REVIEW URRENT C OPINION

Risk factors and management of osteoporosis in inflammatory bowel disease Laura E. Targownik a, Charles N. Bernstein a, and William D. Leslie a,b

Purpose of review To provide a synopsis on established and new research evaluating bone disease in patients with inflammatory bowel disease (IBD). Recent findings Persons with IBD, including Crohn’s disease and ulcerative colitis are believed to be at high risk for osteoporosis and fracture. As osteoporosis is clinically silent and persons with IBD are not universally screened, the burden of bone disease in IBD has been difficult to accurately assess. It is also unclear whether bone disease is due to inflammatory activity, medication use, poor nutrient intake/absorption, or body habitus characteristics. Recent studies using population-wide databases of bone mineral density (BMD) analyses suggest that Crohn’s disease is responsible for a small effect on BMD after adjusting for other risk factors for low BMD, whereas ulcerative colitis does not appear to confer an independent risk. Furthermore, IBD does not appear to be a risk for overall fracture once controlling for factors which are associated with both IBD and fracture risk. The ability to assess BMD on incidentally performed computed tomography scans may allow detection of low BMD in IBD patients. Summary Although reduced BMD and fracture are more common in persons with IBD, the precise burden is not well characterized. Also, the relative impact of IBD-associated factors and IBD-specific inflammation on bone health is still uncertain. Keywords bone mineral density, Crohn’s disease, inflammatory bowel disease, osteoporosis, ulcerative colitis

INTRODUCTION Loss of bone mineral density (BMD) resulting in osteoporosis is more common in persons with inflammatory bowel disease (IBD) [1]. Osteoporosis is defined as a BMD from dual x-ray absorptiometry (DXA) of the proximal femur or lumbar spine measuring 2.5 or more standard deviations below what would be expected for a healthy young adult (T score < 2.5) [2]. It has been estimated that 14–42% of persons with IBD have osteoporosis, though the precise prevalence is unknown, as there are no population-based data with universal case detection [3–5]. Although low BMD is itself asymptomatic, it leaves persons more susceptible to fractures following relatively minor trauma [6,7]. Major osteoporosis fractures, including those of the proximal femur (hip), vertebrae (spine), proximal humerus (shoulder), or distal forearm (wrist), are associated with significant morbidity and excess mortality [8,9]. Recognition and appropriate treatment of www.co-gastroenterology.com

osteoporosis decreases the risk of future major osteoporosis-related fractures [10–12]. However, not all persons with IBD are at equivalent risk for developing osteoporosis or suffering an osteoporosis-related fracture. In this article, we will discuss the prevalence and risk factors associated with the development of accelerated bone mineral loss, osteoporosis, and fracture in IBD. We will also review case-identification strategies and describe the therapeutic options available for the treatment and prevention of osteoporosis and fracture.

a Department of Internal Medicine and bDepartment of Radiology and Nuclear Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

Correspondence to Laura Targownik, MD, MSHS, 805G-715 McDermot Avenue, Winnipeg, Manitoba R3E 3P4, Canada. Tel: +1 204 789 3567; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:168–174 DOI:10.1097/MOG.0000000000000037 Volume 30  Number 2  March 2014

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Osteoporosis in inflammatory bowel disease Targownik et al.

KEY POINTS  The prevalence of osteoporosis appears to be increased in persons with IBD.  Small intestinal involvement may predispose to malabsorption of vitamin D and nutrients, increasing the risk for osteoporosis.  Low BMI, older age, and use and duration of glucocorticoid therapy are associated with a higher risk of osteoporosis and fracture in IBD.  IBD patients should be screened for osteoporosis according to general guidelines, though consideration of screening should be extended to those with low BMI or persistently active inflammatory activity.  Bisphosphonates are efficacious for the treatment and prevention of osteoporosis in IBD.

GENERAL RISK FACTORS FOR OSTEOPOROSIS AND FRACTURE The risk factors for both osteoporosis and fracture can be divided into those that are nonmodifiable and those which are potentially modifiable. Nonmodifiable risk factors include advancing age, female sex, and family history of fracture [13–15]. There is also a large polygenetic heritable contribution to the risk of developing osteoporosis [16,17]. Potentially modifiable risks include dietary deficiency or malabsorption of calcium and/or vitamin D [18,19], low BMI [20,21], and the use of medications which either inhibit new bone formation, increase bone turnover, or both. Loss of natural sex hormones, as occurs following menopause (and to a lesser extent, andropause), promotes acceleration in bone mineral loss [22,23]. Higher rates of osteoporosis have also been reported in a variety of clinical syndromes, including rheumatoid arthritis [24], celiac disease [25], chronic liver disease [26], chronic renal insufficiency [27], hyperthyroidism [28], and conditions which lead to prolonged immobility or decreased opportunities for weightbearing exercise [29]. Decreasing BMD is a strong risk factor for the development of major osteoporosis-related fracture, with each standard deviation decline in BMD being associated with roughly a doubling in the risk of fracture [30,31]. In addition, a previous low-trauma fracture, increasing age, female sex, prolonged glucocorticoid use, parental history of hip fracture, smoking, and high alcohol intake are known to increase the risk of fracture independent of their effects on BMD [32]. Last, an increased risk of falls resulting from conditions and medications, which

affect cognition and/or balance, can also lead to fractures [33].

RISK FACTORS FOR OSTEOPOROSIS AND FRACTURE IN INFLAMMATORY BOWEL DISEASE In addition to the known risk factors for osteoporosis in the general population, there may be other characteristics specific to IBD which may increase the likelihood of osteoporosis and fracture. This may be related to the presence of inflammation or to sequelae thereof, such as altered nutrient and vitamin intake and absorption.

Inflammation Among patients with IBD, it remains uncertain whether the increased intestinal inflammatory activity directly promotes the development of bone mineral loss, or whether the resultant effects of intestinal inflammation lead to a higher prevalence of general risk factors for osteoporosis [34]. There is evidence that increased systemic inflammatory activity increases bone resorption and decreases new bone formation [35,36], and occurs in chronic inflammatory diseases which do not directly affect the gastrointestinal system [24]. Osteoclast maturation and activation are primarily stimulated by nuclear factor kappa B, whose production is in turn regulated by the binding of receptor-activated nuclear factor kappa B ligand (RANK-L) to receptors found on the surface of osteoclast progenitor cells [37,38]. Cytokines such as tumor necrosis factor (TNF) alpha, interleukin 1 and 6, and interferon gamma, which are elaborated in the setting of IBD and other chronic inflammatory diseases including IBD, are known to increase production of RANK-L, thereby promoting increased bone turnover [39]. However, it is difficult to precisely delineate the direct effect of inflammation on bone mineral metabolism in the clinical setting, as the symptoms resulting from inflammation may promote changes in diet, loss of weight, and alterations in behavior, which negatively influence bone homeostasis. Furthermore, symptoms resulting from intestinal inflammation may trigger the use of glucocorticoids, which are well known to rapidly induce bone mineral loss [40]. In support of a direct role for inflammation as being detrimental for bone health, nonglucocorticoid-based treatment of intestinal inflammation with agents which inhibit TNF-alpha activity, has been shown to improve BMD [41]. Also, a higher than expected prevalence of osteoporosis has been demonstrated in patients at the time of initial

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Small intestine

diagnosis, prior to any glucocorticoid exposure [42]. However, as symptoms of IBD may precede definitive diagnosis by months if not years, it is conceivable that other factors such as low BMI, decreased mobility, and poor intake of calcium and vitamin D may also contribute to this finding. In an analysis of a large Canadian BMD dataset, IBD had only a small effect on BMD and the risk of osteoporosis after controlling for age, sex, BMI, use of glucocorticoids, and osteoprotective medications [43 ]. This suggests that although control of inflammation remains a major end point for successful therapy, prevention of osteoporosis requires the consideration of additional factors. Also, although IBD is often reported as a risk factor for the occurrence of major osteoporotic fracture, the magnitude of this risk is attenuated after controlling for other factors associated both with IBD and fracture. Two population-based European studies found that the attributable risk of IBD for major osteoporotic fracture decreased when controlled for recent glucocorticoid use [44,45]. Furthermore, in an analysis of all persons who underwent DXA-based testing in Manitoba, IBD was not associated with an increased risk of major osteoporotic fractures after controlling for BMD and BMD-independent risk factors for fracture, though the risk of hip fracture was significantly increased, albeit with wide confidence intervals [46 ]. &&

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Inflammatory bowel disease subtypes Elevated rates of osteoporosis have been reported both in Crohn’s disease and in ulcerative colitis. In studies that have evaluated cohorts containing both Crohn’s disease and ulcerative colitis patients, rates of osteoporosis in Crohn’s disease either exceed or are no different than in ulcerative colitis [3,47–49]. In a large Canadian study, Crohn’s disease was specifically associated with a significant negative effect on BMD, whereas having a diagnosis of ulcerative colitis did not affect BMD or the risk of osteoporosis after controlling for age, sex, BMI, and the use of osteoactive medications [43 ]. Although both Crohn’s disease and ulcerative colitis are associated with systemic inflammation and frequent use of glucocorticoids, persons with ulcerative colitis do not manifest small bowel involvement and thus are unlikely to have issues of calcium and/or vitamin D malabsorption. Patients with severe small bowel disease in Crohn’s disease may also suffer from generalized malabsorption of nutrients, and may limit oral intake, resulting in weight loss [50,51]. This decrease in body mass in turn may promote bone mineral loss. &&

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Population-based studies are inconsistent over whether IBD subtypes have a differential risk of major osteoporotic fractures. Bernstein et al. [52] performed a population-based analysis for Manitoba, Canada, and reported an approximately 40% increase in the risk of fracture in both Crohn’s disease and ulcerative colitis, compared with matched controls. Similar results have been seen in other population-based studies from the United Kingdom and the Netherlands [44,45]. Conversely, a Danish study found a significant increase in the risk of fracture for Crohn’s disease, but not in ulcerative colitis [53]. Loftus et al. [54] found no association between Crohn’s disease or ulcerative colitis with fracture in a population-based US analysis, though this study was not sufficiently powered to exclude a significant increase in risk.

Surgical status The most common surgical procedure in Crohn’s disease involves resection of the terminal ileum. Although calcium and vitamin D are predominantly absorbed in the duodenum and proximal jejunum, vitamin D absorption is dependent on its dissolution in micelles [55]. The terminal ileum is the primary site of bile acid reabsorption, and thus removal of the terminal ileum may promote depletion of the circulating bile acid pool [56], leading to decreased micelle formation and resulting in vitamin D malabsorption. Although small bowel resection is frequently listed as a risk factor for hypovitaminosis D and secondary hyperparathyroidism in cross-sectional studies [57], its relationship to osteoporosis in Crohn’s disease is less consistent [58,59]. This may be because small bowel resection generally results in the removal of a focus of inflammation, which contributes to bone mineral loss. Small bowel resection may also eliminate the need for glucocorticoid therapy, further removing a contributor to bone mineral loss. An increased prevalence of osteoporosis has also been seen in patients with ulcerative colitis who have undergone a total colectomy with creation of an ileo-anal pouch [60]. Persons with ulcerative colitis most commonly undergo colectomy as a result of having treatment refractory disease, and are highly likely to have used glucocorticoids, which contribute to decreased BMD. However, low BMD has been shown to persist for years after colectomy, when persons with ulcerative colitis are considered to be cured [61]. This is particularly the case among subjects who have persistently low BMI. However, the precise cause of persistently low BMD in patients having undergone an ileo-anal pouch is not well understood. Volume 30  Number 2  March 2014

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Osteoporosis in inflammatory bowel disease Targownik et al.

Calcium and vitamin D homeostasis Adequate intake and absorption of calcium and vitamin D are integral for achieving and maintaining bone density. Negative calcium balance results if calcium intake is less than the amount lost because of bone resorption. Furthermore, low serum levels of vitamin D are correlated with higher parathyroid hormone activity [62], and persons with low serum vitamin D are more likely to suffer from hip fracture [63]. Although vitamin D can also be synthesized through exposure to ultraviolet B radiation, people who live in latitudes with extreme seasonal variation are more dependent on vitamin D intake to maintain adequate serum levels, especially during the winter months [64]. Persons with IBD have been shown to have both decreased intake of foods rich in calcium and vitamin D [65], and up to 65% of persons with IBD have suboptimal of vitamin D status (

Risk factors and management of osteoporosis in inflammatory bowel disease.

To provide a synopsis on established and new research evaluating bone disease in patients with inflammatory bowel disease (IBD)...
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