EDUCATION PRACTICE. Osteoporosis in Patients With Inflammatory Bowel Disease. Clinical Scenario. The Problem

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4: EDUCATION PRACTICE Osteoporosis in Patients With Inflammatory Bowel Disease CHARLES N. BERNSTEIN University of Manitoba IBD Clinical and Research Centre, Winnipeg, Manitoba, Canada Clinical Scenario A 26-year-old woman presents with right lowerquadrant pain, nausea, and nonbloody diarrhea. She estimates that she has lost 15 pounds in the past 6 weeks. She had similar symptoms 11 months earlier; 9 months before this visit she was diagnosed with ileal Crohn s disease on the basis of a colonoscopy and a small-bowel follow-through barium study. She was treated with prednisone 40 mg/day for 2 weeks and achieved complete remission. Prednisone was tapered by 5 mg/wk and then discontinued. She was on no medication intended to maintain remission. Her current symptoms started about 2 months before presentation and gradually have worsened. She has never smoked. She has been active on a league basketball team but in the past 4 6 weeks she has been unable to play because of her symptoms. Her menstrual periods have been regular. She took no medications other than acetaminophen for analgesia, and loperamide when she leaves her house. She has not previously had a bone fracture. On physical examination she looks tired but otherwise is well. She is muscular and appears well nourished. Her abdominal examination revealed a soft abdomen with tenderness in the right lower quadrant. Perineal inspection was unremarkable. Laboratory data included a serum hemoglobin level of 10.5 g/dl, mean corpuscular volume of 71fL, serum ferritin level of 8 mcg/l, serum albumin level of 31 g/l, and a C-reactive protein level of 44 mg/l. She is being treated with oral prednisone 40 mg/day with a plan to remain at this dose for 2 weeks and then taper by 5 mg/wk. She also has been started on azathioprine 100 mg/day with a plan to increase the dose as needed to maintain a corticosteroid-free remission. Should she fail to withdraw from corticosteroids or achieve remission, infliximab or surgery will be considered. The T scores at her spine are 1.8 and at her hip are 1.9 by dual-energy x-ray absorptiometry (DEXA) test. Is osteoporosis a relevant problem in inflammatory bowel disease (IBD)? When is it appropriate to pursue DEXA testing in a patient with IBD? When is boneprotective therapy indicated and what type of therapy should be used? The Problem Several studies, most using DEXA testing, have reported rates of osteopenia (DEXA T score, 1.0 to 2.5) of 40% 50%, and of osteoporosis (DEXA T score, 2.5) of 15%. The terms osteopenia and osteoporosis defined by T scores are based on data in postmenopausal women and not other groups, and it is controversial whether these definitions apply to younger individuals, such as this patient. Nonetheless, these rates of high prevalence of reduced bone mineral density (BMD) would seem to imply that osteoporosis is a potentially large problem in patients with IBD. The most important complication of osteoporosis is bone fracture. Symptoms or metabolic abnormalities are uncommon manifestations of osteoporosis. Population-based studies have not confirmed a high rate of bone fracture. There is an increased risk for fracture in patients with IBD that is greater than that seen in control populations matched for age and sex, but the absolute increase in risk is only of the order of 20% 40%, and is highest among the elderly with IBD. Patients under the age of 40 also have an increased relative risk compared with matched controls, but the absolute risk is small. Although DEXA has secured an important role in screening postmenopausal women for osteoporosis because of the proven association between diminished BMD and increased fracture risk, its dominance as the single approach to developing a clinical strategy to bone management is being re-evaluated. In fact, discordance between bone mass and fracture in IBD has been reported. DEXA now is considered only one of a number of risk markers to consider when evaluating a patient s risk for fracture. There are limited data on Abbreviations used in this paper: BMD, bone mineral density; DEXA, dual-energy x-ray absorptiometry; IBD, inflammatory bowel disease; RANK, receptor for activated nuclear factor kappa-b by the American Gastroenterological Association Institute /06/$32.00 PII: /S (05)

2 February 2006 OSTEOPOROSIS IN IBD 153 therapy for enhancing or protecting bone mass in patients with IBD, but the data currently available do not prove any therapies to be an advantage over and above calcium and vitamin D replacement for the great majority of patients with IBD. Management Strategies and Supporting Evidence In approaching the patient there are 2 issues to address. The first is when to order a DEXA test and the second is what to do with the results. Approaches to osteoporosis diagnosis and treatment in patients with IBD mostly have been based on studies in patients without IBD. No prospective study has addressed whether DEXA results correlate with fracture risk in patients with IBD. Therefore, the use of DEXA results to predict fracture risk has been extrapolated from studies in postmenopausal women. Treatment using bisphosphonates based on DEXA results in patients using corticosteroids also has been extrapolated to IBD patients because many have used or currently use corticosteroids. However, many patients with IBD have low BMD despite never having used corticosteroids. On the other hand, adult patients who have used corticosteroids as children may have normal DEXA bone mass. When corticosteroid use is short term, bone mass changes are minor and reversible. Should This Patient Have a Dual Energy X-Ray Absorptiometry Scan? The patient is at low risk for having low BMD or fractures. The main risk factors for osteoporosis-related fractures include older age, chronic inflammatory activity, chronic or recurrent corticosteroid use, chronic physical inactivity, malnutrition, and hypoestrogenemia. This patient is young and menstruating regularly. Her serum estrogen level has not been measured directly but her regular menses is a reasonable surrogate measure of estrogen status. She had Crohn s disease diagnosed for 9 months and symptoms for less than 1 year. Despite not having a direct measure of the degree of systemic inflammation her recurrently active disease likely poses some risk to her bones. She is starting a second course of corticosteroids within the year, but this time the plan includes the use of an agent intended to maintain remission (azathioprine) to facilitate getting her off of corticosteroids. Simply being in remission can be associated with improved bone mass. The patient has been active in competitive sports and only recently has been inactive physically. She has lost weight, although her muscle mass seems preserved. The low serum albumin level and iron deficiency may reflect active disease and/or may reflect some component of malnutrition. Overall, there are some features that pose a risk for osteoporosis, but the main risk is that she has been using corticosteroids and has had active disease. Although it would not have been appropriate to pursue DEXA testing at diagnosis 9 months earlier, it now is reasonable to screen for osteoporosis at this time using DEXA scan. How Should the Dual Energy X-Ray Absorptiometry Results Be Interpreted? The T score in this patient is 1.8 at the spine and 1.9 at the hip. Osteopenia in postmenopausal women is defined by a T score of less than 1 but may not apply to premenopausal women. The DEXA in this patient is within 2 SDs of the mean and is within the normal range. Approximately 16% of the normal population has a T score between 1.0 and 2.5. This score represents a risk for fracture in postmenopausal women, and in patients on chronic corticosteroid therapy it may indicate the need for bisphosphonate therapy. The treatment strategy embarked on in this patient aims at having her off of corticosteroids within 3 months and subsequently maintained in remission with azathioprine. Infliximab or even surgical therapy would be considered if she cannot be maintained in remission on azathioprine. The goal must be to reduce corticosteroid use according to a reasonable schedule that also will allow an appropriate rebalance of the immune and endogenous corticosteroid dysregulation (ie, a reasonably slow taper of prednisone by 5 mg/wk) and maintenance of reduction of the active inflammation. This should be accompanied by an improvement in weight and nutrition and a return to physical activity. Even though prednisone is at a high dose and posing a bone risk, systemic inflammation, weight, nutrition, and physical activity all can improve, which will rebalance some of the osteoporosis risk. Irrespective of the progress of the Crohn s disease and type of therapy, it is appropriate to repeat a DEXA scan in 1 year to determine the changes in BMD. Why Calcium and Vitamin D and Not a Bisphosphonate? Because the goal of therapy is to have the patient off of corticosteroids early she can be treated with oral calcium supplementation and vitamin D. Bisphosphonates would not be indicated and, moreover, are expensive. Furthermore, if bisphosphonates are initiated it is difficult to predict an end point to this therapy. Preliminary data suggest that alendronate use is associated with improvement in BMD over 1 year in only a small number of patients with IBD. In

3 154 CHARLES N. BERNSTEIN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 2 2 recent controlled studies with the control group receiving oral calcium and vitamin D, bisphosphonate either in the form of etidronate or pamidronate provided no additional benefit. The incidence of fractures over 2 years was only 1% per year. Calcium and vitamin D therapy were found to be inexpensive, safe, and well tolerated, and, most of all, led to improvement in BMD. Calcium should be supplemented at 1000 mg/day and vitamin D at 800 IU/day. Areas of Uncertainty Is Osteoporosis Related to Corticosteroid Use or to Disease Activity? It has remained problematic to distinguish the risk to bones posed by corticosteroids from the risk posed by systemic inflammation. There is increasing evidence for the integration between systemic inflammation and bone loss likely mediated via receptor for activated nuclear factor kappa-b (RANK), RANK-ligand, and osteoprotegerin, proteins that can affect both osteoclastogenesis and T-cell activation and apoptosis. Osteoprotegerin has been proven to be increased in animal models of colitis, in which administration of exogenous osteoprotegerin can both enhance bone mass and reduce colitis. It also has been shown to be increased in the serum of women with Crohn s disease compared with matched controls. Are There any Tests Other Than Dual- Energy X-Ray Absorptiometry That Can Determine Risk for Osteoporosis? It remains uncertain whether any ancillary blood or urine tests can add to the bone risk stratification. Known renal or liver disease pose added risks to bones. Serum or urine markers of bone resorption are of interest in research studies but add little to current clinical management. Serum C-reactive protein and albumin levels may give some indication of either ongoing inflammatory activity, or in the case of albumin together with other tests such as ferritin may indicate nutritional status. In any patient with long-standing IBD, 25-hydroxyvitamin D levels should be measured annually. In Which Patients With Inflammatory Bowel Disease Should Screening for Osteoporosis Be Performed? In IBD it still is somewhat uncertain as to how DEXA results correlate with fracture risk. Although it might be simpler to recommend a DEXA test in either all or none of the patients with IBD, it is most appropriate to consider the use of DEXA in those patients Table 1. Risk Factors for Osteoporosis in IBD Age Chronic or recurrently active disease Chronic or recurrent courses of corticosteroids Physical inactivity Malnutrition Hypogonadism Past history of low-impact fractures a a This is not a true risk factor for osteoporosis but may be a historical clue that osteoporosis already is present. considered at higher risk for osteoporosis. In patients who have a high risk for osteoporosis-related fractures such as postmenopausal women on long-term corticosteroid therapy, treatment may be started without a DEXA scan. In patients at low risk for osteoporosis such as young, otherwise healthy, active men with limited steroid use DEXA scans are not indicated because treatment is not likely to be required irrespective of the DEXA results. Hence it still is incumbent on the physician to determine if patients carry sufficient risk for osteoporosis to warrant DEXA testing. Table 1 outlines the risk factors to consider. It will require more research to determine how to stratify these risk factors. If a patient with IBD is over age 50, postmenopausal, or has at least 2 of the other risk factors then it is reasonable to consider DEXA testing. See Figure 1 for an approach to DEXA testing in IBD. What Is the Role of Bisphosphonates? The efficacy of bisphosphonates in enhancing bone mass in IBD over and above the beneficial effects associated with calcium and vitamin D supplements remains uncertain. Further research will be required to determine if there is a role for bisphosphonates at all in IBD. Based on the available data at present the main role for bisphosphonates is in patients who are corticosteroid dependent, or who have already sustained a low-impact fracture. Patients with low-impact fractures have osteoporosis or at least sufficiently high further fracture risk that regardless of DEXA results a bisphosphonate may be indicated. What Is the Role of Estrogens/Testosterone? Estrogen therapy clearly is indicated for young females who have become hypoestrogenemic or amenorrheic. However, the findings that estrogen replacement can enhance the risk for certain cancers has forced physicians to reevaluate this approach, particularly in postmenopausal women. Serum testosterone levels often are overlooked in the assessment of male patients with IBD. If male patients have signs of

4 February 2006 OSTEOPOROSIS IN IBD 155 Figure 1. Algorithm for the management of suspected osteoporosis in IBD. hypoandrogenism, the serum testosterone level definitely should be measured and if measured for other reasons and found to be low then replacement therapy should be initiated. What Is the End Point of Therapy? It is unclear whether treatment for osteoporosis should be continued indefinitely, until the T score is greater than 1, or until steroids have been discontinued. It is safe to continue calcium 1000 mg/day and vitamin D 800 IU/day indefinitely even after discontinuation of prednisone therapy. It has been shown in studies from the United States and Canada that patients with IBD typically ingest significantly less than the recommended daily amounts of calcium and vitamin D. If bisphosphonates are initiated in premenopausal females or in men younger than age 50, the end point to therapy is not well established. If these agents are initiated in patients with low bone mass on corticosteroids and the corticosteroids are discontinued, other risk factors for osteoporosis are minimized, and bone mass has stabilized or increased, it may be reasonable to discontinue the bisphosphonates. Published Guidelines The American Gastroenterological Association technical review recommended that selective DEXA testing be pursued and bisphosphonate therapy be considered in those patients with known low-impact fractures, patients with T scores less than 2.5, and patients with corticosteroid dependence and T scores less than 1.0. These guidelines of selective DEXA testing are supported by a World Health Organization working group in collaboration with the International Osteoporosis Foundation and the National Osteoporosis Foundation. This group points out that DEXA testing may be unnecessary in those who have a documented need for osteoporosis therapy (radiographic evidence of osteoporosis or osteoporosis-associated fractures) or who have few risk factors for bone loss. In a young patient newly diagnosed with IBD, who has not had previous fractures, is well nourished, physically active, and eugonadal the risk for osteoporosis is so low that DEXA testing is not necessary. Recommendations This patient was started on calcium supplements (1000 mg/day) and oral vitamin D supplemen-

5 156 CHARLES N. BERNSTEIN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 2 tation (800 IU/day). A DEXA scan was to be repeated in a year. Suggested Reading 1. Bernstein CN, Leslie WD, Leboff M. AGA technical review: osteoporosis in gastrointestinal diseases. Gastroenterology 2003;124: Bernstein CN, Blanchard JF, Leslie WD, et al. The incidence of fractures among patients with IBD: a population-based study. Ann Intern Med 2000;133: Loftus EV Jr, Crowson CS, Sandborn WJ, et al. Long-term fracture risk in patients with Crohn s disease: a population-based study in Olmsted County, Minnesota. Gastroenterology 2002;123: Van Staa T-P, Cooper C, Brusse LS, et al. Inflammatory bowel disease and the risk of fracture. Gastroenterology 2003; 125: Kanis J, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int 2005;16: Siffledeen JS, Fedorak RN, Siminoski K, et al. Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn s disease. Clin Gastroenterol Hepatol 2005;3: Address requests for reprints to: Charles N. Bernstein, MD, University of Manitoba, 804F-715 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 3P4. cbernst@cc.umanitoba.ca; fax: (204) Supported in part by a Canadian Institutes of Health Research Investigator Award and by a Crohn s and Colitis Foundation of Canada Research Scientist Award.