Calcium- phosphate homeostasis is usually impaired in patients ex posed to glucocorticoid excess. Glucocorticoids impair the com plex process of transcellular calcium absorption in the duodenum which is regulated by the epithelial Receptor Potential– Vanilloid 6 (TRPV6) and TRPV5 (D ECaC1) and then by calcium binding calbindin- D9K. Moreover, glucocorticoids inhibit renal tubular calcium reabsorption favouring calcium renal loss, leading to negative calcium balance. In addition to these effects on calcium metabolism, glucocorticoids elicit phosphaturia by reducing tubular reabsorption of phosphate through antagonism of the tubular ex pression of the sodium gradient- dependent phosphate transporter. The abnormalities of calcium- phosphate homeostasis in GIO may be favoured by the effects of glucocorticoids on vitamin D metabolism and activity. Glucocorticoids do not directly compete with 1,25- dihydroxyvitamin D binding to its receptor, but rather regulate vitamin D receptor expression. Prolonged exposure to glucocorticoids was associated with diminished expression of duodenal vitamin D receptor which in turn causes a` decrease in transcription of duodenal calbindin- D9K, TRPV5, or TRPV6 activity. Glucocorticoids also modulate vitamin D metabolism with a de crease of 1α- hydroxylase and an increase in 24- hydroxylase activity. Moreover, glucocorticoids inhibit hydroxylation of vitamin D3 in the liver which can lead to reduced plasma 25- hydroxyvitamin D levels.
Parathyroid hormone (PTH) and the PTH receptor play a major role in regulating calcium homeostasis. PTH regulates the con version of 25- hydroxyvitamin D to the active metabolite 1,25- dihydroxyvitamin D. PTH activates dihydropyridine- sensitive channels that mediate calcium entry into the cell. 1,25- dihydroxyvitamin D inhibits PTH secretion and parathyroid cell proliferation via the vitamin D receptor. PTH secretion is regulated by serum ionized calcium levels. While negative calcium balance is expected to cause a secondary hyperparathyroidism in GIO, glucocorticoids do not induce hypertrophy of parathyroid glands in experimental animals [36]. Moreover, fasting PTH values are not consistently reported to be increased in patients exposed to glucocorticoid excess. Perhaps more revealing than static measurements of PTH after glucocorticoid exposure are studies related to the pulsatility of PTH. Chronic glucocorticoid exposure is associated with a redistribution of spontaneous PTH secretory dynamics by reducing tonic and amplifying pulsatile secretion of PTH. This finding may be clinically relevant since it can represent either a compensatory or a pathophysiological mechanism.
Glucocorticoids modulate growth hormone secretion (GH) by various and competing effects on the hypothalamus and pituitary gland, all dependent on hormone concentrations and time of exposure. Specifically, under physiological conditions, glucocorticoids stimulate GH secretion either by direct effects on pituitary cells or by increasing their GH secretory response to GH- releasing hormone. However, when glucocorticoid levels exceed the physiological range, an increase in hypothalamic somatostatin tone may occur with a consequent impairment of GH secretion. This inhibitory effect on pituitary GH secretion was observed even when glucocorticoid excess was mild, as in patients treated with inhaled corticosteroids and in those with subclinical endogenous hypercortisolism. Moreover, glucocorticoid excess may suppress the peripheral expression of GH receptors impairing the GH- mediated synthesis of IGF- 1 and thus amplifying the impact of a functional GH deficiency (GHD) on target tissues. On the other hand, there is a cross- talk between glucocorticoids and the GH- IGF- I axis, since peripheral metabolism of glucocorticoids by 11- βHSD is modulated by GH and activation of cortisone to cortisol in target tissues is amplified by GHD. The real impact of GHD on fracture risk in GIO is largely unknown. However, since GH is an osteoanabolic hormone, one could argue that GHD may contribute to the impairment in bone quality in patients exposed to glucocorticoid excess. As a matter of fact, both exposure to glucocorticoid excess and GHD are associated with ‘low- turnover osteoporosis’ and high risk of vertebral fractures.
Glucocorticoids inhibit the release of gonadotropins, and as a result oestrogen and testosterone production. Central hypogonadism may contribute to bone loss and fractures in GIO not only via negative effects on bone mass but also on muscle function. In particular, hypogonadism may enhance the glucocorticoid- induced sarcopenia, thereby increasing the likelihood of falls and consequent fractures.
