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Recent Bone/aging Studies
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Low Baseline CD4+ Count is Associated with Greater Bone Mineral Density Loss after ART Initiation (see below) Clinical Infectious Diseases Advance Access published August 13, 2013
IAS: Number of regimens rather than cumulative exposure to antiretrovirals associated with lower bone mineral density in HIV-positive subjects - (07/22/13)....."suggesting greater reductions in bone mineral density associated with ART-induced HIV-RNA suppression occurring with multiple ART regimens"
from Jules: Previous research has found that when a patient starts ART for the first time they lose up to 6% of their bone mineral density (BMD) over 48 weeks which then tends to stabilize but there is conflicting data with some studies suggesting there is continuing low loss of BMD. There were 2 studies at IAS supporting that when switching a regimen this might cause further bone loss, the SECOND-LINE bone sub study. Perhaps when switching a regimen bone loss may be associated with increasing viral load and causing dysfunctional immunological & cytokine activity affecting bone turnover etc.
(report on this study by Cotter that the number of regimens is associated with bone loss) IAS: Number of ART Regimens But Not Time on ART or Tenofovir Tied to Low Bone Density - (07/20/13)
CROI: HIV is an Independent Predictor of Lower Bone Mineral Density in HIV-positive Subjects Compared to HIV-negative Subjects - (07/24/13)......"BMD was found to be lower in the HIV+ group at the lumbar spine, total hip and femoral neck after adjustment for demographic factors and BMI. Low BMD (Z-score < -2) was about 2 fold higher in the HIV+ group across the sites. BMD was not related to vitamin D levels or PTH. However, alkaline phosphatase, whose skeletal derived fraction is a measure of bone turnover, was higher in HIV+ subjects and partially, but not completely, explained the difference in BMD by serostatus. This study confirms previous findings regarding low BMD in HIV+ populations"
IAS: Lower bone mineral density independently associated with both increased bone turnover and HIV-1 infection in HIV-positive subjects compared to HIV-negative subjects - (07/11/13) HIV Upbeat Study
IAS: Less Bone Loss With Raltegravir Than NRTIs in 'Second-Line' Regimens - (07/05/13).....People randomized to second-line regimens containing raltegravir and lopinavir/ritonavir lost less bone mineral density (BMD) through 48 weeks than those randomized to nucleosides or tenofovir (NRTIs) plus lopinavir/ritonavir in a multinational study [1]. But incidence of osteopenia or osteoporosis did not differ between the two treatment arms.
IAS: HIV infection was associated with an increased risk of hip fracture, independently of age, gender and co-morbidities: a population-based cohort study - (07/15/13)......"A strong association between HIV infection and hip fracture incidence was found, with an almost 5-fold increased risk in the HIV-infected patients, independently of gender, age, body mass index, smoking, alcohol consumption and co-morbidities. Similarly, a 75% higher risk of all clinical fractures was found among HIV-infected patients." from Jules: notice the increased separation of the graph lines after age 60 between HIV+ & HIV-neg, this has been seen in other studies showing as HIV+ age the risk for bone loss & fracture increases for HIV+ more than for HIV-neg, this same phenomena was reported associated with heart disease with increased risk vs HIV-neg with older age, see pic below-
IAS: Longitudinal study of bone mineral density and vitamin D levels among perinatally HIV-infected Thai adolescents receiving long-term antiretroviral therapy - (07/18/13)......."Perinatally HIV-infected Thai adolescents have high rates of low BMD and vitamin D deficiency. Educational counseling seemed to help improve vitamin D levels, but BMD levels continued to decrease during adolescence. Detection and prevention of osteopenia should be incorporated in routine care for adolescents"
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"We found a significant interaction between lower baseline CD4+ count and higher HIV-1 RNA levels and BMD loss (p=0.043). In subjects with higher HIV-1 RNA levels, the negative effect of lower CD4+ count was greater than in those subjects with lower HIV-1 RNA levels." see recently published study below
CD4 Decline Is Associated With Increased Risk of Cardiovascular Disease, Cancer, and Death in Virally Suppressed Patients With HIV - (08/12/13)
Clin Infect Dis. (July 15 2013)
Marie Helleberg,1 Gitte Kronborg,2 Carsten S. Larsen,3 Gitte Pedersen,4 Court Pedersen,5 Niels Obel,1 and Jan Gerstoft1
HIV[ART] and HCV infections independently contribute to lower bone mineral density but have different effects on bone turnover markers
http://www.natap.org/2013/IAS/IAS_33.htm
Non-Infectious Complications of HIV and Antiretroviral Therapy - IAS 2013 (Kuala Lumpur, Malaysia) written by Roger Bedimo, MD VA North Texas Health Care System - (07/10/13)
"It is well recognized that "traditional" risk factors for decreased bone density are over-represented among HIV-infected patients, including smoking, low BMI and hypogonadism. Knobel et al (3) add to the growing body of literature confirming that even after controlling for these risk factors, HIV infection remains an independent predictor of decreased bone density. In a population-based cohort study, they identified 2,489 HIV-infected patients among 1,118,156 subjects aged 40 or older in Catalonia. Following a median follow-up time of 3 years, they calculated hip and all fracture incidence in the HIV and non-HIV patients. HIV status was associated with a HR 4.7 (2.4-9.5; p< 0.001) for hip fractures and 1.8 (1.2-2.5; p=0.002) for all fractures, adjusting for several factors including age, gender, body mass index (BMI), smoking status, alcohol consumption, oral glucocorticoid use, and co-morbid conditions (as the Charlson Index)."
Also, in a small study of 47 perinatally infected Thai adolescents (4), low bone mineral density (BMD) and low vitamin D levels were significantly prevalent, and increased even further on repeat measurements 12 to 24 months later.
Bone Loss in the HIV-Infected Patient: Evidence, Clinical Implications, and Treatment Strategies- Review
http://www.natap.org/2012/HIV/061812_01.htm
The Journal of Infectious Diseases June 1 2012
Vanessa Walker Harris and Todd T. Brown
"Multiple studies have assessed the impact of ART initiation on bone mineral density and have generally shown a 2%-6% loss of BMD after 48-96 weeks of therapy, regardless of the type of ART initiated [20]. This degree of bone loss is larger than what would be expected by aging alone [28] and is comparable to the bone loss seen in women aged 50-59 over 2 years [29]. Importantly, lower CD4 cell count prior to ART initiation is associated with greater decreases in BMD, implying that earlier initiation of ART would attenuate the bone loss related to ART initiation [10]."
Fractures/Bone Loss in HIV: 'traditional risk factors more important' but HIV & ARV exposure have some impact, Vit D may Improve Bone Health & Reduce Fracture Risk, New Studies
http://www.natap.org/2012/HIV/020812_02.htm
CROI/2013: Lower Baseline CD4 is Associated with Greater Loss of Bone Mineral Density after ART Initiation (same study published in CID reported at CROI this year.
http://www.natap.org/2013/CROI/croi_52.htm
Changes in Bone Mineral Density: two-years follow-up of the ANRS CO3 Aquitaine Cohort - Bone Metabolism Evolves- in 11% from osteopenia to osteoporosis and to osteopenia, bone markers worsen in 41%
http://www.natap.org/2010/CROI/croi_162.htm
Update from 20th CROI: Bones, Vitamin D, Frailty - Todd T. Brown, MD, PhD Association Professor of Medicine and Epidemiology Division of Endocrinology and Metabolism Johns Hopkins University - (04/01/13) "initiation of ART at a higher CD4 cell count may attenuate ART-related bone loss"....."HIV-infected men who had the frailty phenotype (3 of the following 5 characteristics: weight loss, low grip strength, exhaustion, slow walking speed, and low physical activity) had higher levels of IL-6, TNF-alpha, sTNFRII, sCD14, and T cell activation, compared to robust HIV-infected men"......"In the MACS (#444), those with HIV Associated Neurocognitive Disorder had an increased risk of developing the frailty phenotype"......"clinical symptoms (feeling off balance, floating, lightheadedness, faintness) were more common in HIV-infected men and women and strongly associated with falls"
Bone Loss in Young HIV+ Men 'Lifestyle Risk'
http://www.natap.org/2012/HIV/062012_01.htm
studies have found heroin use associated with bone loss; studies have found excessive alcohol use associated with bone loss; smoking cigarettes is associated with bone loss & lifestyle associated with using drugs like not eating properly etc. Also being skinny (low BMI), and not having yet reached peak bone mass due to their young age likely contribute to risk for bone loss"
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Low Baseline CD4+ Count is Associated with Greater Bone Mineral Density Loss after ART Initiation
Clinical Infectious Diseases Advance Access published August 13, 2013
"We found a significant interaction between lower baseline CD4+ count and higher HIV-1 RNA levels and BMD loss (p=0.043). In subjects with higher HIV-1 RNA levels, the negative effect of lower CD4+ count was greater than in those subjects with lower HIV-1 RNA levels."
"The underlying reason for the relationship between low baseline CD4+ count and bone loss with ART initiation is not known but suggests a potential role for the immune system in skeletal maintenance. In animal models, T cells are key mediators of bone loss [19, 20]. T-cell knockout mice do not lose bone with parathyroid hormone administration until after reimplantation of T cells [21].
Potentially, an Immune Reconstitution Inflammatory Syndrome (IRIS)-like phenomenon could underlie ART-associated bone loss. However, our study did not find a relationship between the magnitude of the CD4+ count increase with ART and bone loss, a relationship which would have supported an IRIS-like phenomenon underlying ART-associated bone loss."
"In addition to HIV disease stage, we found traditional osteoporosis risk factors and specific antiretroviral medications placed individuals at increased risk for bone loss after ART initiation. We found older individuals, women, and those with lower BMI to be at greater risk for bone loss with ART initiation. Older HIV-infected individuals and those with lower BMI have been shown to be at increased risk for osteoporosis in prior cross-sectional studies [22]. However, our finding that these groups and also women are at increased risk for BMD loss after ART initiation is concerning given their already lower pre-ART BMD and the potential for falls and subsequent fragility fractures in these groups [23]"
"In addition to HIV disease stage, we found traditional osteoporosis risk factors and specific antiretroviral medications placed individuals at increased risk for bone loss after ART initiation. We found older individuals, women, and those with lower BMI to be at greater risk for bone loss with ART initiation. Older HIV-infected individuals and those with lower BMI have been shown to be at increased risk for osteoporosis in prior cross-sectional studies [22]. However, our finding that these groups and also women are at increased risk for BMD loss after ART initiation is concerning given their already lower pre-ART BMD and the potential for falls and subsequent fragility fractures in these groups [23]."
"In conclusion, we found that low pre-treatment CD4+ count, but not early CD4+ count change with ART, was a strong and independent risk factor for bone loss after ART initiation, providing further evidence for the benefits of the early initiation of ART. Initiation of ART at a higher CD4+ count may reduce the burden of osteoporosis and fragility fractures among HIV-infected patients."
Low Baseline CD4+ Count is Associated with Greater Bone Mineral Density Loss after ART Initiation
Philip M. Grant1, Douglas Kitch2, Grace A. McComsey3, Michael P. Dube4, Richard
Haubrich5, Jeannie Huang5, Sharon Riddler6, Pablo Tebas7, Andrew R. Zolopa1, Ann C Collier8, Todd T. Brown9
Abstract
Background. Bone mineral density (BMD) decreases 2-6% in the two years after antiretroviral therapy (ART) initiation. Pre-ART immune deficiency and early immune recovery may contribute to this loss.
Methods. We pooled data from three treatment-naive ART initiation studies in which serial whole-body dual-energy X-ray absorptiometry scans were performed. We used linear regression to evaluate effects of baseline CD4+ and 16-week CD4+ change (both absolute and relative) on 96-week total BMD change from baseline.
We performed multivariable linear regression to assess associations between baseline variables of age, sex, race/ethnicity, body mass index (BMI), hepatitis C status, parent study, HIV-1 RNA level, and assignment to a protease inhibitor (PI) or tenofovir-containing regimen on 96-week total BMD change.
Results. The included 796 subjects had mean 96-week total BMD loss of 2.0%. In multivariable analysis, baseline CD4+ count was significantly associated with 96-week BMD loss; individuals with baseline CD4+ <50 cells/μL lost significantly more BMD compared to those with CD4+ ≥500 cells/μL. A greater relative, but not absolute, 16-week increase in CD4+ count was significantly associated with greater declines in BMD, but not after controlling for baseline CD4+ count. In multivariable analysis, older age, female sex, lower BMI, higher HIV-1 RNA levels, and PI and tenofovir assignment were also associated with greater BMD decline.
Conclusions. Low pre-treatment CD4+ count, but not greater CD4+ count increase, is a strong and independent risk factor for bone loss after ART initiation. ART initiation at higher CD4+ counts may reduce the burden of osteoporosis and fragility fractures.
Background
With improvements in antiretroviral therapy (ART) and the accompanying aging of the HIV-infected population, HIV-associated non-AIDS (HANA) complications are increasingly impacting the health of HIV-infected individuals [1]. While the rates of other HANA complications appear to decrease with ART, bone mineral density (BMD) loss is unique in that it accelerates after ART initiation, at least over the short term [2]. Low BMD occurs in 40-90% of HIV-infected individuals [3], leading to a 50% increased risk of fragility fracture compared to the risk in uninfected individuals [4].
BMD loss appears most prominent during the first two years of ART, decreasing 2-6%, [5], although recent data suggest this loss may be less with some nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens [6]. In addition to traditional osteoporotic risk factors and antiretroviral medication effects, some data suggest that baseline immune deficiency or ART-associated immune reconstitution could contribute to BMD loss [7]. Here, we pooled data from three treatment-naive ART initiation studies where serial whole-body dual x-ray absorptiometry (DXA) were performed to examine the relationship between baseline CD4+ count and early CD4+ count change with BMD change two years after ART initiation.
Methods
Parent Studies
We accessed subject-level data from three AIDS Clinical Trials Group (ACTG) treatment-naive ART initiation studies in which serial whole-body dual-energy X-ray absorptiometry (DXA) were performed. We included data from ACTG A5005s (enrolled 1998-1999) [8], A5142 (enrolled 2003-2004) [9, 10], and A5224s (enrolled 2005-2007) [5].
ACTG A5005s (a substudy of ACTG 384 [11]) included subjects randomized to nelfinavir, efavirenz, or both combined with either didanosine/stavudine or lamivudine/zidovudine; ACTG A5142 randomized subjects to one of three class-sparing regimens: lopinavir/ritonavir and two NRTIs (lamivudine plus either zidovudine, stavudine or tenofovir disoproxil fumarate - TDF), efavirenz and two NRTIs, or lopinavir/ritonavir and efavirenz [12]; and ACTG A5224s (a substudy of ACTG A5202 [13]) included subjects randomized to atazanavir/ritonavir or efavirenz combined with either abacavir/lamivudine or TDF/emtricitabine.
We included participants from these studies who underwent whole-body DXA scan at baseline (allowable window from 30 days prior to parent study enrollment to 15 days after ART initiation) and 96 weeks (allowable window from 84 to 108 weeks after ART initiation). Because ACTG A5005s and ACTG A5142 did not perform site-specific hip and spine DXA, all assessments of BMD change are based on whole-body BMD, which was collected in all three parent studies. While site-specific DXA is more commonly used to screen for osteoporosis, both total BMD and site-specific BMD predict incident fractures [14, 15]. Additionally, studies in HIV-uninfected and HIV-infected individuals have shown good concordance between BMD measures obtained from whole-body and site-specific DXA (R2=0.88 and 0.83, respectively) [16] [D.K., unpublished data from ACTG A5260]. All DXAs were standardized at the participating sites, then read at the central reading site (Tufts).
Results
Of the 1116 subjects enrolled in the parent studies, 796 subjects had baseline and 96-week DXA evaluations and are included in this analysis. Table 1 displays the baseline characteristics of the included subjects by parent study. Median age was 39 years (IQR 32, 44); 83% were male. The median baseline BMI was 25 (IQR 22, 28). Median baseline CD4+ count and HIV-1 RNA level were 208 cells/μL (IQR 68, 328) and 4.8 log10 copies/mL (IQR 4.4, 5.2), respectively. Sixty-two percent of subjects were randomized to a PI-containing regimen, and 27% received an initial regimen containing TDF.
The mean 96-week total BMD loss from baseline was 2.0% (standard deviation 3.3%). Figure 1 displays the unadjusted relationship between baseline CD4+ count and BMD change 96 weeks after ART initiation. In the base model adjusting for parent study, and PI and TDF use, baseline CD4+ count was associated with BMD loss (p<0.001) with individuals initiating ART at a CD4+ count of <50 cells/μL losing 3.0% more BMD (95% CI:-4.0, -2.0) than those who initiated ART at a CD4+ count of ≥500 cells/μL. Greater relative, but not absolute, 16-week CD4+ count increase was associated with greater BMD decreases at 96 weeks (-2.3% per 10 fold higher; 95% CI: -3.0, -1.7; p<0.001), but this association was no longer significant after controlling for baseline CD4+ count (-0.7% per 10 fold higher; 95% CI: -1.8, 0.4; p=0.21).
In univariate analyses, we also found older age, lower BMI, parent study, higher baseline HIV-1 RNA levels, and assignment to a PI- or TDF-containing regimen each to be significantly associated with 96-week BMD loss (Table 2).
Most associations found in univariate analyses were maintained in multivariable analysis (Table 2). Baseline CD4+ count remained strongly associated with 96-week BMD loss (p<0.001) with individuals in the lowest CD4+ category (i.e., <50 cells/μL) losing a significantly larger BMD percentage than those with a CD4+ count of ≥500 cells/μL (-2.27%; 95% confidence interval: -3.30, -1.25). Additionally, older age, female sex, lower BMI, higher HIV-1 RNA level, and PI and TDF assignment were all independently associated with loss of BMD at 96 weeks in multivariable analysis.
We found a significant interaction between lower baseline CD4+ count and higher HIV-1 RNA levels and BMD loss (p=0.043). In subjects with higher HIV-1 RNA levels, the negative effect of lower CD4+ count was greater than in those subjects with lower HIV-1 RNA levels.
Discussion
In this pooled analysis of nearly 800 individuals initiating ART in randomized clinical trials, we found a strong and independent association between low baseline CD4+ count and total BMD loss in the first two years of treatment. Additionally, we found independent associations between older age, female sex, lower BMI, higher HIV-1 RNA level, PI use, and TDF use and BMD loss. We did not find evidence that the extent of immune reconstitution, as measured by CD4+ count increase at 16 weeks, was associated with BMD change after controlling for baseline CD4+ count.
There are conflicting reports in the literature on the relationship between baseline CD4+ count and the risk for BMD loss on ART [17, 18]. Our study benefits from the large number of included subjects and the comprehensive data that was gathered on subjects in the setting of clinical trials. We found that even after controlling for multiple potential confounders such as BMI that there was a robust relationship between low baseline CD4+ count and greater bone loss after ART initiation. The underlying reason for the relationship between low baseline CD4+ count and bone loss with ART initiation is not known but suggests a potential role for the immune system in skeletal maintenance. In animal models, T cells are key mediators of bone loss [19, 20]. T-cell knockout mice do not lose bone with parathyroid hormone administration until after reimplantation of T cells [21]. Potentially, an Immune Reconstitution Inflammatory Syndrome (IRIS)-like phenomenon could underlie ART-associated bone loss. However, our study did not find a relationship between the magnitude of the CD4+ count increase with ART and bone loss, a relationship which would have supported an IRIS-like phenomenon underlying ART-associated bone loss.
In addition to HIV disease stage, we found traditional osteoporosis risk factors and specific antiretroviral medications placed individuals at increased risk for bone loss after ART initiation. We found older individuals, women, and those with lower BMI to be at greater risk for bone loss with ART initiation. Older HIV-infected individuals and those with lower BMI have been shown to be at increased risk for osteoporosis in prior cross-sectional studies [22]. However, our finding that these groups and also women are at increased risk for BMD loss after ART initiation is concerning given their already lower pre-ART BMD and the potential for falls and subsequent fragility fractures in these groups [23].
TDF use has been associated with BMD loss in multiple studies [5, 24] and more recently has also been associated with fracture risk [25]. Studies evaluating the effect of PI use on bone health have been conflicting, partially dependent on the site being evaluated (e.g., spine vs. hip vs. total BMD) [5, 16]. After pooling studies, we found a strong and independent association between randomization to a PI and BMD loss. Previous studies have also shown an association between the use of certain PIs and incident fractures, reinforcing that PIs can have negative effects on bone metabolism [25].
There are several limitations to our study that deserve highlighting. We assessed change in total BMD rather than site-specific BMD. While there is good correlation between the two measures when measured cross-sectionally, the correlation between the change in the two measures has not been evaluated to our knowledge in an HIV-infected population. In the general population, BMD changes in total body underestimate losses in lumbar spine, total hip, and distal forearm in the early post-menopausal period [26]. However, similar to site-specific BMD, total BMD is also a valid surrogate for fracture risk [15].
The BMD changes found at two years in our study were relatively modest and of unclear clinical significance. It has been noted that fracture incidence is highest in the first two years after ART initiation compared to in subsequent years [27]. Additionally, the significance of the loss could be compounded in persons with pre-existing low BMD or if the loss continues throughout the course of ART. Another potential limitation is that we pooled the bone loss data for all PIs used in our study (nelfinavir, lopinavir/ritonavir, and atazanavir/ritonavir), and it is possible that there are differences in bone effects among the PIs. Some of the regimens in these studies are no longer in common use, but when controlling for parent study in multivariate analysis, study was not a significant factor. We did not have complete data on covariates such as tobacco or alcohol use, testosterone or vitamin D levels, or use of relevant concomitant medications (e.g., calcium, vitamin D, bisphosphonates, etc.) that could affect BMD. However, given the randomized nature of the three studies, it is unlikely that such unmeasured covariates could have biased our estimates of measured covariates. Additionally, since this was a post-hoc analysis with multiple comparisons, marginally significant associations should be interpreted cautiously. Finally, due to inadequate power, we were unable to determine the precise baseline CD4+ count threshold where bone loss after ART initiation was greater than those in the highest CD4+ count stratum.
In conclusion, we found that low pre-treatment CD4+ count, but not early CD4+ count change with ART, was a strong and independent risk factor for bone loss after ART initiation, providing further evidence for the benefits of the early initiation of ART. Initiation of ART at a higher CD4+ count may reduce the burden of osteoporosis and fragility fractures among HIV-infected patients.
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