Growth Hormone Replacement Is Important for the Restoration of Parathyroid Hormone Sensitivity and Improvement in Bone Metabolism in Older Adult Growth Hormone-Deficient Patients

Alterations in PTH circadian rhythm and PTH target-organ sensitivity exist in adult GH-deficient (AGHD) patients and may underlie the pathogenesis of AGHD-related osteoporosis. GH replacement (GHR) results in increased bone mineral density, but its benefit in AGHD patients over 60 yr old has been debated. To examine the effect of age on changes in PTH circadian rhythm and target-organ sensitivity after GHR, we recruited 22 AGHD patients (12 were <60 yr of age, and 10 were >60 yr of age). Half-hourly blood samples were collected for PTH, calcium, phosphate, nephrogenous cAMP (marker of renal PTH activity), type-I collagenβ C-telopeptide (bone resorption marker), and procollagen type-I amino-terminal propeptide (bone formation marker) before and after 1, 3, 6, and 12 months of treatment with GHR. Significant PTH circadian rhythms were present in both age groups throughout the study. After GHR, PTH decreased and nephrogenous cAMP, adjusted calcium, and bone turnover markers increased in both groups, suggesting increased PTH target-organ sensitivity. In younger patients, the changes were significant after 1 month of GHR, but, in older patients, the changes were delayed until 3 months, with maximal changes at 12 months. Older AGHD patients derive benefit from GHR in terms of improvement in PTH sensitivity and bone metabolism. Their response appears delayed and may explain why previous studies have not shown a positive effect of GHR on bone mineral density in older AGHD patients.

Effect of physical activity on calciotropic hormones and calcium balance in rats

The response of calciotropic hormones and bone turnover to exercise and immobilization was examined by the measurement of calcium balance, bone turnover indexes, levels of parathyroid hormone, nephrogenous adenosine 3',5'-cyclic monophosphate (cAMP), and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] weekly for 6 wk in three groups of rats: control, exercise trained, and immobilized. Early in the experiment, increases were observed in excretion of urinary calcium, hydroxyproline, and in serum alkaline phosphatase after both exercise and immobilization. It was not until the latter part of the experimental period that changes were observed in nephrogenous cAMP and intestinal absorption efficiency of calcium. In the fasting state, the exercise group had a drop in serum calcium and phosphate and a rise in nephrogenous cAMP and serum 1,25(OH)2D3 compared with the control group. The exercised animals experienced an increase in bone mass, whereas the immobilized animals had a decline in bone mass. Thus exercise stimulates bone growth, resulting in an increased demand for minerals that is satisfied by an increase in serum 1,25(OH)2D3 levels and increased intestinal absorption of calcium. The increase in calcium absorption suppresses parathyroid hormone production (nephrogenous cAMP) in the exercised animal. Immobilization resulted in increased bone resorption that suppressed parathyroid hormone, nephrogenous cAMP, and the intestinal absorption of calcium.

Effects of estrogen on mineral metabolism in postmenopausal women as evaluated by multiple assays measuring parathyrin bioactivity.

Data on the effect of estrogen on immunoreactive parathyrin (iPTH) in postmenopausal women are conflicting. We administered estrogen or placebo to 21 postmenopausal women for 12 weeks and measured PTH bioactivity (bioPTH), using the renal cytochemical bioassay. Before treatment, there was a negative correlation between nephrogenous cAMP and the tubular maximum for urinary phosphate excretion and a positive correlation between values measured by a mid-region-specific PTH RIA and those measured in an immunoradiometric assay for intact PTH. Values measured by the midregion-specific RIA were also positively correlated with nephrogenous cAMP. BioPTH values were not correlated with other indices of PTH activity but were increased compared with values for younger subjects. After estrogen treatment there was no change in bioPTH activity despite an early decrease in serum osteocalcin and a later increase in nephrogenous cAMP. PTH concentrations measured by mid-region-specific or intact RIAs were unchanged, but sample size may have been insufficient to exclude the possibility of significant changes in these values. The effects of estrogen on mineral metabolism in postmenopausal women are time-dependent. Early effects are independent of PTH, and later effects are variably associated with increased PTH activity.

End-organ resistance to PTH infusion in hypercalcaemic and normocalcaemic patients with solid tumours

Ten hypercalcaemic patients with solid tumours were studied to evaluate the renal response on PTH infusion as assessed by nephrogenous cAMP excretion and maximum tubular re-absorption of phosphate. In addition, 20 normocalcaemic patients, 11 with an adenocarcinoma and 9 with a squamous cell carcinoma, were studied. All cancer patients had moderately extensive disease. Results were compared with those of 9 patients with primary hyperparathyroidism and with 10 elderly controls. All groups studied had comparable renal function, magnesium and 25-hydroxy-vitamin D levels. Comparable results were obtained in patients with an adenocarcinoma and in controls. cAMP response (Δ nephrogenous cAMP) was significantly lower in the hypercalcaemic patients with a solid tumour compared with the controls (8.13 ± 4.68 nmol/100 ml glomerular filtrate vs 29.52 ± 25.62 nmol/100 ml glomerular filtrate; P < 0.005). In the group of patients with primary hyperparathyroidism Δ nephrogenous cAMP was 13.41 ± 7.54 nmol/100 ml glomerular filtrate (P < 0.06 vs controls). The group of patients with a squamous cell cancer showed an intermediate value of 14.83 ± 10.74 nmol/100 ml glomerular filtrate (P < 0.025 vs the normocalcaemic adenocarcinoma patients, but NS vs controls). In two hypercalcaemic patients with a solid tumour in whom PTH infusion was repeated after normalization of serum calcium no influence on renal responsiveness was observed. Responses of maximum tubular re-absorption of phosphate were lowest in the group of hypercalcaemic patients with a solid tumour and in the patients with primary hyperparathyroidism compared with controls (0.11 ± 0.10 vs 0.22 ± 0.09 mmol/l and 0.09 ± vs 0.22 ± 0.09 mmol/l; P <0.025 and P <0.005, respectively). It is concluded that in hypercalcaemic patients with a solid tumour a humoral factor is present which inhibits the interaction of exogenous PTH and its renal receptors. In a subset of normocalcaemic patients with a squamous cell cancer the same circulating factor might be present.