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Fracture risk in hepatitis C virus infected persons: results from the DANVIR cohort study; HIV & HCV/HIV Bone Loss
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Journal of Hepatology March 18 2014
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IAS/2013: 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
CROI/2013: HIV is an Independent Predictor of Lower Bone Mineral Density in HIV-positive Subjects Compared to HIV-negative Subjects .......http://www.natap.org/2013/CROI/croi_200.htm
Bone Loss Worse in HIV+ vs HIV-Neg, Lower Body Weight Predicts Bone Loss in MSM: "Prevalence and determinants of reduced bone mineral density in aging HIV-1-positive and HIV-negative individuals" in AGEhIV Cohort Amsterdam......http://www.natap.org/2013/EACS/EACS_36.htm
CROI/2014:
New Fracture Risk and FRAX 10-Year Probability of Fracture in HIV-infected Adults - (03/10/14)
Low Bone Mineral Density is Associated with Increased Risk of Incident Fracture in HIV-infected Adults "highlighting the potential value of DEXA screening in this population"......median age 42[35-48]....36% osteopenia/2.9% osteoporosis - (03/10/14)
Bone Density Changes after Antiretroviral Initiation with Protease Inhibitors or Raltegravir - (03/10/14)
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Article in Press
Fracture risk in hepatitis C virus infected persons: results from the DANVIR cohort study
Journal of Hepatology March 18 2014
"We conclude that HCV-exposed patients have substantially increased risk of all fracture types, while clearance of HCV only leads to a minor risk reduction. Thus our study suggests that fracture risk is multi-factorial and indicate that a direct metabolic effect of HCV-infection on bone mineral density is not the major determinant of fracture risk among HCV-infected individuals. As the risk of low-energy and other fracture types were equally increased in the HCV-exposed population and the risk estimates were reduced when adjusting for alcohol and drug abuse, we suggest that lifestyle related factors have a substantial impact on the increased risk of fracture in the HCV-infected population. The main preventive measures to decrease risk of fractures in the HCV population should therefore focus on modification of life-style related factors."
Abstract
Background and aims
The association between Hepatitis C virus (HCV)-infection and fracture risk is not well characterized. We compared fracture risk between HCV-seropositive (HCV-exposed) patients and the general population and between patients with cleared and chronic HCV-infection.
Methods
Outcome measures were time to first fracture at any site, time to first low-energy and first non low-energy (other) fracture in 12,013 HCV-exposed patients from the DANVIR cohort compared with a general population control cohort (n = 60,065) matched by sex and age. Within DANVIR, 4500 patients with chronic HCV-infection and 2656 patients with cleared HCV-infection were studied.
Results
Compared with population controls, HCV-exposed patients had increased overall risk of fracture [adjusted incidence rate ratio (aIRR) 2.15, 95% Confidence Interval (CI) 2.03 - 2.28], increased risk of low-energy fracture (aIRR 2.13, 95% CI 1.93 - 2.35) and of other fracture (aIRR 2.18, 95% CI 2.02 - 2.34). Compared with cleared HCV-infection, chronic HCV-infection was not associated with increased risk of fracture at any site (aIRR 1.08, 95% CI 0.97 - 1.20), or other fracture (aIRR 1.04, 95% CI 0.91 - 1.19). The aIRR for low-energy fracture was 1.20 (95% CI 0.99 - 1.44).
Conclusions
HCV-exposed patients had increased risk of all fracture types. In contrast, overall risk of fracture did not differ between patients with chronic versus cleared HCV-infection, although chronic HCV-infection might be associated with a small excess risk of low-energy fractures. Our study suggests that fracture risk in HCV-infected patients is multi-factorial and mainly determined by lifestyle-related factors associated with HCV-exposure.
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HCV-exposed patients were more likely to have a diagnosis of alcohol abuse, IDU, HIV, other comorbidity and a previous diagnosis of fracture than persons from the comparison cohort. Sub-study 2 included 7,156 HCV antibody-positive patients with 42,390 PY, of whom 4,500 (63%) were viremic and 2,656 (37%) were non-viremic at the time of the HCV RNA test. Viremic patients were more likely to be male and to have a diagnosis of IDU and a previous diagnosis of fracture than nonviremic patients (Table 1).
DISCUSSION
In this large population-based, nationwide cohort study we observed a more than two fold increased risk of fracture in HCV-exposed patients compared to the general population and the risk was equally raised for low-energy and other fracture types. Furthermore the overall risk of fracture did not differ between patients with chronic versus cleared HCV-infection.
Both impaired bone strength and increased risk of traumas may contribute to the increased risk of fracture among HCV-exposed patients. The equally increased risk of all fracture types including non low-energy fractures suggests that increased risk of trauma contributes substantially to the increased fracture risk. HCV-infection is a marker of past or on-going intravenous drug use and risk-taking behaviour [26, 27], and alcohol overuse and HCV-infection often coexist [28]. Thus a number of factors may increase risk of falls, violence and traffic accidents in the HCV population [29].
Low BMD may be an effect of HCV-infection induced through inflammation or HCV induced liver disease [30]. Patients with cirrhosis, including HCV related cirrhosis, have a high prevalence of osteoporosis [1, 31]. In our study, adjusting for liver disease did not change the risk estimates substantially indicating that advanced liver disease is not a major driver of fracture risk in our populations. Low BMD may also be induced by risk factors associated with being exposed to HCV-infection including a lifestyle associated with malnutrition [32] and negative effects on bone metabolism associated with alcohol consumption [33-35]. Adjusting for HIV, IDU, alcohol abuse and comorbidity diminished the fracture risk associated with being HCV-seropositive which implies that part of fracture risk can be attributed to these risk factors.
The finding of an increased risk of fracture in HCV-exposed patients was extended by comparing risk of fracture between patients with chronic and cleared HCV-infection. Of interest, fracture risk did not differ significantly between patients with cleared versus chronic HCV-infection in adjusted analyses. Accordingly, factors associated with HCV-infection rather than a direct effect of HCV-infection on bone health, seem to be main determinants of fracture risk. Albeit not a significant finding in adjusted analyses, viremic patients had approximately 20% higher risk of low-energy fracture than non-viremic patients, thus our study cannot discard that chronic HCV-infection per se also exerts negative effects on bone metabolism and thereby fracture risk, especially, when taking into account the rather few patients at the end of follow-up.
Recently, another large cohort study examined fracture risk in HCV-infected patients; this study found that HCV-infected persons had increased risk of hip fracture with a hazard ratio of 2.69 (adjusted hazard ratio of 1.47) compared with uninfected individuals [7]. The risk estimates are comparable with our results as we found a 2.96 fold increased risk of all low-energy fractures in HCV-infected patients (adjusted IRR of 2.13). Lo Re and co-authors only reported data for hip fractures, and they did not report result according to HCV RNA status. Only two small studies in selected groups of post-menopausal women have previously compared fracture rates in patients with chronic versus cleared HCV-infection. In contrast to our results, these studies found significantly increased fracture risk in HCV RNA-positive women compared with HCV RNA-negative women. The results may have been hampered by small number of endpoints [4] or may be confounded by shared risk factors for non-responding to interferon and being prone to fractures [36]. We did not specifically study postmenopausal women, but in stratified analyses, we found approximately the same relative risk estimates among persons older than 50 years or in women when comparing chronic versus cleared HCV-infection.
To our knowledge, this is the first large-scale cohort study designed to compare fracture risk in viremic versus nonviremic HCV-infected patients. The strengths of our study also include the population-based design with unique linkage to validated national registries, which allowed for long and complete follow-up.
Our study also had limitations. We estimated fracture risk starting from time of diagnosis of HCV-infection as we were not able to determine the date of infection. Regular testing for HCV RNA subsequent to an initial diagnosis is not performed systematically in Denmark. Therefore, we could not model HCV viremia as a time updated variable and our analyses did not account for spontaneous or treatment-related viral clearance nor reinfection during followup. However, spontaneous clearance of HCV-infection mainly happens shortly after the initial acute phase of the disease and occurs infrequently in later phases of the disease [37]. In addition, during the study period, only a minority of Danish HCV-patients received antiviral treatment [13]. We did not exclude patients with a diagnosis of fracture before study inclusion. Fracture data were incomplete before 1995 as the DNHR only included data on outpatient and emergency patient visits since 1995. The interpretation of our results should also take into considerations that fracture before the age of 50 years rarely reflects osteoporosis [6]. Another potential shortcoming is inaccuracies in fracture diagnoses reported to DNHR. However, the positive predictive value of the diagnoses registered in DNHR is generally high (70% to 99%) [38], and has for hip fractures been shown to be as high as 93% [39]. Another limitation is the lack of data on known risk factors for osteoporosis, such as menopause, medication and smoking. If these factors were distributed unequally between study groups, which is likely to be the case in sub study 1, but less likely in sub study 2, they might have affected the results.
We conclude that HCV-exposed patients have substantially increased risk of all fracture types, while clearance of HCV only leads to a minor risk reduction. Thus our study suggests that fracture risk is multi-factorial and indicate that a direct metabolic effect of HCV-infection on bone mineral density is not the major determinant of fracture risk among HCV-infected individuals. As the risk of low-energy and other fracture types were equally increased in the HCV-exposed population and the risk estimates were reduced when adjusting for alcohol and drug abuse, we suggest that lifestyle related factors have a substantial impact on the increased risk of fracture in the HCV-infected population. The main preventive measures to decrease risk of fractures in the HCV population should therefore focus on modification of life-style related factors.
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