Bone/Osteoporosis/Vitamin D CROI 2010 Update
Michael Yin, MD MS
Assistant Professor of Clinical Medicine
Columbia University Medical Center
New York, NY
Osteoporosis is defined in the article in this link:
www.natap.org/2006/HIV/120406_09.htmART and the prevalence of osteopenia and osteoporosis: a meta ...
Osteoporosis is defined as a 'systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, ...
Low bone mineral density (BMD) is a recognized metabolic complication of HIV infection and its treatment. Antiretroviral therapy (ART) initiation is associated with short-term bone loss, in the range of 2-6% over 2 years, irrespective of the type of ART regimen 1-6, while BMD remains stable in younger men and women on established ART7-9. Therefore, it is uncertain whether the lower BMD associated with HIV infection or short term bone loss associated with ART initiation will translate to increased fractures in HIV+ individuals. CROI 2010 provided additional confirmation of bone loss with initiation of specific ART regimens, new data on fracture rates and fracture risks in select HIV+ populations, new data on vitamin D metabolism with efavirenz, and interesting data on potential non-skeletal effects of vitamin D.
Bone loss with ART initiation
Grace McComsey presented results from A5224s, a sub-study of A5202, which compared change in BMD and body fat at 96 weeks in 269 subjects randomized to (abacavir/lamivudine) ABC/3TC with efavirenz (EFV) or (atazanavir/ritonavir) ATV/r or (tenofovir/emtricitabine) TDF/FTC with EFV or ATV/r (Oral Abstract 106LB).The mean age of subjects was 38, 87% were male and 47% white with mean CD4=233 cells/ul. Change in BMD was greater in the TDF/FTC than ABC/3TC group at the lumbar spine (-3% vs -1.3%, p=0.04) and total hip (-3.9% vs -2.6%, p=0.03), and greater in the ATV/r than EFV group at the lumbar spine (-3.2% vs -1.7%, p=0.04) but not the hip. Importantly, the decline in BMD occurred predominantly within the first 48 weeks and stabilized thereafter. This study confirmed that there may be detectable differences in short term bone loss between different treatment regimens in carefully performed studies, but what remains uncertain is whether these differences persist and become clinically important with long term follow up.
Bone loss in select HIV+ populations
One unresolved question in the literature is how much of the low BMD in HIV+ patients is due to the HIV infection itself, including its contribution to hormonal and nutritional dysregulation, and how much is due to antiretrovirals. Grijsen et al presented BMD measurements from 26 men with primary HIV infection (Poster 745). The mean age was 38, 77% were Caucasian, and 73% had a negative or indeterminate Western blot. Z-scores were slightly lower than expected (-0.7+/-1.4) at the lumbar spine, but not at the hip. Bone density is dependent on cumulative effects; therefore, the lower than expected BMD in these subjects should not be solely attributed to the effects of acute HIV infection. Importantly, bone turnover markers which reflect current remodeling activity were all within the normal range. Longitudinal BMD evaluations of these subjects would be extremely helpful in defining the effects of HIV infection on bone remodeling.
Longitudinal BMD data for 255 HIV+ subjects on HAART from the French Aquitaine cohort (Poster 747) were presented by Cazanave et al. The mean age was 43 and 68% were male. After two years follow-up, 11% of subjects with osteopenia at baseline met criteria for osteoporosis, while 28% (20/72) with normal BMD at baseline met criteria for osteopenia. They did not present change in absolute BMD by group which makes this data difficult to compare to rates in other studies. They did present change in median Z scores, which were modest: between -0.1 to -0.2 at the femoral neck and lumbar spine, respectively, in men.
Longitudinal BMD data was also presented by Sharma et al. from the CHAMPS cohort in 230 HIV+ and 159 HIV- men with mean age of 56 years, 58% of whom were black, and 88% with a reported lifetime use of cocaine or opioids (Poster 746). After two years follow-up, 12% of the men with osteopenia at baseline met criteria for osteoporosis, while 14% of men with normal BMD at baseline met criteria for osteopenia. Progression to osteoporosis was similar between HIV+ and HIV- groups. In multivariate analysis, there was an interaction between heroin use and AIDS diagnosis, such that the greatest bone loss was in subjects with both heroin use and AIDS diagnosis.
The Aquitane data seems to contradict findings from a predominantly white cohort from the United States which showed that BMD was stabile in younger HIV+ men on established ART 8. But there are important differences in their methodology which make the results difficult to compare. In the Aquitane study, the authors excluded all differences that were less than the scanners' coefficient of variation, which may bias towards finding larger differences, and they report changes in categorization by T scores (osteopenia and osteoporosis) or change in Z scores, instead of the more standard percent change in absolute BMD. The CHAMPS data also illustrates the importance of having appropriate HIV- controls. The proportion of HIV+ subjects that progressed to osteoporosis was actually similar in the Aquitane and CHAMPS studies. It is possible that if the Aquitane cohort had HIV- controls with similar behavioral risks as in the CHAMPS cohort, they would also find no difference evolution of BMD by HIV status.
Fux et al. explored the relationship between proximal renal tubulopathy (PRT) and bone metabolism (Poster 748) in the Swiss HIV Cohort. In this study, they examined bone turnover markers, parathyroid hormone (PTH), and levels of 25-hydroxyvitamin D (25OHD) in subjects with either PRT (>3 of 4 parameters: proteinuria, phosphaturia, uricosuria, glucosuria) or isolated hyperphosphaturia. 10% of all subjects had elevated bone formation markers while 50% had elevated bone resorption markers. More bone turnover marker abnormalities occurred in patients with PRT than isolated hyperphosphaturia. In a companion analysis of 251 consecutive HIV+ subjects treated in the Swiss HIV Cohort, 42% of whom were on tenofovir-containing regimens, Wirz et al. found that 25% of subjects had reduced phosphate reabsorption (TmPO4/GFR<0.08), 40% had 25OHD <30ng/ml, and 5% had PTH>65 ng/L(Poster 749). Tenofovir use was associated with reduced phosphate reabsorption; however, increased bone turnover marker levels associated with tenofovir use were not mediated by 25OHD deficiency or elevated PTH. These studies underscore that the mechanism of tenofovir-associated bone loss is complicated and not well defined, and cannot be entirely attributed to proximal tubular toxicity leading to phosphate wasting and decreased vitamin D metabolites.
Fracture rates and fracture risks
In an oral session, estimates of fracture incidence in HIV+ individuals were presented from analyses of three different HIV cohorts. First, Dao et al. compared fracture incidence data from 8456 subjects in the HIV Outpatient Study (HOPS) with age-standardized rates of fracture in the general population from the National Hospital Discharge Survey (NHDS) (Oral abstract 128). Median age of HIV+ patients was 37, 81% were male and 56% white. Rates of fracture were higher in HIV+ patients than the general population and were higher among HIV+ patients in the current period 2002-2008 than in the 1990's.
Womack et al. compared rates of fracture among over 100,000 HIV+ and HIV- male veterans in the Veterans Aging Cohort Study (VACS) (Oral Abstract 129). Mean age was 47 at time of enrollment (55 at time of fracture) and 50% were African American or Hispanic. HIV status was associated with increased risk of fracture (HR=1.38 95% CI, 1.18, 1.60) after adjustment for other traditional risk factors such as age, white race, weight, and alcohol use. Between-group differences in fracture rates were more apparent when restricting the analysis to older subjects (age>50). Among HIV+ subjects, class of ART was not predictive of fracture events.
Yin et al. compared rates of fracture among 1728 HIV+ and 663 HIV- women in enrolled in the Women's Interagency HIV Study (WIHS) (Oral Abstract 130). Women were predominantly premenopausal and African American (57%), and had a mean age of 38 and body mass index of 29 kg/m2. Incidence density rates of fracture over a median of 5 years follow-up (either considering all fractures or just fragility fractures) were similar between HIV+ and HIV- groups before and after adjustment for traditional fracture risk factors. Among HIV+ women, traditional risk factors (white race and age) and history of AIDS defining illness were more important predictors of fracture than antiretrovirals, defined by type or duration of exposure.
One could conclude from this data that fracture risk is increased among HIV+ men (especially white men) both young and old, but not in premenopausal women because of the protective effects of estrogen. However, it is important to note that the control group from the HOPS study represents the general population, and not a prospectively recruited control group with similar lifestyle risk factors such as in the WIHS or VACS; therefore, the comparison may overestimate the difference between HIV+ and HIV- groups. I am still uncertain how much impact HIV infection or ART has on fracture risk in younger HIV+ men.
Age is known to be the most important risk factor for fracture. The VACS data clearly suggests that risk of fragility fracture is greater among older HIV+ than HIV- men, even after consideration of traditional risk factors. The relative impact of HIV status on fracture risk is modest (HR=1.38) after consideration of traditional risk factors, but similar in magnitude to age, white race and alcohol abuse in multivariate models. The impact of HIV infection on fracture risk in older, postmenopausal women is still undefined, but will probably be similar to the findings in older HIV+ men. None of these studies provided data that differentiated risk of fracture between specific antiretroviral classes or agents; larger studies with longer follow-up in specific populations with increased fracture events, such as older HIV+ individuals, may be necessary to tease out cumulative antiretroviral effects.
Vitamin D: prevalence of insufficiency/deficiency, associations with ART, and immune effects
In a themed poster discussion, data on the prevalence of vitamin D deficiency [serum 25-hydroxyvitamin D (25OHD)<20ng/ml (50nmol/L)] or vitamin D insufficiency/deficiency [25OHD levels<30ng/ml (75nmol/L)] were presented from different HIV cohorts. Data from studies with HIV+ and HIV- subjects suggest that 25OHD levels or prevalence of vitamin D insufficiency/deficiency do not differ by HIV status9, 10. Studies presented at CROI confirm that vitamin D insufficiency/deficiency occurs in approximately 60-90% of HIV+ patients depending on race/ethnicity, and the season in which the 25OHD is obtained (Table).
A recent study found an association between NNRTI use and lower 25OHD levels in patient on established ART regimens, especially when the dataset was restricted to white patients13. Efavirenz induces cytochrome p450 enzymes and may increase the metabolism of 25OHD to inactive compounds through upregulation of the 24-hydroxylase 14, 15. Initiation of efavirenz-containing regimens was associated with an approximately 5mg/dl decrease in serum 25OHD levels, an effect that remained significant even after adjustment for baseline 25OHD, race and season of sampling15. In subset analyses of 116 subjects with 25OHD levels before 12 months after initiation of ART, Broderi et al found no significant difference between EFV-containing and other regimens in change in 25OHD after initiation of ART (Poster 751). With a larger sample size (N=211) Mueller et al. found that subjects starting ART with NNRTI-containing regimens (89% on efavirenz) had a greater decrease in 25OHD levels (approximately 3-4 ng/ml) than subjects on PI-containing regimens after 12 months (Poster 752).
The last two posters in this session provided interesting insights on the extra-skeletal effects of vitamin D. Mehta et al performed post-hoc analysis of baseline serum 25OHD levels in HIV+ pregnant women in Tanazania who were randomized to receive multivitamin supplementation (excluding Vitamin D) (Poster 753). They found that vitamin D insufficiency/deficiency (<32ng/ml) at baseline was associated with a higher risk of developing wasting syndrome (BMI<18kg/m2) or progression to WHO HIV disease stage III or IV during the first two years follow-up. In a previous publication of this dataset, maternal vitamin D insufficiency/deficiency was also associated with higher risk of peri-natal mother-to-child transmission of HIV16. French et al. presented data from the WIHS cohort that demonstrated an association between 25OHD levels and the diagnosis of bacterial vaginosis (BV), a common cause of vaginitis (Poster 754). There was a dose-response relationship between 25OHD levels and BV, and in multivariate analysis, vitamin D deficiency remained independently associated with BV after adjusting for black race and number of sexual partners.
These data confirm that vitamin D insufficiency/deficiency is common in HIV+ patients, especially in patients with highly-pigmented skin, and may be associated with the initiation of efavirenz-containing regimens. The exact mechanisms of the efavirenz and other antiretrovirals on 25OHD metabolism still have to be worked out, as well as its long-term impact on 25OHD levels. The current guidelines on vitamin D levels are based upon physiological studies and clinical data that are based upon skeletal endpoints (osteoporosis and fracture). It is not known what levels of 25OHD are necessary for non-skeletal effects, including effects on innate and adaptive immunity. There is growing interest in the scientific community to study the effects of vitamin D on non-skeletal endpoints. Meanwhile, I think it is reasonable to screen for vitamin D deficiency in all HIV+ patients as promoted by the European AIDS Clinical Society and to provide treatment/supplementation to reach levels in the range of 40-60 ng/ml.
Studies at CROI this year confirmed that initiation of ART is associated with bone loss within the first 48 weeks. Tenofovir-containing regimens may cause greater bone loss than abacavir-containing regimens, but the exact mechanism of tenofovir's effect on bone remodeling has not been established. Certain HIV+ patients on established ART may continue to experience declines in BMD, especially older HIV+ individuals with additional risk factors for osteoporosis/fracture. Risk of fracture is also increased in older HIV+ men, but has not been fully established in younger HIV+ men, and does not appear to be increased in younger HIV+ women. Vitamin D deficiency/insufficiency is very common among HIV+ individuals. Given its known effects on skeletal health and potential effects on the immune system and other non-skeletal endpoints, vitamin D screening and adequate supplementation should be encouraged for all HIV+ individuals.
Poster 750. Assessment of Vitamin D Levels among HIV-infected Persons in the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy: SUN Study. Christine Dao1, P Patel , S Pals , T Bush , F Rhame , T Overton , E Kojic , K Wood , J Brooks , and the SUN Study Investigators. Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010.
Poster 751. Prevalence of Hypovitaminosis D among HIV+ Patients Enrolled in a Large Italian Cohort. Marco Borderi1, F Vescini , A Cozzi-Lepri , A Di Caro , I Shlacht , G Cassola , G Pellizzer , J Vecchiet , MC Re , A d'Arminio Monforte1 , for the Icona Fndn Study Group. . Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010. Poster 751
Poster 752. High Prevalence of Severe Vitamin D Deficiency in cARTnaïve and Successfully Treated Swiss HIV Patients. N Mueller , Christoph Fux , B Ledergerber , L Elzi , P Schmid , T Dang , L Magenta , A Calmy , A Vergopoulos , H Bischoff-Ferrari , and Swiss HIV Cohort Study. Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010.
Poster 753. Vitamin D and HIV-related Complications and HIV Disease Progression in Women in Tanzania. Saurabh Mehta , D Spiegelman , F Mugusi , E Giovannucci , G Msamanga , and W Fawzi1 Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010.
Poster 754. Vitamin D Deficiency and Bacterial Vaginosis among HIVinfected and -uninfected Women in the US. Audrey French , , O Adeyemi , , D Agniel , M Yin , K Anastos , and M Cohen , Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010.
Poster 745. High Prevalence of Reduced Bone Mineral Density in Primary HIV-Infected Men. Marlous Grijsen, S. Vrouenraets, R Steingrover, P Lips, J Lange, P Reiss, F Wit, and J Prins. Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010
Poster 746. Longitudinal Analysis of Bone Mineral Density in Aging Men with or at Risk for HIV Infection. Anjali Sharma, P Flom, J Weedon, and R Klein. Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010
Poster 747. Changes in Bone Mineral Density: 2-year Follow-up of the ANRS C03 Aquitaine Cohort. C Cazanave, S Lawson-Ayayi, N Barthe, B Uwamaliya-Nziyumvira, A Kpozehouen N Mehsen P Mercie, P Morlat, Michel Dupon, F Dabis, and GECSA. Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010
Poster 748. Bone Turnover, and in Particular Osteoclast Activity, Is Increased in Patients with Confirmed Proximal Renal Tubulopathy within the Swiss HIV Cohort Study. Christoph Fux, B Hasse, M Opravil, M Cavassini, A Calmy, V Gurtner-delaFuente, P Schmid, M Stoeckle, M Flepp, H Furer, and Swiss HIV Cohort Study Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010
Poster 749. Renal Phosphate Wassting and Increased Bone Turnover in Tenofovir-treated Patients are not Mediated by Low 25 Vitamin D or Hyperparathyroidism. S Wirz, S Rubeli, A Christen, A Popp, C Largiader, N Mueller, A Calmy, H Furrer, and Christoph Fux. Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010
Oral Abstract 128. Higher and Increasing Rates of Fracture among HIV-infected Persons in the HIV Outpatient Study Compared to the General US Population, 1994 to 2008. Christine Dao , B Young , K Buchacz , R Baker , J Brooks , and the HIV Outpatient Study Investigators. Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010.
Oral Abstract 129. HIV Infection and Fragility Fracture Risk among Male Veterans. Julie Womack , J Goulet , C Gibert , C Brandt , , K Mattocks , , D Rimland , M Rodriguez-Barradas , J Tate , M Yin , J Amy , , and Veterans Aging Cohort Project Team. Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010.
Oral Abstract 130. Fracture Rates Are Not Increased in Younger HIV+ Women. Michael Yin , Q Shi , D Hoover , K Anastos , A Sharma , M Young , A Levine , M Cohen , E Golub , and P Tien10 Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010. Oral 130
Oral Abstract 106LB. Bone and Limb Fat Outcomes of ACTG A5224s, a Substudy of ACTG A5202: A Prospective, Randomized, Partially Blinded Phase III Trial of ABC/3TC or TDF/ FTC with EFV or ATV/r for Initial Treatment of HIV-1 Infection. Grace McComsey , D Kitch , E Daar , C Tierney , N Jahed , P Tebas , L Myers , P Sax , and AACTG Study A5224. Program of the Conference of Retrovirus and Opportunistic Infections. San Francisco February 16-19, 2010. Oral 106LB
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