Glucocorticoid-induced osteoporosis occurs as a result of multiple mechanisms. Corticosteroids have multiple effects on bone including direct inhibition of bone formation, impaired calcium absorption across the intestine, and increased renal calcium excretion, all of which result in a negative calcium balance. As a result of calcium wasting, secondary hyperparathyroidism results and increases bone resorption. Corticosteroids induce a myopathy, which reduces the bone-stimulating effects of muscle activity. In animal models, corticosteroids have been shown to induce apoptosis of osteoblasts and osteocytes thereby resulting in diminished bone formation. More recently, cortico-steroids have been shown to regulate bone metabolism through their effect on members of the TNF receptor family, the OPGs. Osteoclasts express the RANK receptor. Binding of RANKL to RANK activates osteoclastic activity, which can be blocked by a soluble receptor OPG (discussed above). Corticosteroids decrease OPG expression by 90% and increase RANKL expression by threefold resulting in increased osteoclastic activity. Corticosteroids also cause a threefold increase in osteoclast numbers. Finally, corticosteroids inhibit adrenal production of androgens contributing to bone loss.
The effect of corticosteroids on bone loss is most marked in the first 6 to 12 months of therapy; therefore, even short courses of steroids (< 6 months) will result in marked bone loss. Even within 1 week of high dose steroid exposure, markers of bone resorption are increased. Bone loss secondary to steroids is dependent on both the dose and the duration of steroid use, with doses > 7.5 mg/d associated with 5 times the risk of fractures (Ruegsegger et al, 1983; van Staa et al, 2000). In studies of chronic exposure to steroids, average steroid doses of as little as 5.6 mg/d resulted in BMD loss of 2% per year (Buckley et al, 1996). In a large cohort of patients in the United Kingdom, the relative risk of vertebral fracture compared with a control population was 1.55 times higher with a standardized daily dose of steroids of 2.5 mg of prednisolone and increased to 5.18 for standardized doses of > 7.5 mg (van Staa et al, 2000). Importantly, all fracture risks declined rapidly after cessation of steroids suggesting that therapy should be given during the time of cortico-steroid use. The first decision to be made by the clinician is whether glucocorticoids are truly necessary for the management of the underlying disease. If the answer is yes, there must also be a plan in place for successfully withdrawing the glucocorticoids while maintaining remission. In the case of IBD, antimetabolites, such as 6-mercaptopurine or azathio-prine and methotrexate (MTX), have been shown to be effective as steroid-sparing therapy. Infliximab is also steroid-sparing and may have independent effects on bone metabolism (Abreu et al, 2002).
If glucocorticoids cannot be avoided, in certain cases the clinician may choose a safer glucocorticoid alternative. Budesonide in a controlled ileal release (CIR) preparation (Entocort) is effective for mild to moderate ileal and right-sided colonic CD. This preparation is associated with fewer steroid-related side effects and less adrenocortical gland suppression. A prospective study of 98 steroid-naive patients treated with prednisolone versus CIR-budesonide found that patients had a significantly greater drop in BMD with prednisolone treatment compared with CIR-budesonide (-1.04% versus -3.84%, p = .0084) (Schoon et al, 2002). Thus, whenever possible CIR-budesonide should be considered for the patient with CD. For patients with distal colonic IBD, topical rectal steroids in short courses (< 2 weeks) do not increase bone turnover in patients, but long term therapy with these agents does result in bone loss (Robinson et al, 1998). By contrast, however, oral budesonide therapy in patients with PBC or primary sclerosing cholangitis (PSC) resulted in worsening of their osteoporosis (Angulo et al, 2000). Similar to IBD, autoimmune hepatitis is treated with glucocorticoids. Patients with both PSC and underlying IBD may receive glucocorticoids and be at increased risk of osteoporosis (Angulo et al, 1998).
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