Time series prediction of plasma hormone concentration. Evidence for differences in predictability of parathyroid hormone secretion between osteoporotic patients and normal controls.

Recent evidence links osteoporosis, a disease of bone remodeling, to changes in the dynamics of parathyroid hormone secretion. We use nonlinear and linear time series prediction to characterize the secretory dynamics of parathyroid hormone in both healthy human subjects and patients with osteoporosis. Osteoporotic patients appear to lack the periods of high predictability found in normal humans. Our results may provide an explanation for why an intermittent administration of parathyroid hormone is effective in restoring bone mass in osteoporotic patients.

Pulse amplitude and frequency modulation of parathyroid hormone in early postmenopausal women before and on hormone replacement therapy.

Although the pathophysiology of postmenopausal osteoporosis has been investigated extensively, it is still not established in what respect PTH is related to the events. Recently, consistent data on the pulsatile secretion of PTH in man have been published. In this study intact PTH was measured in six early postmenopausal women before and after 6 months of hormone replacement therapy (HRT; 0.6 mg conjugated estrogens and 5 mg medrogestone). In addition to parameters of calcium metabolism and bone mass and to control HRT, intact PTH was measured in blood drawn over 6 h every 2 min. With HRT there was a 30% reduction in PTH secretion. Both the amount secreted per pulse (baseline, 26.8 +/- 6.9 ng/L; HRT, 21.4 +/- 7.6 ng/L; P < 0.05) as well as the basal secretion (baseline, 232.6 +/- 117.6 ng/L.h; HRT, 145.5 +/- 80.0 ng/L.h; P < 0.01) were reduced, whereas the pulse count per h remained constant (baseline, 5.1 +/- 2.2; HRT, 5.1 +/- 1.3). Power spectrum analysis showed a shift in spectral maxima consistent with these findings. Ionized and total calcium were slightly, but nonsignificantly, reduced with treatment. In summary we conclude that in early postmenopausal women, HRT reduces the secretion of PTH by reducing both the basal secretion and the amount secreted per pulse. It is conceivable that some of the known effects of HRT on bone metabolism might be mediated by the modulation of PTH secretion.

Pulse amplitude and frequency modulation of parathyroid hormone in primary hyperparathyroidism.

Pulsatile secretion of PTH in human subjects has been described recently. However, the pattern of PTH secretion in primary hyperparathyroidism (pHPT) remains to be characterized. In this study intact PTH was measured in 9 female patients with pHPT. As a control group we present data from 10 postmenopausal women. In addition to parameters of calcium metabolism and bone mass, PTH was measured in samples drawn over 4 or 6 h every 2 min by central venous blood sampling. The mean intact PTH concentration was 39.0 +/- 20.3 ng/L in healthy women and 193.2 +/- 127.9 ng/L in female patients with pHPT (P < 0.01). Pulse rhythm analysis showed significant differences between both groups for total PTH secretion per h (patients, 1196.4 +/- 485.3 ng/L; control group, 271.7 +/- 132.2 ng/L), basal PTH secretion per h (patients, 852.4 +/- 459.1 ng/L; control group, 185.6 +/- 126.1 ng/L), and average PTH secretion per pulse (patients, 112.6 +/- 54.8 ng/L; control group, 23.2 +/- 7.1 ng/L). Both patients and control subjects had, on an average, five pulses per h, and the pulsatile secretion accounted for about 50% of the total secretion. Differences in power spectrum analysis were consistent with these findings. The cross-correlation of PTH and calcium indicates an impaired feedback regulation in pHPT. PTH secretion in female patients with pHPT results from both an increased basal secretion and an increased amplitude of PTH pulses. Other features of secretion are the same as those in normal women. Feedback regulation of PTH and calcium is impaired in pHPT.

Human parathyroid hormone dilates both pig coronary and human inferior epigastric arteries by a cyclic AMP-dependent pathway.

Human parathyroid hormone (hPTH (1-38)) induced concentration-dependent relaxations in prostaglandin F2 alpha-preconstricted pig coronary arteries in vitro. Removal of endothelial cells or pretreatment with nitro-L-arginine, a specific inhibitor of the endothelium-derived relaxing factor (EDRF) synthesis, impaired, although to a small extent, hPTH-induced relaxations. Human PTH-, but not bradykinin- or nitroglycerin-induced relaxations were potentiated in the presence of the cyclic AMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Human PTH also relaxed preconstricted human inferior epigastric arteries in vitro. In accordance to pig coronary arteries, this relaxation was potentiated in the presence of IBMX. However, the human internal thoracic (mammary) artery did not respond to hPTH (1-100 nM). Thus, acute vasodilatory effects of hPTH may not be present in all human arteries. The physiological significance of this phenomenon is not known. This relaxation, at least in pig arteries, is mediated to a small extent by the release of EDRF. In addition, this relaxation appears to be mainly mediated in both pig and human arteries by a smooth muscle cyclic AMP pathway.

Classification of dynamical diseases by new mathematical tools: application of multi-dimensional phase space analyses to the pulsatile secretion of parathyroid hormone.

The biological importance of dynamic hormonal secretion has been demonstrated. There is good evidence from recent studies that parathyroid hormone (PTH) which plays an important role in bone physiology is secreted in a pulsatile manner. In this study we performed a classification of two 'dynamical diseases' namely osteoporosis and hyperparathyroidism by the visualization of dynamic PTH-secretion in multidimensional phase spaces.

The concept and treatment of osteoporosis.

Osteoporosis is a dynamic process, thought to be caused by an uncoupling between osteoblast and osteoclast activity. Altered pulsatile secretion of growth hormone and parathyroid hormone (PTH) have been proposed as pathogenetic factors for this unbalanced coupling. The anatomical lesions are believed to be reversible until trabecular perforations develop, if fractures already occurred the anatomical defect is permanent. It is helpful to classify osteoporosis in stages of increasing severity depending on bone density and the presence of fractures. Theoretically, if the bone density is above the fracture threshold, then the only therapeutic goal is to maintain the bone mass. If instead the mineral density is below the threshold, an active therapy is needed with drugs that can possibly increase the skeletal mass. Osteoporosis with multiple fractures cannot be reversed. The authors propose a promising pharmacologic treatment for osteoporosis, based on the combination of human PTH-(1-38) and intranasal salmon calcitonin. If started in the early stages of the osteoporotic process, this regimen may restore the initial bone mass. In more advanced stages, only a correction of the metabolic defect is possible, but the irreversible vertebral deformities are not affected. On the basis of the results, cyclic therapy with human PTH-(1-38) and salmon calcitonin represents a good treatment choice for osteoporosis.

Pulse amplitude and frequency modulation of parathyroid hormone in plasma.

Inconclusive reports on pulsatile secretion of PTH in man have been published. In this study PTH was measured by intact and PTH-(44-68) assays. Central venous blood sampling was performed every 2 min in 10 healthy men between 6-9 h and in 3 male patients with osteoporosis for over 6 h. Pulsatile PTH secretion was identified for healthy men and controls. Narrow pulses and bursts of narrow pulses (broad pulse) could be distinguished. Six narrow pulses per h with 26 +/- 16 ng/L amplitude and 1 burst of narrow pulses/h were detected for the intact hormone. One narrow pulse/h with 25 +/- 12 ng/L amplitude and 1 burst of narrow pulses (broad pulse) every 2 h were found (Pulsar) for PTH-(44-68). Intact and PTH-(44-68) exhibit in part a concordant pattern. Results from 3 patients with osteoporosis show a decreased amplitude and frequency of pulsatile PTH secretion. The same decreased pattern was demonstrated in a postmenopausal osteoporotic woman. A constant decline in ionized calcium elicits major secretory episodes of PTH, and ionized calcium increases after major secretory episodes of PTH. We conclude that pulsatile secretion of PTH in healthy young men is the physiological mode of secretion. Low pulsatile secretion of PTH might be related to low turnover osteoporosis.