Despite the recognition that glucocorticoids can cause bone loss and fractures, many patients receiving, or being considered for, long- term glucocorticoid therapy are not evaluated for their skeletal health [2] .
Fractures occur more frequently at sites enriched in cancellous bone, such as the vertebrae and femoral neck. As with vertebral fractures occurring in postmenopausal osteoporosis, vertebral fractures associated with glucocorticoid therapy or endogenous hypercortisolism often are asymptomatic, in which case a radiological approach with morphometric analysis is often necessary, as is the case with many causes of secondary osteoporosis. Vertebral fractures occur early after exposure to glucocorticoids, at a time when BMD declines rapidly. However, a direct relationship between BMD and fracture risk in GIO has not been established. It is likely to be different from that established in postmenopausal osteoporosis because fractures in GIO occur at higher BMD values. This point has to be considered when making treatment decisions in GIO, since therapeutic intervention should be considered at T- scores that may be in the osteopaenic range.
Trabecular bone score (TBS) provides an indirect index of trabecular bone architecture that can be obtained from bone densitometry (DXA) images of the lumbar spine, and has predictive value for fracture independent of BMD. In postmenopausal women exposed to glucocorticoid excess, TBS was significantly lower as compared to control subjects, notwithstanding comparable BMD T- scores. Interestingly, decreases in TBS are substantial in individuals with fractures, supporting the concept that TBS values may be useful for predicting fractures in this clinical setting. A more direct measurement of bone architecture and strength can be provided by high- resolution peripheral computed tomography, but data in subjects with exogenous and endogenous GIO using this approach are sparse.
Fracture Risk Assessment (FRAX), an algorithm that calculates the 10- year probability of major osteoporotic and hip fractures, can be used to estimate fracture risk in GIO. However, its value was initially limited by the fact that the use of glucocorticoids is entered as a dichotomous risk factor without considering the dose or length of exposure to glucocorticoids. Ways to correct for this limitation have been proposed, but this modification has not been rigorously tested. Another confounder to the utility of FRAX in the context of glucocorticoid exposure is the use of the femoral neck BMD which may result in underestimation of fracture risk in patients with differentially low spine BMD. A correction factor for this discordance when there is a greater than a 1 T- score difference between lumbar spine and femoral neck BMD has been proposed. Assessment of fracture risk using FRAX is recommended in several guidelines for the management of GIO, including those from the National Osteoporosis Guideline Group (NOGG), the updated recommendations by the American College of Rheumatology (ACR) and those published by the International Osteoporosis Foundation (IOF) and the European Calcified Tissue Society (ECTS). However, FRAX can be used only in individuals at age 40 and older. In children and young adults, fracture risk assessment should be performed using BMD measurement, together with consideration of other risk factors, particularly previous fractures. It should also be recognized that in children and young adults, their young age is a powerful protection against what otherwise in older subjects would be substantial fracture risk. Based on radiological/ historical assessment of prevalent fractures, glucocorticoid dose, age of patients, BMD values, and FRAX calculations, the guidelines proposed a stratification of fracture risk in GIO for identifying patients for whom treatment with bone- active drugs is cost- effective and indicated (Table 1). It is unclear whether these algorithms may simplify the approach to the prevention and treatment of GIO in real- life clinical practice.
Table1. Criteria proposed for starting treatment with bone- active drugs in patients exposed to glucocorticoid treatment
The guidelines recommend evaluation of calcium metabolism in all subjects in order to select those for whom vitamin D and/ or calcium supplementation are indicated [58]. The role of biochemical markers of bone turnover in the diagnostic work- up in GIO has not been established, and their levels vary and are dependent on the different stages of the disease. Following the initial exposure to glucocorticoids, there is an increase in biochemical markers of bone resorption, which is followed by a prolonged suppression of markers of bone formation and bone resorption.
The assessment of gonadal function may be useful for the sub sequent treatment of GIO. In men receiving glucocorticoids, low total and free- testosterone concentrations are frequently found. Combined with low or normal serum gonadotropin levels, such low testosterone levels are likely to be as manifestation of secondary hypogonadism.
