European Journal of Cardiovascular Medicine

Osteoporosis is characterized by bone tissue structural abnormalities and low bone mass (bone mineral density (BMD) T-score<−2.5) leading to skeletal fragility and increased risk of fractures.¹ Osteoporosis can be primary, as seen in menopausal women and the elderly, or secondary, resulting from a variety of medical conditions or medications.²

Cirrhosis is characterized by fibrosis, nodule formation, and impaired function due to chronic injury from causes like viral infections, alcohol, toxins, or autoimmune conditions with global estimates of 10·6 million cases of decompensated and 112 million cases of compensated cirrhosis in 2017.^3,4 Hepatic cirrhosis is one of the conditions associated with secondary osteoporosis.⁵ According to previous research, osteoporosis affects 15–55.6% of patients with hepatic cirrhosis, making it a significant health concern for these individuals.^5-7

Studies investigating the association between bone diseases and chronic liver disease have mainly focused on cholestatic liver diseases.⁸ Since patients with liver cirrhosis and other liver diseases also exhibit bone diseases, in this review, chronic liver disease encompasses, but is not limited to, liver cirrhosis and cholestatic liver diseases. Severe cholestatic liver diseases are defined as the presence of a serum bilirubin level greater than three times the upper limit of normal for more than six months.⁹

Sarcopenia is a potentially lethal extra-hepatic manifestation in patients with chronic liver disease, particularly in patients with cirrhosis, but its definition remains unclear.¹⁰ Recently, Carey et al. identified and defined the skeletal muscle index (SMI) (SMI cutoffs of 50 cm2/m2 for men and 39 cm2/m2 for women).¹¹ This cutoff value determines the numerical definition of sarcopenia by showing a clear survival difference in patients with end-stage liver disease. Avascular necrosis, also known as osteonecrosis of the femoral head, is a special bone disease that is the final common pathway of a series of derangements which result in a decrease in blood flow to the femoral head, leading to cellular death, fracture and collapse of the articular surface.¹²

The aim of the present study was to determine the effects of chronic liver disease on bone health.

The present study was conducted in the General medicine and Gastroenterology Department at NIMS Hospital, Jaipur for the period of 18months and 171 patients were included in the study.

INCLUSION CRITERIA:

1. Age more than 18 years
2. Chronic liver disease patients

EXCLUSION CRITERIA:

1. Age less than 18 years
2. Patients with Chronic Surgical History
3. Patients refuse to give informed written consent
4. Stupor & Comatose patients
5. H/O of organ transplantation
6. The presence of cancer with known metastasis to bone.
7. Presence of prolonged immobility condition.

METHODOLOGY:

Patients who presented to the General Medicine Department were selected based on the inclusion and exclusion criteria. All patients underwent complete history taking and clinical examination. A clinical proforma was filled, incorporating patients detailed clinical examination and investigations, including BMD assessment.

Statistical Analysis:

After collecting data, suitable statistics were applied to analyze data. All statistical analysis was performed in Statistical Package for the Social Sciences (SPSS) and Microsoft Excel software.

Table 1: Demographic details

In this study a total of 171 patients were included. The mean age of the participants was 53.79 ± 11.79 years. Of the total sample, 85 (49.7%) were female and 86 (50.3%) were male. The anthropometric measurements showed a mean weight of 65.81 ± 8.95 kg, a mean height of 165.17 ± 9.13 cm, and a mean Body Mass Index (BMI) of 24.36 ± 4.36. In terms of occupation, the largest group of participants were laborers (35, 20.5%), followed by self-employed individuals (33, 19.3%), and farmers (32, 18.7%). Smaller proportions of participants were drivers (24, 14.0%), housewives (24, 14.0%), and shopkeepers (23, 13.5%). Regarding dietary habits, 88 (51.5%) of the participants followed a vegetarian diet, while 83 (48.5%) followed a non-vegetarian diet. In terms of alcohol consumption, 88 (51.5%) reported yes to alcohol consumption, while 83 (48.5%) reported no consumption. Similarly, regarding smoking status, 97 (56.7%) were smokers, while 74 (43.3%) were non-smokers.

Table 2: Clinical Parameters

The duration of liver disease among the participants ranged from 3 to 8 years, with a median duration of 5 years. Regarding the provisional diagnosis, the most common diagnosis was Non-alcoholic fatty liver disease (NAFLD), with 39 patients (22.8%). This was followed by PBC (38 patients, 22.2%), PSC (35 patients, 20.5%), Cirrhosis (31 patients, 18.1%), and Hepatitis (28 patients, 16.4%). In terms of osteopenia, 86 patients (50.3%) were found to have osteopenia, while 85 patients (49.7%) did not. For osteoporosis, a larger proportion of the participants, 143 patients (83.6%), did not have osteoporosis, while 28 patients (16.4%) were diagnosed with it. The history of fractures was reported by a small number of participants, with 4 patients (2.3%) having a fracture history, and 167 patients (97.7%) did not report any fractures.

Table 3: Laboratory Parameters

The biochemical parameters of the participants were evaluated. The mean calcium level was 7.95 ± 1.14 mg/dL, while the mean vitamin D level was 29.98 ± 11.55 ng/mL. The Bone Mineral Density (T-score) had a mean of -1.39 ± 0.99. The bilirubin level averaged 3.03 ± 2.69 mg/dL, and the SGOT (serum glutamic oxaloacetic transaminase) level was 191.92 ± 111.48 U/L. The mean SGPT (serum glutamic pyruvic transaminase) level was 222.71 ± 112.43 U/L. The mean albumin level was 3.77 ± 0.71 g/dL, and the mean alkaline phosphatase (ALP) level was 93.78 ± 31.59 U/L.

Osteoporosis, which results in a high risk of fragility fractures, is a frequently observed complication in patients with chronic liver disease, especially in liver cirrhosis, cholestatic liver diseases and hemochromatosis.¹³ In addition, the problem is critical in patients who undergo a liver transplant when bone loss is accelerated, leading to a greater incidence of fractures during the period immediately after transplantation.¹⁴ The importance of a wide range of liver functions in the human body becomes the most visible in chronic liver disease (CLD). The most commonly known CLD complications are portal hypertension, hepatic encephalopathy, ascites, hepatorenal syndrome, variceal bleeding, and hepatocellular carcinoma.^15,16 However, CLD is also associated with changes in the skeleton, previously known as hepatic osteodystroph.^17,18 Among CLD patients, substantial heterogeneity of skeletal changes was noted depending on the etiology, duration, and stage of the liver disorder.^19,20

The mean age of the participants was 53.79 ± 11.79 years, with nearly equal distribution of males (50.3%) and females (49.7%), suggesting a balanced representation of both genders in the sample. The participants had an average weight of 65.81 ± 8.95 kg and height of 165.17 ± 9.13 cm, resulting in a mean BMI of 24.36 ± 4.36. This BMI is within the range of normal to overweight, which could contribute to the risk of metabolic and bone health complications seen in CLD patients. The study participants came from diverse occupational backgrounds, with laborers (20.5%) and self-employed individuals (19.3%) forming the largest groups. Occupational factors, such as physical labor and socioeconomic status, can influence lifestyle habits, including diet, alcohol consumption, and physical activity, which may, in turn, affect bone health. The duration of liver disease among participants ranged from 3 to 8 years, with a median of 5 years, which is consistent with findings in the literature showing that CLD progresses over time, potentially leading to complications like osteopenia and osteoporosis. Epidemiological surveys revealed that 10 million individuals older than 50 years have osteoporosis in the United States, and they have about 1.5 million osteoporotic fractures each year.²¹ Moreover, it was estimated that 27.6 million people in Europe had age-related osteoporosis and that more than 3.5 million fractures occur there each year.²² Many guidelines state that DXA screening should begin at 65 years for women. Because osteoporosis is usually asymptomatic until patient experience a hip or vertebral fracture. Therefore, osteoporosis can be disastrous for patients with liver diseases. Thus, early diagnosis is the key for appropriate osteoporosis management, allowing for adequate prevention and treatment in cirrhotic patients. Our study suggests that for cirrhotic patients, the age for initiating the DXA screening protocol should be earlier.

Among the participants, Non-alcoholic fatty liver disease (NAFLD) was the most prevalent diagnosis (22.8%), followed by PBC (22.2%) and PSC (20.5%). These findings align with global trends, as NAFLD is becoming one of the leading causes of chronic liver disease, with increasing recognition of its association with metabolic syndromes, including bone density loss. Regarding bone health, 50.3% of participants had osteopenia, and 16.4% had osteoporosis. The higher prevalence of osteopenia and lower prevalence of osteoporosis in this cohort may suggest that early stages of bone demineralization are more common in CLD patients. Previous studies have shown that liver disease can disrupt bone metabolism due to factors like altered calcium and vitamin D metabolism, as well as the direct effects of liver damage on bone resorption and formation. Only 2.3% of participants reported a fracture history, which is lower than expected in a population at risk of osteoporosis. This may be attributed to underreporting of minor fractures or the relatively early stages of bone mineral loss in the study cohort. Several factors may contribute to the increased risk of osteoporosis in cirrhosis patients which generally consist of a combination of increased osteoclastic and decreased osteoblastic activity leading to an imbalance in remodeling mechanisms.²³ The mechanisms by which this happens are not yet completely understood but may result from decreased vitamin D, vitamin K, and calcium levels, impaired growth hormone and insulin-like growth factor-1 (IGF-1) secretion, increased inflammatory mediators TNF-alpha and IL-6, hyperbilirubinemia, limited physical activity, malnutrition, and alcohol consumption.^24,25

The calcium level in the study participants was 7.95 ± 1.14 mg/dL, which is lower than the normal reference range, indicating potential hypocalcemia. This is consistent with literature that shows reduced calcium absorption in patients with liver disease due to impaired vitamin D metabolism. The mean vitamin D level was 29.98 ± 11.55 ng/mL, which is on the lower end of the sufficient range, suggesting that many participants may have suboptimal vitamin D levels, which are critical for bone health. Deficiency in vitamin D has been widely recognized in CLD patients and is a major risk factor for bone mineral loss. The mean Bone Mineral Density (T-score) of -1.39 ± 0.99 is consistent with osteopenia, which is defined as a T-score between -1 and -2.5. This finding suggests that the majority of the participants in the study are at risk for developing osteoporosis, particularly given that liver dysfunction can impair bone turnover. Other laboratory parameters such as bilirubin (3.03 ± 2.69 mg/dL), SGOT (191.92 ± 111.48 U/L), SGPT (222.71 ± 112.43 U/L), albumin (3.77 ± 0.71 g/dL), and alkaline phosphatase (93.78 ± 31.59 U/L) were within the expected ranges for CLD patients. Elevated liver enzymes (SGOT and SGPT) indicate ongoing liver dysfunction, which is a known contributor to altered bone metabolism. Alkaline phosphatase is a marker for bone turnover, and while its mean value was elevated, it could indicate increased bone remodeling associated with the liver disease. Calcium citrate is more suitable for patients with achlorhydria or other conditions that potentially impair gastrointestinal absorption.^26,27 Calcium tablets should never be ingested with fluoroquinolones, tetracycline, bisphosphonates, phenytoin, or levothyroxine because the supplements impair the absorption of these drugs.²⁸

In conclusion, this study underscores the critical importance of closely monitoring bone health in patients suffering from chronic liver disease (CLD). The findings reveal a significant prevalence of osteopenia and a noteworthy presence of osteoporosis, highlighting the detrimental impact that liver dysfunction can have on skeletal health. Key contributing factors, such as suboptimal vitamin D levels, hypocalcemia, and altered bone metabolism, were identified, emphasizing the interconnectedness of liver function and bone health.

The study also sheds light on the necessity for early intervention and preventive strategies aimed at addressing bone health complications in this vulnerable population. Optimizing calcium and vitamin D levels through dietary supplementation, lifestyle modifications, and pharmacological interventions could play a pivotal role in reducing the risk of bone mineral loss and associated fractures. Moreover, regular screening for bone mineral density in CLD patients, especially those with prolonged disease duration or severe liver dysfunction, should become a standard practice in clinical settings.

Given the rising prevalence of conditions like NAFLD and autoimmune liver diseases, which are significantly associated with bone health deterioration, there is a pressing need for further research in this area. Longitudinal studies examining the progression of bone health in CLD patients could provide valuable insights into the natural history of bone loss in this group. Additionally, exploring novel therapeutic options, including anti-resorptive agents, anabolic therapies, and personalized treatment protocols, could pave the way for more effective management strategies.

Lastly, the study highlights the importance of a multidisciplinary approach in managing CLD patients, involving hepatologists, endocrinologists, and nutritionists to comprehensively address the multifaceted challenges posed by liver disease and its impact on bone health. Awareness campaigns, patient education, and routine follow-ups could further enhance outcomes, ensuring a better quality of life for those affected by CLD and its associated bone health complications.

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