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PubMed2005

New perspectives on parathyroid hormone therapy.

PURPOSE OF REVIEW: The prevention and treatment of osteoporosis has traditionally involved the use of antiresorptive therapies. The introduction of parathyroid hormone, an anabolic agent that enhances bone formation, has been accompanied by new treatment strategies. This article reviews combination and sequential therapy approaches with parathyroid hormone and antiresorptive agents to optimize efficacy outcomes. RECENT FINDINGS: The distinguishing features of the anabolic and antiresorptive therapies for the treatment of osteoporosis has led to the hypothesis that the appropriate use of both agents, either in sequence or in combination, may result in superior fracture protection compared with either anabolic or antiresorptive treatment alone. This enthusiasm has been tempered by the observations that the transition from daily bisphosphonate therapy may blunt the efficacy of teriparatide. By contrast, more recent studies suggest that once-weekly bisphosphonate therapy may provide a better option with parathyroid hormone either in combination or in sequence. These considerations are critical to understanding the benefits of sequential treatment (parathyroid hormone followed by an antiresorptive agent), which aims to maintain or build on the large gains in efficacy from short-term therapy with parathyroid hormone. Because patients may require an additional treatment course of parathyroid hormone in the future, the choice of antiresorptive agent should be carefully considered. In addition, more recent evidence suggests that the forms of parathyroid hormone may have important differences in action that influence combination and sequence outcomes. SUMMARY: Combination and sequential therapy with parathyroid hormone offers new options to maximize efficacy in patients at risk for osteoporotic fracture.

Anabolic Agents↗
PubMed1992

Responsiveness to synthetic parathyroid hormone in the portal vein of portal hypertensive rats.

In addition to its hypotensive action, the parathyroid hormone also decreases portal pressure in portal hypertensive rats. The purpose of this study was to characterize the vascular effects of the parathyroid hormone on the portal vein of portal vein-stenosed rats. When intravenously infused at the rate of 1.62 x 10(-11) mol/kg per min, the parathyroid hormone lowered portal pressure (15.1 +/- 0.7 vs. 14.0 +/- 0.8 mmHg) without affecting systemic blood pressure. With the portal vein isolated, the parathyroid hormone shifted the dose-response curves of KCl and acetylcholine to the right. However, the vasodilator effect of the parathyroid hormone was significantly less in portal hypertensive rats (EC50 of KCl increased 129.2% and acetylcholine 199.3%), compared to sham-operated rats (EC50 of KCl increased 158.7% and acetylcholine 270.2%). Similar results were found for the vasodilator action of verapamil (10(-9)-10(-6) M). On the other hand, the vasodilator effect of forskolin was similar for both groups. These results suggest that decreased responsiveness to the parathyroid hormone may be associated with calcium utilization by vascular smooth muscles.

Animals↗
PubMed1985

Study of the localization of [3H]bovine parathyroid hormone in bone by light microscope autoradiography.

Bovine parathyroid hormone labeled with tritium on the methionine residues by [3H]methyl exchange ([3H]bPTH) was administered intravenously to 35-day-old mice and localized in tissues by light microscope autoradiography. After 10 min most of the [3H]bPTH had been taken up from plasma. In the kidney and liver, radioactivity was not displaced by simultaneous administration of unlabeled bPTH, and was as intense after giving oxidized [3H]bPTH ([3H]ox bPTH) as [3H]bPTH, suggesting that binding was largely associated with nonspecific processes. In long bones, [3H]bPTH was bound to osteoblasts and preosteoblasts lining the endosteal and periosteal surfaces of compact bone. In the area of the growth-plate there was intense labeling on new endochondrial bone, and on hypertrophic chondrocytes in the region of calcification. There was little labeling in marrow and, in contrast to other tissues, much reduced binding was seen when a large excess of unlabeled parathyroid hormone was administered together with [3H]bPTH, or when [3H]ox bPTH was given. It is concluded that binding of parathyroid hormone to cells in bone is largely specific, and that the hormone has a function in cartilage which relates to the differentiation and calcification of chondrocytes of the growth-plate that occurs prior to its replacement by new bone tissue.

Animals↗
PubMed1998

Dietary calcium and vitamin D intake in elderly women: effect on serum parathyroid hormone and vitamin D metabolites.

In this study, the effect of dietary calcium and vitamin D on serum parathyroid hormone and vitamin D metabolites was measured in 376 free-living women aged 65-77 y. Mean calcium intake in both groups was close to the recommended dietary allowance of 800 mg/d. Mean vitamin D intake in the 245 women not taking vitamin D supplements was 3.53 microg/d (141 IU/d), which is below the recommended dietary allowance of 5 microg/d (200 IU/d). To test the hypothesis that vitamin D is more important than calcium in reducing serum parathyroid hormone, the source of dietary calcium intake was subdivided into milk, which is fortified with vitamin D, and nonmilk sources. The serum parathyroid hormone concentration was inversely correlated with calcium intake derived from milk (r = -0.20, P < 0.01) but not from nonmilk sources (r = -0.06). Furthermore, serum calcidiol correlated with milk calcium intake (r = 0.35, P < 0.001) but not with nonmilk calcium intake (r = 0.10). Multivariate analysis showed a significant effect of season on serum calcidiol but not on serum parathyroid hormone. Serum parathyroid hormone was inversely correlated with serum calcidiol (r = -0.33, P < 0.001) and the regression predicted that mean serum parathyroid hormone would be reduced in the elderly to concentrations considered normal in the young when serum calcidiol is 122 nmol/L (49 ng/mL); this would require a much higher recommended dietary allowance for vitamin D than 5 microg/d (200 IU/d).

Aged↗
PubMed1992

Ga3+ inhibits parathyroid hormone release without interacting with the Ca2+ receptor of the parathyroid cell.

Gallium nitrate is an antihypercalcemic agent with established actions on bone. The effects of Ga(NO3)3 on parathyroid hormone (PTH) release, cytoplasmic Ca2+ concentration ([Ca2+]i) and cAMP production of enzymatically dispersed parathyroid cells from bovine as well as normal and pathological human parathyroid glands have now been studied. Ga3+ at 200 microM inhibited PTH release whereas 600 microM NO3- had no effect. The inhibition was additive to that obtained by elevating extracellular Ca2+. Unlike Ca2+, Ga3+ failed to increase [Ca2+]i or reduce cAMP formation. The results indicate that Ga3+ inhibits PTH release by a mechanism other than activation of the cation receptor of the parathyroid cells. This mechanism may contribute also to inhibition by other cations.

Animals↗
PubMed2002

Na(+)/H(+ ) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling.

The parathyroid hormone 1 receptor (PTH1R) is a class II G-protein-coupled receptor. PTH1R agonists include both PTH, a hormone that regulates blood calcium and phosphate, and PTH-related protein (PTHrP), a paracrine/autocrine factor that is essential for development, particularly of the skeleton. Adenylyl cyclase activation is thought to be responsible for most cellular responses to PTH and PTHrP, although many actions appear to be independent of adenylyl cyclase. Here we show that the PTH1R binds to Na(+)/H(+) exchanger regulatory factors (NHERF) 1 and 2 through a PDZ-domain interaction in vitro and in PTH target cells. NHERF2 simultaneously binds phospholipase C beta 1 and an atypical, carboxyl-terminal PDZ consensus motif, ETVM, of the PTH1R through PDZ1 and PDZ2, respectively. PTH treatment of cells that express the NHERF2 PTH1R complex markedly activates phospholipase C beta and inhibits adenylyl cyclase through stimulation of inhibitory G proteins (G(i/o) proteins). NHERF-mediated assembly of PTH1R and phospholipase C beta is a unique mechanism to regulate PTH signalling in cells and membranes of polarized cells that express NHERF, which may account for many tissue- and cell-specific actions of PTH/PTHrP and may also be relevant to signalling by many G-protein-coupled receptors.

Adenylate Cyclase Toxin↗
PubMed1989

Abnormalities in parathyroid hormone secretion and 1,25-dihydroxyvitamin D3 formation in women with osteoporosis.

We investigated the parathyroid hormone-1,25-dihydroxyvitamin D3 (1,25(OH)2D) axis in osteoporosis by administering phosphate to 8 postmenopausal women with osteoporosis (49 to 78 years old) and to 10 normal women matched for age (50 to 74 years). All subjects responded with a similar increase in the serum phosphorus concentration (women with osteoporosis, 1.15 +/- 0.06 to 1.79 +/- 0.09 mmol per liter; controls, 1.14 +/- 0.05 to 1.73 +/- 0.08 mmol per liter) and a fall in the ionized calcium concentration (women with osteoporosis, 1.12 +/- 0.03 to 1.06 +/- 0.03 mmol per liter; controls, 1.17 +/- 0.01 to 1.11 +/- 0.02 mmol per liter). Parathyroid hormone levels rose 2.5-fold in the control group (15.4 +/- 2.2 to 37.9 +/- 6.1 pg per milliliter) but increased by only 43 percent in the group with osteoporosis (14.8 +/- 2.8 to 21.2 +/- 4.1 pg per milliliter), an increase similar to that previously reported in young normal subjects (53 percent). In healthy older and younger subjects, the levels of 1,25(OH)2D did not change; in the subjects with osteoporosis, however, they decreased significantly (50 percent). We conclude that older women require a greater parathyroid hormone stimulus than younger women to maintain vitamin D homeostasis, because of an age-related decline in the formation of 1,25(OH)2D in response to parathyroid hormone, and that in osteoporosis the age-appropriate parathyroid hormone response to the same hypocalcemic signal is diminished. Our results are consistent with the presence of an abnormality in parathyroid hormone secretory function in osteoporosis in addition to the universal decline in 1,25(OH)2D responsiveness associated with aging.

Aged↗
PubMed1998

Parathyroid hormone suppression by 22-oxacalcitriol in the severe parathyroid hyperplasia.

The suppression of parathyroid hormone (PTH) secretion by the administration of 1,25-dihydroxyvitamin D [1,25(OH)2D3] and 22-oxacalcitriol (OCT) was evaluated in nude mice transplanted with human hyperplastic parathyroid tissue. The parathyroid tissue was obtained for transplantation from a patient with severe secondary hyperparathyroidism who had undergone a parathyroidectomy. Tissue specimens were transplanted into the gluteus muscle of female nude mice. Animals were divided into two groups; one group was fed a normal diet, and the other group was fed a low calcium diet during the administration of OCT and 1,25(OH)2D3. OCT and 1,25(OH)2D3 were intraperitoneally administered two times every week, for a total of eight times. Serum calcium and phosphate levels were significantly higher in the mouse administered 1,25(OH)2D3 than in the mouse administered OCT. Serum alkaline phosphatase activity was elevated similarly in the mouse administered either OCT or 1,25(OH)2D3. OCT strongly suppressed human PTH secretion from the graft in mice with normal serum calcium levels as did 1,25(OH)2D3. However, human PTH secretion from the graft was stimulated by the administration of a low-calcium diet, despite OCT and 1,25(OH)2D3 administration. In summary, OCT and 1,25(OH)2D3 suppress PTH secretion even from severe secondary hyperplastic parathyroid tissue only in mice with normal or high calcium serum levels.

Alkaline Phosphatase↗
PubMed1984

Potential role of parathyroid hormone as an inhibitor of erythropoiesis in the anemia of renal failure.

Patients with varying degrees of renal insufficiency and patients with end-stage renal disease receiving continuous ambulatory peritoneal dialysis or regular hemodialysis therapy were studied to assess the independent relationship between serum parathyroid hormone concentration, and both severity of anemia and degree of serum inhibition of erythropoiesis. In patients with renal insufficiency not receiving dialysis, a significant curvilinear relationship between serum parathyroid hormone and creatinine concentrations was present (r = 65, p less than 0.001). Serum parathyroid hormone (by radioimmunoassay) also correlated with hematocrit level (r = -0.54, p less than 0.001) and degree of serum inhibition of in vitro erythroid progenitor cell growth in fetal mouse liver cultures (r = -0.45, p less than 0.001). However, multiple linear regression analysis revealed that after controlling for the effect of creatinine, m-parathyroid hormone is no longer a significant predictor of hematocrit level or erythroid progenitor cell growth. On the other hand, when a restricted population of patients with creatinine values between 1 and 4 mg/dl was analyzed separately, controlling for the effect of creatinine, there was still a significant correlation between hematocrit level and m-parathyroid hormone, but no such relationship was seen when participants with parathyroid hormone levels of less than or equal to 1000 pg/ml were analyzed. No significant correlation was seen between hematocrit level or inhibition of erythroid colony growth and serum parathyroid hormone concentrations in patients receiving either regular hemodialysis or continuous ambulatory peritoneal dialysis. In 13 patients given regular hemodialysis studied before and after parathyroidectomy, there was no significant change in serum erythropoietin (by radioimmunoassay) or serum inhibition of erythropoiesis, although hematocrit levels increased in six of the 13 patients. The 1-34 human parathyroid hormone, 1-84 bovine parathyroid hormone, and 1,25-dihydroxycholecalciferol had no effect on in vitro erythroid burst-forming unit growth. Parathyroid hormone (8 mu/ml) inhibited and 1,25-dihydroxycholecalciferol (4.0 ng/ml) stimulated erythroid colony-forming unit growth only in the absence of exogenous erythropoietin in culture. In summary, it was not possible to demonstrate a significant relationship between serum parathyroid hormone levels and anemia or inhibition of erythropoiesis in patients with uremia either before starting dialysis or after receiving long-term dialysis treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1997

Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism.

BACKGROUND: Surgery is the usual therapy for patients with primary hyperparathyroidism. We investigated the ability of a calcimimetic drug that inhibits parathyroid hormone secretion in vitro to decrease serum parathyroid hormone and calcium concentrations in patients with this disorder. METHODS: We performed a randomized, placebo-controlled study of single oral doses of 4 to 160 mg of the calcium-receptor agonist drug R-568 in 20 postmenopausal women with mild primary hyperparathyroidism. At base line, the mean (+/-SE) serum calcium concentration was 10.7+/-0.2 mg per deciliter (2.67+/-0.05 mmol per liter). Serum parathyroid hormone and calcium were measured repeatedly after each dose, and safety was assessed. RESULTS: Administration of R-568 resulted in a dose-dependent inhibition of parathyroid hormone secretion. The mean serum parathyroid hormone concentration, which was 77+/-11 pg per milliliter (18.8+/-2.7 pmol per liter; normal range, 16 to 65 pg per milliliter [3.9 to 15.9 pmol per liter) at base line, fell by 26+/-8 percent after 20 mg of R-568 (P=0.03), by 42+/-7 percent after 80 mg (P = 0.01), and by 51+/-5 percent after 160 mg (P=0.005). Serum ionized calcium concentrations fell only after the 160-mg dose, with the decrease closely following the decrease in the serum parathyroid hormone concentration. CONCLUSIONS: The calcimimetic drug R-568 reduces serum parathyroid hormone and ionized calcium concentrations in postmenopausal women with primary hyperparathyroidism.

Aged↗
PubMed1983

Suppression of parathyroid hormone secretion by aluminum.

The effect of aluminum on parathyroid hormone secretion was examined using collagenase-dispersed bovine parathyroid cells. An increase in the medium aluminum concentration over the range of 0.5 to 2.0 mM, in low calcium medium, progressively inhibited the secretion of radioimmuno-assayable hormone. At 2.0 mM aluminum hormone secretion was inhibited by 68% while high medium calcium, without aluminum, maximally inhibited parathyroid hormone secretion only 39%. Individually, 2.0 mM aluminum or 2.0 mM calcium inhibited isoproterenol-stimulated hormone secretion by 43%. Either metal suppressed basal and isoproterenol-stimulated cyclic AMP levels of the parathyroid cells. That the inhibitory effect of aluminum on parathyroid hormone secretion was not due to an irreversible toxic effect was demonstrated by a restoration of normal secretion when cells were returned to 0.5 mM calcium medium without aluminum. The incorporation of [3H]leucine into total cell protein, parathyroid secretory protein, proparathyroid hormone, or parathyroid hormone was not affected by aluminum. The secretion of radiolabeled protein was, however, inhibited by aluminum. These results suggest that aluminum does not affect protein biosynthesis of the parathyroid cell or the conversion of proparathyroid hormone to parathyroid hormone. Aluminum appears to directly affect the secretion of protein from dispersed parathyroid cells.

Aluminum↗
PubMed1992

Hormonal regulation of intercellular communication: parathyroid hormone increases connexin 43 gene expression and gap-junctional communication in osteoblastic cells.

The presence of gap junctions between osteoblastic cells has been previously reported. For this study we used the rat osteosarcoma cell line UMR 106, which expresses the osteoblastic phenotype, as a model to characterize further the nature, physiology, and regulation of gap junctions. Northern blot analysis identified a 3.0-kilobase RNA species corresponding to the gap junction protein connexin 43. The presence of two other connexin RNA species (26 and 32) could not be detected by this method in these cells. The identified connexin RNA was amplified by reverse transcription coupled to polymerase chain reaction; the sequence of the amplified product appears identical to the sequence of a cloned rat heart connexin 43 gene. After treatment with PTH, forskolin, and 8-Br-cAMP (a cAMP analog), the levels of connexin 43 RNA in UMR 106 cells increased. Further evidence for the role of PTH and cAMP in the physiology of gap junctions in these cells was obtained with Lucifer yellow dye transfer experiments. Gap-junctional intercellular communication increased in response to PTH and forskolin (an inducer of adenylate cyclase activity). Expression of connexin 43 RNA increased severalfold in response to PTH in a concentration- and time-dependent fashion. Connexin 43 RNA and its PTH-mediated stimulation were also observed in several other osteoblastic cell lines. The roles of PTH and forskolin in regulating the physiological state of gap junctions were confirmed in primary cultures of rat calvaria osteoblasts.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

Solution structure and adenylyl cyclase stimulating activities of C-terminal truncated human parathyroid hormone analogues.

Analogues of human parathyroid hormone (hPTH) truncated at the C-terminal end have been studied for adenylyl cyclase (AC) activity and for solution conformation by circular dichroism (CD) spectroscopy. Analogues of hPTH-(1-34)-NH2, containing the first 28-31 residues, had only a slightly diminished ability to stimulate AC in rat osteosarcoma (ROS) cells as compared to that of the parent analogue. CD data on hPTH-(16-34)-NH2 and C-terminal deletion mutants of hPTH-(1-34)-NH2 supported the presence of a partially stable alpha-helix over residues 17-28. A carboxyl-terminal mutant, hPTH-(1-30)-OH, showed both reduced helix and greatly reduced AC-stimulating activity as compared to the corresponding amide analogue. In contrast, both of these analogues, in the presence of palmitoyloleoylphosphatidylserine (POPS) vesicles, showed an equal stabilization of alpha-helix. All other analogues showed at least some enhancement of alpha-helix in the presence of POPS. However, both in neutral, aqueous buffer and in POPS, the relative amount of alpha-helix decreased greatly as the peptide was shortened below the 1-28 sequence. These data provide additional support for an amphiphilic alpha-helix over residues 21-28 being the conformation for receptor binding of hPTH for stimulation of AC activity. Modeling human parathyroid hormone-related peptide as an alpha-helix over this same region, and comparison to hPTH, suggests that both may bind via the hydrophobic face to the receptor.

Adenylyl Cyclases↗