The Impact of Gastrointestinal and Liver Diseases on Bone: It Ain't Like Menopause!
published online 25 November 2010.
Volume 140, Issue 1
Page 6, January 2011
iSee “Histomorphometric analysis reveals reduced bone mass and bone formation in patients with quiescent Crohn's disease,” by Oostlander AE, Bravenboer N, Sohl E, et al, on page 116; and “Bone disease in patients with primary sclerosing cholangitis,” by Angulo P, Grandison GA, Fong DG, et al, on page 180.
The skeleton is a metabolically active tissue that serves as a protective mechanical scaffold for all other organ systems, forms a functional unit with striated muscle that permits locomotion, and is an interactive harbor of the hematopoietic bone marrow. The skeleton is the largest source of calcium and phosphate in the body and releases calcium upon demand, a process that is mainly controlled by parathyroid hormone. During adult life, bone is constantly remodeled to maintain its structural integrity. In response to damage or metabolic needs, osteoclasts dissolve bone, followed by bone matrix formation by osteoblasts to repair the defect. Bone matrix then becomes mineralized by calcium and phosphate crystals. Osteocytes, which are derived from mature osteoblasts, are the most abundant cell type in bone and form a network that senses mechanical strain.1 Osteocytes instruct osteoblasts to form more or less bone matrix with soluble factors such as sclerostin, an inhibitor of the Wnt pathway.2 It is important to recognize that osteoclastic bone resorption is relatively rapid compared with bone reconstitution (3 weeks vs 3 months, respectively). Therefore, bone mass can easily be lost if the careful cellular orchestration of bone remodeling is perturbed. The best known alteration of bone remodeling is caused by menopause, where bone formation is increased but cannot keep up with augmented resorptive activity, resulting in decreased bone mass, microarchitectural damage, and increased risk of fracture.3, 4 The World Health Organization defines osteoporosis as a bone mineral density (BMD) T-score (which measures the number of standard deviations of the measured BMD from the mean BMD for young adults of the same gender) of below −2.5, and osteopenia as a T score below −1 and −2.5 or higher. Besides BMD scores, other factors such as age, race, smoking, alcohol intake, body mass index (BMI), history of previous fracture and family history of osteoporosis significantly modify fracture risk.5 It is worth noting that these World Health Organization definitions of osteopenia and osteoporosis based on BMD T scores are specific to postmenopausal osteoporosis and have not been validated for other conditions, such as bone loss associated with digestive and liver disorders.
Bone remodeling can also be affected by systemic disease. Chronic gastrointestinal diseases such as inflammatory bowel disease (IBD), celiac disease, and liver diseases including primary biliary cirrhosis, and primary sclerosing cholangitis (PSC) have been associated with significant bone mass deficits and increased fracture risk.6 The effects of these diseases on bone remodeling are complex and involve disease and treatment factors, including malnutrition, inactivity, hypogonadism, cytokines, medications (eg, glucocorticoids, methotrexate) and sarcopenia. Additionally, in the case of cholestatic liver diseases, products of cholestasis such as bile acids and bilirubin may also affect bone remodeling.7, 8 Consequently, the pathophysiology of bone loss associated with chronic digestive and liver diseases is distinct from postmenopausal osteoporosis, and is likely to have unique effects on osteoclast and osteoblast function and consequently on bone mass, architecture, strength, and fracture risk
In this issue of Gastroenterology, 2 papers address bone loss associated with gastrointestinal and liver diseases from different perspectives. In one paper, Angulo et al9 conducted a prospective, longitudinal cohort study of 237 patients with well-documented PSC, with the aim of determining the prevalence of bone disease and its progression over a mean follow-up period of 4 years. The study was adequately powered to conduct multivariate analyses to identify risk factors for bone loss. BMD of the lumbar spine was performed by dual x-ray absorptiometry at the first visit and then annually. All patients were screened for IBD with endoscopy, given the known association between IBD and PSC. As expected, IBD was present in large proportion of subjects with PSC (74%, most with ulcerative colitis). Importantly, the BMD was first measured when the subjects were in clinical remission, because IBD itself can negatively affect bone mass. Most of the study cohort was comprised of young adults, but 17% were postmenopausal women. At their first visit, lumbar spine BMD, T-score and Z-scores (which compare the observed BMD to BMD of healthy subjects matched for age and gender) were significantly lower in subjects with PSC, and the 15% prevalence of severe bone demineralization was much higher compared with a reference healthy control population. Multivariate analysis revealed that age >54 years, BMI < 24 kg/m2, and duration of IBD > 19 years were associated with severe bone mass deficits. Subjects steadily lost 1% of bone mass per year at the lumbar spine, total body, and femoral neck, about twice as fast as a control reference healthy population, and comparable with bone loss rates after menopause. In multivariate analysis, duration of IBD was the best predictor of rapid bone loss. The observations of Angulo et al9 should help clinicians to identify patients with PSC at risk for severe bone disease who may be eligible for BMD screening and therapy to help restore bone mass if BMD is low. Their recommendation of obtaining a BMD at diagnosis of PSC is reasonable, and the frequency of follow-up should be determined by BMD results and the presence of risk factors, such as advanced age, low BMI, and long duration of IBD.
The study by Angulo et al9 has some limitations, however. The effect of age on bone mass may have been confounded by the relatively large number of postmenopausal women, and was only present for T-scores but not for Z-scores. The BMI does not discriminate between gains or losses in fat and muscle compartments; therefore, a low BMI may increase the risk of bone loss not because of decreased adipose mass, as suggested by the authors, but because of sarcopenia. Large skeletal muscle forces are critical to maintaining skeletal mass.10 In patients with PSC and other chronic gastrointestinal and liver conditions, disease and treatment factors may negatively affect muscle mass, strength, and power and consequently negatively affect bone. It would have been helpful if the authors had analyzed the body composition data obtained by dual x-ray absorptiometry to study the prevalence and severity of lean body mass deficits. Muscle mass may be improved by a combination of weight-bearing exercise and balanced nutrition, which may help to restore bone mass in patients with PSC. To put their data in proper context, it would have been helpful to know whether subjects with PSC and low T-scores received bisphosphonates or other therapies besides calcium, vitamin D, and hormone replacement, which could have affected the BMD and the progression of bone loss. Moreover, it would have been informative to measure biomarkers of bone metabolism to establish if bone loss was due to increased resorption, decreased formation, or both. This information would have been valuable to help choose the most appropriate drug (anticatabolic vs anabolic or both), to treat bone mass deficits associated with PSC. Other studies in patients and in experimental models suggest that decreased bone formation may be primarily responsible for bone mass deficits in cholestasis.11, 12, 13 Although past occurrence of fractures was noted during the first study visit, it is not known whether subjects sustained fractures over the course of the study. Ultimately, low BMD in PSC and other diseases would be clinically significant if fracture risk is increased.
In the other article, Oostlander et al14 examined bone histomorphometry of transiliac biopsies of 23 young adults (12 female, 11 premenopausal) with clinically quiescent Crohn's disease (CD), compared with healthy controls matched for age and gender. Bone histomorphometry measures indicators of bone mass and architecture, bone cell number, abundance of bone matrix, and bone formation rate. Bone histomorphometry is considered the gold standard to study the features of metabolic bone disorders. Oostlander et al14 selected patients based on quiescent IBD, a BMD T-score in the lumbar spine below −1 and −2.5 or higher, no recent use of glucocorticoids or bisphosphonate, and vitamin D sufficiency. They observed that trabecular bone volume and trabecular thickness were significantly reduced in patients with CD when compared with healthy controls, but trabecular number and cortical thickness were not affected. Some indicators of bone formation (mineral apposition rate) were reduced in all subjects, although a subset of 9 patients had more marked reductions in mineralizing surface, bone formation rate, and trabecular bone volume. The number of osteoclasts and their surface area were decreased, suggesting a reduction in bone remodeling in clinically silent CD. This is consistent with recent observations by Ward et al15 in transiliac bone biopsies from children newly diagnosed children with CD. It is possible that subclinical inflammation, persistent muscle mass deficits, and other IBD-related factors may affect the proliferation, differentiation, and activity of bone cells. The observations of Oostlander et al14 should bring into question the current paradigm, adopted from the treatment of postmenopausal osteoporosis of starting a bisphosphonate (an antiresorptive agent) in patients with CD that have low BMD. Although bisphosphonates can increase bone mass in patients with IBD, the metabolic activity of bone in IBD is distinct from estrogen deficiency. As in PSC, bone formation seems to be reduced in IBD, even when the disease is clinically quiescent. It should be noted that effective anti-inflammatory therapies primarily increase biomarkers of bone formation in patients with active IBD, suggesting a state of low bone turnover.16, 17 Based on current evidence, it seems that anabolic drugs like teriparatide, along with effective control of inflammation, may be more appropriate than antiresorptive agents alone in improving bone mass in patients with IBD. This possibility requires further study.
In summary, these 2 papers contribute to our emerging knowledge that gastrointestinal and liver diseases have distinct effects on bone health that differ from those associated with estrogen deficiency and menopause. The time has come to evaluate treatments that improve bone health based on the unique effects of gastrointestinal and liver disease on the skeleton.