2001糖皮质激素诱导的骨质疏松症的预防和治疗指南(英文)美国风湿病学会.doc

Recommendations for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis2001 Update American College Of Rheumatology Ad Hoc Committee On Glucocorticoid-Induced OsteoporosisMembers of the American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis are as follows. Lenore Buckley, MD, MPH: Medical College of Virginia, Richmond; Maria Greenwald, MD: Palm Springs, California; Marc Hochberg, MD, MPH: University of Maryland School of Medicine, Baltimore; Nancy Lane, MD: University of California San Francisco School of Medicine; Stephen Lindsey, MD: Ochsner Clinic, Baton Rouge, Louisiana; Stephen Paget, MD: Cornell University School of Medicine, New York, New York; Ken Saag, MD, MSc: University of Alabama School of Medicine, Birmingham; Lee Simon, MD: Harvard University School of Medicine, Boston, Massachusetts.The American College of Rheumatology is an independent professional, medical, and scientific society which does not guarantee, warrant, or endorse any commercial product or service.Address correspondence and reprint requests to American College of Rheumatology, 1800 Century Place, Suite 250, Atlanta, GA 30345. Submitted for publication March 19, 1999; accepted in revised form April 11, 2001.Funded by:Merck & Co., Aventis Pharmaceuticals, Wyeth Ayerst, Bristol-Myers Squibb, Procter & Gamble, La Jolla Pharmaceuticals, Amgen, Novartis Pharmaceuticals, AstraZeneca Pharmaceuticals, Forest Pharmaceuticals,Abgenix, Vertex, G. D. Searle & Co., PharmaciaGlucocorticoid therapy is associated with a number of significant side effects, of which bone loss resulting in glucocorticoid-induced osteoporosis and an increase in fracture risk is the most serious (1-4). However, studies show that many patients treated with glucocorticoids do not receive treatment to prevent bone loss (5-7). This suggests that physician awareness of bone loss and the increase in fracture risk caused by glucocorticoid treatment is low, and that there is inadequate information about the effectiveness of preventive treatment strategies.Glucocorticoids are used to treat a wide variety of allergic and inflammatory diseases and are prescribed by a wide variety of physicians, both specialists and generalists. A recent survey revealed significant variability in physicians' knowledge about glucocorticoid-induced osteoporosis, by specialty (8). While most physicians recognized that postmenopausal women have a high risk of fracture during glucocorticoid treatment, many reported that they did not routinely consider either hormone replacement therapy (HRT) or calcium and vitamin D supplementation. Physicians with the greatest experience with steroid therapy, such as rheumatologists and pulmonologists, were the most likely to report that they would prescribe preventive treatments, but the majority of other specialists reported taking no preventive measures. Even among rheumatologists, there is considerable variation in practice patterns regarding the use of pharmacologic agents for prevention and treatment (9). Also, many physicians are unaware that men and premenopausal women also are at great risk for glucocorticoid-induced osteoporosis, despite the existence of published studies demonstrating this (10, 11).In 1996, the American College of Rheumatology (ACR) summarized available information about the pathophysiology, diagnosis, prevention, and treatment of glucocorticoid-induced osteoporosis and developed recommendations for clinical practice (12). Because of the recent publication and presentation of results of several randomized controlled trials of agents for the prevention and treatment of glucocorticoid-induced osteoporosis, as well as systematic reviews and meta-analyses of previously published trials (13-16), the ACR appointed an ad hoc committee, the ACR Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis, to update these earlier recommendations. In addition, the Committee reviewed advances in the field of bone mass measurement and legislation that affects the availability of and reimbursement for this technology for patients receiving glucocorticoid therapy in the US.These recommendations are intended to educate and update physicians on the prevention and treatment of glucocorticoid-induced osteoporosis. The Committee emphasizes that the recommendations are not fixed, rigid mandates and recognizes that the final decision concerning the treatment regimen for an individual patient results from an informed discussion between the patient and his or her health care provider.Bone mass measurementThe US Congress passed the Bone Mass Measurement Act in 1997, and the Health Care Financing Administration published guidelines for its implementation in 1998 (17). Bone mass measurement is reimbursed by Medicare for 5 categories of persons at risk for osteoporosis in general; one category specifically includes patients receiving long-term glucocorticoid therapy at doses of 7.5 mg/day. Bone mass measurement is reimbursed for any procedure approved by the Food and Drug Administration (FDA) for detecting bone loss; the effect of this rule is that all forms of bone mass measurement, except dual-photon absorptiometry, are covered by Medicare.The Committee recommends obtaining a baseline measurement of bone mineral density (BMD) at the lumbar spine and/or hip when initiating long-term (i.e., >6 months) glucocorticoid therapy. Longitudinal measurements may be repeated as often as every 6 months for monitoring glucocorticoid-treated patients to detect bone loss. In patients who are receiving therapy to prevent bone loss, annual followup measurements are probably sufficient. A review of the clinical considerations in bone mass measurement was recently published; this review discussed not only the interpretation of bone mass measurement with dual x-ray absorptiometry (DXA), but also the interpretation with other techniques including quantitative computed tomography (QCT), single x-ray absorptiometry, and quantitative ultrasound of bone (18).Calcium and vitamin D In 1996, Buckley and colleagues reported the results of a 2-year randomized controlled trial demonstrating that calcium and vitamin D supplementation prevented bone loss in the lumbar spine and greater trochanter in rheumatoid arthritis (RA) patients receiving long-term, low-dose glucocorticoid treatment (mean prednisone dosage 5.6 mg/day) (19). Patients who received placebo lost bone at a rate of 2% and 0.9% per year in the lumbar spine and greater trochanter, respectively, while patients who received 1,000 mg of calcium carbonate and 500 IU of vitamin D daily gained bone at a rate of 0.7% and 0.9% in the lumbar spine and greater trochanter, respectively.Other data support the effectiveness of calcium and vitamin D supplementation in preserving bone mass in patients receiving regular glucocorticoid therapy. In a randomized placebo-controlled clinical trial of alendronate in the treatment of patients receiving glucocorticoids (median prednisone dosage 11 mg/day), bone mass at the lumbar spine was maintained in patients treated with placebo rather than alendronate who received supplementation with calcium at 800-1,000 mg/day and vitamin D at 250-500 mg/day (20). Similar results were noted in placebo-treated patients taking prednisone at a mean dosage of 15 mg/day who received 1,000 mg of calcium and 400 IU vitamin D daily during a randomized controlled trial of risedronate in patients receiving long-term glucocorticoid treatment (21). These patients had stable BMD at both the lumbar spine and the greater trochanter after 48 weeks of treatment. Furthermore, randomized controlled trials of the active vitamin D metabolites alfacalcidiol (1 OH-D3) at a dosage of 1 g/day and calcitriol (1,25OH2-D3) at 0.5-1 g/day in addition to calcium have demonstrated prevention of bone loss, compared with calcium and placebo, in patients starting glucocorticoid treatment (22,23). In addition, the results of meta-analyses of randomized controlled trials of calcium and vitamin D supplementation confirm the efficacy of this intervention (13,14), while a decision analysis suggested that supplementation with calcium and vitamin D would be cost effective for the prevention of glucocorticoid-induced osteoporosis in a patient with normal BMD (24).Thus, supplementation with calcium and vitamin D, either plain or in an activated form, can preserve bone mass in patients receiving long-term treatment with glucocorticoids at an average dosage of 15 mg/day. However, calcium alone does not prevent bone loss in patients receiving glucocorticoid therapy (22,25,26). Therefore, supplementation with both calcium and vitamin D should be required for glucocorticoid-treated patients. It should be noted that if activated forms of vitamin D are used, especially in patients who are just beginning glucocorticoid therapy, these patients should be carefully monitored for the development of hypercalcemia and hypercalcuria; if these adverse events develop, the dosage of the activated vitamin D supplement should be reduced.Antiresorptive agents Glucocorticoids alter bone metabolism such that bone formation is reduced and resorption is increased, leading to rapid bone loss after initation of therapy. The mechanisms for the development of glucocorticoid-induced bone loss have been reviewed in detail in other recent publications (27-29). A number of antiresorptive agents are available to both prevent and treat glucocorticoid-induced bone loss.Replacement of gonadal sex hormones Patients receiving prolonged glucocorticoid therapy may develop hypogonadism due to inhibition of secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary gland, as well as direct effects on hormone production by the ovary and testes. All patients receiving long-term glucocorticoid treatment should be assessed for hypogonadism, and when present, this should be corrected if possible. In a trial of postmenopausal women with RA who were taking prednisone and were randomized to receive either HRT or placebo, those who received HRT had a significant (3-4%) increase in their lumbar spine BMD compared with controls, while there was no significant change in femoral neck BMD in either group (30). In a randomized controlled trial of injectable parathyroid hormone (1-34) (PTH (1-34), postmenopausal women receiving long-term low-dose glucocorticoid therapy and HRT in the control group showed no change in BMD at the lumbar spine, hip, or distal radius over the course of 1 year (31).These data suggest that HRT is adequate therapy to prevent bone loss in postmenopausal women receiving prolonged low-to-moderate-dose glucocorticoid therapy. Currently, however, there are no published reports regarding the efficacy of HRT in preventing bone loss at the initiation of glucocorticoid treatment, or the degree of the protective effect of HRT when moderate-to-high doses of glucocorticoids are used for long-term treatment.There is less information available regarding men with hypogonadism secondary to glucocorticoid treatment. A randomized crossover trial demonstrated the effectiveness of testosterone replacement therapy in 15 men with glucocorticoid-treated asthma (32). All of the men had low serum testosterone levels prior to therapy. Lumbar spine BMD, but not hip BMD, was significantly increased (nearly 4%) after 12 months of monthly intramuscular testosterone injections; in addition, there was an increase in lean body mass and a reduction in fat mass. Thus, men with low serum levels of testosterone who are receiving glucocorticoids should receive replacement therapy. Based on recommendations published by the American Association of Clinical Endocrinologists and the American College of Endocrinology, men with serum testosterone levels below the physiologic range (<300 ng/mL) should receive replacement therapy (33). Multiple different testosterone preparations are available, including short- and long-acting intramuscular injections and transdermal patches and gels. The goal of testosterone replacement therapy is to provide physiologic-range serum testosterone levels. It is important to emphasize that if testosterone replacement therapy is to be used in a hypogonadal man, the patient should be adequately assessed for the possibility of prostate cancer, with a digital rectal examination and measurement of prostate-specific antigen at baseline and annually thereafter. Prostate cancer is an absolute contraindication to testosterone replacement therapy.Although no studies of HRT in premenopausal glucocorticoid-treated women have been performed, observational studies in premenopausal female athletes with menstrual irregularities suggest that women who receive oral contraceptives have higher adjusted bone mineral content and BMD than do women who do not take oral contraceptives (34,35). Therefore, premenopausal women who experience menstrual irregularities (oligo- or amenorrhea) while taking glucocorticoids should be offered oral contraceptives or cyclic estrogen and progesterone if contraindications are not present. At this time, no data are available on the efficacy of selective estrogen receptor modulators (SERMs) in the prevention or treatment of glucocorticoid-induced bone loss. The SERM raloxifene is approved by the FDA and is available for the prevention and treatment of postmenopausal osteoporosis (36,37). A SERM could theoretically be used to prevent glucocorticoid-induced bone loss in selected postmenopausal glucocorticoid-treated women who either have contraindications to or do not wish to take HRT or other antiresorptive medications.Bisphosphonates Results from 5 large randomized controlled clinical trials provide evidence that the bisphosphonates etidronate, alendronate, and risedronate are effective in both the prevention and the treatment of glucocorticoid-induced osteoporosis (20,21,25,26,38-40) (Table 1). Significant increases in BMD with bisphosphonate treatment, most consistently observed in the lumbar spine, were seen in patients with many different glucocorticoid-treated disorders, most often RA and polymyalgia rheumatica, and occurred generally irrespective of patient age, sex, and menopausal status in women. In addition, statistically significant reductions in the absolute risk and relative risk of incident radiographic vertebral fractures (11% and 70%, respectively) were demonstrated after 1 year of treatment with risedronate (40). A similar significant reduction in the risk of incident radiographic vertebral fractures (0.7% with alendronate versus 6.8% with placebo; P < 0.05) was seen in alendronate-treated patients who completed 2 years (1-year study and 1-year extension) of a study of alendronate in the prevention and treatment of glucocorticoid-induced osteoporosis (39). Serious drug toxicity was uncommon in all studies, with only a slight increase, compared with placeb