Increased serum osteoprotegerin in patients with primary adrenal insufficiency receiving conventional hydrocortisone substitution.

Patients treated for primary adrenal insufficiency (PAI) are at risk of steroid over-replacement, which may affect their skeleton. The study was aimed to investigate the effect of steroid substitution on serum osteoprotegerin and receptor activator of nuclear factor kappa-beta ligand (RANKL) levels in relation to bone mineral density (BMD) in PAI. Eighty patients (mean age 47.2±14.5 years, mean hydrocortisone dose 0.49±0.14 mg/kg/day) and 63 healthy subjects were included. Serum osteoprotegerin, RANKL, 25-hydroxyvitamin D₃, calcium, phosphate, alkaline phosphatase, intact parathormone, and dehydroepiandrosterone-sulfate levels were evaluated in patients and controls. BMD was assessed in affected subjects using dual-energy X-ray absorptiometry. Mean osteoprotegerin concentration in PAI patients appeared significantly higher vs. controls (p=0.002), while RANKL levels were similar (p=0.430). Serum osteoprotegerin increased with age (p<0.001), but showed no correlation with daily hydrocortisone dose. Osteoprotegerin was negatively correlated with serum dehydroepiandrosterone-sulfate (p=0.008) and with BMD at the lumbar spine (p<0.001) and femoral neck (p=0.003). RANKL correlated negatively with PAI duration (p=0.029) and positively with daily hydrocortisone dose (p=0.018). Lumbar spine osteoporosis and osteopenia were found in 12 and 31 patients, respectively, whereas in femoral neck: in 5 and 33 individuals. Patients with osteoporosis displayed higher osteoprotegerin levels, but after the age-adjustment the correlation was lost. In conclusion, increased osteoprotegerin in PAI might reflect a compensatory response to enhanced bone resorption due to exogenous steroid excess and/or result from a deficit in adrenal androgens. RANKL levels remain within normal range on standard steroid replacement.