Amsterdam, Netherland (special for SIIC):

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, has a chronic, relapsing course of exacerbations and remissions of intestinal inflammation, causing anatomic and functional intestinal damage over time. It is a disease believed to result from an exaggerated intestinal immunological response, probably against intestinal (dysbiotic) flora in genetically predisposed subjects. Skeletal or bone health is defined as a balance between bone degrading (osteoclast activity) and bone upgrading (osteoblast activity) mechanisms, which allows growth and maintenance of bone tissue. It is clinically assessed by dual-energy X-ray absorptiometry, and expressed as a T- or Z-score, which encompasses comparison with age, sex or race dependent standards. Complaints due to intestinal disease are associated with an unbalanced diet, often incorporating insufficient intake of macro and micronutrients. Moreover, due to intestinal disease, absorption of nutrients may become disturbed. This may include important micronutrients for bone health such as calcium, potassium, and vitamins K and D. In addition, bone health is promoted by physical activity, which is commonly below average in chronically diseased patients. Sunlight exposure, necessary for generation of vitamin D in the skin, is usually less due to disease complaints, lack of outdoor activities or prohibited due to specific IBD drug use (immune suppressives). These diet and life style factors lead to a decreased quality of bone, increased risk of osteopenia, osteoporosis, and, finally, bone fractures with a reported increased odds ratio of global fractures to 1.38 (95% CI 1.11-1.73), and for vertebral fractures of 2.26 (95% CI 1.04-4.90), respectively. In case of IBD the inflammatory process contributes to a decreased bone health. Particularly during relapses, many pro-inflammatory cytokines are generated, locally and systemically. Many of these cytokines have a detrimental effect on bone metabolism. Pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNF-a), interleukin 1beta, -4, -5, -6 and -17, have been shown to circulate in higher concentrations. The various pro-inflammatory cytokines usually hamper the function of (pre-)osteoclasts. This is mediated by increased production of receptor activator of nuclear factor kappa-B (RANKL), followed by osteoclastogenesis causing increased bone tissue degradation. Also, osteoblast maturation may be inhibited. As a result, bone resorption is increased and repair is reduced. The anti-inflammatory cytokines involved in the pathophysiology of IBD, and produced as response to the pro-inflammatory intestinal status during exacerbations, comprise, amongst others, interferon-gamma, interleukin-4 and -13. These cytokines may inhibit osteoclastogenesis. Therefore, the resulting balance of pro-inflammatory and counteracting anti-inflammatory cytokines not only determines the intestinal inflammatory status, but the bone health status as well. In vitro experiments with a cytokine mixture derived from IBD patients to elucidate the effects on bone health are sparse, but in these studies bone formation has been shown to be decreased. In addition, bone quality was decreased with discontinuous and uneven mineralized bone matrix and dysmorphic osteoblasts. In vitro blockade of interleukin-6 counteracted these disadvantageous changes of bone tissue. Vitamin D plays also a pivotal role in bone health, and it has been suggested that it influences course of IBD as well due to immunomodulatory effects. As vitamin D concentrations are commonly low in IBD patients, calcium absorption may be diminished in this population. Together, this negatively influences bone health, as can be found clinically by elevated concentrations of parathormone. However, several aspects of vitamin D effects on bone, particularly in the context of a mixture of cytokines as in IBD patients, remain to be elucidated. The over-all approach to improve bone health in IBD patients contains general and disease specific factors. The first is characterized by an optimal diet with sufficient calcium, magnesium, potassium and vitamin D, quitting of smoking, low/no alcohol intake, enough physical exercise, with optimization of nutritional status as assessed by adequate body mass index and fat free mass. Medical therapy of active IBD should be aimed to induce remission by strict anti-inflammatory therapy in a treat-to-target strategy. Corticosteroids should be circumvented as much as possible and at the lowest dose in a short course, if unavoidable, with concomitantly calcium and vitamin D supplementation. A strict treat-to-target therapy is believed to restore the misbalanced, IBD associated mixture-of-cytokines and is likely to reduce gastrointestinal damage overtime. In case of clinical relevant disturbance of bone health, i.e. osteopenia, osteoporosis or low energy impact bone fractures, bone-specific therapy is advocated to be initiated. This includes sufficient calcium and vitamin D, the latter based on 25-OH-vitamin D concentrations in blood. Bisphosphonates are indicated when osteoporosis or bone fractures are present, or in case of osteopenia if concomitant risk factors for decreased bone health are present. Potentially, more recently introduced bone protecting drugs, such as denosumab, a RANKL-inhibitor, may be beneficial as well, in particularly in systemic, pro-inflammatory diseases, such as IBD is. Formal trials however are lacking. Parathormone therapy, known as teriparatide, with anabolic effects on bone metabolism, has been investigated in corticosteroid-associated osteoporosis, but once again not in the target population of IBD patients.