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Experts break down connection between HCV and bone disorders
An increasing body of evidence is showing associations between hepatitis C virus and bone disorders, such as osteoporosis, low bone mineral density and fractures.
However, the clinical community has yet to determine whether hepatitis C virus (HCV) is causing these disorders or whether the connection exists because of comorbid factors frequently seen in patients with chronic HCV infection. As millions of new patients flood the system for treatment with novel direct-acting antiviral (DAA) therapies, clinicians may find themselves dealing with an unexpected influx of brittle and broken bones.
Much of the research in this area involves patients coinfected with HIV/HCV. Because these two patient populations share several risk factors for bone disorders — smoking, injection drug use and poor nutrition among them — researchers have struggled to untangle the various causes and effects.
Endocrine Today asked experts to provide insight on the history of HCV and bone loss and to address strategies for managing HCV patients with bone disorders, given that osteoporosis and other such conditions may be treated by a rheumatologist, an endocrinologist, an orthopedist or even a primary care physician. In addition, the impact of novel DAA therapies on HCV seems to be predictable at this point, but whether curing HCV will lead to improvements in bone health remains uncertain.
Nelson Watts, MD, FACP, MACE, director of Mercy Health Osteoporosis and Bone Health Services in Cincinnati, said bone disorders in patients with liver disease have been on the radar of researchers and clinicians for some time. “Patients with end-stage liver disease waiting for liver transplant have about a 10% disadvantage in terms of bone density compared with healthy age-matched controls,” Watts told Endocrine Today. “One of the challenges with the information that patients with chronic HCV may have an increased risk for fracture is that it’s one thing to know that fracture risk is increased, but it’s another thing to figure out why, because that’s the necessary information to come up with a plan on how to deal with it.”
Ongoing association
Todd T. Brown, MD, PhD, associate professor of medicine and epidemiology in the division of endocrinology, diabetes, and metabolism at Johns Hopkins University, highlighted a number of reasons why liver complications, particularly end-stage liver disease (ESLD), may be associated with bone loss. “Hormonal reasons, including lower testosterone in men, lower insulin-like growth factor concentrations and abnormal metabolism of vitamin D, all play a role,” he said. “Another is increased levels of inflammation. All of this contributes to this phenotype in ESLD patients.”
Perhaps more worrisome is that there is increasing recognition that even HCV populations without advanced liver disease are experiencing more osteoporosis, according to Brown. “Studies show increased fracture risk” among this population, he said.
One such study was conducted by Vincent Lo Re III, MD, MSCE, assistant professor of medicine and epidemiology at the University of Pennsylvania, and colleagues, who reported an increase in hip fracture risk among HCV-monoinfected individuals compared with uninfected individuals. The risk was more than threefold (HR = 3.56; 95% CI, 2.93-4.32) for women aged 18 to 39 years and more than double (HR = 2.4; 95% CI, 2.02-2.84) for men in the same age group. This longitudinal study was conducted in 2009.
“We also found that HCV-infected patients with liver decompensation had modest increased rates of fracture compared with those without decompensated cirrhosis,” Lo Re told Endocrine Today.
Roger Bedimo, MD, MS, chief of the infectious diseases section at VA North Texas Health Care System and associate professor of medicine at the University of Texas Southwestern Medical Center, has conducted many studies in this area. “It has taken some time for people to figure this out,” he said. “Many of our studies include patients with HIV/HCV coinfection, but when we look at HCV alone, we see a significantly high risk for fractures. The data are becoming abundantly clear, but we still need prospective analyses to confirm these findings.”
Mechanisms of disease
More research, hopefully, will shed light on if and how HCV causes bone disorders. “The big question is whether or not the increased risk for osteoporosis and fracture is due to something intrinsically related to chronic HCV infection or due to risk factors associated with HCV,” Brown said.
“The mechanisms for the association between HCV infection and both low BMD and hip fracture remain unclear,” Lo Re said. “It is thought that chronic HCV-induced inflammation is a key driver of the observed decrements in BMD and increased hip fracture rates. Elevated serum levels of inflammatory cytokines associated with chronic HCV infection — particularly, tumor necrosis factor-alpha, interleukin-1 and interleukin-6 — could increase receptor activator of nuclear factor kappa-B ligand, promoting osteoclastogenesis and increasing bone resorption.”
He added that tumor necrosis factor-alpha also inhibits osteoblast differentiation and collagen synthesis in osteoblasts and promotes osteoblast apoptosis. “The net effect of this inflammatory cascade could contribute to reduced BMD and increased fracture risk,” he said.
Bedimo and colleagues recently found that lower BMD in HCV is due to a low bone turnover state with no significant effect on bone turnover markers and is not correlated with liver severity as measured by aminotransferase-to-platelet ratio index (APRI) score.
For Lo Re, HCV-induced liver synthetic dysfunction might also be an important contributor to low BMD and increased fracture risk. “Liver synthetic dysfunction in the setting of hepatic decompensation could increase the risk for hypogonadism, reduce hepatic hydroxylation of vitamin D and impair hepatic production of insulin-like growth factor, which promotes bone formation, and these conditions could further reduce bone density and contribute to fractures,” he said.
Bedimo summarized the discussion. “HCV is independently associated with fracture risk,” he said. “That increased fracture risk is associated with lower BMD. HCV does not increase bone resorption but might decrease bone formation. This is where the black box remains: in the association with hormonal imbalance that HCV creates.”
Coinfection with HIV/HCV
Dong and colleagues investigated whether HIV/HCV coinfection conferred an increased risk for osteoporosis and fractures compared with HIV monoinfection or controls uninfected with HIV or HCV. They reviewed data for tens of thousands of patients from 15 studies conducted in the United States, Europe and Taiwan.
The pooled estimate for osteoporosis prevalence in coinfected individuals was 22% (range, 5%-45%). Compared with monoinfected patients, coinfection significantly increased low BMD risk (OR = 1.63; 95% CI, 1.27-2.11). This trend persisted — the prevalence rate was 20% — even when a study involving postmenopausal women was removed from the analysis (OR = 1.61; 95% CI, 1.23-2.12).
Coinfection also yielded increased fracture risk compared with HIV monoinfection (IRR = 1.77; 95% CI, 1.44-2.18). People in the coinfected group also were significantly more likely to experience fragility fractures compared with people with HIV-monoinfection (IRR = 1.7; 95% CI, 1.18-2.43). Other results indicated increased incidence of bone fractures in the coinfected group compared with controls (IRR = 2.95; 95% CI, 2.17-4.01).
Independent associations with osteoporosis were reported for many factors, including HIV/HCV coinfection, older age, lower BMI, postmenopausal status and longer duration of therapy with an HIV protease inhibitor, according to the results.
“Low BMD is a recognized metabolic complication of both HIV and chronic HCV infection,” Lo Re said. He added that BMD further decreases 2% to 6% during the initial 2 years of antiretroviral therapy. “Each of these chronic infections has been associated with an increased risk for fracture compared with uninfected individuals.”
Women with HIV are more likely to experience reductions in BMD than men with HIV, according to Lo Re. Other results from a study he conducted in 2009 indicated an association between viral hepatitis and low BMD among women (OR=2.87; 95% CI 1.31-6.29) but not men (OR = 1.19; 95% CI 0.74-1.91).
“Rates of hip fracture have also been shown to be significantly higher in HIV/HCV-coinfected [persons] compared with HIV-monoinfected, HCV-monoinfected, and uninfected persons,” he said.
Lifestyle factors
Although there is little doubt that there is significant crossover in HIV and HCV populations in terms of lifestyle factors that impinge on bone health, such as smoking, poor nutrition and drug and alcohol use, how those factors affect bone loss and fractures remains unclear.
“This is a little bit tricky because populations that are HIV/HCV coinfected might be different from HIV or HCV monoinfected in terms of the behavioral risk factors,” Brown said. “Selection of control groups is important to match on these behavioral risk factors to determine the exact contribution of HCV.”
Lo Re took this one step further. “We need to look at how illicit drug use, alcohol abuse, poor nutrition and fragility among HCV-infected patients might also contribute to increased fracture risk from trauma, irrespective of the impact of HCV infection on BMD,” he said. “Additional research is needed to determine the mechanisms by which chronic HCV and HIV/HCV coinfection affect BMD and fracture incidence.”
DXA screening
Dong and colleagues concluded that DXA screening should be considered for individuals aged 50 years with HIV/HCV coinfection.
Brown supported DXA screening in younger populations with particular risk factors. “This is certainly a good idea if other risk factors besides HCV are present, including HIV in men and women,” he said. “But there is probably enough evidence now to suggest that HCV should be considered a risk factor and prompt screening in the youngest of the older population, including men aged 50 to 70 years and postmenopausal women younger than 65 years.”
The most important risk factor for osteoporotic fracture is age, according to Brown. “Since osteoporosis is generally a silent disease until there is a fracture, screening is worthwhile in people with increased risk,” he said.
Watts also suggested that HCV be considered an additional risk factor for osteoporosis — like a family history of the condition, cigarette smoking, corticosteroid use, and presence of other diseases and medication used — that would prompt DXA screening at age 50 years for men and at menopause for women.
For the clinician
The bottom line, according to these experts, is that HCV infection is associated with a greater risk for fracture, but the underlying mechanisms are unclear, which makes it hard to determine whether HCV-infected patients should be screened and treated for osteoporosis differently from non-HCV infected patients.
No population-specific guidelines are currently available for management of osteoporosis in people with HCV, according to Brown.
“Once osteoporosis is identified, we generally follow the algorithms that are set up for the general population,” he said. “We evaluate and eliminate secondary causes of low BMD and treat them with the same kind of therapies.”
Watts agreed that lack of clear data makes choice of therapy a non-choice. Until research determines whether the osteoporosis in HCV is due to increased bone resorption, decreased bone formation, both or something else, drug therapies cannot be targeted as they can in osteoporosis due to some other conditions, such as corticosteroid use or menopause, he said.
“We have a number of good medications out there that are used for patients with postmenopausal osteoporosis and for men with osteoporosis,” Watts said. “Until we have a clearer understanding of what’s going on in these patients, at least part of the fracture risk for women with HCV would be the same as for other postmenopausal women who don’t have HCV. Likewise for men with HCV, part of the risk would be age-related bone loss that likely would respond to the standard therapies.”
Clearing the virus
Moving forward, researchers should begin investigating the extent to which novel DAA therapies affect bone health. “Another way to talk about the mechanism has to do with treatment,” Bedimo said. “If you clear your HCV, will you reverse the trends in bone loss? We are working on that now.”
Lo Re agreed that there are limited data on this issue.
“That’s where we are now,” Brown said. “With effective HCV treatments, there is an opportunity is to find out if clearing the virus improves BMD. It is a basic scientific concept. One of the best ways to test a causal hypothesis is to take away the factor of interest to see if the endpoint changes.” – by Rob Volansky and Jill Rollet
- References:
- Cuttrell J. Poster 783. Presented at: 2014 CROI; March 3-6, 2014; Boston.
- Dong HV. AIDS. 2014;doi:10.1097/QAD.0000000000000363.
- Lo Re V 3rd. AIDS. 2009;23:2191-2198.
- Lo Re V 3rd. Hepatology. 2012;56:1688-1698.
- For more information:
- Roger Bedimo, MD, MS, can be reached at VA North Texas Health Care System, 4500 South Lancaster Road, 111-D, Dallas, TX 75216; email: Roger.Bedimo@va.gov.
- Todd T. Brown, MD, PhD, can be reached at Johns Hopkins University, 1830 E. Monument St., Suite 333,Baltimore, MD, 21287; email: tbrown27@jhmi.edu.
- Vincent Lo Re III, MD, MSCE, can be reached at 836 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104; email: vincentl@mail.med.upenn.edu.
- Nelson Watts, MD, FACP, MACE, can be reached at 4760 E Galbraith Road #212, Cincinnati, OH 45236; email: nwatts@mercy.com.
Disclosures: Bedimo reports associations with Bristol-Myers Squibb, Merck and ViiV Healthcare. Brown reports associations with AbbVie, EMD-Serono, Gilead, Merck, Theratechnologies and ViiV Healthcare. Lo Re reports associations with AstraZeneca, Gilead Sciences and Merck. Watts reports associations with AbbVie, Amgen, Merck, NPS, OsteoDynamics and Radius.