Glucocorticoids and bone: consequences of endogenous and exogenous excess and replacement therapy

Osteoporosis associated with long-term glucocorticoid therapy remains a common and serious bone disease. In addition, in recent years it has become clear that more subtle states of endogenous glucocorticoid excess may have a major impact on bone health. Adverse effects can be seen with mild systemic glucocorticoid excess but there is also evidence of tissue-specific regulation of glucocorticoid action within bone as a mechanism of disease. This review article will examine a) the role of endogenous glucocorticoids in normal bone physiology, b) the skeletal effects of endogenous glucocorticoid excess in the context of endocrine conditions such as Cushing’s disease/syndrome and autonomous cortisol secretion (subclinical Cushing’s syndrome), and c) the actions of therapeutic (exogenous) glucocorticoids on bone. We will review the extent to which the effect of glucocorticoids on bone is influenced by variations in tissue metabolising enzymes and glucocorticoid receptor expression and sensitivity. We will consider how the effects of therapeutic glucocorticoids on bone are complicated by the effects of the underlying inflammatory disease being treated. We will also examine the impact that glucocorticoid replacement regimens have on bone in the context of primary and secondary adrenal insufficiency. We conclude that even subtle excess of endogenous or moderate doses of therapeutic glucocorticoids are detrimental to bone. However in patients with inflammatory disorders there is a complex interplay between glucocorticoid treatment and underlying inflammation, with the underlying condition frequently representing the major component underpinning bone damage.