Effects of gonadal steroid suppression on skeletal sensitivity to parathyroid hormone in men

Hypogonadism is associated with osteoporosis in men. GnRH-agonist-induced h ypogonadism increases bone turnover and bone loss in men, but the mechanism underlying these changes is unknown. To determine whether gonadal steroid deprivation increases the skeletal sensitivity to PTH or blunts the ability of PTH to promote 1,25-dihydroxyvitamin D formation, we infused human PTH- (1-34) at a dose of 0.55 U/kg.h for 24 h, in 11 men (ages, 50-82 yr) with l ocally advanced, node-positive, or biochemically recurrent prostate cancer but no evidence of bone metastases. PTH infusions were performed before ini tiation of GnRH agonist therapy (leuprolide acetate, 22.5 mg im, every 3 mo nths) and again after 6 months of confirmed GnRH agonist-induced hypogonadi sm. Serum osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), N-te lopeptide (NTX), whole-blood ionized calcium, and 1,25-dihydroxyvitamin D w ere measured at baseline and every 6 h during each PTH infusion. Urinary NT X and free deoxypyridinoline (DPD) were assessed on spot morning samples be fore PTH infusion and on 24-h samples collected during the PTH infusions. S ex steroid levels were lowered to the castrate range in all subjects. Basel ine serum NTX levels (drawn before PTH infusion) increased from 9.1 +/- 3.7 before leuprolide therapy to 13.9 +/- 5.0 nmol bone collagen equivalents ( BCE)/L after leuprolide therapy (P = 0.003). Spot urine NTX collected befor e PTH infusion increased from 28 +/- 8 before leuprolide therapy to 49 +/- 17 nmol BCE/mmol creatinine after leuprolide therapy (P < 0.001), and urina ry DPD increased from 4.7 +/- 1.1 to 7.4 +/- 1.8 nmol BCE/mmol creatinine ( P < 0.001). Baseline serum OC and BSAP levels drawn before each PTH infusio n did not change before us. after leuprolide therapy. Serum NTX levels incr eased significantly during PTH infusion pre-GnRH agonist therapy (P < 0.001 ), and the rate of increase was greater after 6 months of GnRH agonist-indu ced hypogonadism (P < 0.01 for the difference in rates of change before and after GnRH agonist administration). Serum OC and BSAP levels decreased dur ing PTH infusion (P < 0.001 for OC and P = 0.002 for BSAP), but the rates o f decrease did not differ before or after leuprolide therapy (P = 0.45 for OC and P = 0.19 far BSAP). Whole-blood ionized calcium levels increased dur ing PTH infusion (P < 0.001), and the rate of increase was greater after Gn RH agonist-induced hypogonadism (P = 0.068). Serum 1,25-dihydroxyvitamin D levels increased in response to PTH infusion before leuprolide therapy (P = 0.022), but there was no difference in the rate of increase before or afte r leuprolide therapy (P = 0.66). The incremental increase in urinary NTX ex cretion, but not DPD, during PTH infusion was greater after 6 months of leu prolide therapy (P = 0.029 for NTX, P = 0.578 for DPD). We conclude that su ppression of sex steroids in elderly men increases the skeletal responsiven ess to the bone resorbing effects of PTH infusion but does not affect the r esponse of bone formation markers or 1,25-dihydroxyvitamin D to PTH. Change s in skeletal sensitivity to PTH may play an important role in the pathogen esis of hypogonadal bone loss in men.