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Osteoporosis is characterised by a reduction in bone mineral density and increased bone fragility. Patients suffering from a number of chronic GI conditions have an increased risk of developing low bone mineral density. This includes inflammatory bowel disease (IBD), coeliac disease, chronic pancreatitis, post-gastrectomy, short bowel syndrome, chronic hepatitis and cirrhosis. Routine assessment of serum vitamin D and dual energy x-ray absorptiometry (DXA) scans are essential parts of the surveillance of these chronic conditions. Supplementation of calcium and vitamin D, however, is often overlooked. Risk factors for osteoporosis in patients with GI disease include chronic steroid use, vitamin D deficiency, chronic inflammation, smoking and reduced physical activity. In this article, we review common, chronic GI conditions and their relationship with bone metabolism.
Osteoporosis is a condition characterised by low bone mass and micro-architectural deterioration of bone tissue. This results in increased bone fragility and susceptibility to fracture. While osteoporosis is a condition generally observed in the elderly, it is increasingly recognised in younger individuals with chronic GI diseases. The increased risk of fracture and its associated morbidity is well established and recent studies have now demonstrated an overall negative effect on quality of life in patients with osteoporosis. While malnutrition and malabsorption contribute to decreased bone density in chronic GI disease, there are also other significant factors. These include the chronic inflammatory process itself, corticosteroid treatment and lifestyle factors, including lack of physical activity and smoking.
While osteoporosis is a condition generally observed in the elderly, it is increasingly recognised in younger individuals with chronic GI diseases.
While osteoporosis is a condition generally observed in the elderly, it is increasingly recognised in younger individuals with chronic GI diseases
Osteoporosis is detected by measurement of bone mineral density (BMD) and DXA is the current gold standard technique for the measurement of BMD. Measurements are generally obtained at the femoral neck and lumbar spine. DXA results are expressed as the number of standard deviations (SD) above or below the expected mean for individuals of the same age, ethnicity and gender (Z score) or the mean of peak bone mass in young adults (T score). The World Health Organisation reported formulated diagnostic ranges for osteoporosis based on T scores. Osteoporosis and osteopaenia are defined by a T score below -2.5 and between -1 and -2.5, respectively.
Bone metabolism is a dynamic and continuous remodelling process that is normally maintained in a tightly-coupled balance between resorption of old, damaged, or injured bone and the formation of new bone. In most situations, the amount of new bone formed is closely matched to the amount of old bone lost. Vitamin D in the form of 1,15-dihydroxyvitamin D and parathyroid hormone (PTH) play an important role in regulation of bone metabolism. The bone remodelling cycle refers to the co-ordinated interaction between osteoclasts, which break down bone, and osteoblasts, which are involved in new bone, which then mineralises. The bone remodelling cycle takes approximately three-to-six months, and the annual turnover rate is 4 per cent for cortical bones and 25 per cent for lamellar bones. Increasing age is a well-established factor that results in a small negative balance, resulting in age-related decline in BMD.
Contributors to bone density loss in GI diseases
Vitamin D deficiency and malabsorption
Vitamin D is a major regulator of calcium and phosphorus metabolism and is a key factor in maintaining bone health. It helps to maintain calcium homoeostasis by acting on the small intestinal epithelium and osteoblasts. Vitamin D deficiency leads to reduction in serum levels of ionised calcium, leading to secondary hyperparathyroidism, resulting in osteoclastogenesis, a disproportionate increase in bone resorption, osteopaenia and ultimately, osteoporosis. In adults with vitamin D deficiency, there is defective mineralisation of the newly-formed bone collagen matrix, resulting in osteomalacia, which manifests as bone pain, fractures and proximal muscle weakness.
In addition to the well-established effects on bone metabolism, recent studies have shown that vitamin D also plays a role in immune regulation, particularly the innate immune system. A less well-known function of vitamin D is its role in the activation of T lymphocytes that maintain the integrity of intestinal mucosal immunity. Vitamin D deficiency is considered a trigger of autoimmune and inflammatory diseases.
Vitamin D deficiency can arise in patients with chronic GI disease for a number of reasons. Some causes are disease-related, while others are in common with the general population. These include inadequate exposure to sunlight (either related to lifestyle or persistent symptoms restricting physical activity), inadequate dietary intake due to symptoms of disease, impaired absorption, impaired conversion of vitamin D to its active products, increased catabolism and increased excretion. Malabsorption contributes to low vitamin D, particularly in patients with coeliac, Crohn’s disease or chronic pancreatitis.
The best measure of an individual’s vitamin D status is serum 25(OH)D. Serum 25(OH)D levels of less than 50nmol/L indicate vitamin D deficiency, while levels between 50 and 75nmol/L represent vitamin D insufficiency. Levels between 75 and 250nmol/L represent normal values.
The inflammatory process
Inflammation is characterised by the production of cytokines, which have a myriad of effects, some of which include increased bone resorption and reduced bone formation. These cytokines — which include interleukin-1 (IL-1), IL-6, IL-11, IL-15, IL-17 and tumour necrosis factor alpha (TNF-α) — affect osteoblasts and osteoclasts through complex mechanisms involving a homeostatic system known as the RANK/ RANKL/ osteoprotegerin system. Essentially, increased production of RANKL leads to upregulation of osteoclast activity, whereas osteoprotegerin downregulates this action. Activated T cells produce RANKL, which in turn directly triggers bone loss via the induction and activation of osteoclasts. Active inflammatory disease is a strong risk factor for low bone mineral density (BMD) in patients with chronic GI disease, with BMD improving with increasing duration of remission.
Steroids have a number of deleterious effects on bone. They suppress circulating sex hormones in men and women, which results in increased activity of the cytokine IL 6, which is a stimulator of osteoclastic activity and thus bone resorption. Steroids also inhibit osteoblast maturation and new bone formation, reduce intestinal calcium absorption and enhance urinary calcium excretion.
Glucocorticoids increase the expression of RANKL and decrease the expression of its soluble decoy receptor OPG in osteoblastic cells. These alterations cause a greater differentiation of precursors into osteoclasts, which increases their resorptive activity and enhances bone reabsorption. Glucocorticoid therapy is frequently required in the treatment of many chronic GI diseases including IBD, auto-immune hepatitis and more rarely, in refractory coeliac disease. Steroids are the most common cause of drug-induced osteoporosis. Approximately 50 per cent of patients receiving chronic glucocorticoid therapy will develop osteopaenia and fractures, and 17 per cent of these patients will develop fractures within the first year of therapy. Cumulative prednisolone dose is an independent factor in predicting low BMD, even with low levels of steroid exposure. Significant bone loss is caused by doses of prednisolone 7.5mg daily or greater in most patients. The current screening guidelines by the European Crohn’s and Colitis Organisation (ECCO) and the American Gastroenterological Association (AGA) recommend DXA screening for all IBD patients with cumulative prior use of corticosteroids exceeding three months. The bone loss observed in corticosteroid treatment is more rapid in the early weeks of treatment, which highlights the importance of tapering steroids as quickly as clinically possible. Every attempt should be made to limit the duration of steroid exposure and ensure concurrent calcium/vitamin D supplementation.
The development of steroids with less systemic bioavailability may reduce the adverse effects on bone metabolism. Oral budesonide selectively binds with inflammatory sites, has a high first-pass metabolism and is rapidly excreted in the urine. Studies have shown significantly less bone loss associated the use of budesonide compared to conventional steroids, such as prednisolone.
Cigarette smoking is associated with reduced BMD and increased fracture risk. There are basic, clinical and observational studies that define the underlying pathophysiologic mechanisms that predispose smokers to bone loss. Such mechanisms include alterations in intestinal calcium absorption, alterations in adrenal cortical hormone metabolism, and in the RANK/ RANKL/osteoprotegerin system. Direct cellular effects of cigarette use on bone cells have also been reported. Smoke toxins interact with bone receptors to induce osteoclastic bone resorption through the activation of cytochrome P450 enzymes.
Patients with Crohn’s disease (CD), chronic pancreatitis and chronic liver diseases smoke more than the general population. This has a deleterious effect on the underlying disease, as well as on their bone health. A recent study evaluating the effect of smoking on BMD in IBD patients found that female IBD patients who currently smoked or with a previous history of smoking exhibited lower Z scores for the lumbar spine and femoral neck than female patients who had never smoked. Smoking is also associated with relapses and increased disease activity in CD, with the resultant need for steroids, which also negatively interferes with bone metabolism. Studies have also shown an association between heavy smoking in chronic pancreatitis and reduced BMD. Heavier smoking and a longer exposure are associated with greater bone loss. As there is evidence of reversibility of bone mineral density loss with smoking cessation, all patients should be advised on smoking cessation.
GI diseases associated with increased risk of osteopaenia/osteoporosis
Coeliac disease is an autoimmune disorder characterised by activation of the immune system in response to ingestion of dietary gluten. Exposure to gluten in the diet results in inflammation and villous atrophy in the small intestine, which leads to malabsorption. The mechanism underlying osteoporosis/osteopaenia in coeliac disease is predominantly related to calcium malabsorption and vitamin D deficiency, leading to raised parathyroid hormone secretion which, in turn, increases bone turnover and cortical bone loss.
Reduction in BMD and increased risk of bone fracture are frequently seen in patients with coeliac disease. It is estimated that by the time childhood coeliac disease is diagnosed, one-third of affected children have osteoporosis, one-third have osteopaenia and only the remaining third retain a normal BMD.
Children can recover bone density with time, once a gluten-free diet is commenced and they become vitamin D- and calcium-replete. In adults with coeliac disease, the prevalence of osteoporosis is at least twice that of the unaffected population in the same age range and over 50 per cent of asymptomatic adult coeliac patients with positive antibodies may have bone disease at the time of diagnosis.
In adults, loss of BMD in the peripheral skeleton may persist despite apparent normalisation at axial skeletal sites after patients are on a gluten-free diet. One in 80 people in Ireland suffers with coeliac disease and many of these are asymptomatic and undiagnosed. Coeliac disease is often missed, particularly in adulthood, and should be considered in all patients found to have osteopaenia or osteoporosis, particularly in the absence of other risk factors, and even in the absence of any digestive symptoms.
Inflammatory bowel disease
Osteoporosis is common in patients with both ulcerative colitis (UC) and CD. IBD patients have a significantly higher risk for bone loss than the general population and cross-sectional studies of patients with IBD have shown a prevalence of osteoporosis of 18-to-42 per cent. The cause is usually multifactorial, with a number of the aforementioned factors often contributing in any one patient.
These include reduced absorption or vitamin D and calcium in patients with chronic inflammation of the small bowel, or a short bowel syndrome secondary to previous surgery, chronic inflammation itself, and corticosteroid therapy.
Elevated TNF-α concentrations appear to play an important role in dysfunctional bone metabolism in IBD. TNF-α is a major factor in the inactivation of osteoclasts. This cytokine induces osteoclast differentiation and increases osteoclast activity and bone resorption. Anti-TNF-α therapies, including the biologics infliximab, adalimumab and golimumab, are highly efficacious in inducing disease remission in many patients with IBD. In doing so, they reduce circulating pro-inflammatory cytokines.
Several studies have shown that down-regulation of the inflammatory cascade in patients on anti-TNF-α therapies has a beneficial effect on bone metabolism. Furthermore, these therapies will often enable withdrawal of steroids, which has an additive benefit on bone health.
IBD patients have a significantly higher risk for bone loss than the general population and cross-sectional studies of patients with IBD have shown a prevalence of osteoporosis of 18-to-42 per cent
The current guidelines recommend DXA screening in IBD patients with one or more of the following risk factors: History of vertebral fractures; postmenopausal; male >50 years of age; chronic corticosteroid therapy; or hypogonadism.
Chronic pancreatitis is a progressive inflammatory disease in which the pancreas becomes increasingly fibrosed and scarred, ultimately affecting both exocrine and endocrine function. Pancreatic exocrine insufficiency (PEI) leads to malabsorption of fats and associated fat-soluble vitamins (A,D,E and K). These patients also often have poor diets, low levels of physical activity, smoking and (often) alcohol-excess, all of which increase the risk of bone demineralisation and osteoporosis.
A number of meta-analyses reported a pooled prevalence of osteoporosis and osteopaenia of 65 per cent in chronic pancreatitis cohorts. Ten-year fracture prevalence in this cohort has been estimated at 4.82 per cent, which is comparative with other GI conditions such as coeliac disease (5 per cent), Crohn’s (3 per cent) and cirrhosis (4.8 per cent). Despite this, no current consensus guidelines exist to direct BMD screening in this population.
Treatment of pancreatic exocrine insufficiency (PEI) with pancreatic enzyme supplements will improve absorption of fat-soluble vitamins, including vitamins D and K, both of which are vital to bone health.
Chronic liver disease
Chronic liver disease is associated with malabsorption of calcium and phosphate, reduced concentration of 25OHD, increase in PTH level and reduction in the number and activity of osteoblasts. The osteoporotic fracture rate in patients with chronic liver disease is approximately twice that of age-matched control individuals.
About 66 per cent of patients with moderately-severe cirrhosis and 96 per cent of patients awaiting liver transplantation have vitamin D deficiency. Both vitamin D binding protein (VDBP) and albumin (the binding proteins that transport vitamin D3 from the skin to the liver) are produced in the liver, and levels of these proteins decrease in patients with liver disease. As the liver is the major site for 25-hydroxylation of vitamin D, impaired hepatic metabolism of vitamin D results in low 25-hydroxyvitamin D levels in patients with liver disease. Chronic liver inflammation secondary to either autoimmune diseases or chronic viral hepatitis is also associated with chronically-raised pro-inflammatory cytokines, which adversely affects bone metabolism, as previously discussed.
Most guidelines recommend calcium and vitamin D supplementation in patients with cirrhosis and low bone density, but there have been no randomised, controlled studies of an adequate scale to assess the effects of such supplementation on bone density or osteoporotic fracture rates.
Vitamin D deficiency is common and is more prevalent in patients with GI diseases.
Vitamin D and parathyroid hormone levels should be measured and monitored in patients with chronic GI diseases. DXA scan should be considered in their management.
Documented vitamin D deficiency should be treated with high-dose vitamin D supplementation, as per current guidelines.
Lifestyle modification, including smoking cessation and increasing physical activity, are important to emphasise.
Steroid use should be minimised and if prescribed, concurrent calcium supplementation given.
Steroids with less systemic bioavailability (eg, oral budesonide) should be considered.
Consider coeliac disease in patients with an unexpected finding of osteoporosis, even in the absence of GI symptoms.
The risk of osteoporosis and osteoporotic fractures in gastrointestinal diseases depends on the type of disease and a range of risk factors that may be present in any given patient. The principles of the treatment of osteoporosis/osteopaenia are similar in all diseases of the gastrointestinal tract.
For prophylaxis, consideration should be given to the adequate intake of 1,200mg/day of Ca and 800-1,000IU/day of vitamin D in the diet. Vitamin D deficiency should be treated with 2,000-4,000IU daily for six-to-10 weeks, followed by 800IU daily.
Established osteoporosis is treated in the same way as for patients who do not have GI diseases. For inflammatory diseases such as IBD, good disease control and attainment of disease remission are important goals and benefit bone health both directly and indirectly. Patients should take regular physical exercise where possible, be encouraged to stop smoking and avoid excessive consumption of alcohol. The dose of corticosteroids should be reduced to a minimum. Any patient who is unexpectedly found to have osteoporosis/osteopaenia should be screened for coeliac disease, even in the absence of any digestive symptoms.