The purpose of the current study was to determine the prevalence of low BMD, to estimate the bone turnover and hormonal status, and to identify the factors associated with bone disease in patients with CLD. The only available Indian data on this subject are those of Sachdev et al[4
] from 1976. The current study shows that patients with CLD have a high prevalence of decreased BMD, with the lumbar spine being the most frequently and intensely affected site. Furthermore, there was no relation between severity of hepatic dysfunction (Child class) and incidence of low BMD. These factors point to the need for early evaluation for HO in patients with CLD.
In the present cohort, low BMD was found in 68% of patients. This is comparable to the only available Indian data of Sachdev et al[4
], in which 64% of cirrhotic patients had low BMD. The method of evaluation and diagnosis differed greatly in that era. In the earlier study of 25 patients with cirrhosis (all aged < 40 years), diagnosis of cirrhosis was made from liver biopsy and osteoporosis from iliac crest biopsy. Scanning through western studies has indicated marked heterogeneity in BMD findings in CLD, ranging from no effect to a large BMD deficit. Leslie et al[7
] have pooled the results from uncontrolled and controlled studies of bone mineral content in CLD. They have shown a Z score less than -2 in 21% of patients. Studies on patients with end-stage liver disease of varying etiology confirm a high but variable incidence of osteoporosis (11%-48%) and osteopenia (18%-35%)[3
]. The incidence of 68% in the present study is much higher than that in any previous study. This may be because Indians have a lower BMD as compared to Caucasians[8,9
]. Thus, the use of Z scores based on a Caucasian database might have resulted in overestimation of osteoporosis. However there are no published data for BMD in healthy Indian populations.
The major influences on bone metabolism are genetic, but also essential are mechanical stress (exercise and muscle activity), good nutrition, adequate calcium and vitamin D, and a normal hormonal environment. The patient with CLD could have any of these factors acting alone or in concert, which potentially predispose him/her to thin bones. Each of the above factors were assessed and compared between patients with low and normal BMD. It was found that patients with CLD had all the above and known risk factors: low sunlight exposure, reduced physical activity, low lean body mass, vitamin D deficiency and hypogonadism. The presence of risk factors in the low and normal BMD groups was probably the reason for the absence of a statistically significant difference in risk factors between the normal and low BMD groups. This indicates that all patients with cirrhosis, unless prevented, will develop the disease. In addition, although the calcium intake was adequate by ICMR guidelines, it was well below the internationally accepted daily allowance. This added to an unfavorable calcium:protein ratio of 8.5-11.5 mg/g, and calcium:phosphorus ratio of 0.45 may have resulted in inadequate recommended daily allowance of calcium in these patients.
Vertebrae consist of 50% trabecular bone, while other bones (hip, neck and trochanter) consist mainly of cortical bone. Sites with a high proportion of trabecular bone are affected earliest in diseases that produce increased bone turnover[10
]. In the present study, serum osteocalcin was low in 68% and UDPD: creatinine ratio was high in 79% of patients, which indicated a high resorptive state added to low formation. This suggests uncoupling of bone remodeling as the cause of low BMD in CLD. This can explain the predominant involvement of the spine in HO. This is also compatible with other similar studies[11,12
In the present study, 41% of patients were hypogonadal, although this was not correlated with the severity of bone loss. Diamond et al[13
] and Monegal et al[11
] have shown that hypogonadism is common in men with cirrhosis but it is not correlated with osteoporosis. A particularly interesting finding in the present study was the significantly elevated estradiol level (P
< 0.05) in patients with normal compared with low BMD. Estrogen is known to have a positive influence on the male skeleton[14
]. It is also known to be increased in men with cirrhosis. Probably the anabolic and antiresorptive qualities of estrogens in bone act as protective factors in preventing bone loss in these patients with cirrhosis.
More than 90% of circulating IGF-1 is synthesized in the liver. It is a proven early marker of hepatocellular functional capacity[15,16
], and shows a marked decline in the early stages of cirrhosis (Child-Pugh class A). It starts decreasing before other liver-function parameters such as albumin, bilirubin and prothrombin become involved[15
]. GH levels are increased correspondingly, which creates a state of IGF resistance[17
]. IGF-1 is also a major determinant of BMD in healthy men[18
]. In the present study, IGF-1 levels were below the age-related normal range in both groups, and were significantly lower (P
< 0.05) in patients with low BMD. IGF-1 values were low in 89% of patients with CLD. Previous studies have shown IGF-1 levels to correlate directly with BMD and inversely with disease severity[12,19,20
]. Studies have described a role for decreased serum IGF-1, even in idiopathic osteoporosis[21
]. IGF-1 expression is increased during early osteoblast recruitment, but declines as these cells undergo differentiation. It is known to stimulate osteoblast proliferation[22
] and play a key role in bone remodeling and maintenance of bone mass. Simonet et al[23
] have shown that low levels of IGF-1 may lead to increased bone resorption. Thus, the link between cirrhosis and bone loss also involves low levels of IGF-1. A significant difference in IGF-1 level between normal and low BMD patients may be a pointer to why some patients deteriorate faster, despite sharing equally all the risk factors.
IGFBP3 play a very important role in bioavailability of circulating IGF-1. It forms a stable ternary complex with an acid-labile subunit and IGF-1, and binds > 95% of circulating IGF-1. In the present cohort, low IGFBP3 was seen in 97% of patients with CLD, although this did not differ significantly between the normal and low BMD groups (P
= 0.071). This is plausible because hepatocytes are the major site of IGFBP3 synthesis. This may have further decreased the tissue bioavailability of IGF-1[24,25
In conclusion, the present study confirms the high incidence of low BMD in patients with CLD. Disease onset is early in the course of cirrhosis. Decreased bone formation with increased bone resorption imply that uncoupling of bone remodeling is the mechanism involved. Contributing factors are inadequate sunlight exposure, reduced physical activity, low lean body mass, vitamin D deficiency and hypogonadism. The presence of most risk factors in low and normal BMD groups indicates that all patients with cirrhosis are vulnerable, and unless prevented, will develop the disease. Our results provide evidence of the key roles played by IGF-1 and estrogen in this condition. Although risk factors are prevalent in all patients, the severity of bone loss may be accelerated in patients with low IGF-1 level. The present study also suggests a possible protective role for the high estrogen level seen in cirrhosis.