Clinical practice Glucocorticoid induced[PMIDS21732837]

T h e ne w engl a nd jour na l o f medicine

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations.

n engl j med 365;1 43e7f582af1ffc4fff47accc july 7, 2011

62An audio version

of this article

is available at 43e7f582af1ffc4fff47accc Glucocorticoid-Induced Bone Disease

Robert S. Weinstein, M.D.

From the Division of Endocrinology and

Metabolism, the Center for Osteoporosis

and Metabolic Bone Diseases, the Depart-

ment of Internal Medicine, and the Central

Arkansas Veterans Healthcare System at the

University of Arkansas for Medical Sciences,

Little Rock. Address reprint requests to

Dr. Weinstein at the Division of Endocrinol-

ogy and Metabolism, University of Arkansas

for Medical Sciences, 4301 W. Markham St.,

Slot 587, Little Rock, AR 72205-7199, or at

weinsteinroberts@43e7f582af1ffc4fff47accc.

N Engl J Med 2011;365:62-70.Copyright ? 2011 Massachusetts Medical Society.

A 55-year-old woman with severe, persistent asthma requiring glucocorticoid thera-

py for the past 3 months presents for care. Her medications include albuterol, inhaled

fluticasone with salmeterol, montelukast, and prednisone (at a dose of 10 mg per

day). In the past, she received several intermittent courses of prednisone at a dose of

15 mg or more per day. Her weight is 45.5 kg (100 lb), and her height 157.5 cm (62 in.);

the body-mass index (the weight in kilograms divided by the square of the height in

meters) is 18. Scattered wheezing is heard during expiration. Findings on vertebral

percussion and rib-cage compression are unremarkable. How should her case be

evaluated and managed to minimize the risk of fractures?

The Clinical Problem

Glucocorticoid therapy is the most common cause of secondary osteoporosis and the leading iatrogenic cause of the disease.1-3 Often, the presenting manifestation is fracture, which occurs in 30 to 50% of patients receiving long-term glucocorticoid therapy.4 Glucocorticoid-induced osteoporosis predominantly affects regions of the skeleton that have abundant cancellous bone, such as the lumbar spine and proximal femur. In patients with glucocorticoid-induced osteoporosis, the loss of bone min-eral density is biphasic; it occurs rapidly (6 to 12% loss) within the first year and more slowly (approximately 3% loss yearly) thereafter.5 However, the risk of fracture escalates by as much as 75% within the first 3 months after the initiation of therapy, typically before there is a substantial decline in bone mineral density, suggesting that there are adverse effects of glucocorticoids on bone that are not captured by bone densitometry.6 Several large case–control studies have shown strong associa-tions between exposure to glucocorticoids and the risk of fractures.4,6,7 An increase in the risk of vertebral and hip fractures occurs rapidly after the start of treatment and has been reported to occur with doses as small as 2.5 to 7.5 mg of prednisolone per day (equivalent to 3.1 to 9.3 mg of prednisone per day). In a cohort study involv-ing patients 18 to 64 years of age, continuous treatment with 10 mg of prednisone per day for more than 90 days, for a variety of indications, as compared with no ex-posure to glucocorticoids, was associated with an increase in hip fractures by a fac-tor of 7 and an increase in vertebral fractures by a factor of 17.7 Furthermore, an increase in the risk of fractures has been reported with the use of inhaled glucocor-ticoids, as well as with alternate-day and intermittent oral regimens.3

Risk Factors

Risk factors associated with glucocorticoid-induced osteoporosis are listed in Table 1. One factor whose importance has been recognized in the past decade is the activity of the 11β-hydroxysteroid dehydrogenase (11β-HSD) system, a prereceptor modula-tor of glucocorticoid action.11 Two isoenzymes, 11β-HSD1 and 11β-HSD2, catalyze

The New England Journal of Medicine

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clinical practice

n engl j med 365;1 43e7f582af1ffc4fff47accc july 7, 2011

63conversion between hormonally active glucocorti-coids (e.g., cortisol or prednisolone) and inactive glucocorticoids (e.g., cortisone or prednisone). The 11β-HSD1 enzyme is an activator, and the 11β-HSD2 enzyme is an inactivator. The increased risk of fracture with glucocorticoid administra-tion in the elderly may be explained in part by the increase in 11β-HSD1 that occurs with aging. The risk of glucocorticoid-induced osteoporosis appears to be similar in men and women and among var-ious ethnic groups.13Pathogenesis Histomorphometric studies in patients with gluco-corticoid-induced osteoporosis consistently show fewer osteoblasts and an increased prevalence of osteocyte apoptosis, as compared with normal con-trols 1,3,4,14,15 (Fig. 1). The increased osteocyte apop-tosis is associated with decreases in vascular en-dothelial growth factor, skeletal angiogenesis, bone interstitial fluid, and bone strength.16 Thus, glu-cocorticoid-induced apoptosis of osteocytes could account for the loss of bone strength that occurs before the loss of bone mineral density 17 and the observed mismatch between bone mineral density and the risk of fracture in patients with glucocor-ticoid-induced osteoporosis.3,4 Gluco c orticoid ex-cess also directly reduces osteoclast production, but the lifespan of osteoclasts is prolonged, in contrast to the decrease in the lifesp …… 此处隐藏：35047字，全部文档内容请下载后查看。喜欢就下载吧 ……