The impact of different glucocorticoid replacement schedules on bone turnover and insulin sensitivity in patients with adrenal insufficiency

Objective: Glucocorticoid (GC) therapy is associated with adverse effects on bone metabolism, yet the effects of different GC physiological replacement regimens in hypopituitarism are not well characterised. We aimed to assess the effect of three hydrocortisone (HC) replacement dose regimens on bone turnover. Study design: An open cross-over study randomising ten hypopituitary men with severe ACTH deficiency to three commonly used HC dose regimens: dose A (20 mg mane and 10 mg tarde), dose B (10 mg mane and 10 mg tarde) and dose C (10 mg mane and 5 mg tarde). Methods: Following 6 weeks of each regimen, the participants underwent 24-h serum cortisol sampling and measurement of bone turnover markers: bone-specific alkaline phosphatase, procollagen type I N-propeptide (PINP), intact osteocalcin (OC(1-49)), C-terminal cross-linking telopeptide (CTX-I) and tartrate-resistant acid phosphatase 5b (TRACP5b). Bone remodelling balance was estimated as an absolute ratio (PINP:CTX-I) and as an index using standardised scores derived from the matched controls. Results: There were significant increases in the concentrations of the formation markers PINP (PZ0.045) and OC(1-49) (PZ0.006) and in the PINP:CTX-I ratio (PZ0.015), and a more positive bone remodelling balance index (PZ0.03) was observed in patients on the lowest dose C than in those on the highest dose A. Mean 24-h cortisol concentrations correlated negatively with CTX-I (rZK0.66 and PZ0.04) and TRACP5b (rZK0.74 and PZ0.01) in patients on dose B and with OC(1-49) (rZK0.66 and PZ0.04) and CTX-I (rZK0.81 and P!0.01) in patients on dose C. In patients receiving the lower-dose regimen, trough cortisol concentrations correlated with increased bone formation and resorption. Conclusion: Low-dose HC replacement (10 mg mane and 5 mg tarde) is associated with increased bone formation and a positive bone remodelling balance. This may have a long-term beneficial effect on bone health.

Section: European Journal Of Endocrinologymentioning

confidence: 90%

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Low-dose hydrocortisone replacement therapy is associated with improved bone remodelling balance in hypopituitary male patients

Behan

Kelleher²,

Hannon³

et al. 2014

“…On the one hand, hypopituitary patients on conventional replacement showed higher total plasma glucose and insulin when given glucocorticoid before an oral glucose tolerance test (OGTT), compared with when it was given after the OGTT, with the difference in glucose exposure correlating with the maximal cortisol level (8). On the other hand, over a 4-week observation period in patients suffering from primary adrenal insufficiency, no significant difference was observed in fasting plasma insulin, insulin resistance or b-cell function when taking either HC 10 mg morning/5 mg mid-day or HC 10 mg morning/5 mg mid-day/5 mg evening or dexamethasone 0.1 mg/15 kg body weight at breakfast, although values for the dexamethasone tended to be higher (25). Furthermore, when comparing low-dose oral HC replacement therapy (15 mg at 0800 h, 5 mg at 1700 h) to a physiological HC infusion, endogenous glucose production was similar (26).…”

Section: Glucocorticoid Replacement and Glucose Homeostasismentioning

confidence: 95%

Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy

Debono

Ross²,

Newell‐Price

2009

114

Patients with adrenal insufficiency need lifelong glucocorticoid replacement, but many suffer from poor quality of life, and overall there is increased mortality. Moreover, it appears that use of glucocorticoids at the higher end of the replacement dose range is associated with increased risk for cardiovascular and metabolic bone disease. These data highlight some of the inadequacies of current regimes.The cortisol production rate is estimated to be equivalent to 5.7-7.4 mg/m 2 per day, and a major difficulty for replacement regimes is the inability to match the distinct circadian rhythm of circulating cortisol levels, which are low at the time of sleep onset, rise between 0200 and 0400 h, peaking just after waking and then fall during the day. Another issue is that current dose equivalents of glucocorticoids used for replacement are based on anti-inflammatory potency, and few data exist as to doses needed for equivalent cardiovascular and bone effects. Weight-adjusted, thrice-daily dosing using hydrocortisone (HC) reduces glucocorticoid overexposure and represents the most refined regime for current oral therapy, but does not replicate the normal cortisol rhythm. Recently, proof-of-concept studies have shown that more physiological circadian glucocorticoid therapy using HC infusions and newly developed oral formulations of HC have the potential for better biochemical control in patients with adrenal insufficiency. Whether such physiological replacement will have an impact on the complications seen in patients with adrenal insufficiency will need to be analysed in future clinical trials.

“…Whether glucocorticoid-induced osteoporosis (GIOP) is also a problem with slight over-replacement, as commonly seen in patients with PAI, has not been well studied until recently. Some studies showed that reduction of glucocorticoid replacement doses improved markers of bone turnover (25,66). A series of studies has shown an inconsistent correlation between bone mineral density (BMD) and disease duration, glucocorticoid type and dose in PAI (27,67,68,69,70,71,72).…”

Section: Bonementioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Epidemiology, quality of life and complications of primary adrenal insufficiency: a review

Bensing

Hulting

Husebye

et al. 2016

In this article, we review published studies covering epidemiology, natural course and mortality in primary adrenal insufficiency (PAI) or Addison's disease. Autoimmune PAI is a rare disease with a prevalence of 100-220 per million inhabitants. It occurs as part of an autoimmune polyendocrine syndrome in more than half of the cases. The patients experience impaired quality of life, reduced parity and increased risk of preterm delivery. Following a conventional glucocorticoid replacement regimen leads to a reduction in bone mineral density and an increase in the prevalence of fractures. Registry studies indicate increased mortality, especially evident in patients diagnosed with PAI at a young age and in patients with the rare disease autoimmune polyendocrine syndrome type-1. Most notably, unnecessary deaths still occur because of adrenal crises. All these data imply the need to improve the therapy and care of patients with PAI.