Table 1.
Representative clinical studies for osteoporosis in chronic liver disease.
| Studies on Patients with Primary Biliary Cholangitis (PBC) or Primary Sclerosing Cholangitis (PSC) | |||||
|---|---|---|---|---|---|
| Author, Year | Study Aim | Study Design | Study Population | Method to Diagnosis Osteoporosis | Outcome |
| Menon et al., 2001 [19] | To evaluate the prevalence and risk factor of bone disease in patients with PBC and to determine the rate of bone loss over time. | Retrospective study | 176 patients with PBC | DEXA | The prevalence of osteoporosis is 20% in patients with PBC. Age (OR 1.2 (1.1–1.2)), BMI (OR 0.8 (0.7–0.9)), advanced stage (3 or 4) (OR 6.3 (1.8–21.6)), and history of fractures (OR 4.1 (1.0–16.8)) were independent indicators of osteoporosis. Serum bilirubin level was independently associated with the rate of bone loss over time. |
| Guanabens et al., 2005 [20] | To find out the prevalence and risk factors for osteoporosis in women with PBC | Cross-sectional study | 142 women with PBC and 1305 age-matched control subjects |
DEXA | Prevalence of osteoporosis was higher in PBC (32.4%) than in normal women (11.1%). Older age, higher Mayo risk score, lower BMI and advanced histological stage were independent risk factors for osteoporosis. |
| Solaymani-Dodaran et al., 2006 [22] | To quantify the excess fracture risk in people with PBC | Retrospective cohort study | 930 patients with PBC and 9202 age- and sex-matched control subjects. | NA | There were approximately 2-fold relative increases in the risk of any fracture (HR 2.03 (1.70–2.44)), hip fracture (HR 2.14 (1.40–3.28)), and ulna/radius fracture (HR 1.96 (1.42–2.71)) for the PBC cohort compared with the general population. |
| Guanabens et al., 2010 [23] | To assess the prevalence and risk factors for fractures and the fracture threshold in women with PBC | Prospective study | 185 women with PBC |
DEXA | The prevalences of vertebral, non-vertebral, and overall fractures were 11.2%, 12.2%, and 20.8%, respectively. Vertebral fractures, are associated with osteoporosis (OR 8.48 (2.67–26.95)). Osteoporosis and osteopenia are associated with the severity of liver damage. |
| Angulo et al., 2011 [21] | To identify prevalence and rate of progression of bone disease in patients with PSC and to identify predictors of bone disease and progression. | Retrospective longitudinal cohort study | 237 patients with PSC | DEXA | Osteoporosis was found in 15% of patients (RR 23.8 (4.6–122.8)). Old age (OR 7.8 (3.3–18.3), BMI (OR 4.9 (1.9–12.6), and long duration of inflammatory bowel disease (OR 3.6 (1.5–8.4)) correlated with the presence of osteoporosis. |
| Studies on Patients with Viral Hepatitis | |||||
| Author, Year | Study Aim | Study Design | Study Population | Method to Diagnosis Osteoporosis | Outcome |
| Schiefke et al., 2005 [28] | To evaluate BMD and bone turnover markers in patients with non-cirrhotic CHB or CHC | Cross-sectional study | 43 patients with HCV (n = 30) or HBV (n = 13) infection without histological evidence for liver cirrhosis. | DEXA | Osteoporosis is observed in 32% of non-cirrhotic CHB or CHC patients. Altered bone metabolism with increased bone-specific ALP and iPTH already occurred in advanced liver fibrosis without cirrhosis. |
| Orsini et al., 2013 [24] | To identify the prevalence of osteoporotic vertebral fractures and low BMD measurements in men with non-cirrhotic CHC. | Cross-sectional study | 60 non-cirrhotic CHC patients and 59 healthy controls | DEXA | Non-cirrhotic untreated CHC patients have lower BMD at the femur as compared to healthy men in spite of the absence of significant bone and mineral abnormalities. |
| Hansen et al., 2014 [29] | Comparison of fracture risk between HCV-seropositive (HCV-exposed) patients and the general population, and between patients with cleared and CHC infection. | Retrospective cohort study | 12,013 HCV-exposed patients from the Danish HCV cohort, and 60,065 general population | NA | HCV-exposed patients had increased risk of all fracture types (adjusted incidence rate ratio (aIRR) 2.13–2.18) whereas overall risk of fracture did not differ between patients with chronic vs. cleared HCV-infection. |
| Lai et al., 2015 [25] | Association between BMD, systemic inflammation, and markers of bone turnover in CHC without cirrhosis | Cross-sectional study | 60 non-cirrhotic CHC patients | DEXA | Low BMD was observed in 42% (30% had osteopenia, 12% had osteoporosis) of non-cirrhotic CHC patients, but not associated with systemic inflammatory markers. Patients with low BMD had higher serum phosphorus and pro-peptide of type 1 collagen. |
| Huang et al., 2017 [26] | To assess BMD and prevalence of osteoporosis in CHB patients | Case-control study | 148 CHB patients and 148 age- and gender-matched healthy controls | DEXA | The prevalence of osteoporosis in either of lumbar spine, total hip or the femur neck was significantly higher in the CHB patients group (12.8%, 11.5%, 12.2%) compared with the healthy control (4.7%, 4.1%, 4.7%). CHB infection was associated with low BMD and increased the risk of osteoporosis. |
| Wei et al., 2019 [27] | To identify the effect of ETV and TDF on the development of osteopenia/osteoporosis | Retrospective cohort study | 1224 Asian CHB patients | DEXA | There is no significant increase in the incidence of osteopenia/osteoporosis for patients with CHB treated with TDF (HR 0.74 (0.34–1.59)) or ETV (HR 0.98 (0.51–1.90)) during a median follow-up of about 4 to 5 years. |
| Studies on Patients with Liver Cirrhosis (LC) | |||||
| Author, Year | Study Aim | Study Design | Study Population | Method to Diagnosis Osteoporosis | Outcome |
| Monegal et al. 1997 [33] | To find out the prevalence and risk factor of bone disease in patients with end-stage liver disease waiting for OLT. | Prospective study | 58 cirrhotic patients | DEXA | 43% patients had osteoporosis and vitamin D deficiency, reduced PTH levels, and hypogonadism are observed in cirrhotic patients. Alcoholic and Child-Pugh C patients showed the lowest femoral BMD. |
| Sokhi et al., 2004 [31] |
To assess the BMD in different subgroups among pretransplant cirrhotic patients. | Retrospective study | 104 cirrhotic patients | DPA | The overall prevalence of osteopenia and osteoporosis were 34.6% and 11.5%, respectively, being significantly higher in females than in males. BMD is significantly lower in those with CTP class C than those with CTB class B in both males and females. |
| Goubraim et al., 2013 [30] | To evaluate prevalence and risk factors for metabolic bone disease in patients with viral cirrhosis | Prospective study | 46 cirrhotic patients | DEXA. | Osteopenia and osteoporosis is observed in 52.2% and 28.2% patients, respectively. There was no independent factor associated with bone disorders although bone disorders were significantly more frequent in old patients with low BMI, long duration of liver disease, and low vitamin D level. |
| Zheng et al., 2018 [32] | To evaluate osteoporosis or osteopenia in patients with cirrhosis | Retrospective study | 217 LC patients and 229 subjects without liver diseases | DEXA | Osteoporosis was found in 20.3% and older age (OR 1.78), lower BMI (OR 0.63), greater fibroscan score (OR 1.15), and alcoholic liver cirrhosis (OR 3.42) were independently associated with osteoporosis in cirrhotic patients. |
| Studies on Patients Who Underwent Liver Transplantation | |||||
| Author, Year | Study Aim | Study Design | Study Population | Method to Diagnosis Osteoporosis | Outcome |
| Monegal et al., 2001 [34] | To determine the incidence and risk factors of skeletal fractures and to analyze the long-term evolution of bone mass, bone turnover and hormonal status after LT | Prospective study | 45 patients following LT | DEXA | Fifteen patients (33%) developed fractures after liver transplantation, and pre- transplant risk factors for fractures were age and low bone mass (OR 5.69 (1.32–24.53)). Bone mass decreased during the first 6 months and after then bone formation parameters is increased. |
| Guichelaar et al., 2006 [35] | To identify the prevalence and predictive factors for low bone mass before OLT, Posttransplant bone loss, and bone gain at the lumbar spine with long-term follow-up after OLT | Prospective cohort study | 360 patients with end-stage PBC and PSC | DPA & DEXA | Most patients (77%) with advanced PBC and PSC have osteopenic bone disease, and risk factors for hepatic osteopenia are low BMI, older age, postmenopausal status, the presence of muscle wasting, high ALP, and low serum albumin. After OLT, aggressive bone loss occurs during the first 4 months, with risk factor of younger age, PSC, higher pretransplant BMD, no IBD, shorter duration of disease, current smoking and ongoing cholestasis at 4 months. After the first 4 postoperative months, bone gain occurs during the first 2 years with favoring factors for improvement of lower baseline and/or 4-month BMD, premenopausal status for females, lesser glucocorticoids, no ongoing cholestasis, and higher levels of vitamin D and parathyroid function. |
| Studies on Patients with Non-Alcoholic Fatty Liver Disease (NAFLD) | |||||
| Author, Year | Study Aim | Study Design | Study Population | Method to Diagnosis Osteoporosis | Outcome |
| Li et al., 2012 [36] | Association between NAFLD and osteoporotic fracture | Cross-sectional study | 7797 Chinese adults (including 2352 patients with NAFLD) | NA | The prevalence of osteoporotic fractures was significantly higher in men with NAFLD (3.6 vs. 1.7%), and the presence of NAFLD was significantly associated with osteoporotic fracture among men. (OR 2.53 (1.26–5.07)) |
| Purnak et al., 2012 [37] | Association between BMD and liver function in patients with NASH. | Cross-sectional study | 102 patients with NAFLD and 54 healthy controls | DEXA | The presence of elevated serum ALT and hs-CRP levels, which are suggestive of NASH, was associated with lower BMD although simple steatosis of the liver does not affect BMD. |
| Kim et al., 2017 [38] | Association between liver fibrosis and BMD in patients with NAFLD | Retrospective cross-sectional study | 231 subjects (including 129 patients with NAFLD) | DEXA | Significant liver fibrosis was independently associated with overall osteopenia and osteoporosis in subjects with NAFLD. (OR 4.10 (1.02–16.45)). |
| Ahn et al., 2018 [39] | Association between fatty liver index (scoring model for NAFLD) and BMD | Population-based, cross-sectional study | 4264 adults | DEXA | Fatty liver index was negatively correlated with total hip (p = 0.004), femoral neck (p < 0.001), and whole body BMD (p = 0.01) in men independent of insulin resistance. |
| Studies on Alcoholics | |||||
| Author, Year | Study Aim | Study Design | Study Population | Method to Diagnosis Osteoporosis | Outcome |
| Peris et al., 1994 [42] | To evaluate the effect of abstinence on bone mass and bone mineral metabolism in chronic alcoholics. | 2 year longitudinal follow-up study | 30 chronic alcoholic males | DPA | After 2 years of abstinence, Lumbar and femoral neck BMD increased in alcoholics and Baseline low osteocalcin increased after 1 year and 2 years of abstinence. |
| Peris et al., 1995 [41] | Association between vertebral facture and osteopenia in chronic alcoholics patients. | Cross-sectional study | 76 chronic alcoholics and 62 age matched healthy males. | DPA | Chronic alcoholics frequently have traumas (68%) and vertebral fractures (36%) in spite of having a lumbar BMD above the fracture threshold. |
| Malik et al., 2009 [40] | To evaluate BMD according to alcohol consumption and sex. | Cross-sectional study | 57 noncirrhotic alcoholic patients | DEXA | 24.3% of men and 5% of women had low BMD and 75.7% of the men and 90% of the women had vitamin D insufficiency or deficiency. |
| Studies on Patients with Genetic Hemochromatosis (GH) or Wilson Disease (WD) | |||||
| Author, Year | Study Aim | Study Design | Study Population | Method to Diagnosis Osteoporosis | Outcome |
| Sinigaglia et al., 1997 [43] | To evaluate the prevalence and risk factor of osteoporosis in GH | Cross sectional study | 32 patients with histologically proven GH | DEXA | Osteoporosis is observed in 28% and osteoporosis is highly associated with degree of iron overload (OR 3.23 (1.09–9.58)) |
| Guggenbuhl et al., 2005 [44] | To assess BMD and bone remodeling in patients with GH | Retrospective study | 38 men with HFE-related GH | DEXA | Osteopenia was observed in 78.9% of patients and osteoporosis in 34.2% that cannot solely be explained by hypogonadism or cirrhosis |
| Valenti et al., 2009 [45] | To identify the prevalence, clinical characteristics and genetic background associated with osteoporosis in patients with HHC | Retrospective study | 87 patients with HHC | DEXA | Osteoporosis was identified in 25.3%, and osteopenia in 41.4% patients regardless of genetic background. Lumbar spine osteoporosis was independently associated with lower BMI (OR 0.73 (0.54–0.94)), total ALP (OR 1.17 (1–1.39)), and the amount of iron removed (OR 1.53 (1–2.5)). |
| Quemeneur et al., 2014 [47] | To assess the prevalent fractures, BMD and related risk factors in patients with WD. | Prospective cross-sectional study | 85 patients with WD | DEXA | Prevalent peripheral fractures were presented in 51%, and vertebral fracture in 8% patients. Patients with severe neurological involvement, low BMI, old age are at risk factors for vertebral fractures |
| Weiss et al., 2015 [46] | Comparison of BMD between adult WD and healthy control population | Cross sectional study | 148 adult WD patients and 345 age and gender matched control subjects | DEXA | Osteoporosis (8.8% vs. 4.1%) and osteopenia (50.0% vs. 41.2%) is significantly more prevalent in patient with WD than healthy population. There was no significant correlation between BMD and any of the WD disease parameters (e.g., the severity of liver disease), lab results, type of treatment or known osteoporosis risk factors. |
PBC, Primary biliary cholangitis; PSC, primary sclerosing cholangitis; DEXA, dual energy X-ray absorptiometry; BMI, body mass index; OR, Odds ratio; HR, hazard ratio; BMD, body mineral density; RR, relative risk; CHC, Chronic hepatitis C; CHB, chronic hepatitis B; ETV, entecavir; TDF, Tenofovir; ALP, alkaline phosphatase; PTH, parathyroid hormone; LC, Liver cirrhosis; IGF-1, insulin-like growth factor-1; DPA, dual-photon absorptiometry; CTP, Child-turcotte-Pugh; OLT, orthotopic liver transplantation; NAFLD, non-alcoholic fatty liver disease; ALT, alanine aminotransferase; CRP, c-reactive protein; NASH, non-alcoholic steatohepatits; GH, genetic hemochromatosis; WD, Wilson disease; HHC, Hereditary hemochromatosis.