-containing Regimen in HIV-1-infected Patients: A Substudy of the HIPPOCAMPE-ANRS 121 Trial. Proceedings of the 15th Conference on Retroviruses and Opportunistic Infections 2008. Boston, MA: Abstract 967.
5. Brown T, McComsey G, M King M, Qaqish R, Bernstein B, da Silva B. Bone Mineral Density 96 Weeks after ART Initiation: A Randomized Trial Comparing Efavirenz-based Therapy with a Lopinavir/Ritonavir-containing Regimen with Simplification to LPV/r Monotherapy. Proceedings of the 15th Conference on Retroviruses and Opportunistic Infections 2008. Boston, MA: Abstract 966.
6. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292(2):191-201.
7. Tebas P, Umbleja T, Dube M, et al. Initiation of ART is Associated with Bone Loss Independent of the Specific ART Regimen. The Results of ACTG A5005s. Proceedings of the 14th Conference on Retroviruses and Opportunistic Infections 2007. Los Angeles, CA: Abstract 837.
8. Fux C, Rauch A, Simcock M, et al. Tenofovir Use Is Associated with an Increase in Serum Alkaline Phosphatase in the Swiss HIV Cohort Study. Powderly W. Contributions of Age-Related Comorbidities. Proceedings of the 15th Conference on Retroviruses and Opportunistic Infections 2008. Boston, MA: Abstract 968.
9. Powderly W. Contributions of Age-Related Comorbidities. Proceedings of the 15th Conference on Retroviruses and Opportunistic Infections 2008. Boston, MA: Abstract 107.
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