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Vascularized bone transplantation enables reconstruction of large skeletal defects, but this process needs a long time. Since short-term intermittent parathyroid hormone (PTH) enhances rat fracture healing, we investigated the effects of 4-week intermittent low-dose (10 μg/kg/day) or high-dose (100 μg/kg/day) PTH followed by 4-week vehicle, low-dose or high-dose intermittent PTH, or zoledronic acid (ZOL, 2 μg/kg/week), a potent bisphosphonate, on large skeletal reconstruction by vascularized tibial grafting in rats. Compared to 8-week vehicle, 8-week low-dose PTH did not significantly increase the serum osteocalcin level as well as the urinary deoxypyridinoline level, while 4-week low-dose or high-dose PTH followed by 4-week ZOL decreased both of these levels. Eight-week PTH increased the bone mass of the graft and strength of the reconstructed skeleton in a dose-dependent manner; notably, the reconstructed skeleton showed an obviously higher response to PTH compared to the contralateral nonoperated femur. In contrast, 4-week PTH followed by 4-week vehicle reduced these effects and caused local bone loss at the host-graft junctions. Four-week PTH followed by 4-week ZOL did not induce such bone loss; however, 4-week high-dose PTH followed by 4-week ZOL caused a large callus in the distal cortical junction. Four-week PTH followed by 4-week ZOL increased the bone mass and strength similarly to 8-week PTH. These preliminary findings suggest, for the first time, that sequential treatment with short-term intermittent low-dose PTH and bisphosphonate as well as long-term intermittent low-dose PTH treatment enhance large skeletal reconstruction by vascularized bone transplantation, though early timing of sequential antiresorptive treatment could result in delay of bone repair. [ABSTRACT FROM AUTHOR]

Treatment of monkeys and humans with parathyroid hormone (PTH) 1-84 stimulates skeletal remodeling, which increases trabecular (Tb) bone mineral density (BMD) but decreases cortical (Ct) BMD at locations where these bone types predominate. We report the effects of daily PTH treatment (5, 10, or 25 μg/kg) of ovariectomized (OVX) rhesus monkeys for 16 months on bone structure and biomechanical properties at the proximal femur, a mixed trabecular and cortical bone site. PTH reversed the OVX-induced decrease in BMD measured by dual-energy X-ray absorptiometry at the proximal femur, femoral neck, and distal femur. Peripheral quantitative computed tomography confirmed a significant decrease in Ct.BMD and an increase in Tb.BMD at the total proximal femur and at the proximal and distal femoral metaphyses. The decrease in Ct.BMD resulted primarily from increased area because cortical bone mineral content was unaffected by PTH. Histomorphometry revealed that PTH significantly increased the trabecular bone formation rate (BFR) as well as trabecular bone volume and number. PTH did not affect periosteal or haversian BFR at the femoral neck, but cortical porosity was increased slightly. PTH had no effects on stiffness or peak load measured using a shear test, whereas work-to-failure, the energy required to fracture, was increased significantly. Thus, PTH treatment induced changes in trabecular and cortical bone at the proximal femur that were similar to those occurring at sites where these bone types predominate. Together, the changes had no effect on stiffness or peak load but increased the energy required to break the proximal femur, thereby making it more resistant to fracture. [ABSTRACT FROM AUTHOR]

We have studied the effects of the treatment with corticosterone (CORT), parathyroid hormone (PTH), or both (CORT + PTH), and of their withdrawal (CORT-rec and CORT + PTH-rec), on the osteoprotegerin (OPG) and receptor activator of nuclear factor-kB ligand (RANKL) localization and expression and on histomorphometric parameters in primary and secondary spongiosa of rat femur and tibia metaphyses. In the secondary spongiosa of the CORT group, the bone remodeling and the OPG/RANKL mRNA ratio decreased. In the PTH group, the bone turnover and the structural and connectivity indices increased, and the OPG/RANKL mRNA ratio fell; this ratio rose, however, in the primary spongiosa. In the CORT + PTH group, remodeling values intermediate between those of the CORT and PTH groups, were detected in the secondary spongiosa, where OPG and RANKL mRNA rose. Return towards control values was found in the recovery groups. The Cartilage Growth Plate Width was reduced in the CORT and CORT + PTH groups and returned to normal values in the recovery groups, while it was not affected by PTH. Independently of treatments, both OPG and RANKL mRNA and proteins were co-localized in the same cartilage and bone cells and in several bone marrow cells. In conclusion, the catabolic effects induced by CORT treatment occur together with an OPG fall and a RANKL rise. In the PTH group in which the bone turnover increase, the OPG and RANKL mRNA expressions differ in the primary and secondary spongiosa, confirming that the bone tissue in these sites can have different metabolic trends. [ABSTRACT FROM AUTHOR]

The article discusses the importance of recombinant full-length parathyroid hormone in treating osteoporosis. Osteoporosis occurs when the rate of bone resorption exceeds the rate of bone formation. The resulting loss of bone mass and strength can lead to fragility fractures. Available treatments for postmenopausal osteoporosis include agents that inhibit bone resorption such as bisphosphonates. Synthetic versions of endogenous parathyroid hormone have been shown to increase new bone formation.

Secreted frizzled-related protein (sFRP)-1 is a Wnt antagonist that when deleted in mice leads to increased trabecular bone formation in adult animals after 13 weeks of age. Treatment of mice with parathyroid hormone (PTH) also increases trabecular bone formation, and some of the anabolic actions of this hormone may result from altered expression of Wnt pathway components. To test this hypothesis, we treated +/+ and -/- female sFRP-1 mice with PTH 1–34 for 30 days and measured distal femur trabecular bone parameters by peripheral quantitative computed tomography (pQCT) and high-resolution micro-computed tomography. During the course of the 32-week study, volumetric bone mineral density (vBMD) declined 41% in vehicle-treated +/+ mice, but increased 24% in vehicle-treated -/- animals. At 8 weeks of age when vBMD was not altered by deletion of sFRP-1, treatment of +/+ and -/- mice with PTH increased vBMD by 147 and 163%, respectively. In contrast, at 24 weeks of age when vBMD was 75% higher in -/- mice than in +/+ controls, treatment with PTH increased vBMD 164% in +/+ animals, but only 58% in -/- mice. Furthermore, at 36 weeks of age when vBMD was 117% higher in -/- mice than in +/+ controls, treatment with PTH increased vBMD 74% in +/+ animals, while no increase was observed in -/- mice. At each of these time points, PTH treatment increased vBMD to a similar level in +/+ and -/- mice, and this level declined with age. In addition, at 36 weeks of age, the vBMD level reached by PTH treatment of +/+ mice was the same as that achieved solely by deletion of sFRP-1. These results indicate that loss of sFRP-1 and PTH treatment increase vBMD to a similar extent. Moreover, as the effects of sFRP-1 deletion on vBMD increase, the ability of PTH to enhance vBMD declines suggesting that there are overlapping mechanisms of action. J. Cell. Physiol. 210: 352–357, 2007. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The kidney of vertebrates plays a key role in excretion of endogenous waste products and xenobiotics. Active secretion in the proximal nephron is at the basis of this excretion, mediated by carrier proteins including multidrug resistance protein 2 (Mrp2). We previously showed that Mrp2 function is reduced by endothelin-1 (ET-1) through a basolateral B-type receptor, nitric oxide (NO), cGMP, and PKC (Notenboom S, Miller DS, Smits P, Russel FGM, Masereeuw R. Am J Physiol Renal Physiol 282: F458-F464, 2002; Notenboom S, Miller DS, Smits P, Russet FG, Masereeuw R. Am J Physiol Renal Physiol 287: F33-F38, 2004). This pathway was rapidly activated by several nephrotoxicants and appeared to be calcium dependent. In the present study, we studied the effect of the calciotropic hormones parathyroid hormone (PTH), PTH-related protein (PTHrP), and stanniocalcin (STC) to interfere with ET-regulated Mrp2 transport. Like ET-1, PTH reduces Mrp2- mediated transport by 40% in killifish renal proximal tubules. When given in combination, an additive effect was seen, which is partially reversed by the PKC inhibitor calphostin C. Recombinant PTHrP shows a comparable inhibitory effect, which is concentration dependent and additive to the inhibition by ET. STC fully reverses PTHrP- inhibited transport as does a guanylyl cyclase inhibitor. Finally, to confirm PTHrP bioactivity in a homologous assay, we performed immunolocalization and transport studies in sea bream kidney tubules. Mrp2 immunoreactivity was observed in ~40% of the tubules and is associated with the brush-border and apical plasma membrane of cells. Both proximal tubules and distal (collecting) tubules express the antigen. A highly significant 40% inhibition of Mrp2-mediated transport was observed with PTHrP in sea bream tubules. In conclusion, ET-regulated Mrp2 transport is influenced by calciotropic hormones and involves PKC and cGMP signaling. [ABSTRACT FROM AUTHOR]

Activation of parathyroid hormone 1 (PTH-1) receptors on vascular smooth muscle cells causes relaxation and decreases blood pressure in rats and humans. However, when PTH(1-84) and PTH(1-34) were injected in anesthetized rats, PTH(1-34) produced a greater decrease in blood pressure. This study quantified the dose-response relationship of the hypotensive response to intravenously injected PTH(1-84) and PTH(1-34) in conscious rats and assessed the role that the C-terminal region of PTH(1-84) played in the differences. Mean arterial pressure (MAP) decreased rapidly following injection of both peptides (0–100 nmol/kg) and reached a nadir at 1–2 minutes before increasing at a rate that was dose- and time-dependent. PTH(1-34) produced a greater hypotensive effect than PTH(1-84) at most doses tested and was significantly different from PTH(1-84) at 1–10 nmol/kg. The greatest difference in MAP decrease between PTH(1-84) and PTH(1-34) (24 and 35 mm Hg, respectively) occurred at 10 nmol/kg. Median effective dose (ED50) values for PTH(1–84) and PTH(1-34) were significantly different (5.9 and 1.3 nmol/kg, respectively). The C-terminal PTH fragments PTH(7–84), PTH(39–84), and PTH(53–84) did not affect MAP when injected alone (10 nmol/kg), nor did they influence the hypotensive response when given at a 10–fold molar excess in combination with PTH(1-84) or PTH(1-34) (1.4 nmol/kg). In conclusion, PTH(1-84) is a less potent but, because it induced the same maximum response, not a less efficacious hypotensive agent than PTH(1-34) when administered by bolus intravenous injection in conscious rats. We found no evidence to support the concept that the C-terminal region of PTH is responsible for this difference in potency. [ABSTRACT FROM AUTHOR]

Most studies that have investigated the anabolic effects of parathyroid hormone (1-84) (PTH) or PTH fragments on the skeleton of ovariectomized (OVX) rats have evaluated the short-term effects of high-dose PTH(1-34) in young animals. This study used densitometry, histomorphometry, and biomechanical testing to evaluate the effects of 12-month daily treatment with low-dose PTH (15 or 30 μg/kg) in rats that were 10 months old at baseline, 4 months after OVX. Bone mineral density (BMD) and bone strength were reduced substantially in control OVX rats. The 15 μg/kg dose of PTH restored BMD to levels similar to those in sham animals within 6 months at the lumbar spine, distal and central femur, and whole body and maintained the BMD gain from 6 to 12 months. The 30 μg/kg dose produced greater effects. Both PTH doses normalized the trabecular bone volume-to-total volume ratio (BV/TV) at lumbar vertebra 3 but not at the proximal tibia (where baseline BV/TV was very low), solely by increasing trabecular thickness. PTH dose-dependently increased bone formation by increasing the mineralizing surface, but only the 30 μg/kg dose increased resorption. PTH increased cortical BMD, area, and thickness, primarily by increasing endocortical bone formation, and restored all measures of bone strength to levels similar to those in sham animals at all skeletal sites. PTH increased bone mass safely; there was no osteoid accumulation, mineralization defect, or marrow fibrosis and there were no abnormal cells. Thus, long-term PTH therapy normalized bone strength in the aged OVX rat, a model of postmenopausal osteoporosis, through increased bone turnover and enhanced formation of both trabecular and cortical bone. [ABSTRACT FROM AUTHOR]

▴ Full-length parathyroid hormone (PTH) 1-84 is a recombinant version of human PTH. It is approved in the EU for the treatment of postmenopausal women with osteoporosis who have a high risk of fractures. Once-daily subcutaneous administration of PTH(1-84) stimulates new bone formation and increases bone mass.▴ In the pivotal, randomised, double-blind, multicentre, 18-month TOP trial in 2532 postmenopausal women with osteoporosis, subcutaneous PTH(1-84) 100 µg/day significantly reduced the incidence of new or worsened vertebral fractures relative to placebo (primary endpoint). Moreover, the increase from baseline in bone mineral density (BMD) at the lumbar spine, total hip, femoral neck and trochanter was also significantly greater than in the placebo group.▴ In another well designed study (PaTH; n = 238), 1 year of subcutaneous PTH(1-84) 100 µg/day followed by 1 year of alendronate 10 mg/day resulted in significantly greater increases in total spine, femoral neck and total hip BMD at 24 months compared with patients who received placebo for the second year. During the first year, PTH(1-84) in combination with alendronate was no more effective than PTH(1-84) monotherapy in terms of increasing areal lumbar spine BMD.▴ PTH(1-84) is generally well tolerated, although patients should be monitored for elevated serum calcium.(Table is included in full-text article.) [ABSTRACT FROM AUTHOR]

Continuous elevation of parathyroid hormone (PTH) increases osteoclast precursors, the number of osteoclasts on cancellous bone, and bone turnover. The essential molecular mediators of these effects are controversial, however, and both increased receptor activator of NF-κB ligand (RANKL) and IL-6 have been implicated. The goal of these studies was to determine whether continuous elevation of endogenous PTH alters IL-6 gene expression in vivo and whether IL-6 is required for PTH-induced bone loss. To accomplish this, we generated transgenic mice harboring a luciferase reporter gene under the control of IL-6 gene regulatory regions to allow accurate quantification of IL-6 gene activity in vivo. In these mice, induction of secondary hyperparathyroidism using a calcium-deficient diet did not alter IL-6-luciferase transgene expression, whereas RANKL mRNA expression was elevated in bone tissue. Moreover, secondary hyperparathyroidism induced an equivalent amount of bone loss in wild-type and IL-6-deficient mice, and PTH elevated RANKL mRNA and osteoclast formation to the same extent in bone marrow cultures derived from wild-type and IL-6-deficient mice. These results demonstrate that IL-6 is not required for the osteoclast formation and bone loss that accompanies continuous elevation of PTH. [ABSTRACT FROM AUTHOR]

Inorganic phosphate (P[sub i]) is absorbed by proximal tubules through a cellular pathway that is inhibited by parathyroid hormone (PTH). The calcium-sensing receptor (CaSR) is expressed on apical membranes of proximal tubules. In the present studies, we determined the effect of luminal and/or basolateral PTH on phosphate absorption and tested the hypothesis that CaSR activation blocks PTH-inhibitable phosphate absorption. Single proxima] S3 tubules were dissected from the kidneys of mice and studied by the Burg technique. Tubules were bathed with DMEM culture media supplemented with 6% BSA and perfused with an ultrafiltrate prepared from the bathing solution. [sup 33]P and FITC-inulin were added to the luminal perfusate to measure phosphate absorption (J[sub Pi]) and fluid absorption (J[sub v]), respectively. J[sub Pi] averaged 2.9 pmol·min[sup -1]·mm[sup -1] under control conditions and decreased by 20% upon addition of serosal PTH. PTH had no effect on J[sub v]. Inclusion of PTH in the luminal perfusate reduced J[sub Pi] to 2.1 pmol·min[sup -1]·mm[sup -1]. Combined addition of PTH to perfusate and bathing solutions reduced J[sub Pi] to 1.5 pmol·min[sup -1]·mm[sup -1] without affecting J[sub v]. Indirect immunofluorescence studies revealed abundant PTH receptor (PTH1R) expression on brush-border membranes, with lower amounts on basolateral membranes. CaSRs were localized primarily, but not exclusive]y, to brush-border membranes. CaSR activation with luminal Gd[sup 3+] abolished the inhibitory action of PTH on J[sub Pi]. Addition of Gd[sup 3+] to the serosal bathing solution had no effect on PTH-sensitive J[sub Pi]. Gd[sup 3+] did not affect basal, i.e., PTH-independent J[sub Pi]. Gd[sup 3+] had no effect on J[sub v] when added to lumen or bath. Dopamine-inhibitable J[sub Pi] was not affected by Gd[sup 3+]. Experiments with proximal-like opossum kidney cells showed that elevated extracellular Ca[sup 2+] or NPS R467, a type II calcimimetic, inhibited PTH action on P[sub i] uptake. In conclusion, PTH1Rs are expressed on apical and basolateral membranes of mouse proximal tubules. Stimulating apical or basolateral PTH1R inhibits phosphate absorption. CaSR activation specifically regulates PTH-suppressible phosphate absorption. [ABSTRACT FROM AUTHOR]

Parathyroid hormone (PTH) functions as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis. In addition to the well-established catabolic effects (activation of bone resorption) of PTH, it is now recognized that intermittent PTH administration has anabolic effects (promotion of bone formation). The aim of this study was to investigate whether intermittent administration of PTH in rodents would block the alveolar bone loss observed in rats when a ligature model of periodontitis is used. Morphometric analysis showed that intermittent PTH administration (40 μg/kg) was able to protect the tooth site from periodontitis-induced bone resorption. In addition, there was a significant reduction in the number of inflammatory cells at the marginal gingival area in sections obtained from animals receiving PTH compared with control animals. These findings demonstrated that intermittent PTH administration was able to protect against periodontitis-associated bone loss in a rodent model. [ABSTRACT FROM AUTHOR]

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Investigates the role of protein kinase C (PKC) signal transduction pathways in parathyroid hormone (PTH) regulation of insulin-like growth factor-binding protein-5 (IGFBP-5) gene expression in the rat osteoblast-like cell line UMR-106-01. Background on the role of the parathyroid hormone; Inhibition of the effect of PTH by bisindolylmaleimide I and PKC-δ-specific inhibitor rottlerin; Dependence of the induction of IGFBP-5 by PTH on protein kinase A and PKC.

Parathyroid hormone (PTH), especially intact human PTH [hPTH(1-84)] and its various fragments [hPTH(1-31), (1-34), (1-36), (1-38) and their modifications], has been used for the treatment of osteoporosis over the last 10 years. Although chronic continuous excess of PTH markedly increases bone resorption, as seen in the typical example of primary hyperparathyroidism and osteitis fibrosa generalisata, intermittent PTH administration has been found to stimulate bone formation in animals, providing a basis for the use of PTH as a therapeutic agent for osteoporosis. In addition to dramatically increasing trabecular bone density and also sustaining cortical bone density, PTH administration increases bone strength and reduces the fracture rate, despite occasional increases in cortical porosity. Administration of PTH in combination with antiresorptive agents such as estrogen, calcitonin, vitamin D and bisphosphonates augments its effect. Because of its bone anabolic action, PTH is expected to be effective for osteoporosis in those of advanced age with suppressed bone remodelling, which might not respond favourably to antiresorptive agents. [ABSTRACT FROM AUTHOR]

Presents information on a study which examined the cellular mechanisms involved in legand-induced parathyroid hormone (PTH) and PTH-related peptide receptor internalization. Materials and methods; Results and discussion.

Background: We have previously found decreased serum levels of both ionized calcium and 1,25(OH)[sub 2] D and an increase in serum phosphate levels at 1 year after hemithyroidectomy. However, basal and stimulated parathyroid hormone (PTH) secretions were not altered. To investigate whether the observed biochemical changes after unilateral thyroid surgery may be due to a relative end-organ resistance to PTH, we studied the peripheral effects of infused hPTH-(1–34) in 6 patients preoperatively and 3 months after hemithyroidectomy. Methods: Serum levels of TSH, FT[sub 4] and FT[sub 3] were measured pre- and postoperatively. hPTH-(1–34) was infused at 0.9 IU/kg/h during 6 h. Blood samples for analysis of ionized calcium, intact PTH, phosphate, 25(OH)D, 1,25(OH)[sub 2] D and urinary samples for calcium, phosphate and nephrogenous(n)-cAMP analysis were taken at baseline, when the infusion was discontinued after 6 h and at 24 h. Results: Three months after hemithyroidectomy, serum levels of FT[sub 3] were decreased and TSH levels increased. Pre- and postoperative hPTH-(1–34) infusions induced increased serum levels of ionized calcium, 1,25(OH)[sub 2] D, increased urinary excretion of phosphate and elevated n-cAMP levels. The changes in the studied biochemical variables during the hPTH-(1–34) infusions did not differ between the two study occasions. Conclusion: By using a 6-hour hPTH-(1–34) infusion protocol, we have shown that the peripheral PTH effect is not altered by a slight reduction in thyroid hormone levels at 3 months after hemithyroidectomy.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Different regions within the parathyroid hormone (PTH) molecule are known to have different biological activities. In the heart, the physiological actions of the intact PTH molecule are known as positive chronotropy and coronary vasodilatation. However, it is unclear which region of the PTH exerts which physiological action in the heart. Therefore, to clarify this point, we examined the hemodynamic effect of intact PTH(1-84) and selected PTH analogs, namely, PTH(1-34), PTH(2-34), [Nle8, 18Tyr34]PTH(3-34), PTH(4-34), [Tyr34]PTH(7-34), and PTH(13-34) in isolated perfused rat hearts. Both PTH(1-84) and PTH(1-34) significantly increased heart rate and decreased coronary perfusion pressure. In contrast, neither PTH(2-34) nor [Nle8,18Tyr34]PTH(3-34) increased heart rate, but they did decrease coronary perfusion pressure. Peptides further truncated at the amino terminus, PTH(4-34), [Tyr34]PTH(7-34), and PTH(13-34), had no effect on hemodynamics. Furthermore, the protein kinase A inhibitor H89, but not the protein kinase C inhibitor H7, attenuated the hemodynamic effects of PTH(1-34) or PTH(2-34), while it prevented those of [Nle8,18Tyr34]PTH(3-34). These results clearly demonstrate that the first amino acid of PTH is essential for its chronotropic property whereas the first 3 amino acids of PTH are involved in its coronary vasodilatory action. Furthermore, protein kinase A, but not protein kinase C, appears to be involved in the chronotropic and coronary vasodilatory actions of PTH. [ABSTRACT FROM AUTHOR]

Provides information on a study which investigated the effect of the 1-34 and 3-34 parathyroid hormone peptides on the distribution of renal type IIa Na-Pi cotransporter in rat kidneys. Materials and methods used; Results and discussion.

Summary The effect of the frequency of administration of synthetic human parathyroid hormone fragment 1-38 [hPTH-(1-38)] on bone formation and on the balance of calcium, phosphorus, and magnesium was investigated in 32 9-week-old female Sprague-Dawley rats, using a randomly complete block design. Rats received subcutaneously during 14 days either the vehicle solution once a day or 50 micro g hPTH-(1-38)/kg BW once a day at 8:00 a.m., twice a day at 8:00 a.m. and 5:00 p.m. or three times a day at 8:00 a.m., 0:30 p.m., and 5:00 p.m. The balance study was performed during the last 48 h of the hPTH-(1-38) treatment schedule after which femora, tibiae, and lumbar vertebrae were removed for the determination of the dry weight, volume, and contents of Ca, P, Mg, hydroxyproline, and DNA. PTH treatment was associated with a significant increase of the apparent intestinal absorption of Ca, P, and Mg. Mean urinary Ca excretion augmented with the increase of the frequency of dosing. Urinary Ca excretion correlated negatively with the Ca apparent intestinal absorption and with the Ca content of the tibiae in the 2 groups with the highest frequency of dosing. The mean Ca, P, and Mg balances, the mean contents of bone Ca, P, and Mg and the mean bone dry weights were significantly increased with PTH treatment. In contrast to the mean volume of tibiae which was not affected by the PTH administration, the mean volume of the fifth lumbar vertebrae increased with the treatment. With the 2 times and 3 times daily treatments, mean hydroxyproline concentrations in the femora were significantly higher than the control values. An increase of the mean hydroxyproline content of the third lumbar vertebrae was evidenced with the 1 time and 2 times daily treatment,... [ABSTRACT FROM AUTHOR]

Both PGE2 and PTH (1-34) caused a time- and concentration-dependent stimulation of proliferation by embryonic chick periosteal cells. Cells were exposed to the agents for different periods of time, the medium was replaced with fresh medium, and 3H-TdR incorporation was measured after 16 hours. Challenge with 10(-6) M prostaglandin E2 (PGE2) or 10(-7) M parathyroid hormone (1-34) (PTH) for 5 minutes produced 4- and 5.5-fold increases in 3H-TdR incorporation, respectively. Longer exposures, however, produced diminishing responses and after 45 minutes, only minimal effects or slight inhibitions were seen. These time-dependent effects were also seen with forskolin and dibutyryl-cAMP; TPA on the other hand stimulated DNA synthesis after both short- and long-term exposure. Both PGE2 and PTH (1-34) stimulated cAMP synthesis in periosteal cells but neither could be shown to stimulate protein kinase-C (PKC) at concentrations required for stimulation of proliferation, and dibutyryl-cyclic AMP (cAMP) effectively inhibited endogenous PKC activity. It is possible that the stimulation of proliferation by short-term exposure to PGE2 and PTH (1-34) is mediated by cAMP and that the time dependency possibly stems from the inhibition of endogenous PKC activity by increased intracellular cAMP levels. [ABSTRACT FROM AUTHOR]

Background: Several studies have demonstrated specific influence of parathyroid hormone (PTH) on immune parameters, especially on T- and B-cell function, migration of polymorphonuclear leucocytes (PMNLs) and antibody synthesis, in patients with secondary hyperparathyroidism and chronic renal failure and recently also in patients with primary hyperparathyroidism (pHPT). Methods: We therefore examined 12 patients with pHPT before and 6 months after parathyroidectomy (PTX) and nine sex- and age-matched control subjects to determine the impact of PTH and serum calcium concentrations on several immune parameters, including (a) serum concentrations of immunoglobulins, (b) immunophenotype of peripheral blood lymphocytes, (c) phytohaemagglutinin (PHA)-induced lymphocyte proliferation and (d) monocytic surface marker expression. Results: Serum concentrations of immunoglobulins (IgG, IgA, IgM) were unaffected by elevated serum PTH and calcium levels. T lymphocytes (CD3), B lymphocytes (CD19), NK cells (CD16/56) and monocytes (CD16) revealed a normal distribution and were not different before and after PTX in patients with pHPT when compared with the control group. CD4+ T-helper lymphocytes were significantly elevated pre- and post-operatively in patients with pHPT. The lymphocyte proliferation response to PHA in the highest concentration (12.5 μg L[sup -1]) tested was significantly suppressed in patients with pHPT preoperatively when compared with the patients post-operatively and the control group. In addition, both CD4+ and CD8+ lymphocytes showed a lower expression of activation markers, interleukin 2 (IL-2) receptor (CD25) and transferrin receptor (CD71), which could be partially restored 6 months after PTX, but did not reach normal values. Conclusion: In summary, in contrast to the findings in patients with secondary HPT, pHPT appears to be associated with less alterations of immune functions. Chronically elevated serum PTH and calcium concentrations in pa... [ABSTRACT FROM AUTHOR]

Intermittent administration of parathyroid hormone (PTH) stimulates skeletal remodeling and is a potent anabolic agent in bone. PTH‐related protein (PTHrP) is anabolic acting on the same PTH1 receptor and is in therapeutic use for osteoporosis. The body of literature for PTH actions in fracture healing is emerging with promising yet not entirely consistent results. The objective of this review was to perform a literature analysis to extract up‐to‐date knowledge on the effects of intermittent PTH and PTHrP therapy in bone fracture healing. A literature search of the PubMed database was performed. Clinical case studies and articles related to "regeneration," "implant," and "distraction osteogenesis" were excluded. A narrative review was performed to deliberate the therapeutic potential of intermittent PTH administration on fracture healing. A smaller number of studies centered on the use of PTHrP or a PTHrP analog were also reviewed. Animal studies clearly show that intermittent PTH therapy promotes fracture healing and revealed the strong therapeutic potential of PTH. Human subject studies were fewer and not as consistent as the animal studies yet provide insight into the potential of intermittent PTH administration on fracture healing. Differences in outcomes for animal and human studies appear to be attributed partly to variable doses, fracture sites, age, remodeling patterns, and bone architectures, although other factors are involved. Future studies to examine the dose, timing, and duration of PTH administration will be necessary to further delineate the therapeutic potential of PTH for fracture healing in humans. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]