It has been suspected for some time, that secondary osteoporosis and bone fractures in postmenopausal women depend to a certain extent on glucocorticosteroids. The primary glucocorticoid in women is cortisol. It is produced by the body internally, or can be administered by ointments (prednisolone) or other routes as a treatment for some conditions. It was shown in the literature that increased incidence of fractures has been described in patients on daily doses as low as 2.5 mg prednisolone equivalents. Bone fractures were shown to be enhanced for patients with Cushing’s syndrome. In one of the studies vertebral fractures occurred in more than half of women with subclinical hypercortisolism due to adrenal incidentaloma.
Cortisol and Bone
Cortisol exerts direct and indirect effects on bone, enhancing its resorption first and then inhibiting its formation. The direct effect is such that cortisol affects mesenchymal cells not to differentiate into osteoblasts (bone cells), but to turn into the cells of adipocytic pathway instead. It also induces apoptosis (programmed cell death) for osteoblasts. Cortisol excess reduces the production of growth factors and bone matrix proteins, and decreases calcium absorption. All these effects contribute to reduced bone resistance and quality. Cortisol excess could also have an effect on estrogens causing their reduction and leading in some cases to amenorrhea, the lack of menstrual cycle.
Having all that information, a group of scientists from Naples, Italy decided to answer the question on how bone density and possible bone fractures are related to sex steroids. They selected a group of over 70 women, half of them with hypercortisolism (high cortisol) due to pituitary adenoma, another half also with high cortisol, but due to adrenal incidentalomas. They were compared with 71 matched controls. They have analyzed bone mineral density (BMD) and vertebral fractures in relation to body mass index (BMI), menstrual history, estimated disease duration, levels of serum cortisol (F), testosterone (T), androstenedione, DHEAS, and 17-b-estradiol (E2), and the ratios between serum F, androgens, and E2.
Cortisol, Androgens and BMD
As expected, cortisol and androgen levels, BMD values, and fracture prevalence were significantly different between patients and controls. This study confirmed the lack of any difference in BMD values and fracture rates between adrenal and pituitary overt hypercortisolism in a female population; only DHEAS was significantly higher in women with pituitary Cushing’s.
BMD Correlated with BMI
Higher femoral BMD values were observed in subjects with higher BMI, most likely due to a major mechanical loading (increased weight bearing is correlated with increased bone density). A strong correlation was observed between DHEAS and lumbar/femoral BMD values in healthy women.
Menstrual Cycle Protective against Osteoporosis
Menstrual status was a significant predictor only in the subgroup with subclinical Cushing’s syndrome. Amenorrhoic (no menstrual cycle) women when combined with subclinical hypercortisolism had higher urinary cortisol excretion suggesting that more severe hypercortisolism may lead to amenorrhea. Both factors can contribute to bone loss in the subclinical setting. Moreover, researchers observed a protective effect of preserved menstrual cycles in this group.
Cortisol to DHEAS Ratio and Vertebral Fractures
In this study, a significantly higher F-to-DHEAS ratio was found to be associated with vertebral fractures. This study also found that patients with cortisol excess were at risk for bone loss and vertebral fractures, regardless of the severity or origin of the excess cortisol. The high prevalence of vertebral fractures observed at the diagnosis of endogenous cortisol excess and their irreversibility highlights the necessity of a very precocious preventive treatment to reduce the detrimental effects of cortisol excess on the bone. The data also suggest that bone demineralization and spinal fractures are frequent at any degree of cortisol excess. Higher BMI and androgen levels appear to counterbalance some of the bone loss observed with hypercortisolism. In addition, preserved menstrual cycles had protective effects only in women with less severe, i.e. subclinical disorder. Women affected by either overt or subclinical hypercortisolism should receive adequate evaluation of bone status and appropriate treatment at the moment of diagnosis of cortisol excess.