Elsevier

Joint Bone Spine

Volume 70, Issue 2, 1 April 2003, Pages 109-118
Joint Bone Spine

Review article
Glucocorticoid-induced osteoporosis: pathophysiological data and recent treatments

https://doi.org/10.1016/S1297-319X(03)00016-2Get rights and content

Abstract

Long-term glucocorticoid therapy promptly induces osteoporosis, whose severity depends on the dose and duration of the treatment. Recent data suggest that there is no safety threshold for adverse effects on bone. Glucocorticoid therapy impairs calcium intestinal absorption, dramatically suppresses osteoblastic formation, and stimulates osteocyte apoptosis. In contrast, the contribution of secondary hyperparathyroidism and increased bone resorption, although frequently mentioned, is now a focus of controversy. Beneficial effects on bone have been obtained with calcium and vitamin D supplementation, as well as with hormone replacement therapy (HRT) in postmenopausal women. Bisphosphonates are clearly effective in preventing and treating glucocorticoid-induced osteoporosis, although their mechanism of action in this condition remains poorly understood. Parathyroid hormone (PTH) is being evaluated as a potential therapeutic agent for glucocorticoid-induced osteoporosis.

Introduction

Recent American College of Rheumatology (ACR) recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis [1] point out that the knowledge and management of glucocorticoid-induced osteoporosis varies widely across physicians. In the United States, awareness of this classic complication of long-term glucocorticoid therapy is greatest among pneumologists and rheumatologists [2]. A study in Canadian rheumatologists found that selection of preventive measures was based mainly on patient’s age and sex, whereas selection of curative treatment was based on bone mineral density (BMD) [3]. In general, the level of information seems to play a prominent part in the attitude of physicians toward glucocorticoid-induced osteoporosis. Recent data in the literature are generating new and hotly debated pathophysiological hypotheses and are suggesting new treatment methods.

Section snippets

Clinical data

Long-term glucocorticoid therapy induces bone loss, thereby increasing the fracture risk. It is the most common cause of secondary osteoporosis [4]. The rate of bone loss is highest (5-15%) during the first 6 months of treatment and slows subsequently to about 2% per year. Trabecular bone is more severely affected than is cortical bone. The extent of bone loss varies with the dose and duration of glucocorticoid therapy; classically, bone loss is significant when the daily dose is 7.5 mg or more

Pathophysiology

The effects of glucocorticoids on bone tissue are complex. The mechanisms that underlie glucocorticoid-induced osteoporosis remain poorly elucidated and controversial (Fig. 2). Models in large animals, such as pigs [15] and ewes [16], more closely replicate the human disease than does the glucocorticoid rat model. This has contributed in part to the paucity of information on glucocorticoid-induced osteoporosis [17], [18].

Vitamin D and calcium

Sound evidence indicates that calcium supplementation alone fails to prevent the bone loss induced by glucocorticoid therapy [80], [81], [82]. Conversely, combined calcium and vitamin D supplementation seems effective. In a 2-year randomized study, Buckley et al. [83] found that calcium and vitamin D supplementation prevented bone loss at the spine and greater trochanter in patients receiving glucocorticoid therapy for rheumatoid arthritis (mean dose, 5.6 mg/d). The rates of bone loss at the

Conclusions

Long-term glucocorticoid therapy (for longer than 3 months) is associated with rapid bone loss and bone quality deterioration. The best management consists in preventive measures initiated at the start of glucocorticoid treatment. Routine calcium and vitamin D supplementation is now widely accepted. Bisphosphonate therapy remains controversial. In patients with a negative history for fractures, the decision to use bisphosphonates is based on age and sex, the glucocorticoid dose, and menopausal

References (116)

  • A.M Delany et al.

    Cortisol increases interstitial collagenase expression in osteoblasts by post-transcriptional mechanisms

    J Biol Chem

    (1995)
  • B.P Lukert et al.

    Glucocorticoid-induced osteoporosis

    Rheum Dis Clin North Am

    (1994)
  • D Morrison et al.

    Testosterone levels during systemic and inhaled corticosteroid therapy

    Respir M

    (1994)
  • S.J Wimalawansa et al.

    Prevention of corticosteroid-induced bone loss with nitric oxide donor nitroglycerin in male rats

    Bone

    (1997)
  • S Adami et al.

    The prevention of corticosteroid-induced osteoporosis with nandrolone decanoate

    Bone Miner

    (1991)
  • R.F Van Vollenhoven

    Dehydroepiandrosterone in systemic lupus erythematosus

    Rheum Dis Clin North Am

    (2000)

  • Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology ad hoc committee on glucocorticoid-induced osteoporosis

    Arthritis Rheum

    (2001)
  • L.M Buckley et al.

    Variations in physicians' judgments about corticosteroid induced osteoporosis by physician specialty

    J Rheumatol

    (1998)
  • E Soucy et al.

    A Canadian survey on the management of corticosteroid induced osteoporosis by rheumatologists

    J Rheumatol

    (2000)
  • C.E McEvoy et al.

    Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease

    Am J Respir Crit Care M

    (1998)
  • T.P Van Staa et al.

    Use of oral corticosteroids and risk of fractures

    J Bone Miner Res

    (2000)
  • K Fujita et al.

    Inhaled corticosteroids reduce bone mineral density in early postmenopausal but not premenopausal asthmatic women

    J Bone Miner Res

    (2001)
  • J.A Hughes et al.

    One-year prospective open study of the effect of high dose inhaled steroids, fluticasone propionate, and budesonide on bone markers and bone mineral density

    Thorax

    (1999)
  • R.A Pauwels et al.

    Safetyand efficacy of fluticasone and beclomethasone in moderate to severe asthma. Belgian Multicenter Study Group

    Am J Respir Crit Care M

    (1998)
  • M Luengo et al.

    Vertebral fractures in steroid dependent asthma and involutional osteoporosis: a comparative study

    Thorax

    (1991)
  • N.F Peel et al.

    Risk of vertebral fracture and relationship to bone mineral density in steroid treated rheumatoid arthritis

    Ann Rheum Dis

    (1995)
  • L Dalle Carbonare et al.

    Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis

    J Bone Miner Res

    (2001)
  • D Chappard et al.

    Altered trabecular architecture induced by corticosteroids: a bone histomorphometric study

    J Bone Miner Res

    (1996)
  • K.E Scholz-Ahrens et al.

    Bone mineral density and trabecular structure in steroid-induced osteoporosis in minipigs

    J Bone Miner Res

    (2000)
  • C.S King et al.

    Effects of continuous glucocorticoid infusion on bone metabolism in the rat

    Calcif Tissue Int

    (1996)
  • A Voulgaris et al.

    Effect of low-dose methylprednisolone on calcium balance and bone composition in rats

    J Endocrinol Invest

    (1997)
  • R.G Klein et al.

    Intestinal calcium absorption in exogenous hypercortisonism. Role of 25-hydroxyvitamin D and corticosteroid dose

    J Clin Invest

    (1977)
  • F Cosman et al.

    High-dose glucocorticoids in multiple sclerosis patients exert direct effects on the kidney and skeleton

    J Bone Miner Res

    (1994)
  • J.E Zerwekh et al.

    Low-dose prednisone therapy in rheumatoid arthritis: effect on vitamin D metabolism

    Arthritis Rheum

    (1984)
  • T.J Hahn et al.

    Effects of short term glucocorticoid administration on intestinal calcium absorption and circulating vitamin D metabolite concentrations in man

    J Clin Endocrinol Metab

    (1981)
  • J.J Braun et al.

    Short-term effect of prednisone on serum 1,25-dihydroxyvitamin D in normal individuals and in hyper- and hypoparathyroidism

    Clin Endocrinol (Oxford)

    (1982)
  • C Gennari et al.

    Effects of prednisone and deflazacort on mineral metabolism and parathyroid hormone activity in humans

    Calcif Tissue Int

    (1984)
  • P Lakatos et al.

    Prevention of corticosteroid-induced osteoporosis by alfacalcidol

    Z Rheumatol

    (2000)
  • E Paz-Pacheco et al.

    Intact parathyroid hormone levels are not elevated in glucocorticoid-treated subjects

    J Bone Miner Res

    (1995)
  • G Pearce et al.

    Corticosteroid-induced bone loss in men

    J Clin Endocrinol Metab

    (1998)
  • A.T Hattersley et al.

    The effect of long-term and short-term corticosteroids on plasma calcitonin and parathyroid hormone levels

    Calcif Tissue Int

    (1994)
  • H.K Nielsen et al.

    The effects of high-dose glucocorticoid administration on serum bone gamma carboxyglutamic acid-containing protein, serum alkaline phosphatase and vitamin D metabolites in normal subjects

    Bone Miner

    (1988)
  • E.O Abu et al.

    The localization of the functional glucocorticoid receptor alpha in human bone

    J Clin Endocrinol Metab

    (2000)
  • H Kaji et al.

    Dexamethasone stimulates osteoclast-like cell formation by directly acting on hemopoietic blast cells and enhances osteoclast-like cell formation stimulated by parathyroid hormone and prostaglandin E2

    J Bone Miner Res

    (1997)
  • G Gronowicz et al.

    Glucocorticoids stimulate resorption in fetal rat parietal bones in vitro

    J Bone Miner Res

    (1990)
  • J Tobias et al.

    Glucocorticoids impair bone resorptive activity and viability of osteoclasts disaggregated from neonatal rat long bones

    Endocrinology

    (1989)
  • D.W Dempster et al.

    Glucocorticoids inhibit bone resorption by isolated rat osteoclasts by enhancing apoptosis

    J Endocrinol

    (1997)
  • L.C Hofbauer et al.

    Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis

    Endocrinology

    (1999)
  • T Thomas et al.

    Contribution of genetically modified mouse models to the elucidation of bone physiology

    Rev Rhum Engl

    (1999)
  • L.D Quarles

    Prednisone-induced osteopenia in beagles: variable effects mediated by differential suppression of bone formation

    Am J Physiol

    (1992)

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