Osteoporosis

Osteoporosis is a common skeletal health problem characterised by low bone mass and bone microstructural deterioration leading to bone fragility and susceptibility to fracture. Peak bone mass depends on many factors, such as nutritional, hormonal, genetic and environmental factors. Vitamin D and calcium absorption, and the consequent parathormone levels, determine the degree of bone loss. Low bone mass can derive from a diminished bone formation/resorption ratio and/or increased remodeling process. Bone mass is evaluated and diagnosed by measuring bone mass density [29]. Bone mass density is measured in many different ways, but the preferred method is dual energy X-ray absorptiometry (DEXA), which measures X-ray attenuation during its passage through bone. This method is highly sensitive and can evaluate bone mass in both cortical (radius) and trabecular (lumbar spine) bone.

Criteria for assessing bone loss are expressed by two densitometric parameters, called T and Z scores, which are standard deviation scores expressed in relation to reference values for young healthy subjects (T score) and for gender- and age-matched healthy controls (Z score). A review of studies using DEXA demonstrated that osteopenia occurs in 40-50% and osteoporosis in 30% of patients with IBD. Osteoporosis and osteopenia are also reportedly more frequent in CD than in UC [30]. A recent literature review showed that, in uncontrolled studies, patients with IBD had a prevalence of severe demineralisation ranging from 18% to 42%. On the other hand, larger studies including a healthy control group showed a prevalence of severe bone mass density reduction in only 2-16% of IBD cases [31, 32]. Bone disease is of relevance in IBD, but most data in studies on this issue are pooled from IBD clinics, so the problem may be overestimated. Longitudinal changes in bone mass in IBD patients were found much the same as in the general population.

Osteoporosis in IBD is probably caused by many factors, such as corticosteroid therapy, inflammatory cytokines and malnutrition/malabsorption. Dinca et al. evaluated the frequency and evolution of osteope-nia in IBD patients and found that a low bone density is frequent in both CD and UC but apparently remains stable in CD. The evolution of bone mass density suggests that a low bone density is associated with the pathogenesis of CD whereas in UC, it seems to be correlated with the effects of corticosteroids [33].

Corticosteroids are an important cause of bone demineralisation in IBD patients. They suppress bone formation through a direct inhibitory effect on osteoblasts, inhibiting growth factors, increasing osteoblast apoptosis and accelerating bone resorption by reducing androgens and oestrogens and increasing secretion of parathyroid hormone. They also reduce intestinal calcium absorption and increase its renal excretion. Corticosteroids cause osteoporosis in 50% of treated patients, irrespective of the disease involved. The role of corticosteroids is hard to distinguish from the role of active inflammation. Bone loss occurs mostly during the first weeks of treatment and persists throughout the treatment. A study has demonstrated a 27% loss of bone mass density after 1 year of treatment with prednisone [34,

35]. Many studies have demonstrated a direct correlation between corticosteroid treatment and loss of bone mass density. A recent large population-based study showed that CD patients with fractures were significantly more likely to have used corticosteroids in the previous 2 years than those without fractures. Patients with CD and osteoporosis were also more likely to be on steroid treatment and at a higher cumulative dose than patients without osteoporosis. New bone formation is also reduced in IBD patients treated with steroids [36].

Other steroids, e.g. budesonide, are rapidly metabolised and poorly absorbed by comparison with standard steroids such as prednisone, but a recent study by Greenberg et al. demonstrated that budesonide offered no advantage over low-dose prednisone in terms of preserving bone mass density, possibly due to its more limited effect on inflammation [37]. Steroids are often prescribed for children with IBD, and a study on 119 children with IBD treated with corticosteroids at a dose of more than 7.5 mg/day for 12 months revealed a significant reduction in their bone mass density. A similar study reported that bone density of the lumbar spine was lower the higher the cumulative dose of prednisone. Other studies found no such bone loss correlating with concurrent or past corticosteroid intake, however, and osteoporosis has also been observed in IBD children who have never been exposed to corticos-teroids.

Corticosteroids may be responsible for loss of bone mass, but their use may also be indicative of a more severe disease - which may be the real culprit [38]. Therapy with corticosteroids is only one of the many causes of bone loss in IBD. The inflammatory condition is characterised by an increase in circulating cytokines, which increases osteoclast activity. Tumour necrosis factor (TNF) alpha inhibits osteoblast differentiation and induces osteoclast differentiation, increasing osteoclast survival and decreasing osteoclast apoptosis. A recent study demonstrated that the TNF-receptor-based interaction between osteoblasts and osteoclasts is the common pathway of bone metabolism alteration [39]. Although inflammation itself is an important cause of bone metabolism alteration, malnutrition is common in IBD patients due to anorexia, malabsorption, greater loss of nutrients and increased metabolic demand. In some patients, calcium and vitamin D are low due to a poor dietary intake and malabsorption, and any reduction in these elements that are so important to bone metabolism may contribute to bone loss. Some studies on the weekly dietary records of inactive CD patients showed they had a lower vitamin D intake (1 ^g/day) than the recommended daily amount of 5 ^g/day. Similarly, IBD patients had a lower calcium intake than healthy people, and the active vitamin D levels were found significantly lower in CD and UC patients than in healthy controls. In CD patients with extensive ileal disease, bone loss was related not only to vitamin D deficiency but also with deficiency of vitamin-K-dependent proteins. Among these proteins is osteocalcin, the function of which is dependent on vitamin K; an altered gut microflora and fat malabsorption can cause vitamin K deficiency, which contributes to bone mass loss.

There are several pharmacological options for treating osteoporosis and, since its course varies in different patients and is not easily predictable, treatment of the bowel disease itself could be a kind of prophylaxis against bone disease, as inflammatory cytokines play an important role in altering bone metabolism [40]. Among treatment options for osteoporosis in IBD, hormone replacement therapy (HRT) has only been evaluated in an open study in postmenopausal women with CD. HRT has been shown to stop progression of bone loss in post-menopausal women and increase bone mass density in the long term although it does not seem to alter patients' fracture rate. HRT could be recommended in postmenopausal women with CD providing they have no contraindications, such as personal history or strong family history of breast cancer.

Dietary supplementation with calcium and vitamin D is one of the front-line therapies for preventing bone loss but is not enough in patients taking corticosteroids (such as IBD patients). A randomised controlled trial involving 103 patients comparing calcium (1,000 mg/qd) and calcitriol (0.6 mg/qd) showed that calcitriol prevented yearly bone loss from the lumbar spine more effectively than calcium alone [41 ]. Another study showed that long-term oral vitamin D substitution was able to prevent forearm bone loss in CD whereas in unsupplemented patients, bone mass density decreased significantly (7%). Combined calcium (800-1,000 mg) and vitamin D (800-1,000 IU) intake increased lumbar spine bone mineral density by 2.2-3.2% in the first year of treatment.

Calcitonin is a nonsteroidal hormone that directly inhibits osteoclast activity: its use seems to increase bone mass by 4-5% and it is now available in nasal sprays or rectal suppositories. It has not been approved for glucocorticoid-induced osteoporosis, however, and there are no published data available on its efficacy in this IBD patient population [42].

Sodium fluoride has been found to increase bone mass density in patients with CD, and its effect increases over 2 years of treatment whereas calcium and vitamin D supplementation is only beneficial in the first year of treatment.

Bisphosphonates are the only effective therapy for glucocorticoid-induced osteoporosis, and there are different types of medication that bind tightly to hydroxyapatite crystals in the bone and inhibit osteo-clastic bone resorption. Recent meta-analyses demonstrated that etidronate, alendronate and rise-dronate increase bone mass density at the hip and spine in a dose-dependent manner, and their use is associated with a 30-50% reduction of vertebral fractures. Alendronate and risedronate also reduce rates of nonvertebral fractures both in women with osteoporosis and in adults with corticosteroid-induced osteoporosis. The efficacy of bisphosphonates beyond 1 year of treatment and on spinal fractures remains to be seen, however. Similarly, a recent review on etidronate demonstrated that it increased bone mass density in the lumbar spine and femoral neck, but the beneficial effect was only evident for vertebral fractures [43].

Adequate use of corticosteroids and agents that can facilitate their tapering are of fundamental importance in prevention of osteoporosis in IBD patients. The latter agents include: mesalamine, which has been effective in reducing the number of steroid-dependent CD patients, and azathioprine, 6-mercaptopurine and infliximab, which are also effective in reducing the number of steroid-dependent patients and treating refractory patients.

Many efforts have been made to reduce the use of conventional steroids, which should be used while maximising the use of other effective therapies to contain the risk of severe osteoporosis and fractures. Clinical evidence suggests that steroid dosage correlates with bone mass density but not with fracture risk and that ongoing steroid therapy only worsens bone mass density in cases of UC. There are scant data on the reversibility of these effects (only one small study on patients after colectomy), and topical steroids apparently offer no advantage because they may be less effective in controlling inflammation.

The most important measures in managing osteoporosis are treating intestinal inflammation, identifying patients with osteoporosis and promptly starting adequate therapy. Bone mass density measurements can be recommended at diagnosis and repeated every 2-3 years. In the event of osteopenia, or if corticosteroids are needed, then preventive therapy should be considered.

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