Brief Report: Are Serious Falls Associated With Subsequent Fragility Fractures Among Veterans Living With HIV?

BACKGROUND: The extensive research on falls and fragility fractures among persons living with HIV (PWH) has not explored the association between serious falls and subsequent fragility fracture. We explored this association. SETTING: Veterans Aging Cohort Study. METHODS: This analysis included 304,951 6-month person- intervals over a 15-year period (2001-2015) contributed by 26,373 PWH who were 50+ years of age (mean age 55 years) and taking antiretroviral therapy (ART). Serious falls (those falls significant enough to result in a visit to a health care provider) were identified by the external cause of injury codes and a machine learning algorithm applied to radiology reports. Fragility fractures were identified using ICD9 codes and included hip fracture, vertebral fractures, and upper arm fracture and were modeled with multivariable logistic regression with generalized estimating equations. RESULTS: After adjustment, serious falls in the previous year were associated with increased risk of fragility fracture [odds ratio (OR) 2.10; 95% confidence interval (CI): 1.83 to 2.41]. The use of integrase inhibitors was the only ART risk factor (OR 1.17; 95% CI: 1.03 to 1.33). Other risk factors included the diagnosis of alcohol use disorder (OR 1.49; 95% CI: 1.31 to 1.70) and having a prescription for an opioid in the previous 6 months (OR 1.40; 95% CI: 1.27 to 1.53). CONCLUSIONS: Serious falls within the past year are strongly associated with fragility fractures among PWH on ART-largely a middle-aged population-much as they are among older adults in the general population.

Veterans Aging Cohort Study Index as a Marker of Bone Disease in HIV-Infected Patients.

People living with human immunodeficiency virus (HIV) infection have higher risk of low bone mineral density (BMD) and fragility fracture than general population. The aim of our retrospective study was to explore if HIV-specific Veterans Aging Cohort Study (VACS) Index and its specific components could help identify patients at risk for low BMD. A total of 195 HIV-infected patients with dual-energy X-ray absorptiometry (DXA) scan between 2007 and 2014 were included and DXA scan results were used to classify patients with osteopenia. VACS Index was calculated for all patients using laboratory values closest to the date of DXA scan. Logistic regression was used to assess the association between VACS Index score or individual components of VACS Index with the presence of low BMD after adjusting for confounding variables. A total of 109 (56%) patients were diagnosed with low BMD. VACS Index score was significantly associated with low BMD, with the odds of low BMD increasing 1.21 times for each 10 unit increase in VACS Index score [confidence interval (95% CI) 1.03-1.42; p = .02]. The two groups differed significantly on patient weights, proportion of white patients, and hepatitis C-coinfected patients. After adjusting for white race and weight, hepatitis C coinfection was significantly associated with increased risk of low BMD (odds ratio 24.4; 95% CI 7.45-80.16). VACS Index score, previously demonstrated to be a marker of frailty in HIV-infected patients, is significantly associated with risk of low BMD and could be used to develop a prediction tool to screen for low BMD in resource-limited setting where DXA scans are not easily available.

Evaluation of screening practices for low bone mass and prevalence of osteoporosis and fractures in people living with human immunodeficiency virus attending a sexual health clinic.

BACKGROUND: Adults with human immunodeficiency virus (HIV) infection commonly experience fractures and have a high prevalence of osteoporosis. The reasons for low bone mineral density (BMD) in HIV patients are multifactorial and there are now guidelines for screening. AIMS: The aims of this study were to determine the screening practices for osteoporosis at this sexual health clinic, the prevalence of osteoporosis and to examine the risk factors for bone disease. METHODS: We performed a retrospective cohort study of all HIV patients attending the Sunshine Coast Health Service District Sexual Health Clinic. Through chart review we collected the following details: patient demographics, co-morbid conditions, HIV status and anti-retroviral therapy, BMD screening, fractures, screening for secondary causes of bone disease and treatment interventions for osteoporosis. RESULTS: A total of 243 patients with HIV attended the sexual health clinic. Of these, 149 met screening criteria for BMD assessment and 93 (61%) of those eligible underwent BMD examination. In those who had a BMD performed, 13 (19%) had sustained a previous fracture, 28 (30%) had osteoporosis and 42 (45%) had osteopenia. In the osteoporosis group, 21 (78%) were treated with vitamin D and calcium, 7 (26%) had a change in ART, 19 (68%) were treated with anti-resorptive therapy and 9 received testosterone replacement. CONCLUSIONS: In this cohort, there was a high prevalence of low bone mass and BMD screening rates of 60%. Our results highlight the importance of this condition and the need to improve screening and availability of BMD assessment.

The Differential Effects of Human Immunodeficiency Virus and Hepatitis C Virus on Bone Microarchitecture and Fracture Risk.

Background: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected individuals have a significantly greater osteoporotic fracture risk than HIV-monoinfected persons, despite the fact that HIV/HCV coinfection has not been associated with lower bone mineral density (BMD) than HIV or HCV alone. To evaluate if changes in bone microarchitecture, measured by trabecular bone score (TBS), could explain these differences, we performed a prospective, cross-sectional cohort study of virologically suppressed HIV-infected subjects, untreated HCV-infected subjects, HIV/HCV-coinfected subjects, and uninfected controls. Methods: We enrolled 532 male subjects: 57 HIV/HCV coinfected, 174 HIV infected, 123 HCV infected, and 178 controls. We conducted analysis of covariance comparing BMD and TBS between groups, controlling for age, race, body mass index, and smoking. We used linear regression to evaluate predictors of BMD and TBS and evaluated the effects of severity of HCV infection and tenofovir disoproxil fumarate use. Results: Despite both infections being associated with decreased BMD, only HCV, but not HIV, was associated with lower TBS score. Also, HIV/HCV-coinfected subjects had lower TBS scores than HIV-monoinfected, HCV-monoinfected, and uninfected subjects. Neither the use of TDF or HCV viremia nor the severity of HCV liver disease was associated with lower TBS. Conclusions: HCV infection is associated with microarchitectural changes at the lumbar spine as assessed by the low TBS score, suggesting that microstructural abnormalities underlie some of the higher fracture risk in HCV infection. TBS might improve fracture risk prediction in HCV infection.

Antiretrovirals, Fractures, and Osteonecrosis in a Large International HIV Cohort.

BACKGROUND: Antiretrovirals (ARVs) affect bone density and turnover, but their effect on risk of fractures and osteonecrosis of the femoral head is less understood. We investigated if exposure to ARVs increases the risk of both bone outcomes. METHODS: EuroSIDA participants were followed to assess fractures and osteonecrosis. Poisson regression identified clinical, laboratory and demographic predictors of either bone outcome. Ever, current, and cumulative exposures to ARVs were assessed. RESULTS: During 86118 PYFU among 11820 included persons (median age 41y, 75% male, median baseline CD4 440/mm3, 70.4% virologically suppressed), there were 619 fractures (incidence/1000 PYFU 7.2; 95% CI 6.6-7.7) and 89 osteonecrosis (1.0; 0.8-1.3). Older age, white race, lower BMI, IV drug use, lower baseline CD4, HCV coinfection, prior osteonecrosis, prior fracture, cardiovascular disease, and recent non-AIDS cancer (last 12 months) were associated with fractures. After adjustment, persons who had ever used tenofovir disoproxil fumarate (TDF) (1.40; 1.15-1.70) or who were currently on TDF (1.25; 1.05-1.49) had higher incidence of fractures. There was no association between cumulative exposure to TDF and fractures (1.08/5 y exposure; 0.94-1.25). No other ARV was associated with fractures (all P > .1). Risk of osteonecrosis was associated with white race, lower nadir CD4, prior osteonecrosis, prior fracture, and prior AIDS. After mutual adjustment, no ARV was associated with osteonecrosis. CONCLUSIONS: In human immunodeficiency virus (HIV) infection, host factors, HIV-specific variables, and comorbidities contribute to risk of fractures and osteonecrosis. Exposure to TDF, but not other ARVs, was an independent risk factor for fractures.

HIV infection, bone metabolism, and fractures.

With the advent of high active antiretroviral therapy there was a significant improvement on HIV subjects survival. Thus, bone changes related to HIV became an important aspect of these individuals. HIV affects bone remodeling causing bone fragility. In addition, antiretroviral therapy may also negatively affect bone metabolism. Several studies describe an increased incidence of fractures in these patients when compared with controls without the disease. The European Society of AIDS (EACS), and other societies, have included guidance on management of osteoporosis in HIV-infected patients emphasizing the identification of patients with low bone mass. Supplementation of calcium and vitamin D and the use of alendronate in these individuals should be recommended on a case base.

HIV infection, bone metabolism, and fractures / Infecção pelo HIV, o metabolismo ósseo e fraturas

With the advent of high active antiretroviral therapy there was a significant improvement on HIV subjects survival. Thus, bone changes related to HIV became an important aspect of these individuals. HIV affects bone remodeling causing bone fragility. In addition, antiretroviral therapy may also negatively affect bone metabolism. Several studies describe an increased incidence of fractures in these patients when compared with controls without the disease. The European Society of AIDS (EACS), and other societies, have included guidance on management of osteoporosis in HIV-infected patients emphasizing the identification of patients with low bone mass. Supplementation of calcium and vitamin D and the use of alendronate in these individuals should be recommended on a case base.

Com o advento da terapia antirretroviral, houve uma melhora considerável na sobrevida dos indivíduos portadores do vírus HIV. Dessa forma, as alterações ósseas referentes ao HIV se tornaram um fator importante no cuidado desses indivíduos. O HIV altera o remodelamento ósseo causando fragilidade óssea. As alterações causadas por esse vírus nos linfócitos T afetam a produção de RANKL e de citocinas pró-inflamatórias levando à osteoclastogênese. Ademais, a terapia antirretroviral também pode afetar negativamente o metabolismo ósseo. Vários estudos descrevem aumento da incidência de fraturas nesses indivíduos quando comparados a controles sem a doença. Diretrizes da Sociedade Europeia de SIDA (EACS) têm orientado o manejo da osteoporose nesses sujeitos, enfatizando a identificação de pacientes com baixa massa óssea. A suplementação de cálcio e vitamina D e o uso de alendronato nesses indivíduos devem ser recomendados caso a caso.

Relationship between vitamin D, parathyroid hormone, bone mineral density, fracture and antiretroviral therapy in HIV patients.

BACKGROUND: Vitamin D deficiency and abnormal bone mineral density (BMD) have been reported in HIV patients. We aimed to find out the effects of antiretroviral therapy (ART) on serum vitamin D, parathyroid hormone (PTH) levels, BMD changes and fragility fracture rates in HIV patients. METHODS: We collected information about baseline demography, risk factors for fracture, viral load (VL), CD4 count, serum 25-OH vitamin D (n=357), PTH (n=277), phosphate, ionised calcium, creatinine and BMD of spine and hip by DEXA scan (hologic, n=142). Statistical analysis used one-way ANOVA followed by Dunn's multiple comparison tests. Results Table 1: Total 357 patients, mean age 41.1 (+/- 11.9) years, 249 (66%) black African, 197(52%) females, baseline CD4 count 451 (+/- 184) cells/dl, VL 1.4 log (+/- 1.2) copies/ml, duration of ART 52 (+/- 35) months were included in the analysis. Serum vitamin D was 15.3 (+/- 11.0) ng/ml, PTH (intact) 5.5 (+/- 3.9) pmol/l, corrected calcium 2.13 (+/- 0.9), phosphate 1.0 (+/- 0.2) and creatinine was 73.4 (+/- 21.1) mmol/l. Ninety four (66%) patients had abnormal BMD (T-score of spine or hip or both ≤ 1.0). Vitamin D levels were deficient (< 30 ng/ml) in 297 (78.7%) and PTH was high (>4.1 pmol/l) in 177 (64.8%) patients. Of 91 (30.9%) patients who had vitamin D levels below 10.0 ng/mL, PTH was high in 70 (n=91, 76.9%) and abnormal BMD in 50 (n=61, 75.4%) patients. Thirteen patients (3.2%) had possible fragility fractures. Tenofovir (TDF) users had higher PTH (P=0.002) and lower BMD of spine (0.01) and hip (0.002) and efavirenz (EFV) users had lower vitamin D (0.01) levels. On multivariate analysis including all significant variables, female sex (OR 1.5 CI 1.3-5.9), age over 40 years (OR 1.2 CI 0.9-5.1) and TDF use (OR 1.9 CI 1.6-6.9) were associated with abnormal BMD of hip but not spine. CONCLUSION: Female patients over 40 years old on tenofovir containing regimens may have increased risk of BMD loss from hip. Whether Vitamin D replacement will prevent further bone loss needs further work.

Physiologic frailty and fragility fracture in HIV-infected male veterans.

BACKGROUND: The Veterans Aging Cohort Study (VACS) Index is associated with all-cause mortality in individuals infected with human immunodeficiency virus (HIV). It is also associated with markers of inflammation and may thus reflect physiologic frailty. This analysis explores the association between physiologic frailty, as assessed by the VACS Index, and fragility fracture. METHODS: HIV-infected men from VACS were included. We identified hip, vertebral, and upper arm fractures using ICD-9-CM codes. We used Cox regression models to assess fragility fracture risk factors including the VACS Index, its components (age, hepatitis C status, FIB-4 score, estimated glomerular filtration rate, hemoglobin, HIV RNA, CD4 count), and previously identified risk factors for fragility fractures. RESULTS: We included 40 115 HIV-infected male Veterans. They experienced 588 first fragility fractures over 6.0 ± 3.9 years. The VACS Index score (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.11-1.19), white race (HR, 1.92; 95% CI, 1.63-2.28), body mass index (HR, 0.94; 95% CI, .92-.96), alcohol-related diagnoses (HR, 1.65; 95% CI, 1.26-2.17), cerebrovascular disease (HR, 1.95; 95% CI, 1.14-3.33), proton pump inhibitor use (HR, 1.87; 95% CI, 1.54-2.27), and protease inhibitor use (HR, 1.25; 95% CI, 1.04-1.50) were associated with fracture risk. Components of the VACS Index score most strongly associated with fracture risk were age (HR, 1.40; 95% CI, 1.27-1.54), log HIV RNA (HR, 0.91; 95% CI, .88-.94), and hemoglobin level (HR, 0.82; 95% CI, .78-.86). CONCLUSIONS: Frailty, as measured by the VACS Index, is an important predictor of fragility fractures among HIV-infected male Veterans.

Fracture risk by HIV infection status in perinatally HIV-exposed children.

The objective of this study was to examine the incidence of fractures in HIV-infected children and comparable HIV-exposed, uninfected (HEU) children in a multicenter, prospective cohort study (PACTG 219/219C) in the United States. The main outcome was first fracture during the risk period. Nine fractures occurred in 7 of 1326 HIV-infected and 2 of 649 HEU children, corresponding to incidence rates of 1.2 per 1000 person-years and 1.1 per 1000 person-years, respectively. The incidence rate ratio was 1.1 (95% CI 0.2, 5.5). There was no evidence of a substantially increased risk of fracture in HIV-infected compared to HEU children.

Low bone mineral density, renal dysfunction, and fracture risk in HIV infection: a cross-sectional study.

BACKGROUND: Reduced bone mineral density (BMD) is common in adults infected with human immunodeficiency virus (HIV). The role of proximal renal tubular dysfunction (PRTD) and alterations in bone metabolism in HIV-related low BMD are incompletely understood. METHODS: We quantified BMD (dual-energy x-ray absorptiometry), blood and urinary markers of bone metabolism and renal function, and risk factors for low BMD (hip or spine T score, -1 or less) in an ambulatory care setting. We determined factors associated with low BMD and calculated 10-year fracture risks using the World Health Organization FRAX equation. RESULTS: We studied 153 adults (98% men; median age, 48 years; median body mass index, 24.5; 67 [44%] were receiving tenofovir, 81 [53%] were receiving a boosted protease inhibitor [PI]). Sixty-five participants (42%) had low BMD, and 11 (7%) had PRTD. PI therapy was associated with low BMD in multivariable analysis (odds ratio, 2.69; 95% confidence interval, 1.09-6.63). Tenofovir use was associated with increased osteoblast and osteoclast activity (P< or = .002). The mean estimated 10-year risks were 1.2% for hip fracture and 5.4% for any major osteoporotic fracture. CONCLUSIONS: In this mostly male population, low BMD was significantly associated with PI therapy. Tenofovir recipients showed evidence of increased bone turnover. Measurement of BMD and estimation of fracture risk may be warranted in treated HIV-infected adults.

Osteoporosis and multiple fractures in an antiretroviral-naive, HIV-positive child.

As a result of the increased incidence of osteopenia and osteoporosis in HIV-infected patients, numerous publications have suggested that there may be a link between bone metabolism alterations and HIV infection. The early bone loss seen in these patients was initially attributed to the use of highly active antiretroviral treatment (HAART) that included protease inhibitors. Recent studies, however, have suggested that it may be a direct consequence of the viral infection on bone metabolism, persistent activation of pro-inflammatory cytokines (TNFa), or altered vitamin D metabolism secondary to the virus, combined with subsequent factors (e.g., antiretroviral treatment) that aggravate the bone demineralization. We present an antiretroviral-naive 6-year-old girl with vertically transmitted HIV infection who presented with severe osteoporosis and multiple pathological fractures of the vertebrae, ribs, and upper and lower limbs. The child was treated with HAART, appropriate nutritional support for her age, physiotherapy and rehabilitation, calcium and vitamin D supplements, and alendronate therapy. After 6 weeks of treatment, the intense pain and muscle atrophy had disappeared and she was able to walk unassisted. At 6 months, bone mass had increased by 72%. The interest of this case lies in the presence of severe osteoporosis and multiple pathological fractures in an HIVinfected naive child. To date, this condition has only been described in patients treated with antiretrovirals. Moreover, this is the first reported HIV-positive pediatric patient treated with bisphosphonates, which proved to be highly successful.

Localized viral vector delivery to enhance in situ regenerative gene therapy.

A lyophilization method was developed to locally release adenoviral vectors directly from biomaterials for in situ regenerative gene therapy. Adenovirus expressing a beta-galactosidase reporter gene (AdLacZ) was mixed with different excipient formulations and lyophilized on hydroxyapatite (HA) disks followed by fibroblasts culturing and 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal) staining, suggesting 1 M sucrose in phosphate-buffered saline had best viability. Adenovirus release studies showed that greater than 30% virus remained on the material surface up to 16 h. Lyophilized adenovirus could be precisely localized in defined patterns and the transduction efficiency was also improved. To determine if the lyophilization formulations could preserve viral bioactivity, the lyophilized AdLacZ was tested after being stored at varying temperatures. Bioactivity of adenovirus lyophilized on HA was maintained for greater than 6 months when stored at -80 degrees C. In vivo studies were performed using an adenovirus encoding BMP-2 (AdBMP-2). AdBMP-2 was lyophilized in gelatin sponges and placed into rat critical-size calvarial defects for 5 weeks. Micro-computed tomography (micro-CT) analysis demonstrated that free-form delivery of AdBMP-2 had only modest effects on bone formation. In contrast, AdBMP-2 lyophilized in gelatin sponges led to more than 80% regeneration of critical-size calvarial defects.