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. Author manuscript; available in PMC: 2015 Feb 1.
Published in final edited form as: Curr Infect Dis Rep. 2014 Feb;16(2):393. doi: 10.1007/s11908-014-0393-1

Bones, Fractures, Antiretroviral Therapy and HIV

Linda A Battalora 1, Ben Young 2,3, Edgar T Overton 4
PMCID: PMC4240510  NIHMSID: NIHMS567774  PMID: 24535243

Abstract

The course of HIV infection has been dramatically transformed by the success of antiretroviral therapy from a universally fatal infection to a manageable chronic disease. With these advances in HIV disease management, age-related comorbidities, including metabolic bone disease, have become more prominent in the routine care of persons living with HIV infection. Recent data have highlighted the role of HIV, initiation of antiretroviral therapy (ART), and hepatitis C virus (HCV) co-infection in bone mineral density (BMD) loss and fracture incidence. Additionally, the underlying mechanism for the development of metabolic bone disease in the setting of HIV has received considerable attention. This review will highlight recently published and presented data and synthesize the current state of the field. These data highlight the need for proactive prevention for fragility fractures.

Introduction

Among individuals who successfully engage in HIV care, combination antiretroviral therapy (cART) has resulted in dramatic reductions in HIV-associated morbidity and mortality, increased life expectancy, and an increase in age-related comorbidities. Clinicians are reporting a premature aging phenotype among HIV-infected individuals, manifest by an increasing incidence of therapy-related metabolic complications, including frailty, neurocognitive dysfunction, hyperlipidemia, insulin resistance, diabetes mellitus, cardiovascular disease, osteoporosis and related fractures [1, 2]. Specifically, low bone mineral density (BMD) is a frequent complication of HIV infection and/or its treatment with cART [3]. Several cohort studies have reported that a majority of HIV-infected persons have low BMD despite the fact that most of the HIV-infected persons included in these studies were under the age of 50, an age below which osteoporosis is a rare diagnosis in the general population [4, 5]. Metabolic bone disease may have a dramatic impact on the health of the HIV population, as multiple studies show that HIV-infected individuals experience significantly elevated rates of bone fractures [6]. This review will focus on recent data related to three areas of interest for HIV-related metabolic bone disease: the effects of specific antiretroviral strategies, possible mechanisms for BMD loss, and the risk of fracture.

ART and Bone Loss

The expanding list of available antiretroviral agents allows care providers to develop a myriad of virologically suppressive regimens but how do these affect bone health? Given that tenofovir (TDF) has been consistently associated with BMD loss, numerous studies have looked at alternatives to this agent. One approach is switching from TDF to an alternative agent. At the 2012 Conference on Retroviruses and Opportunistic Infections (CROI), Negredo reported on a small study assessing 54 persons on a suppressive TDF-containing regimen who either continued TDF (n=28) or switched to abacavir (ABC, n=26) [7]. Those persons who switched to ABC had a 2.1% increase in BMD at the femoral neck while there was no change in the TDF group (p=0.04). In the lumbar spine, the ABC switch group experienced a 0.2% increase in BMD at 48 weeks while the TDF group had a 2.9% decrease in BMD (p=0.09). At CROI 2013, Bloch reported on a study evaluating an open-label switch from TDF to raltegravir (RAL), an integrase inhibitor, in 37 persons with fully suppressed HIV viremia and femoral neck T score < −1.0 [8]. There were significant increases in BMD at lumbar spine, femoral neck and total hip (1.5%, 2.1%, and 2.5%, respectively; p <0.05 for all). Markers of both bone formation (osteocalcin) and resorption (N-telopeptide and bone alkaline phosphatase (BAP)) declined significantly at both week 24 and 48. These studies suggest that switch strategies may be an effective approach to mitigate TDF-associated bone loss although clinical guidance regarding which patient to switch remains undefined.

Given the specific concern of bone toxicity from nucleoside/tide reverse transcriptase inhibitors (NRTIs), other studies have evaluated bone markers during treatment with novel NRTI-sparing regimens. The RADAR Study, presented at the 2013 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS), presents a cautionary tale [9]. Ritonavir-boosted darunavir (DRV/rtv) was paired with either RAL or tenofovir/emtricitabine (TDF/FTC) in 80 ART-naïve persons. After 48 weeks of treatment, the RAL arm was associated with a 1.2% increase in total body BMD while the TDF/FTC arm experienced a 0.7% loss. Bone biomarkers remained stable over 48 weeks for the RAL arm but increased significantly in the TDF/FTC arm. Unfortunately, the RAL arm was less effective at maintaining HIV virologic suppression (63% vs. 83% at 48 weeks, p =0.045) highlighting the importance in focusing first on virologic success before considering metabolic consequences.

Data from virologically successful NRTI-sparing regimen have also been presented. Hoy presented 96 week data from the SECOND-LINE study at IAS 2013 comparing two second line regimens: lopinavir/ritonavir (LPV/rtv) combined with either RAL or 2 or 3 NRTIs [10]. Those persons randomized to the NRTI arm had significantly greater bone loss at both the proximal femur (−5.2% vs. −2.9%, p< 0.001) and the lumbar spine (−4.2% vs. −2.0%, p< 0.001). A multivariate analysis found that BMD loss was independently associated with lower BMI, exposure to TDF, and non-Asian ethnicity. Another NRTI-sparing study (INROADS) was presented at the 15th International Workshop on Comorbidities and Adverse Reactions [11]. In this single arm study, 54 HIV-infected persons (12 ART naïve persons with baseline resistance to NNRTIs and 42 persons with previous failure to PI-based ART) were given DRV/rtv with etravirine. At 48 weeks, there was no change in median BMD at the total hip (1.0 g/cm2 at both time points) and a non-significant decline in BMD at the lumbar spine (1.2 to 1.1 g/cm2). Taken together, these three studies highlight than BMD loss can be reduced by the selection of NRTI-free (specifically TDF) regimen.

Alternative NRTI strategies for ART-naïve subjects have also been explored. Moyle and colleagues recently published 96-week data from an open label randomized study that evaluated bone, renal and metabolic consequences of treatment with efavirenz paired with either TDF/FTC or abacavir/lamivudine (ABC/3TC) [12]. Of 385 subjects enrolled, 249 completed the study. Total hip BMD declined in both groups with the greatest decline in the first 48 weeks and stabilization in the second 48 weeks. At 96 weeks, total hip BMD loss was significantly greater in the TDF/FTC arm compared to the ABC/3TC arm (−3.6% vs. −2.2%. p<0.001). Similarly, ABC/3TC was associated with less bone loss at the lumbar spine (−0.8% vs. −1/9%, p=0.112). Wohl recently presented data from the ASSURE Study comparing unboosted atazanavir (ATV) with ABC/3TC to ritonavir-boosted atazanavir (ATV/rtv) with TDF/FTC in 296 ART-naïve subjects who were HLA B*5701 negative [13]. In this study, changes in markers of bone formation and turnover were evaluated. In the ABC/3TC arm, there were reductions in markers of bone formation (osteocalcin) and bone resorption (C-telopeptide and BAP) as well as parathyroid hormone, while the markers were relatively stable in the TDF/FTC arm. The differences in the changes in these markers was highly significant (p<0.001 for all). The mean 25-OH vitamin D levels declined for the ABC/3TC group (28 to 25 ng/mL) and increased for the TDF/FTC/rtv group (26 to 29 ng/mL, p< 0.05 for both). These two studies confirm previous studies highlighting that ABC/3TC is associated with less BMD decline and bone turnover than TDF/FTC [14,15].

Perhaps more provocative on the ART front has been the arrival of tenofovir alafenamide fumarate (TAF), an investigational tenofovir prodrug. Zolopa shared the 24-week data from the phase 2 trial at CROI 2013 comparing TAF vs. TDF combined with elvitegravir, cobicistat, and emtricitabine in ART naïve persons [16]. Bone loss was significantly reduced with TAF at both the lumbar spine and (−0.8% vs. −2.5%, p=0.002) and total hip (−0.3% vs. −2.0%, p<0.001). Subsequent 48 week data from this study confirmed the superiority of TAF over TDF at both total hip (−0.6% vs. −2.4%, p<0.001) and lumbar spine (−1.0% vs. −3.4%, p< 0.001) [17]. Specifically, no decline in total hip BMD was reported in 32% persons in the TAF arm compared to only 7% in the TDF arm (p<0.001). Markers of bone formation and resorption increased to a greater degree over the 48 weeks in the TDF arm: P1NP (109% vs. 169% baseline value) and CTx (119% vs. 178%, p < 0.001 for both). Taken as a whole, TDF-sparing regimens, regardless of the agents chosen, significantly reduce BMD loss.

Mechanisms behind Bone Loss

The pathogenesis of bone disease among people living with HIV is unclear, but an area of active research. Several groups have focused on different aspects of the pathogenesis. Failure to reach peak BMD is commonly cited as a cause for the low BMD in persons who are infected with HIV before age 30, the age at which peak BMD is achieved. Tanchaweng presented data on changes in BMD among 46 HIV-infected Thai adolescents [18]. At a median age of 14.5 years, 23% had low BMD (defined as a z-score < −2.0) and 19% had low BMD when re-evaluated 2 years later. Only male sex was associated with low BMD. Notably no ART agents, and specifically TDF, were associated with low BMD. The limited sample size likely provided inadequate power to demonstrate any effect related to ART. In another cohort study, Yin and colleagues compared BMD in 30 HIV-infected youth with 15 uninfected youth (ages 20–25) [19]. The HIV-infected youth were all receiving ART; 15 were infected perinatally and 15 during adolescence. By routine DXA scanning, the HIV-infected youth had lower z-scores at all sites evaluated (spine, total hip, radius). CTX, a marker of bone resorption, was significantly higher in the HIV-infected youth. These investigators also utilized high resolution CT scanning at the distal radius and tibia and demonstrated that HIV-infected youth had reduced trabecular BMD and cortical thickness at these sites indicating not only a reduction in bone mass but also in bone strength. In another observational study presented at CROI, Jiminez reported BMD data from a cohort of 24 perinatally infected children and identified low BMD (defined as z-score < −1.0) in 38% of the cohort [20]. Low BMD was associated with nadir CD4 count and time with detectable HIV viremia but no relationship to TDF exposure or markers of systemic inflammation. Taken as a whole, these studies indicated that a significant proportion of HIV-infected youth are failing to achieve peak BMD although the factors driving this process remain to be fully elucidated.

The association between the severity of HIV disease and lower BMD is well established. A recent analysis by Grant and colleagues from the AIDS Clinical Trials Group demonstrates that the loss of BMD with ART initiation is greatest for those individuals with low CD4 cell counts, particularly those persons with a CD4 count < 50 cells/mm3 [21]. Additional factors that were independently associated with BMD loss included older age, female sex, lower BMI, higher HIV-1 plasma viral loads, initiation of protease inhibitor, and initiation of TDF. A separate analysis by Erlandsen (CROI 2013) confirmed the relationship between low nadir CD4 levels and BMD loss during ART initiation [22].

Another mechanistic study presented at CROI 2013 focused on the role that B cells play in osteoclast activation and increased bone resorption. Titanji reported on a cross sectional evaluation including 45 HIV-infected and 45 seronegative persons [23]. When they evaluated the B cells from these two groups, intracellular levels of osteoprotegerin (OPG) was reduced and receptor activator of nuclear factor kappa-B ligand (RANKL) was increased with HIV infection. RANKL binds to osteoclasts to increase bone formation while OPG binds to RANKL to prevent its action on osteoclasts. The HIV-infected persons had elevated markers of boner turnover (CTX) while markers of bone formation (osteocalcin) were similar between the groups. These data suggest that aberrant B cell activity in HIV infection contributes to bone loss by increasing osteoclast activity. Given that B cell dysfunction is a prominent component of advanced HIV disease, this may partially explain why advanced HIV disease is associated with the greater BMD loss.

As noted above in the study by Grant, an association between protease inhibitors and low BMD has long been recognized [24, 3]. A provocative presentation at CROI 2013 by Beaupere focused on the toxicity of HIV proteins and two boosted PIs (ATV/rtv and DRV/rtv) on osteoblast and adipocyte development [25]. Both cells are derived from the mesenchymal stem cells (MSC). In the presence of HIV proteins or these boosted PIs, the MSCs lost proliferative capacity, increased reactive oxygen species production, increased expression of senescence markers and markers of cellular aging (farnesylated pre-lamin A). Strikingly, the differentiation into osteoblasts and adipocytes was greatly reduced as a consequence. Hence, the authors provide a potential mechanism by which this class of agents potentially induces bone loss: a reduction in bone formation due to inhibition of osteoblast formation and imbalance towards bone turnover. A final experiment by this group demonstrated that the disruption of osteoblast formation was corrected by administration of pravastatin suggesting that bone loss due to PIs could be abrogated by blocking the mevalonic acid pathway and hence demonstrating positive non-lipid effects of statins.

Clearly, antiretroviral agents that induce less bone loss than TDF are of interest but we must be mindful to select ART regimens that will durably suppress HIV viremia. The next steps are to understand the causes of bone loss among our patients and the mechanisms behind this process. To further explore the reduced loss of BMD with TAF, Liu studied the in-vitro effects of TAF on osteoblasts at concentrations that are achieved with oral therapy [26]. First, the authors demonstrated that in-vitro drug levels achieved in osteoblasts are similar to in-vivo levels achieved in lymphocytes. Secondly at clinically relevant concentrations, TAF induced no cytotoxic effects on osteoblasts with normal cell viability in-vitro. Thus, a possible explanation for the improved BMD outcomes seen with TAF as compared to TDF related to lessened osteoblast toxicity and hence normal bone turnover.

Taken together, these studies highlight several key aspects of bone disease pathogenesis: 1) initiating ART earlier in HIV disease progression makes a positive impact on preservation of BMD, 2) we should not forget the relationship between lean body mass and BMD and to counsel patients to perform weight-bearing exercise, and 3) as noted above, the selection of initial regimen plays a big role in bone health. If we have equivalent regimen for viral efficacy, we should consider regimens with better toxicity profiles.

HIV and Fractures

While BMD loss, ART effects and mechanism of this process are intriguing, the key question for many has been: does loss of BMD lead to increased fractures? This year, the National Osteoporosis Foundation (NOF) included HIV infection and ART as risk factors for osteoporosis and fragility fractures [27]. In support of this, several cohort studies have previously concluded that when matched for age and gender, people living with HIV are at greater risk of bone fractures. For example, a nearly 3-fold increase in incident fracture rates was identified among participants in the HIV Outpatient Study (HOPS) as compared to the National Hospital Ambulatory Medical Care Survey (NHAMCS-OPD), a representative sample of the U.S. general population. This study suggested that younger HIV-infected adults, particularly those between the ages of 25–54 years of age, are at an increased risk of bone fracture [28].

Interesting data was presented at CROI 2013. Warriner reported on fracture risk comparisons from US Medicare data in a cohort of 2.5 million HIV-negative and 13,000 HIV-infected persons. In the final adjusted model, risk of any fracture was approximately 50% higher in HIV-infected compared with the HIV-uninfected population. This risk was greater for older HIV-infected patients (> 65 years; relative risk, 1.52, 95% CI (1.34, 1.73)) but still present for younger HIV-infected patients (<65 years; 1.32 (1.21, 1.45)) and the authors suggest that osteoporotic fractures may occur at younger age in HIV-infected persons [29]. Gotti provided data demonstrating the need to consider occult spinal fractures. In a cohort of 175 HIV-infected and 120 uninfected age-matched patients, 30% of HIV-infected patients had morphometric vertebral fractures compared with 4% of the uninfected patients. Vertebral fracture risk factors included age, osteoporosis, BMI >25, AIDS event and TDF. The authors suggest that screening for vertebral fractures is useful and may provide rationale to begin earlier treatment in patients with osteopenia [30].

At the 2013 Joint Session of the 15th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV and the 14th European AIDS Conference, Battalora reported on fracture risk among 1008 HIV-infected participants (median baseline age 42) from two Centers of Disease Control and Prevention (CDC)-funded cohorts in the US that had baseline DEXA testing [31]. During 5,032 person-years of observation, 95 incident fractures occurred, including rib/sternum (n=18), hand (n=17), foot (n=15) and wrist (n=11). In multivariable analyses, baseline osteoporosis (adjusted hazard ratio [aHR] 3.04, 95% confidence interval [CI] 1.47–6.30) and increasing age (aHR 1.35 per 10 years, 95% CI 1.07–1.70) were associated with incident fracture. These data provide an important link between the presence of low BMD and risk of future fracture, even among young adults.

The role of specific ARVs and relationship to therapy initiation remains an area of controversy. A recent publication from the Veteran’s Health Administrative Data Clinical Case Registry (VHA CCR), Bedimo and colleagues characterized the risk of osteoporotic fractures (defined as wrist, vertebral or hip fracture) among a cohort of 56,600 HIV-infected veterans [32]. Cumulative exposure to the antiretrovirals TDF and LPV/rtv were both independently associated with fracture. Another recent publication evaluated fracture risk after ART initiation among 4640 HIV-infected individuals [33], identifying 135 persons who experienced 151 incident fractures occurring a median 2.3 years after ART initiation. Fracture rates were significantly higher in the first 2 years after ART initiation compared to subsequent time periods. Interestingly, type of ART, baseline CD4 count or HIV viral loads were not associated with fracture incidence. The authors suggest that BMD decline with ART initiation is linked with change in bone mass and quality leading to increased fracture risk. Further, as patient health improves over time with ART, the risk of falls and subsequent fractures may decrease with overall improved health suggesting there may be a catabolic window after ART initiation that leaves patients susceptible to fracture.

Several studies focused on the contribution of chronic HCV and fracture risk among HIV-infected person. In an analysis utilizing Medicaid data from 5 states comparing fracture rates among 36,950 HCV/HIV co-infected, 276,901 HCV mono-infected, 95,827 HIV mono-infected and 3,110,904 HCV/HIV-uninfected persons, Lo Re and colleagues reported fracture incidence rates lowest among uninfected persons ((1.29 events/1000 person-years), and increased with either HIV infection (1.95 events/1000 person-years) or HCV infection (2.69 events/1000 person-years) [34]. Increasing relative hazards of hip fracture were found in HCV/HIV co-infection comparisons with HCV mono-infection (HR, 1.38; 95% CI: 1.25–1.53), HIV-mono-infection (females: HR, 1.76; 95% CI: 1.44–2.16; males: HR, 1.36; 95% CI: 1.20–1.55), and HCV/HIV-uninfected persons (females: HR, 2.65; 95% CI: 2.21–3.17; males: HR, 2.20; 95% CI: 1.97–2.47). Hansen similarly evaluated fracture risk among a cohort that included HIV-infected, HIV/HCV co-infected, and uninfected persons [35]. HIV-infected patients had increased risk of fracture [IRR 1.5, 95% confidence interval (CI) 1.4–1.7] compared with uninfected participants. Relative risk was lower in HIV monoinfected patients (IRR 1.3, 95% CI 1.2–1.4) than in HIV/HCV-coinfected patients (IRR 2.9, 95% CI 2.5–3.4). The increased fracture risk with HCV infection appears to be additive with HIV infection. Analysis of fracture risk factors among HIV-infected veterans followed in the VHA CCR found that HCV co-infection was associated with a 24% increased relative risk of osteoporotic fracture over HIV alone and HCV was an independent risk factor for fracture when the models controlled for cirrhosis [36]. Womack and colleagues assessed the risk for first fragility fracture among 40,115 HIV-infected veterans followed in the Veterans Aging Cohort Study (VACS) and failed to confirm the association with HCV infection [37]. This study included 588 fragility fractures (210 hip, 111 vertebral, and 267 upper arm fractures) and included a majority of persons with uncontrolled HIV viremia. The authors speculated that by accounting for fibrosis using the FIB-4 in the models, this reduced any impact of HCV infection. These disparate results raise questions related to the overall impact of chronic HCV infection on metabolic bone disease. Additional research is warranted to determine whether the role of HCV is attributable to fibrosis and the development of cirrhosis rather than a specific viral effect.

Conclusions

It is clear that HIV, particularly advanced disease, and ART initiation play a significant role in the bone health of people living with HIV infection. We must be wise in assessing baseline risk factors and our initial ART selection to achieve virologic success and minimize potential metabolic toxicities such as low BMD and subsequent fractures. ART initiation not only induces a 2–6% loss in BMD but also leaves patients susceptible to fractures in this early catabolic window period. The mechanisms causing bone loss in our patient are likely complex and include viral, medication, host and environmental factors. We must take a proactive approach to prevention to minimize consequences of bone loss and the morbidity associated with fragility fractures [38].

Footnotes

Conflict of Interest

Edgar T. Overton was a consultant for Gliead Science and Janssen. Edgar T. Overton received a grant from Vertex Pharmaceuticals. Linda A. Battalora has no conflicts. Ben Young was a consultant for Gilead Sciences, Merck & Co, Viiv Healthcare and Bristol-Meyers Squibb. Ben Young received honoraria from Merck & Co, Viiv Healthcare, Gilead Sciences, Monogram Biosciences and Bristol-Meyers Squibb. Ben Young received payment for development of educational presentations from Viiv Healthcare.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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