Osteoporosis is a systemic skeletal disease characterized by a low bone mass and a micro-architectural deterioration leading to an increased bone fragility and susceptibility to fracture.37
Osteoporosis depends on the peak bone mass and the rate of bone loss. Peak bone mass is determined by nutritional, hormonal, environmental and genetic factors. The rate of bone loss is predominantly determined by calcium and vitamin D absorption, and the resulting parathormone levels.
A low bone mass can result from a decreased bone formation/resorption ratio and/or an increased remodelling process. The diagnosis is preferentially based on bone mass density measurements and their related risk for fracture in post-menopausal women. Although it seems reasonable to suppose that, for the same bone mass density, the risk for fractures differs in different age categories, and perhaps between men and women, no other reference populations are available.
Bone mass densitometry
Bone mass density can be measured by several techniques. The preferred method is the dual energy X-ray absorptiometry (DEXA) measuring the attenuation of X-ray during its passage in bone. This method is highly sensitive and precise and can assess the bone mass simultaneously in cortical (radius or femur) and trabecular (lumbar spine) bone.
Densiometric criteria of bone loss are based on T and Z scores which are standard deviation scores expressed in relation to reference values in young healthy subjects (T score) or sex- and age-matched healthy controls (Z score).
Osteopenia is defined as a score of between −1 and −2.5. Osteoporosis is defined as a score lower than −2.5.37
Prevalence of low bone mass density in inflammatory bowel disease population
As defined previously, osteopenia is found in about 50% of inflammatory bowel disease patients and osteoporosis in about 30% ( Table 1).38–45 Particularly, Crohn’s disease seems to be associated with a decreased bone mass, not only in long-standing disease but also at the moment of diagnosis.46 In contrast to earlier studies, recent studies have found no correlation between bone mass density and the location or extension of the disease or ileal resection.39, 41, 47
Table 1. . Prevalances of osteopenia and osteoporosis in inflammatory bowel disease
Several longitudinal studies confirmed an increased rate of bone loss in inflammatory bowel disease patients.39, 40, 42, 43, 46 However, a marked heterogeneity in these rates has been observed between the studies and among the patients within the individual studies. Whereas Clementset al. reported a mean annual change in radial bone mass of −0.74% in women but not in men,43 Motley et al. found no differences between sexes.42 Changes in trabecular and cortical bone are also variable: Motley et al. reported a mean annual change of −2.8% in the spine and only −0.7% in the radius,42 but Staun et al. found only a mean annual change of −1.2% in the femoral bone and no change in the spine.48 Finally, rates of annual bone loss are also very disparate: Roux et al. described a mean change of −3.1% in Crohn’s disease and −6.4% in ulcerative colitis, Vogelsang et al. a decrease of −7.3% in Crohn’s disease, but Ghosh et al. reported no changes.39, 46, 49
Studies with biochemical markers are divergent. It seems unclear whether a decreased bone formation 38, 50 or increased bone resorption41 is the dominant cause of the disease. Very few studies have investigated the changes in bone remodelling associated with bone loss in patients with inflammatory bone disease, but suggest, at least in the later stages of the disease, a remodelling imbalance.50, 51
The pathogenesis of osteoporosis in inflammatory bowel disease is likely to be multifactorial.
‘Corticosteroids’ are frequently considered as the major cause of the changes in bone mass. They stimulate bone resorption and inhibit bone formation. The former is mainly mediated by a hyperparathyroidism secondary to calcium malabsorption and renal loss of calcium; the latter is mediated by a direct inhibitory effect on the proliferation and differentiation of osteoblast precursors and on the function of mature osteoblasts. Trabecular bone is preferentially affected.
Most cross-sectional studies support the contributive role of corticosteroids in the decrease in bone mass density observed in inflammatory bowel disease patients.38,47, 52–54 However, other studies were unable to demonstrate a relationship between the past or current use of steroids,39, 41 although very low T scores are most often observed in patients receiving large doses.41 Moreover, osteopenia has been reported in 28–30% of patients who never received such treatment.38, 46 Because the use of corticosteroids and life-time dosage reflect the severity of the disease, both effects interfere and so are difficult to evaluate separately.
Results of longitudinal studies are also variable. Ghosh et al. found no additional bone loss at 1 year.46 Similarly, Staun et al. found no relationship between the changes in bone mass density, over a mean period of 5.5 years, and the duration of the use of prednisolone.48 In contrast, Roux et al. found significantly higher bone loss in patients with steroids than without, although 26% of patients on steroid therapy did not lose bone, whereas 34% with significant bone loss did not receive steroid therapy during a follow-up period of 19 ± 8 months.39 Finally, Motley et al. only found a significant correlation between the total dose of steroids and spiral trabecular bone loss in males.42
Calcium and vitamin D malabsorption, secondary to extensive ileal disease, may result in secondary hyperparathyroidism leading to increased bone resorption. However, in most studies no correlation between the changes in bone mass density and disease location could be observed.41, 46, 54 Normal calcium homeostasis is mostly reported.41, 46 The importance of vitamin D deficiency is also controversial: low serum levels of vitamin D metabolites40, 53, 55 and a correlation with subsequent risk for significant bone loss39 suggest an aetio-pathogenetic role. Long-term oral vitamin D supplement seems to prevent bone mineral loss in patients with Crohn’s disease.49 However, in other studies, serum levels of vitamin D metabolites are normal even in patients with osteopenia.38, 44, 46
Inflammation on its own may be one of the principle aetio-pathogenetic mechanisms of osteopenia in inflammatory bowel disease. This statement is supported by a recent study in rats reporting a rapid and reversible bone loss in TNBS-induced colitis.56 In man, osteopenia has been observed in about 50% of Crohn’s disease patients at the moment of diagnosis, before any treatment.46 Finally, a correlation has been described between the control of disease activity and the increase in Z score.46 Cytokines like IL1, IL6 and TNFα are candidates because of their effect on osteoclasts: IL1 and TNFα have an inhibitory effect on bone formation and increase osteoclasts activity, whereas IL6 increases the number of osteoclast progenitor cells.57
Secondary amenorrhoea may be an important factor in the development of the disease in women. Hormone replacement therapy has been shown to prevent bone loss in the spine and radius in post-menopausal women with inflammatory bowel diseases.58 Mild hypogonadism may play a role in men.59
Finally, female ex- or current smokers with inflammatory bowel disease have lower Z scores than non-smoking counterparts suggesting a role of nicotine.60 This association was not related to the body mass index, the medical treatment, current or previous symptoms, or use of oestrogen preparations. The exact mechanism remains unknown: lower urinary oestrogen excretion, accelerated hepatic metabolism of oestrogen and an anti-oestrogen effect of nicotine have been suggested.
The aetio-pathogenesis of osteoporosis in inflammatory bowel disease is multifactorial. The failure to demonstrate clear relationships between one of these several factors and the presence of bone disease reflects the heterogeneity of the studied patients and the variable course of the disease.
Body mass density measurements can be recommended at diagnosis and repeatedly at 2–3 yearly intervals. If osteopenia is present, or if corticosteroids have to be started, preventive measures with oral calcium (1–1.5 g/day) should be considered, although a recent prospective study failed to show a significant benefit at 1 year.61 Long-term oral vitamin D supplementation (1000 IU/day) can be recommended, especially for patients at high risk of osteoporosis.55
In post-menopausal or amenorrhoeic pre-menopausal women, hormonal treatment should always be considered. It is important to detect and treat hypogonadism in men. There is also some evidence of the effectiveness of calcitonin and fluoride in this context.
Studies are in progress to confirm the beneficial effect biphosphanates (cyclic oral etidronic acid) on the prevention and treatment of corticosteroid-induced osteoporosis. The biphosphanates are analogues of pyrophosphate that binds avidly to bone mineral and inhibits osteoclastic bone resorption. Recently, prevention of bone loss was demonstrated with an intermittent therapy with etidronate in a large trial, including more than 100 patients who had recently begun high-dose glucocorticoid therapy.62 However, in this study the number of inflammatory bowel disease patients was extremely small.
Because the aetiology of osteoporosis in inflammatory bowel disease is multifactorial, and probably related not only to the use of corticosteroids but also to intestinal inflammation, trials are mandatory to evaluate the possible additional beneficial effect of immunomodulatory drugs by controlling the inflammation.