Corticosteroids - A Balanced View

Willem Lems, MD, University Medical Centre, Amsterdam, The Netherlands, discussed the pathogenesis of glucocorticoid-induced osteoporosis.

Glucocorticoids have been shown to stimulate apoptosis of osteoblasts and osteocytes, interfere with the Wntsignaling pathway (a pivotal pathway for modulating osteoblastic activity, bone formation, and bone strength), and increase the lifespan of osteoclasts [Shoback D. J Clin Endocrinol Metab 2007]. They also reduce the intestinal absorption of calcium and augment calcium excretion in the urine [van Staa T. Calcif Tissue Int 2006].

The increased fracture risk in patients who receive glucocorticoid therapy may be offset by alendronate [Saag KG et al. N Engl J Med 1998], risedronate [Reid DM et al. J Bone Miner Res 2000], active vitamin D3, and bisphosphonates [de Nijs RN et al. Osteoporos Int 2004]. Teriparatide, the first anabolic agent, appears to significantly (p<0.001) increase bone mineral density (BMD) and decrease fracture incidence more than alendronate [Saag KG et al. N Engl J Med 2007].

Despite increases in the frequency of screening for and treatment of glucocorticoid-induced osteoporosis, adequate prophylaxis is only prescribed in roughly 50% of glucocorticoid-treated patients [Saag K et al. J Rheumatology 2006].

Cancer Treatment-Induced Bone Loss

Jean-Jacques Body, MD, PhD, CHU Brugmann, Universite Libre de Bruxelles, Brussels, Belgium, discussed recent data that concern osteoporosis that is induced by adjuvant antineoplastic treatment in pre- and postmenopausal women with early breast cancer and by androgen deprivation therapy (ADT) in men who are being treated for prostate cancer.

Chemotherapy, GnRH analogs, tamoxifen in premenopausal women, ADT, and aromatase inhibitors (anastrozole, letrozole, and exemestane) can increase bone turnover, reduce bone mass (up to 4% to 5% per year), and increase fracture rates as much as 35% to 50%. Risedronate and to a greater extent zoledronic acid as adjunctive therapy, however, have been shown to significantly (p<0.01) prevent bone loss and reduce bone turnover in women with breast cancer and chemotherapy-induced menopause or those who are treated with aromatase inhibitors (anastrozole/letrozole) [Greenspan SL et al. J Clin Endocrinol Metab 2007; Gnant MF et al. J Clin Oncol 2007; Brufsky A et al. J Clin Oncol 2007]. In men who are being treated with leuprolide, a gonadotropin-releasing hormone agonist, pamidronate significantly (p<0.02) prevents bone loss [Smith MR et al. N Engl J Med 2001]. Zoledronic acid and alendronate even can increase BMD in such patients [Greenspan SL et al. Ann Intern Med 2007]. Prof. Body stated that “the initiation of therapy should begin early, prior to the occurrence of severe osteoporosis.”

Which Other Dugs Cause Problems?

Besides the glucocorticoids, Peter Vestergaard, MD, PhD, The Osteoporosis Clinic, Aarhus Amtssygehus, Aarhus, Denmark, summarized studies on other drugs that are used to treat rheumatologic diseases, such as immunosuppressives (methotrexate, cyclosporine, azathioprine) and the older disease-modifying antirheumatic drugs (DMARDs; gold, penicillamine, chloroquine, sulphasalazine). Methotrexate, most DMARDs, and the newer biological agents seem safe in terms of the risk of osteoporosis and fractures, although the number of studies is limited. Some of the newer biological agents may even have positive effects on bone density. For pain medication, nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates also have been associated with an increased risk of fractures, which, in the case of opiates, may be linked to an increased risk of falls. An important confounder is “confounding by indication,” which means that the effects of the underlying disease may be confounded with the effects of the drugs that are given to control the disease in question. For example, many patients with advanced disease have a higher risk of decreased bone density and fractures due to the effects of the disease per se. However, these patients also may be more likely to receive drugs in high doses for their disease, and the drug treatment may thus be confounded with the effect of the disease. The increase in fracture risk that is shown in some studies may be due to the underlying disease, not the treatment, concluded Prof. Vestergaard.

A Victory in the War on Osteoporosis?

In contrast to the negative news about osteoporosis, Ms. Amrita Sehgal, a student at Menlo-Atherton High School, Atherton, CA, presented data that showed that in the United States, inpatient days that were attributed to hip fractures dropped by almost 73% between 1988 and 2005 (p<0.0001), despite an 11.4% increase in all-cause hospitalizations. However, the total cost of care for such hospitalizations (in 2005 US dollars, assuming 3% inflation rate) increased from $4.04 billion to $5.9 billion (p<0.05), suggesting that hip fractures continue to be associated with significant costs of care.