Osteoporosis, Osteoarthritis and Rheumatoid Arthritis: An Agonizing Skeletal Triad

By Puneetpal Singh

This comprehensive compendium unravels the intricacies of three common and daunting skeletal disorders: osteoporosis, osteoarthritis, and rheumatoid arthritis. These ailments afflict people across all age groups, demanding a deeper understanding of their diagnostic, prognostic, preventive, and therapeutic dimensions.
 
 
 
It presents seven key topics written by medical experts that explore research on these diseases:
 
    Chronic Lung Disease and Osteoporosis
        An exploration of the intricate link between chronic lung ailments and osteoporosis.
    AI Detection of Knee Osteoarthritis
        Recent use of artificial intelligence aiding knee osteoarthritis identification.
    Inflammatory Signalling in Rheumatoid Arthritis
        Covers the role of cytokines and chemokines in the context of rheumatoid arthritis.
    Vitamin D, Immune System, and Bone Health
        Unveils the vital implications of Vitamin D on the immune system and bone health.
    Bone Water and Hydration Effects
        A review of the impact of drugs on bone hydration status through the lens of bone water.
    Dietary Patterns and Rheumatoid Arthritis
        An analysis of the connection between dietary habits and rheumatoid arthritis.
    Quality of Life in Rheumatoid Arthritis Patients (Chapters 112-130):
        An examination of the self-perceived quality of life in Rheumatoid Arthritis patients, comparing South Asian and British White populations.
 
 
 
This knowledge-rich treatise is a valuable resource for patients and their families battling these skeletal ailments. It's equally beneficial for medical students, orthopedists, researchers, and anyone eager to grasp the complexities of these widespread skeletal pathologies. 

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Nov 7, 2023
• ISBN: 9789815196085

Book preview

Osteoporosis and Chronic Liver Disease

Tsai Yi-Liang¹, *

¹ Department of Nuclear Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 622401, Taiwan

Abstract

The liver is composed of hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and hepatic sinusoidal endothelial cells. It also plays an important role in the digestive system and immune system at the same time. The different types of hepatitis, including viral liver diseases, autoimmune liver diseases, and metabolic liver diseases, are all closely related to osteoporosis. People with liver disease have a significantly higher risk of developing osteoporosis than people without hepatitis. Fibrosis is part of the wound-healing response that maintains organs after tissue injury, but excessive fibrosis may also contribute to a variety of human diseases. Hepatic stellate cells are the key to liver fibrosis. The apoptotic hepatocytes stimulate fibrosis in hepatic myofibroblasts, and activated hepatic stellate cells are the main source of myofibroblasts in the liver. Activated hepatic stellate cells possess many voltage-operated calcium channels. Changes in the concentration of calcium ions mediate hepatic stellate cell activation and fibrosis regression. The skeleton is one of the main regulatory mechanisms of calcium ions in the body. Therefore, chronic hepatitis leads to a disturbance of calcium homeostasis in vivo, which may be one of the factors causing bone loss.

Keywords: Autoimmune liver disease, Bone mineral density, Fibrosis, Metabolic liver disease, Osteoporosis, Viral liver disease.

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* Corresponding author Tsai Yi-Liang: Department of Nuclear Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 622401, Taiwan; Tel: [phone] #4971; E-mail: [e-mail]

INTRODUCTION

There are three main causes of osteoporosis caused by chronic kidney disease: abnormal calcium and phosphorus metabolism, vitamin D deficiency, and secondary hyperparathyroidism. Parathyroid hormone (PTH) can activate osteoclasts to break down bone, release calcium ions and increase blood calcium concentration. When PTH acts on the kidney, it helps the kidney to produce vitamin D and increase calcium reabsorption [1, 2]. Low vitamin D levels stimulate PTH production, but high vitamin D levels do not always lead to low

PTH levels. Serum PTH levels will be low and stable when vitamin D is above 30 ng/mL [3-5].

Both chronic kidney disease and chronic hepatitis are known to increase the risk of osteoporosis. The common causes are disturbed calcium metabolism and vitamin D deficiency.

The liver is an important organ that maintains the normal life activities of the body and is a key hub for many physiological processes. It is composed of hepatocytes, biliary epithelial cells, stellate cells, Kupffer cells, and hepatic sinusoidal endothelial cells. Its functions include controlling endocrine growth signaling pathways, blood volume regulation, lipid and cholesterol homeostasis, breakdown of exogenous compounds, and nutrient metabolism (carbohydrates, lipids and proteins) [6].

In addition, the liver plays an important role in the immune system. Overexpressed inflammation leads to tissue damage and remodeling, and chronic inflammation when immunity is compromised [7]. In chronic liver disease, viral, toxic, metabolic, or autoimmune triggers lead to hepatocyte death, followed by inflammation and compensatory proliferation, associated with the development of fibrosis, cirrhosis, and even hepatocellular carcinoma [8].

Osteoporosis & Liver Diseases

Vitamin D not only plays an important role in regulating bone, calcium, and phosphate metabolism [9], but also plays a key role in liver diseases. Vitamin D deficiency is often observed in chronic liver diseases, including hepatitis B virus [10, 11], hepatitis C virus [12, 13], and non-alcoholic fatty liver disease [14, 15]. Osteoporosis is a common complication in patients with chronic liver disease, with a prevalence ranging from approximately 4% to 21% [16]. It is currently known that liver diseases predisposing to osteoporosis include viral liver diseases (hepatitis B and hepatitis C), autoimmune liver diseases (ALD) (autoimmune hepatitis (AH), primary biliary cirrhosis (PBC), and sclerosing cholangitis) and metabolic liver diseases (alcoholic hepatitis and non-alcoholic fatty liver disease).

Viral Liver Disease

Both hepatitis B virus (HBV) and hepatitis C virus (HCV) are hepatotropic viruses. HBV is a partly double-stranded DNA virus [17]; HCV is a single-stranded RNA virus [18]. The main route of infection is the virus-infected blood and body fluids entering human body, through the skin or mucous membranes, especially the blood.

Hepatitis B Virus

The cross-sectional study of Chen et al. assessed the association between the patients with HBV infection and bone mineral density (BMD) using a multiple linear regression model. The covariates are age, gender, body mass index, proteinuria, serum total cholesterol, uric acid, creatinine, glutamic-oxaloacetic transaminase, albumin, C-reactive protein, thyrotropin, history of smoking and drinking. The results of the fully adjusted model have shown that HBV infection is significantly negatively correlated with BMD (β= -0.17, p<0.05) [19].

Another 12-year longitudinal study has assessed the association between HBV infection and osteoporosis risk. Of 180,730 patients admitted, 36,146 and 144,584 patients were divided into an HBV-infected group and a control group, respectively. The factors adjusted in the model included age, gender, frequency of hospital visits, hypertension, diabetes, hyperlipidemia, heart failure, liver cirrhosis, chronic kidney disease, thyroid disease, steroid drugs, warfarin, proton pump inhibitor, aspirin and estrogen replacement therapy. Compared with the control group, the HBV-infected group had a 1.13-fold higher risk of developing osteoporosis [20].

In the terms of vitamin D, low serum 25(OH)D3 levels are associated with high levels of HBV replication in patients with chronic hepatitis B [21]. HBV can utilize multiple mechanisms to increase intracellular Ca²+ concentration, creating a cellular environment to facilitate its infection [22].

A prospective study by Mohamed et al. has reported a change in serum 25(OH)D3 levels in chronic hepatitis B patients before and during antiviral therapy. A total of 50 treatment-naive chronic HBV patients and 30 healthy subjects were enrolled in the study. The cases received treatment in the form of Lamivudine 100 mg tablet, once daily. Serum 25(OH)D3 levels were assessed twice, once before initiation of antiviral treatment and again at least 6 months later. The studied cases showed significantly low mean serum vitamin D levels when assessed before treatment (21.6 ± 5.8 ng/ml) as compared to the levels after 6 months of treatment (31.1 ± 7.3 ng/ml) which was comparable to that of the control group (33.4 ± 5 ng/ml) [23].

Hepatitis C Virus

69 chronic HCV-infected participants were enrolled in a prospective cohort study. The results showed that the mean BMD, Z-score, and T-score of the lumbar spine in patients with chronic hepatitis C were significantly lower than the control group without chronic hepatitis C (p<0.001). The results also showed that bone alkaline phosphatase and the C-terminal cross-linked telopeptide of type I collagen were significantly elevated in chronic hepatitis C patients with reduced BMD [24]. The findings are similar to those of Lai et al. Procollagen type I amino-terminal pro-peptide, one of the bone turnover biomarkers [25, 26], is useful in identifying chronic HCV patients at increased risk of bone loss [27].

Vitamin D not only plays an important role in calcium metabolism [25, 28], but also acts as an immune modulator. It can reduce inflammation while enhancing protective immune responses [29]. Gutierrez et al. have shown that bone loss in HCV patients is related to the high prevalence of 25-hydroxyvitamin D deficiency [29]. Moreover, low vitamin D level has been associated with high hepatic necro-inflammatory activity and progression of liver fibrosis, and it can affect the response to antiviral therapy in HCV patients [30].

Autoimmune Liver Diseases

Autoimmune liver diseases are caused by immune-mediated damage to tissues. Autoimmune liver disease and rheumatic disease coexist in approximately 30% of cases and may share a common pathogenic mechanism [31]. The common autoimmune liver diseases, with a high risk of osteoporosis, include primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) targeting hepatocytes.

Primary Biliary Cholangitis

PBC is an autoimmune cholestatic liver disease clinically characterized by bile duct destruction, sometimes with granulomas. Osteoporosis is a common complication of PBC [32]. It mainly affects middle-aged women and is characterized by chronic progressive destruction of small intrahepatic bile ducts, with portal inflammation and eventual fibrosis [33]. Osteoporosis is more common in women with PBC than in the general population. Age and disease severity are major risk factors for osteoporosis in PBC, but are not associated with menopausal status [34]. At present, the pathogenesis of PBC is not well known, but it is mainly due to low bone formation [35]. Therefore, the American Association for the Study of Liver Disease has recommended that the treatment of PBC can use vitamin D, calcium supplementation, and alendronate to increase bone mass effectively and to prevent bone loss [36].

The best form of vitamin D for PBC is calcitriol because it is the active form of the vitamin D3 metabolite. Its receptors are present in sinusoidal endothelial cells, Kupffer cells, and stellate cells of normal liver, as well as cholangiocyte lineages [37]. The study by Wang et al. measured the serum vitamin D levels in 185 PBC patients in which patients with late-stage PBC had lower mean vitamin D levels (9.15 ± 5.33 ng/ml) than patients with early-stage PBC (13.68 ± 6.33 ng/ml) (p< 0.001). Vitamin D levels tended to rise in patients taking calcitriol, as compared to those who were not taking calcitriol (p = 0.027). In addition, vitamin D-deficient PBC patients have higher bilirubin and lower albumin [38]. Also of interest, seasonal changes in PBC may be partly related to vitamin D. From 1987 to 2003 in the North East of England, a clear peak in the local diagnosis of PBC was observed in June, but the mechanism has not yet been understood [39].

Autoimmune Hepatitis

AIH shows prominent portal and lobular lymphoplasmacytic inflammation [40]. AIH is a rare autoimmune disease, about 5% of all chronic liver diseases. It is characterized by female predominance, hypergammaglobulinemia, extrahepatic syndrome and favorable response to immunosuppressive therapy [41].

Osteoporosis is a common complication of AIH. A study has shown that almost 20% of AIH patients with age greater than 50 years have osteoporosis. Aging, duration of corticosteroid use, low body mass index, and liver fibrosis are independent risk factors for bone loss [42].

The 25(OH)D deficiency plays an important role in predicting AIH severity via inflammatory cytokine production. A study investigates 66 AIH patients (7 males, 59 females), the results of which indicate that serum total 25(OH)D levels are significantly lower in patients with acute-onset AIH than in patients with chronic-onset AIH. Serum total 25(OH)D levels are significantly reduced in patients with severe AIH [43]. Another study also shows that unresponsiveness to treatment is more common in patients with severe vitamin D deficiency (59%) than in patients without deficiency (41%) (p = 0.04). Moreover, severe vitamin D deficiency is also independently associated with a higher risk of developing cirrhosis (hazard ratio = 3.40, p = 0.01), and liver-related mortality or requirement for liver transplantation (hazard ratio = 5.26, p = 0.008) [44].

Metabolic Liver Diseases

Metabolic liver diseases can be divided into alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), the latter is also called metabolic-associated fatty liver disease (MAFLD).

Alcoholic Liver Disease

The liver is the main organ responsible for metabolizing ethanol [45]. The alcohol metabolism would generate reactive oxygen species. These active radicals are usually produced by the mitochondria, endoplasmic reticulum or Kupffer cells. These rapidly form a variety of active metabolites which can further contribute to oxidative stress in hepatocytes [46].

Alcohol intake is an important factor in the development of osteoporosis, but moderate drinking can reduce fracture rates and increase BMD. The study has shown that BMD is higher in men and postmenopausal women, who drink alcohol as compared to those who refrain from it. Drinking alcohol in moderate amount appears to be beneficial to bone health [47]. It has a good effect on high-density lipoprotein cholesterol levels and has an inhibitory effect on platelet aggregation [48]. In addition, suitable alcohol consumption may help to maintain bone density in postmenopausal women by increasing endogenous estrogens or promoting the secretion of calcitonin [49].

Acute alcoholism causes transient hypoparathyroidism, leading to hypocalcemia and hypercalciuria. However, long-term moderate alcohol consumption increases serum PTH levels. Chronic alcoholics are characterized by low serum vitamin D metabolite levels, leading to calcium malabsorption, hypocalcemia, and hypocalciuria [50]. This finding is consistent with the idea that moderate alcohol consumption increases BMD but excessive drinking decreases BMD.

However, there has been no consensus so far on how much amount of alcohol is to be considered moderate. The study by de Lorimier has suggested that it should not exceed 2 to 4 drinks per day for men, and 1 to 2 drinks per day for women [48]. The male subjects in a study population of Tucker et al. are predominantly beer drinkers. The results show that alcohol intake in men greater than 2 glasses per day is associated with significantly lower BMD [51]. Feskanich et al. recommend that the weekly alcohol intake should be less than 75 grams [49].

Although drinking alcohol has inconsistent effects on bones, it is one of the causes of osteoporosis [52]. Chronic alcoholic patients are frequently deficient in one or more vitamins, including folate, vitamin B6, thiamine, vitamin A and vitamin D [53, 54]. 90% of patients with alcoholic cirrhosis have vitamin D deficiency (80nmol/L) [54]. The pathogenesis of loss of BMD in ALD is multifactorial, including the toxic effects of alcohol on bone and endocrine, nutritional disturbances secondary to alcoholism and deficiencies in osteocalcin, vitamin D and insulin growth factor-1. These factors may be the result of imbalances in bone formation and resorption