Clinical review 151: The role of parathyroid hormone in the pathogenesis of glucocorticoid-induced osteoporosis: a re-examination of the evidence

One of the most important of the secondary causes of osteoporosis is chronic exposure to glucocorticoids, which are used for an extraordinarily large number of disorders. The adverse effects of hypercortisolism on bone metabolism were recognized more than half a century ago (1). Today, glucocorticoid exposure in the context of medicinal use has become far more common than excess endogenous exposure (Cushing’s syndrome). Glucocorticoid-induced osteoporosis (GIO) is the third most common cause of osteoporosis, trailing only postmenopausal and age-related osteoporosis (2). As many as 50% of individuals on chronic glucocorticoid therapy will suffer an osteoporotic fracture (3). Recently, a large-scale retrospective cohort study by Van Staa et al. (4) in England clearly demonstrated that fracture risk is increased across virtually the entire dosage range of oral glucocorticoids. A large number of subjects with a history of glucocorticoid exposure (n 244,235) were matched to the same number of control patients who had no history of glucocorticoid exposure. The average age of the subjects was 57 yr; respiratory diseases were the common indication for therapy, being prescribed in 40% of the patients (4). Referent to nonglucocorticoid users, subjects with a history of glucocorticoid therapy had significantly greater risk for fractures at the spine (rr 2.6), the hip (rr 1.6), and at any nonvertebral site (rr 1.3). The magnitude of the fracture risk was directly related to dosage, with subjects receiving as little as 2.5 mg of prednisolone at significantly greater risk than control subjects (4). Bone loss from glucocorticoid use was also found to occur rapidly, within the first 3 months of treatment. A similarly precipitous loss of bone mass has also been observed prospectively when glucocorticoids are used in the setting of organ transplantation (5, 6), and in other clinical situations (7–10). Even inhaled steroids have been implicated as a cause of bone loss (11, 12). The cardinal feature of GIO on skeletal dynamics is a reduction in bone formation. Bone formation is inhibited, in part, through a decrease in osteoblast life span and function. Histomorphometric studies demonstrate a marked reduction in indices of bone formation, such as reduced mineral apposition rate and prolonged mineralization lag time. The amount of bone that is replaced in each remodeling cycle can be reduced by as much as 30% (13–17). Biochemical markers of bone formation, osteocalcin and bone-specific alkaline phosphatase, are suppressed. In addition to this primary suppressive effect on bone formation, glucocorticoids also induce an early phase of accelerated bone resorption (18). Osteoclast number and activity increase, along with an increase in the fraction of eroded bone surface (14, 15). Biochemical markers of bone resorption, urinary N-telopeptide and pyridinoline cross-link excretion, rise during early glucocorticoid exposure (17, 19, 20). This early phase of glucocorticoid use, therefore, can be associated with rapid bone loss due to both reduced bone formation and accelerated bone resorption. With continued use of glucocorticoids, the rapid rate of osteoclast-mediated bone resorption slows (14), but suppression of bone formation continues as the dominant skeletal dynamic. Thus, bone loss is progressive because bone resorption chronically exceeds bone formation. Although bone loss due to glucocorticoid use tends to be diffuse, the axial skeleton is targeted preferentially. The cancellous bones of the vertebral spine are typically affected, whereas cortical bone sites of the appendicular skeleton (i.e. forearm) are affected to a lesser extent (21, 22). Spontaneous fractures of the vertebrae or ribs are common complications of GIO (23).