LAUSR

We read with great interest the study by Braun and colleagues regarding the natural course of bone turnover markers (BTMs) after biochemical remission in endogenous Cushing’s syndrome (CS). In this study, the documentation of increased (net) bone formation over 1 to 2 years post-remission and its association with improved bone mineral density (BMD) supports the wait-andwatch policy for the management of bone fragility in CS. After biochemical remission of CS, the BTM response was similar to the anabolic window found with teriparatide use, where bone formation is uncoupled to bone resorption (rise in formation markers much greater than resorption markers in the first follow-up year). This could be explained by the release of osteoblast-proliferating genes like Runx2 from the chronic inhibitory effects of excess glucocorticoids. Furthermore, the study promotes osteocalcin (OC) as a diagnostic tool for CS (Table 2: results of the regression analysis). Given the high prevalence of low BMD/osteoporosis in endogenous CS, the prospect of OC assisting in the diagnosis of CS is appreciated. However, upon careful analysis of the article, we were able to discern certain irregularities in themethods and interpretation of the results. First, the maximum improvement in BMD (femoral neck 4%; Table 5) did not exceed the least significant change (5.04%) of the dual-energy X-ray absorptiometry (DXA) machine, so how can the authors then conclude that there is net increase in BMD post-remission? Also, the name and version of the DXA machine and the thresholds for low BMD are not mentioned. Second, hypogonadism and other hormone deficiencies due to endogenous CS, menopause, and/or pituitary surgery can affect bone turnover/metabolism and could be incorporated in baseline parameters and the regression analysis. Also, nonimprovement of BMD in some patients post-remission could be explained by menopause, persistent hypogonadism, or growth hormone deficiency. Third, the results would gain reliability if the improvements in BTMs (particularly formation markers) could be correlated with BMD change at both years of followup. Fourth, although OC was unequivocally low in cases of CS, it could have been adjusted for the presence/absence of dysglycemia (30% in CS group), as high glucose/HbA1c is associated with low OC. Fifth, while the authors highlight the pre-surgery fragility fractures, they only write about clinical fractures postremission, when it is known that fragility fractures are often diagnosed incidentally on radiographs. The authors could perform follow-up radiographs in patients previously having fragility fractures. These results (if consistent on suitable modifications) show that the skeletal system holds immense power to regenerate from months/years of chronic glucocorticoid excess. However, it is not possible to determine whether the bone attains its predisease mass completely. The use of bone-specific treatment(s) in such a scenario should be avoided unless there is high risk of a major osteoporotic fracture or multiple fractures. For the latter group of patients, prolonging the natural anabolic window after biochemical remission with antiresorptive drugs could be an exciting therapeutic option. Further studies can aim to correlate improvements in BTMs with volumetric BMD gain in patients of CS in biochemical remission.