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Bone & HIV...3-4 Fold increased osteoporosis
& fractures, a worrisome bone future
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3-4 fold increased osteoporosis ......HIV infection was associated with a three-fold increased fracture risk, compared with age-matched and sex-matched individuals in Denmark.....ART dysregulates bone function...frailty, comorbidities, damaged immunity & inflammation due to HIV all contribute .....fracture increases mortality .......Over the next 15 years, the population of older people living with HIV is expected to increase markedly. In the Dutch ATHENA cohort, for example, the proportion of HIV-infected persons 60 years and older will increase from 8% in 2010 to 39% in 2030, with expected increases in aging-related comorbidities [1].Osteoporotic fracture is a quintessential disease of aging whose incidence increases exponentially after age 65-70 years in the general population. It is also a major cause of morbidity, mortality, reduced quality of life, and healthcare expenditure.
from Jules: In current issue of Current Opinion in HIV & AIDS there are a series of about 15 articles on various topics related to Bone & HIV, I have attempted to esceprt key comments and information from most of the articles to present in this report the very worrisome current & future problems of bone, fractures & falls & comorbidoties in HIV.
CROI: Single Dose Zoledronic Acid Prevents Antiretroviral-Induced Bone Loss - (02/24/16)
Veterans Aging Cohort Study (VACS) Index, Functional Status, and Other Patient Reported Outcomes in Older HIV-positive (HIV+) Adults in SF.....Poor Outcomes in HIV+ Aging age 53-61 - (10/23/14)......"Our surveys also revealed a high prevalence of functional, social and cognitive deficits in this population."
CROI:Factors Associated with Limitations in Daily Activity Among Older HIV+ Adults - (02/29/16)
CROI: Vitamin D Supplementation Decreases Immune Activation and Exhaustion in HIV+ Youth...high dose did best & increased Vit D levels best too - (03/17/16)
CROI:Effects of Vitamin D Supplementation on BMD and Bone Markers in HIV+ Youth - (03/14/16)
CROI: Update from CROI 2016: Bones, Vitamin D, Frailty - Todd T. Brown, MD, PhD Associate Professor of Medicine and Epidemiology Division of Endocrinology, Diabetes, & Metabolism Johns Hopkins University - (03/17/16)
Low bone mineral density and risk of incident fracture in HIV-infected adults.....'reconsider when to screen for low BMD with DEXA' - (04/01/16)
CROI: Mitochondrial DNA Copy Number and Neurocognitive Impairment in HIV-Infected Persons....."mtDNA associated with worse cognitive outcomes".....both HIV & ART duration associated with mtDNA damage - (03/28/16)
"HIV+ persons have 1.5-3.0-fold greater risk of fractures"......CROI: Antiretrovirals, fractures and osteonecrosis in a large European HIV cohort - EuroSIDA........TDF Is Only Antiretroviral Implicated in EuroSIDA Fracture Study
"HIV infection is now an established risk factor for osteopenia and osteoporosis.....cART further aggravates rather than alleviates HIV-associated bone loss by inducing an additional 2-6% loss in bone mineral density (BMD) within the first 2 years of therapy, a rate of bone loss comparable with that seen in postmenopausal osteoporosis, the archetype of fragility bone disease [7 ,9,10]. The rate of BMD loss decreases after 1-2 years of cART [11-13], but whether bone resorption returns to baseline (already elevated in HIV-infected subjects) or to levels associated with uninfected subjects remains unclear. Importantly, the bone effects of cART appear to be universal across all regimens, although the magnitude of the effect may vary by regimen [12,14,15]. In one meta-analysis, the odds ratio (OR) of osteoporosis among HIV-infected individuals compared with HIV-uninfected controls was 3.7 [95% confidence interval (CI) 2.3-5.9]; cART use conferred an additional 2.5-fold increased odds of low BMD among HIV-infected patients [16]........Frailty increases the risk of falls, which is significant for those with low BMD, as falls increase the risk of fragility fractures. The prevalence of frailty is between 9 and 12% in HIV-positive cohorts......Self-reported falls were described among 359 middle-aged, HIV-infected adults on effective ART in a Colorado cohort; 30% sustained at least one fall during the prior year, similar to fall rates reported among HIV-uninfected adults aged 65 or older.....The rate of falls among middle-aged HIV-infected adults is similar to that of HIV-uninfected adults 65 years and older. Many of the clinical factors that contribute to low BMD overlap with risk factors for falls, resulting in a high risk of a serious fall among older adults with the greatest risk for a fracture. Low muscle mass, increased adiposity and metabolic syndrome, physical function impairment and frailty, common among older HIV-infected adults, contribute to an increased risk for low BMD and falls, and subsequently, may increase the risk of fracture among HIV-infected older adults.
HIV and hepatitis C coinfection have consistently been reported to be associated with an increased fracture risk - both traumatic and fragility, compared with those with HIV monoinfection (Incidence rate ratio (IRR) 1.77, 95% CI 1.44-2.18) and uninfected individuals (IRR 2.95, 95% CI 2.17-4.01) in a systematic review....hepatitis C coinfection was found to be an independent significant predictor of incident fractures (hazard ratio = 1.27, 95% CI 1.08-1.50), which is possibly partly explained by the severity of chronic liver disease (cirrhosis) present (hazard ratio = 1.74, 96% CI 1.23-2.47).
Several large cohort studies' elevated rates of bone fracture have been reported in PLWH compared with matched controls [1-4,5,6 ]. Comparison of fracture prevalence rates between HIV-infected and HIV-uninfected individuals in a large US Healthcare system reported a significantly increased prevalence in HIV-positive individuals (2.87 per 100 persons) compared with an HIV-negative group (1.77 per 100 person years). The increased fracture rates were observed for both men and women, and occurred predominantly at the hip, spine and wrist in the HIV-positive group [1]. Fragility fracture (hip, vertebra and arm) incidence in the Veterans Aging Cohort Study (VACS) cohort (over 40 000 HIV-positive men) was 2.6 per 1000 person-years [7]. For those with HIV and hepatitis C virus coinfection, the crude incidence rate of all fractures varies between 26.8 and 62.3 per 1000 person-years [8], whereas for fragility fractures 2.6 per 1000 person-years [9]. HIV infection was associated with a three-fold increased fracture risk, compared with age-matched and sex-matched individuals in Denmark [10].
In a cross-sectional study of PLWH and matched HIV-uninfected controls, the prevalence of asymptomatic vertebral fractures was double that of the controls (26.9 versus 12.9%) [11], and was similar to the prevalence reported elsewhere [12]. Two-thirds of vertebral fractures occurred in PLWH who did not have osteoporosis in a recent cohort study [13].
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Current Opinion in HIV & AIDS May 2016
Brown, Todd T.; Mallon, Patrick W.G., Hoy, Jennifer; Young, Benjamin, Erlandson, Kristine M.; Guaraldi, Giovanni; Falutz, Julian, Negredo, Eugenia; Warriner, Amy H., Moran, Caitlin A.; Weitzmann, M. Neale; Ofotokun, Ighovwerha
Over the next 15 years, the population of older people living with HIV is expected to increase markedly. In the Dutch ATHENA cohort, for example, the proportion of HIV-infected persons 60 years and older will increase from 8% in 2010 to 39% in 2030, with expected increases in aging-related comorbidities [1]. Osteoporotic fracture is a quintessential disease of aging whose incidence increases exponentially after age 65-70 years in the general population. It is also a major cause of morbidity, mortality, reduced quality of life, and healthcare expenditure.
HIV infection, even in the setting of effective ART, is a state of immune activation and inflammation that can affect the expression and regulation of key immunological factors involved in bone remodelling. This complex interaction is likely influenced by other parameters, including traditional risk factors for low BMD and fragility fracture.
Although there are data supporting the interplay between immune activation and chronic inflammation and the development of low BMD in HIV, longitudinal studies are needed to establish the role this may have in the pathogenesis of fragility fractures in PLWH.
Pre-ART levels of inflammation have been shown to impact the degree of postviral suppression, immune activation, and the development of serious non-AIDS comorbidities......HIV infection is characterized by gut microbial translocation, thought to result from dysfunction in the gut barrier which leads to subsequent activation of both innate and adaptive immune pathways via monocyte activation [51]. Indeed, elevated levels of systemic bacterial cell wall product lipopolysaccharide (LPS) have been reported in those infected with HIV [51]. LPS was the first microbial product shown to induce bone resorption in vitro[52], and to increase the number of osteoclast precursors in vivo[53]. LPS, a potent activator of innate immune cells [51], also promotes the expression of RANKL by osteoblasts in vitro, stimulating osteoclast differentiation. HIV infection is associated with an increase in the frequency of activated and exhausted CD4+ and CD8+ T cells, an increase in monocyte activation markers [58], a reduction in B-cell numbers, an increase in the frequency of immature/transitional B cells, and increased circulating levels of inflammatory mediators [23]. This state of hyperimmune activation and inflammation favours RANKL expression, reflected in higher circulating RANKL in those with HIV infection [37 ,40,59 ,60], while circulating OPG levels have been reported to be unchanged or lower in HIV-infected study participants [31,37 ,38 ,39,40]. This imbalance may potentially bring about a shift in the RANKL: OPG ratio, which would favour osteoclastogenesis in HIV-infected individuals. The role of HIV as an independent predictor for low BMD and a risk factor for increased rate of fractures has been well documented [2,9 ,63-66]. Additionally, multiple studies have shown a 2-6% loss in BMD in the first 2 years post-ART initiation [41,67-69]. Increased levels of bone turnover markers (BTM), such as the bone resorption markers osteocalcin, and serum type 1 procollagen (P1NP), have been consistently observed with ART initiation in ART-naïve patients and have been associated with increased TNFα levels at ART initiation [9 ,39,70]. Similarly, pre-ART HIV disease severity, measured by absolute CD4+ T-cell counts and HIV RNA, have been associated with a greater subsequent loss of BMD at ART initiation
Larger, well-designed studies evaluating calcium and vitamin D supplementation and the available osteoporosis medications are needed specifically for PLWH to further guide clinicians caring for these patients.
The benefit of calcium and vitamin D is variable in osteoporosis literature in general, but evidence supports the use of these supplements in PLWH to prevent the loss of bone mineral density when initiating antiretroviral therapy and in enhancing the effectiveness of anti osteoporosis treatments. The benefit of calcium and vitamin D supplementation in PLWH has shown to be of some benefit for bone health, but large randomized clinical trials are lacking. In a cross-sectional study in which optimal daily calcium was defined as more than 1000 mg calcium per day, calcium supplement use in a population of PLWH was found to be associated with lower rates of low BMD but was also found to be a characteristic of participants with an increased cardiovascular risk [3]. This association deserves further investigation as some analyses have found an association between calcium supplementation and cardiovascular disease in the general population [4], but many others refute this finding [5]. In a randomized controlled trial of 165 PLWH over 48 months, the use of a calcium and vitamin D supplement compared with placebo at the time of initiation of the participants' first antiretroviral regimen (efavirenz/emtricitabine/tenofovir disoproxil fumarate) led to reduced loss of BMD at the total hip with the median decline being -1.36% [interquartile range (IQR), -3.43 to 0.50%] and -3.22% (IQR, -5.56 to -0.88%), respectively (P = 0.004) and at the lumbar spine [median decline -1.23% (IQR, -3.73 to 0.20%) and -2.94% (IQR, -4.87 to -0.94%), respectively] (P = 0.033) while concurrently increasing 25(OH)-vitamin D levels [6 ]. There was one reported case of nephrolithiasis among the persons treated with the calcium/vitamin D supplements, raising a concern previously found among postmenopausal women in the Women's Health Initiative study wherein calcium supplementation was found to be associated with an increased risk of kidney stones. Further study is still needed to guide calcium supplementation in PLWH. In the meantime, it is recommended that PLWH consume adequate calcium through dietary or supplement sources [8] and take vitamin D supplementation. Adequate daily calcium intake for PLWH is 1000 mg for men 50-70 years old and 1200 mg for postmenopausal women and men over age 70, in divided doses [9 ]. Guidelines for vitamin D supplementation were developed by a group of HIV osteoporosis experts [9 ] with recognition that well-designed studies to evaluate the optimal calcium and vitamin D supplementation in PLWH are lacking. Vitamin D supplementation is effective in normalizing vitamin D levels in PLWH despite the recognized alterations of vitamin D metabolism with concomitant use of some antiretrovirals.
How to predict the risk of fracture in HIV?.....The few published studies that have calculated the 10-year FRAX® risk for both major osteoporosis and hip fractures without BMD generally show limited precision in predicting the presence of osteoporosis severe enough to initiate treatment. It remains uncertain whether using HIV as a secondary risk factor and adding dual X-ray absorptiometry (DXA)-BMD information improves case-finding compared with using DXA results only. Not incorporating risks relevant to aging HIV patients such as antiretroviral exposure, hepatitis C virus coinfection and history of falls is other potential limitation.
In PLWH, bisphosphonates are the most common approach to treat osteoporosis. An increasing number of PLWH requires specific therapy for osteoporosis because of continued loss of BMD or a heightened fracture risk, based on clinical risk factors or fracture risk calculators. As stated above, treatment of osteoporosis should always be accompanied by sufficient intake of calcium and vitamin D. Guidelines from the American Association of Clinical Endocrinologists [11], which were published in 2010, recommend the following drugs for the treatment of postmenopausal osteoporosis: alendronate, risedronate, zoledronic acid and denosumab as first-line agents; ibandronate as a second-line agent; raloxifene as a second-line or third-line agent; and calcitonin when the previous agents cannot be used. Teriparatide is recommended for patients with a very high risk of fracture or in whom therapy with bisphosphonates has failed. Zoledronate, the most recently approved bisphosphonate, is indicated for the treatment of postmenopausal osteoporosis in women or older men at high risk of bone fractures [23]. A key advantage of zoledronate over oral bisphosphonates is its once-yearly administration. In addition, because it is administered intravenously, the risks of esophageal irritation and poor gut absorption associated with oral bisphosphonates are avoided. In addition, a greater and faster increase in BMD and a decrease in bone turnover markers with zoledronate than with alendronate have been observed in postmenopausal women. Although bisphosphonates are generally well tolerated, one potential short-term adverse event in patients who receive intravenous bisphosphonate therapy is a transient acute-phase reaction characterized by fever, myalgia and arthralgia. It usually occurs within 3 days of treatment, lasts 24-72 h and the frequency decreases markedly with subsequent infusions [26]. However, the administration of acetaminophen/paracetamol or ibuprofen during the zoledronic infusion and 2-3 days postinfusion significantly reduces these symptoms. the chronic and systemic inflammation associated with HIV infection could explain in part the lower BMD observed in PLWH. Statins exert anti-inflammatory effects and reduce immune activation and inflammation [42]. These potential effects have proven to be beneficial for bone metabolism in non-HIV-infected adults [43].
Metabolic diseases, including type II diabetes mellitus, dyslipidemia, obesity, and the metabolic syndrome occur with increasing frequency among older adults. These disorders often occur together and may share underlying pathogenic features. The concept of an "allostatic load" suggests that the accumulated dysregulation across physiologic systems including chronic inflammation, cardiovascular disease, lipid, and glucose disorders is associated with decreased bone strength, despite the lack of an independent effect of each condition on BMD. Comorbidities associated with obesity, including hypertension, inactivity, and neurocognitive disease add additional fall risk [74]. Type II diabetes mellitus may increase fall risk via peripheral neuropathy, visual impairment, and autonomic dysfunction. Similarly, metabolic syndrome has been associated with impaired exercise capacity [75] and may be an independent risk factor for falls
As the proportion of HIV-infected adults aged 50 or older is projected to reach nearly 70% by 2030 [5 ], the interaction between falls and fracture risks is an area of increasing clinical relevance. Little information is known, however, about the issues unique to HIV-infected adults.
Self-reported falls were described among 359 middle-aged, HIV-infected adults on effective ART in a Colorado cohort; 30% sustained at least one fall during the prior year, similar to fall rates reported among HIV-uninfected adults aged 65 or older [3]. In a similar cross-sectional analysis from the University of California San Francisco SCOPE cohort, 26% of 155 HIV-infected adults (94% male) aged 50 or older on ART reported at least one fall in the prior year.
Falls are a common geriatric syndrome, and are the consequence of multiple interrelated factors including comorbidities (arthritis, diabetes, pain, depression), physical impairments (vision, cognition, neuropathy, strength, gait), and polypharmacy (Fig. 1) [15]. A high prevalence of comorbidities, physical impairments, and polypharmacy associated with falls are also seen among HIV-infected older adults [16]. Similarly, many of the clinical factors that contribute to low BMD overlap with risk factors for falls, resulting in a high risk of a serious fall among older adults with the greatest risk for a fracture. For example, use of antidepressants, sedatives, and opiates are established risk factors for low BMD and were some of the strongest predictors of falls in the Colorado cohort [3]. Similarly, a greater number of prescribed medications were associated with an increased risk of falling in both the Colorado and MACS/WIHS cohorts [14,17]. In contrast to the strong associations between HIV-specific factors and low BMD discussed in prior articles in this journal issue, HIV-related characteristics and substance abuse appear to have minimal effect on fall risk. Outside of increased fall risk with current tobacco use or prior didanosine [3], and decreased fall risk with current protease inhibitor use (MACS/WIHS cohort) [14], no association was found with other HIV-specific variables or with substance abuse-related factors (hepatitis C, alcohol use, current illicit drug use).
The rate of falls among middle-aged HIV-infected adults is similar to that of HIV-uninfected adults 65 years and older. Many of the clinical factors that contribute to low BMD overlap with risk factors for falls, resulting in a high risk of a serious fall among older adults with the greatest risk for a fracture. Low muscle mass, increased adiposity and metabolic syndrome, physical function impairment and frailty, common among older HIV-infected adults, contribute to an increased risk for low BMD and falls, and subsequently, may increase the risk of fracture among HIV-infected older adults. Interventions with dual benefit on reducing fall risk and improving BMD are likely to have the greatest impact on fracture prevention in the older, HIV-infected adult.
HIV infection is clearly associated with an increased risk of fracture compared with age-matched and sex-matched individuals. This is likely because of the increased prevalence of low bone mass. Risk factors for increased fracture risk include not only traditional risk factors (low BMI, smoking and alcohol) but also HIV-related (low CD4+ cell count) and ART-related increased bone turnover. Hepatitis C coinfection increased the risk of fracture over and above that of HIV infection alone. With the recent move to commence ART at the time of HIV diagnosis, and the unlikely probability of a cure for HIV in the short term, it will be important to continue research into the effects of long-term ART on bone health.
In the general population, osteoporotic fractures are associated with significant morbidity and increased 12-month risk of mortality [29]. Given the recent findings from the Strategic Timing of AntiRetroviral Treatment study [30] and changes in WHO HIV treatment guidelines' recommendation for initiation of ART at the time of HIV diagnosis, independent of CD4+ cell count, bone disease and fragility fractures are likely to significantly contribute to morbidity in PLWH. Long-term follow-up of individuals who initiate ART at higher CD4+ cell counts is needed to understand the fracture risk in these individuals. Studies to determine whether interventions such as the use of vitamin D and calcium to mitigate that risk are effective are also needed.
Bone turnover is increased in both HIV infection alone [31] and in those treated with ART [32,33]. Calcitriol has been shown to reduce fracture risk in postmenopausal women. The combination of calcitriol, cholecalciferol or calcium reduced the markers of bone turnover in HIV-positive individuals to a greater extent than cholecalciferol or calcium supplementation alone [34].
It is apparent that both the effects of HIV infection alone and initiation of ART are associated with significant bone loss in individuals with HIV infection, resulting in osteopenia and osteoporosis. The clinical consequence of low bone mineral density is a greater risk of fragility fractures that are more common in older HIV patients, and those on ART. Frailty occurs at a prevalence of about 10% (about twice that of the general population), and the increased propensity of falls results in greater fracture prevalence, morbidity and mortality.
Over the next 15 years, the population of older people living with HIV is expected to increase markedly. In the Dutch ATHENA cohort, for example, the proportion of HIV-infected persons 60 years and older will increase from 8% in 2010 to 39% in 2030, with expected increases in aging-related comorbidities [1]. Osteoporotic fracture is a quintessential disease of aging whose incidence increases exponentially after age 65-70 years in the general population. It is also a major cause of morbidity, mortality, reduced quality of life, and healthcare expenditure.
Over the past 15 years, evidence has been mounting that the risks of fracture and of osteoporosis among those living with HIV are higher than would be expected based on the contribution from traditional osteoporosis risk factors alone. Similar to other comorbidities in HIV, the pathogenesis of osteoporosis in HIV-infected persons is complicated and multifactorial, with contributions from certain antiretroviral therapies, other coinfections and comorbidities, behavioral risk factors, and chronic HIV infection, with both HIV infection itself and the associated persistent immune dysfunction having an impact. In addition, both frailty and falls risk, issues that transect both older age and HIV, are emerging challenges to those treating people living with HIV.
There is no evidence to suggest that the increased immune activation and inflammation, and increased bone turnover reported in both HIV infection alone and with introduction of ART have an impact on bone healing after traumatic or fragility fractures.
In healthy adults, a decline in both muscle quality (function) and quantity (mass) begins in the fourth or fifth decade of life [18]. Without intervention or if hastened by concomitant disease, the decline in muscle may result in sarcopenia, a term which refers to the loss of muscle mass alone, but has been more recently defined as a condition consisting of both impaired muscle function and low muscle mass. Although sarcopenia and osteoporosis are two distinct processes, there is increasing evidence of important interactions which significantly impact on fracture risk. The interconnectedness of bone and muscle are seen at several levels from direct muscle-bone interactions to shared pathways including endocrine influence, nutrition and lifestyle factors, demographics, and genetic features. As the FRAM study previously confirmed that both sarcopenia and visceral adiposity are independent predictors of mortality in treated HIV-infected persons [42], the potential for clinically important consequences of low LBM is evident. The association between LBM, in particular, and bone density was first described early in the AIDS era [46]. Subsequent cross-sectional and longitudinal studies have corroborated these findings [47]. Among HIV-infected naïve participants initiating ART through the AIDS Clinical Trials Group Study 5224s, a greater increase in LBM after 96 weeks of ART was independently associated with greater week 96 increases in both hip and lumbar spine BMD [48]. Among participants with available follow-up DXA scans, low LBM was a significant predictor of subsequent decline in BMD over an average of 7 years of follow-up [49].....In addition to the decline in muscle mass and function, an increase in the amount of fat content within and surrounding skeletal muscle is seen with aging among HIV-uninfected populations [50]. The fatty infiltration of skeletal muscle, as defined by lower attenuation on computed tomography (CT), has been associated with fall and fracture risk beyond that predicted by muscle mass or low BMD. In the Health, Aging, and Body Composition (Health ABC) study of HIV-uninfected adults at least 70 years, low CT-attenuation of skeletal muscle was associated with increased risk of hip fracture independent of BMI, percentage body fat, age, height, race, sex, and BMD. Furthermore, skeletal muscle fat infiltration was the only significant muscle parameter of fracture risk in models including muscle strength, physical performance score, and thigh muscle cross-sectional area.
Frailty is a geriatric syndrome often overlapping with obesity and/or sarcopenia, and is characterized by decreased physiologic reserve. Several diagnostic criteria are used to define frailty clinically. Regardless of the definition, frailty is considered the end result of multiple potential insults including alterations in hormones (growth hormone, estrogen, testosterone), heightened inflammation, low physical activity, and poor or undernutrition. These alterations are associated with the clinical manifestations of slowness, weakness, and fatigue. Thus, many of the risk factors for frailty overlap with the risks for low BMD, sarcopenia, and falls, which may subsequently result in fractures. Not surprisingly, frailty and other impairments in physical function such as balance impairment, slow gait speed, or weakness are also strong predictors of both falls and fractures in cohorts of older, HIV-uninfected adults [81-86]. The association between frailty and low BMD in HIV-uninfected populations is not well established and may depend on the definition of frailty used and the prevalence of osteoporosis in the population under investigation [87-91]. Most existing data are cross-sectional but a recent study of older women found that although baseline osteoporosis was not associated with frailty, frail participants were more likely to develop osteoporosis in follow-up
Comorbid conditions including frailty
Frailty is usually characterized by weakness, slow motor performance and low physical activity. Frailty increases the risk of falls, which is significant for those with low BMD, as falls increase the risk of fragility fractures. The prevalence of frailty is between 9 and 12% in HIV-positive cohorts [21].
The Veterans Aging Cohort Study (VACS) Index predicts all-cause mortality, hospitalizations and functional performance and has been proposed as a surrogate for a frailty index. In a recent analysis in HIV-positive male veterans, the VACS Index was also shown to be an independent predictor of fragility fractures [22]. HIV and hepatitis C coinfection have consistently been reported to be associated with an increased fracture risk - both traumatic and fragility, compared with those with HIV monoinfection (Incidence rate ratio (IRR) 1.77, 95% CI 1.44-2.18) and uninfected individuals (IRR 2.95, 95% CI 2.17-4.01) in a systematic review [6 ,8]. Using the Veterans Health Administration Clinical Case Registry (98% men and 44% white race) to examine the factors associated with fragility fractures, hepatitis C coinfection was found to be an independent significant predictor of incident fractures (hazard ratio = 1.27, 95% CI 1.08-1.50), which is possibly partly explained by the severity of chronic liver disease (cirrhosis) present (hazard ratio = 1.74, 96% CI 1.23-2.47) [9]. These observations have been confirmed in another study of hip fractures [23]. A modest higher cumulative incidence of hip fracture has also been reported for dual-treated hepatitis B-HIV coinfected patients compared with ART-treated HIV monoinfection [24].
HIV-related factors
Some studies have reported an increased fracture rate in individuals with low nadir CD4+ cell counts (<200 cells/μl) [3,25], whereas others have reported no association between CD4+ cell count and fragility fracture [4,7,12,13,15]. As with CD4+ cell counts, inconsistent associations of fracture risk with HIV RNA levels have been reported. Most studies show neither association of HIV viremia, nor duration of virological suppression with increased fracture risk [3,12,26], whereas one study shows increased fracture risk with lower HIV viral load levels [22].
EFFECTS OF ANTIRETROVIRAL THERAPY
The effects of ART on fracture risk have been evaluated in cohort studies and to a less extent in randomized controlled trials, which generally recruit younger participants and have shorter follow-up. Whether ART, specific ART agents or duration of ART predisposes to incident fracture remains uncertain with studies reporting contradictory results. Several studies report no association with ART [3,12,13,15,25,26] or specific ART drugs [4,27], whereas others have reported a modest association [4,7,17]. In one study from the Veterans Affairs Clinical Case Registry, the rate of fractures in the pre-highly active antiretroviral therapy era was 1.61 fractures/1000 person-years, whereas in the post-HAART era, the fracture rate was 4.09 per 1000 person-years [17]. A small, but significant, increased incident fragility fracture risk was associated with cumulative exposure to tenofovir disoproxil (12% per year exposed), protease inhibitors (5% per year exposed) and the combination of tenofovir disoproxil and protease inhibitor (16% per year exposed) after controlling for traditional risk factors in HIV-positive patients initiating ART from 1996 onward [17]. There was no increased risk from abacavir exposure in this Veterans Affairs study. The AIDS Clinical Trials Group (ACTG) Longitudinal-Linked Randomized Trial database included participants from 26 randomized trials performed in the ACTG, with predominantly no specified reporting of fracture events. The incidence of fractures in this study was 4.0 per 1000 person-years for all participants and 3.8 per 1000 person-years for those who were ART naive at baseline. Interestingly, unlike other studies, neither age (median age 39 years), sex, race nor BMI were independent predictors of fracture. The fracture rate was significantly higher in the first 2 years after ART initiation (5.3 per 1000 person-years), and this reduced to 3.0 per 1000 person-years in subsequent years [26]. This suggests that the acute reduction in BMD during the first 12 months of initial ART is associated with changes in bone quality or bone strength resulting in increased risk of fracture for 12-24 months. When there is stabilization in bone mass after this time, the risk of fracture returns to a rate similar to that reported in longitudinal cohorts. Finally, one nested case-control study has reported a 36% reduced risk of fractures in ART-treated individuals [28] and another reported a protective effect of nonnucleoside reverse transcriptase inhibitor use [15].
CHARACTERISTICS OF FRACTURES
In order to discuss the risk of bone fractures, it is useful to review the types of fractures as they relate to BMD.
Fragility versus nonfragility fractures
Fragility fractures are the clinical consequence of significant reductions in BMD. The National Osteoporosis Foundation defines a fragility fracture as one that results from a fall from a standing height or less. The most common fragility fractures occur in the spine, wrist and hip, though in principle fragility fractures can occur at any anatomic site.
Vertebral fractures
Compression vertebral fractures are often the consequence of significant trauma, and commonly are located in the thoracic or lumbar regions. Osteoporosis increases the risk of vertebral fractures. Other causes of vertebral fractures include preexisting disease (such as metastatic cancer or osteomyelitis).
Atypical fractures
Atypical femoral fractures are an uncommon consequence of long-term bisphosphonate treatment. The American Society for Bone and Mineral Research recently developed a case definition for atypical femoral fractures that include the absence of major trauma, subtrochanteric or femoral shaft location and specific anatomic configuration (transverse or short oblique, noncomminuted and medial cortical spike).
Incidence of fractures
Several large cohort studies' elevated rates of bone fracture have been reported in PLWH compared with matched controls [1-4,5,6 ]. Comparison of fracture prevalence rates between HIV-infected and HIV-uninfected individuals in a large US Healthcare system reported a significantly increased prevalence in HIV-positive individuals (2.87 per 100 persons) compared with an HIV-negative group (1.77 per 100 person years). The increased fracture rates were observed for both men and women, and occurred predominantly at the hip, spine and wrist in the HIV-positive group [1]. Fragility fracture (hip, vertebra and arm) incidence in the Veterans Aging Cohort Study (VACS) cohort (over 40 000 HIV-positive men) was 2.6 per 1000 person-years [7]. For those with HIV and hepatitis C virus coinfection, the crude incidence rate of all fractures varies between 26.8 and 62.3 per 1000 person-years [8], whereas for fragility fractures 2.6 per 1000 person-years [9]. HIV infection was associated with a three-fold increased fracture risk, compared with age-matched and sex-matched individuals in Denmark [10].
In a cross-sectional study of PLWH and matched HIV-uninfected controls, the prevalence of asymptomatic vertebral fractures was double that of the controls (26.9 versus 12.9%) [11], and was similar to the prevalence reported elsewhere [12]. Two-thirds of vertebral fractures occurred in PLWH who did not have osteoporosis in a recent cohort study [13].
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