Glucocorticoid-induced osteoporosis: an update

doi:10.1016/j.tem.2006.03.009

Trends in Endocrinology & Metabolism

Volume 17, Issue 4, May 2006, Pages 144-149

https://doi.org/10.1016/j.tem.2006.03.009 Get rights and content

Glucocorticoid-induced osteoporosis occurs in two phases: a rapid, early phase in which bone mineral density is reduced, possibly as a result of excessive bone resorption, and a slower, progressive phase in which bone mineral density declines because of impaired bone formation. Although the indirect effects of glucocorticoids on bone are evident, their direct effects on osteoblasts, osteoclasts and osteocytes are primarily operative in the pathogenesis of glucocorticoid-induced osteoporosis. The management of patients exposed to glucocorticoids includes general health measures, sufficient calcium and vitamin D, and reducing the therapeutic regimen to the minimal effective dose. The gold standard in the pharmacological treatment of glucocorticoid-induced osteoporosis in postmenopausal women involves the use of bisphosphonates, which should be started soon after beginning chronic glucocorticoid therapy. Anabolic and alternative therapeutic strategies are currently under investigation in glucocorticoid-induced osteoporosis.

Introduction

Although the adverse effects of glucocorticoids (GCs) on the skeleton have been known for over 70 years, attention to GC-induced osteoporosis (GIO) has increased dramatically in recent decades with the widespread use of synthetic GCs in the treatment of autoimmune, pulmonary and gastrointestinal disorders, as well as in patients after organ transplantation and with neoplastic diseases 1, 2, 3, 4, 5. Bone loss with risk of fractures resulting from GC therapy is a relatively common disorder, and it is the most prevalent form of secondary osteoporosis. However, studies have suggested that often patients receiving GC therapy are not routinely considered to be at risk for bone loss [6]. Recently, several studies have helped to clarify the mechanisms responsible for GIO, highlighting the molecular events occurring in skeletal cells 7, 8.

This article focuses on newer molecular aspects of GIO and selected clinical topics and is based on presentations that were held at the 4th International Congress on GIO in Trieste, Italy, October 2005.

Section snippets

Indirect effects of GCs on bone

In human subjects, GIO occurs in two phases: a rapid, early phase in which bone mineral density (BMD) falls, possibly as a result of excessive bone resorption, and a slower, more progressive phase in which BMD declines because of impaired bone formation [4]. In the presence of GCs, calcium absorption from the gastrointestinal tract is inhibited by mechanisms that oppose vitamin D action. Renal tubular calcium reabsorption is also inhibited by GCs. As a consequence of these effects, secondary

Epidemiological aspects

Fractures occur in 30–50% of patients on chronic GC therapy [5]. The incidence of vertebral and nonvertebral fractures is related to the dose and duration of GC exposure, although fractures can also be observed with doses as low as 2.5–7.5 mg of prednisone equivalents per day 2, 29. Fracture risk declines after discontinuation of GCs [2]. Patients receiving more than 10 mg of prednisone equivalents per day, continuously rather than sporadically, and for a period as long as 90 days, had a

BMD measurement: when to perform, how to perform and how to interpret the results in terms of fracture risk

Some guidelines recommend that a BMD measurement should be made in individuals starting on GC therapy [5]. Although it is appropriate to measure BMD in subjects receiving GCs, therapeutic intervention thresholds to prevent fractures are different from those established for postmenopausal osteoporosis 34, 35, 36. For a typical postmenopausal Caucasian population, the densitometric threshold below which most authoritative bodies recommend treatment is a T-score of −2.5 standard deviation (sd)

Therapeutic aspects

Guidelines published by the American College of Rheumatology (ACR) and the Royal College of Physicians advocate the following measures for the prevention and treatment of GIO: general health awareness, administration of sufficient calcium and vitamin D, reduction of the dose of corticosteroids to a minimum and, when indicated, therapeutic intervention with bisphosphonates and other agents [5]. The ultimate goal is to prevent fractures. Appropriate prevention measures include intake of calcium

Future approaches

An understanding of the mechanisms involved in the skeletal effects of PTH has led to the identification of a new protein, sclerostin, a bone morphogenetic protein antagonist produced by osteocytes. This protein acts as a negative regulator of bone formation through selective control of apoptosis of bone cells 60, 61. Interest in this protein derives from the observation that individuals with a deficiency in sclerostin have an increase in BMD 62, 63. Indeed, there is evidence that the

Conclusions

GIO is the most common form of drug-induced osteoporosis. The clinical impact of this disease is related to the high prevalence of osteoporotic fractures with associated impairment of quality of life. The recent increase in the understanding of the cellular mechanisms responsible for GIO should help in the quest for effective new therapeutic strategies.

Acknowledgements

This work was in part supported by grants DK45227 from the National Institutes of Health. The authors wish to thank the ‘Centro di Ricerca sull'Osteoporosi’, University of Brescia, EULO and GISGO.

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Citation Excerpt :
However, glucocorticoids cause serious adverse effects on the skeletal system that is undergoing robust modeling [1]. Moreover, glucocorticoid-induced osteoporosis is known as secondary osteoporosis [2]. The pivotal role of cellular senescence has been well documented in different types of bone loss [3].
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Trends in Endocrinology & Metabolism

Glucocorticoid-induced osteoporosis: an update

Introduction

Section snippets

Indirect effects of GCs on bone

Epidemiological aspects

BMD measurement: when to perform, how to perform and how to interpret the results in terms of fracture risk

Therapeutic aspects

Future approaches

Conclusions

Acknowledgements

Trends Endocrinol. Metab.

Bone

Endocrinol. Metab. Clin. North Am.

Chest

Cytokine

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Bone

Autoimmun. Rev.

J. Biol. Chem.

Trends Endocrinol. Metab.

J. Biol. Chem.

Use of oral corticosteroids and risk of fractures

J. Bone Miner. Res.

Glucocorticoid-induced osteoporosis: summary of a workshop

J. Clin. Endocrinol. Metab.

Patient knowledge, beliefs, and behavior concerning the prevention and treatment of glucocorticoid-induced osteoporosis

Arthritis Rheum.

Mechanisms of glucocorticoid action in bone

Curr Osteoporos Rep.

Glucocorticoid-induced osteoporosis: from basic mechanisms to clinical aspects

Neuroimmunomodulation

Chronic glucocorticoid treatment alters spontaneous pulsatile parathyroid hormone secretory dynamics in human subjects

Eur. J. Endocrinol.

The role of glucocorticoids in the regulation of growth hormone secretion. Mechanisms and clinical significance

Trends Endocrinol. Metab.

Glucocorticoid suppression of IGF I transcription in osteoblasts

Mol. Endocrinol.

Growth hormone in glucocorticoid-induced osteoporosis

Front. Horm. Res.

Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength

Endocrinology

Prevention of glucocorticoid-induced apoptosis in osteocytes and osteoblasts by calbindin-D28k

J. Bone Miner. Res.

Caspases: enemies within

Science

Bone morphogenetic protein-2 restores mineralization in glucocorticoid-inhibited MC3T3-E1 osteoblast cultures

J. Bone Miner. Res.

Bone morphogenetic proteins

Growth Factors

Sensitivity of bone to glucocorticoids

Clin. Sci.

The ER22/23EK polymorphism in the glucocorticoid receptor gene is associated with a beneficial body composition and muscle strength in young adults

J. Clin. Endocrinol. Metab.

11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response

Endocr. Rev.

11beta-Hydroxysteroid dehydrogenase expression and glucocorticoid synthesis are directed by a molecular switch during osteoblast differentiation

Mol. Endocrinol.

Mice deficient in 11beta-hydroxysteroid dehydrogenase type 1 lack bone marrow adipocytes, but maintain normal bone formation

Endocrinology

Oral glucocorticoid use is associated with an increased risk of fracture

Osteoporos. Int.