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PubMed2005

Anabolic therapy for osteoporosis: parathyroid hormone.

Recombinant human parathyroid hormone (PTH 1-34) is the only anabolic agent currently approved for the treatment of osteoporosis. The term anabolic is based on mechanism of action. PTH stimulates bone formation, in contrast to antiresorptive agents, which reduce bone resorption and formation. Recent investigations involving the PTH(1-34) and PTH(1-84) peptides, alone and in combination or sequential regimens with antiresorptive agents, have provided a greater understanding of the place of PTH in the armamentarium against osteoporosis. These studies indicate that adding a bisphosphonate to PTH in previously untreated individuals does not produce additional bone benefit; however, sequential use of PTH followed-up by an antiresorptive agent is highly effective at increasing BMD. Adding PTH after an antiresorptive agent also produces substantial bone density increments, though the magnitude of bone density increase may differ for different antiresorptive agents. PTH can repair underlying micro-architectural defects in bone, improve bone mass substantially, and perhaps change macro-architecture and geometry of bone. There are still many unanswered questions regarding PTH treatment of osteoporosis, including the optimal duration of treatment, optimal dosing regimen, mechanism of resistance to its effect after 18-24 months, and the effect of subsequent rechallenge.

Bone Density Conservation Agents↗
PubMed2006

Anabolic therapy for osteoporosis: parathyroid hormone.

Recombinant human parathyroid hormone (PTH 1-34) is the only anabolic agent currently approved for the treatment of osteoporosis. The term anabolic is based on mechanism of action. PTH stimulates bone formation, in contrast to antiresorptive agents, which reduce bone resorption and formation. Recent investigations involving the PTH(1-34) and PTH(1-84) peptides, alone and in combination or sequential regimens with antiresorptive agents, have provided a greater understanding of the place of PTH in the armamentarium against osteoporosis. These studies indicate that adding a bisphosphonate to PTH in previously untreated individuals does not produce additional bone benefit; however, sequential use of PTH followed-up by an antiresorptive agent is highly effective at increasing bone mineral density. Adding PTH after an antiresorptive agent also produces substantial bone density increments, though the magnitude of bone density increase may differ for different antiresorptive agents. PTH can repair underlying micro-architectural defects in bone, improve bone mass substantially, and perhaps change macro-architecture and geometry of bone. There are still many unanswered questions regarding PTH treatment of osteoporosis, including the optimal duration of treatment, optimal dosing regimen, mechanism of resistance to its effect after 18-24 months, and the effect of subsequent rechallenge.

Journal Article↗
PubMed1998

Addressing the tertiary structure of human parathyroid hormone-(1-34).

Parathyroid hormone (PTH) regulates mineral metabolism and bone turnover by activating specific receptors located on osteoblastic and renal tubular cells and is fully functional as the N-terminal 1-34 fragment, PTH-(1-34). Previously, a "U-shaped" conformation with N- and C-terminal helices brought in close proximity by a turn has been postulated. The general acceptance of this hypothesis, despite limited experimental evidence, has altered the direction of the design of PTH-analogs. Examining the structure of human PTH-(1-34) under conditions that encompass the different environments the hormone may experience in the approach to and interaction with the G-protein-coupled receptor (including benign aqueous and saline solutions and in the presence of dodecylphosphocholine), we observe no evidence for a U-shape conformation or any tertiary structure. Instead, the N- and C-terminal helical domains, which vary in length and stability depending on the conditions, are separated by a highly flexible region of undefined conformation. These observations are in complete accord with recent conformational studies of PTH-related protein analogs containing lactams (Mierke, D. F., Maretto, S., Schievano, E. , DeLuca, D., Bisello, A., Mammi, S., Rosenblatt, M., Peggion, E., and Chorev, M. (1997) Biochemistry 36, 10372-10383) or a model amphiphilic alpha-helix (Pellegrini, M., Bisello, A., Rosenblatt, M., Chorev, M., and Mierke, D. F. (1997) J. Med. Chem. 40, 3025-3031). Reliable structural data from different environmental conditions are absolutely requisite for the next step in the design of non-peptide PTH analogs.

Circular Dichroism↗
PubMed1975

Pre-operative localization of parathyroid tissue by selective neck vein catheterization and radioimmunoassay of parathyroid hormone.

Preoperative localization of parathyroid tissue by selective neck vein catheterization and radiommunoassay of parathyroid hormone (PTH) was used in 18 patients with primary hyperparathyroidism (PHPT), 9 or whom had earlier been subjected to surgical neck exploration. Sampling from large and small neck veins provided localizing data in 11 of 15 patients with parathyroid adenomas. In 3 other patients, diffuse parathyroid hyperplasia was also correctly predicted preoperatively. In 3 patients hyperplasia was found, the surgical procedure was not influenced in a negative way by the failures. Large vein sampling was less helpful then selective small vein sampling. The results show that selective venous sampling from the neck and radioimmunoassay of PTH are valuable preoperative adjuncts to surgical exploration, escpecially in patients who have had previous neck surgery. Since the catheterization procedure is uncomfortable to the patient and difficult for the investigator, its use should be restricted to patients with previous neck surgery, Neck vein catheterization can probably not be used to establish the diagnosis of PHPT in uncertain cases.

Adenoma↗
PubMed1984

Bioactive parathyroid hormone in canine progressive renal insufficiency.

Bioactive parathyroid hormone and hormonal actions were monitored as hyperparathyroidism evolved in a model of progressive canine renal failure. Circulating levels of bioactive and immunoreactive parathyroid hormone rose as renal insufficiency worsened, but elevations, especially in bioactivity, were most marked in the final stage of uremia. By gel filtration analysis, the major circulating bioactive moiety was similar to the major glandular form of parathyroid hormone, although a smaller-molecular-weight entity was seen in the final stage of renal failure. Renal phosphate threshold fell, urinary hydroxyproline corrected for glomerular filtration rose, and plasma 1,25-dihydroxyvitamin D fell but remained detectable, as renal function deteriorated. The results demonstrate a progressive rise in bioactive parathyroid hormone, show the appearance of a small-molecular-weight bioactive entity in severe renal disease, and correlate effects of the rising bioactive parathyroid hormone with changes in renal phosphate handling and with skeletal resorption.

Animals↗
PubMed1995

[The metabolic mode of circulating parathyroid hormone].

The circulating immunoreactive parathyroid hormone (PTH) exists in more than one form in plasma. These immunoreactive forms of PTH consists of intact hormone (large molecular weights) and lower molecular weight hormonal fragments from both the carboxyterminal and aminoterminal portions of PTH molecules. The most of the secreted intact PTH is cleaved or degraded in kidney and liver with forming C-terminal PTH. A little amounts of PTH are metabolized in bone or in other tissues bearing PTH/PTHrP receptor. This chapter reviews the mode of PTH metabolism in the peripheral tissues.

Animals↗
PubMed1992

Circulating parathyroid hormone and calcitonin in rats after spaceflight.

Parathyroid hormone and calcitonin, two major calcium-regulating hormones, were measured in the plasma of five experimental groups of rats to evaluate postflight calcium homeostasis after the 14-day COSMOS 2044 flight. Parathyroid hormone values were slightly higher in the flight animals (F) than in the appropriate cage and diet controls (S) (44 +/- 21 vs. 21 +/- 4 pg/ml, P less than 0.05), but they were the same as in the vivarium controls (V), which had different housing and feeding schedules. Neither V nor S showed the increase in plasma creatinine phosphorus and magnesium found in F, features of early renal insufficiency. F showed the lowest mean plasma calcitonin that was statistically different from V only. This difference in F and V (22 +/- 11 vs. 49 +/- 16 pg/ml, P less than 0.05) was most likely due to failure of circulating calcitonin in F to show the normal age-dependent increase we demonstrated in age-matched controls in a separate experiment. Basal values for parathyroid hormone and calcitonin were unchanged after 2 wk of hindlimb suspension, a flight simulation model, in age-matched and younger rats. From a time course experiment serum calcium was higher and parathyroid hormone lower after 4 wk than in ambulatory controls. Postflight circulating levels of parathyroid hormone appear to reflect disturbances in calcium homeostasis from impaired renal function of undetermined cause, whereas levels of calcitonin reflect depression of a normal growth process.

Adrenal Glands↗
PubMed1981

[Immunocytochemical detection in Stannius corpuscles of the eel (Anguilla anguilla L.) of a hormone similar to the mammalian parathyroid hormone].

In eels the parathyrin of the corpuscles of Stannius (PCS), mammalian parathyroid-like hormone, has been localized in the cytoplasm of all the cells in the corpuscles. This detection was done by indirect immunofluorescence with an antiserum anti 1-84 bovine parathormone. The specificity of the reaction was demonstrated by inhibition of the coloration obtained with the 1-84 bovine parathormone and the active fragment 1-34 of human parathormone. Variations of the cellular localization of the PCS or a complete depletion of the hormonal content were observed in eels made hypercalcaemic by calcium overloading.

Anguilla↗
PubMed1983

Rapid localization of parathyroid tumors by selective venous catheterization and parathyroid hormone bioassay.

Selective venous catheterization with parathyroid hormone radioimmunoassay has been used effectively to localize parathyroid tumors in patients who have previously had failed parathyroid operations. We have analyzed our experience comparing radioimmunoassay and bioassay of parathyroid hormone for localization of parathyroid tumors by selective venous sampling. The bioassay, which uses a guanyl nucleotide-amplified adenylate cyclase assay with canine renal plasma membranes, localized the tumors in six of nine patients who had previously undergone neck operations. The radioimmunoassay localized the tumors in eight of the nine patients. The advantage of the bioassay is that it requires only 50 microliter serum per per sample and 1 day of assay time compared with the radioimmunoassay, which requires 700 microliter serum per sample and 7 days of assay time. The bioassay may be important in patients with severe hyperparathyroidism who require an urgent operation.

Biological Assay↗
PubMed2004

Impact of intraoperative parathyroid hormone monitoring on the prediction of multiglandular parathyroid disease.

Optimal interpretation of the results of intraoperative parathyroid hormone (IOPTH) monitoring during neck exploration for primary hyperparathyroidism (pHPT) is still controversial. The reliability of the "50% rule" in multiglandular disease (MGD) is often disputed, mostly because of competing pathophysiologic paradigms. The aim of this study was to ascertain and corroborate the ability of IOPTH monitoring to detect MGD in a practice, combining conventional and alternative parathyroidectomy techniques. This is a retrospective single institution analysis of 69 consecutive patients undergoing cervical exploration for pHPT by various approaches. The IOPTH measurements were performed after induction of anesthesia but prior to skin incision and 10 minutes after excision of the first visualized enlarged parathyroid gland. In this series, 55 patients (80%) had single adenomas, and 14 patients (20%) had MGD. In 8 of the 14 patients with MGD, IOPTH levels were obtained sequentially after removal of every enlarged gland. Of these 8 patients, 6 (75%) had a false-positive decrease (decrease below 50% of baseline value in presence of another enlarged gland) failing to predict the presence of a second enlarged gland. In 2 cases IOPTH monitoring provided a true-negative result, correctly predicting MGD. If MGD is defined by gross morphologic criteria, IOPTH monitoring fails to predict the presence of MGD reliably. However, if MGD is defined by functional criteria, the course of these patients does not seem significantly affected. The importance of these findings must be further investigated, especially with regard to the outcome of minimally invasive parathyroid procedures.

Adenoma↗
PubMed2003

The effects of parathyroid hormone, alendronate, or both in men with osteoporosis.

BACKGROUND: Because parathyroid hormone increases both bone formation and bone resorption, it is possible that combining parathyroid hormone with an antiresorptive agent will enhance its effect on bone mineral density. METHODS: We randomly assigned 83 men who were 46 to 85 years of age and had low bone density to receive alendronate (10 mg daily; 28 men), parathyroid hormone (40 microg subcutaneously daily; 27 men), or both (28 men). Alendronate therapy was given for 30 months; parathyroid hormone therapy was begun at month 6. The bone mineral density of the lumbar spine, proximal femur, radial shaft, and total body was measured every six months with the use of dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured at base line and month 30 by means of quantitative computed tomography. Serum alkaline phosphatase levels were measured every six months. The primary end point was the rate of change in the bone mineral density at the posteroanterior spine. RESULTS: The bone mineral density at the lumbar spine increased significantly more in men treated with parathyroid hormone alone than in those in the other groups (P<0.001 for both comparisons). The bone mineral density at the femoral neck increased significantly more in the parathyroid hormone group than in the alendronate group (P<0.001) or the combination-therapy group (P=0.01). The bone mineral density of the lumbar spine increased significantly more in the combination-therapy group than in the alendronate group (P<0.001). At 12 months, changes in the serum alkaline phosphatase level were significantly greater in the parathyroid hormone group than in the alendronate group or the combination-therapy group (P<0.001 for both comparisons). CONCLUSIONS: Alendronate impairs the ability of parathyroid hormone to increase the bone mineral density at the lumbar spine and the femoral neck in men. This effect may be attributable to an attenuation of parathyroid hormone-induced stimulation of bone formation by alendronate.

Absorptiometry, Photon↗
PubMed1995

Growth hormone does not enhance the anabolic effect of human parathyroid hormone (1-34) on bone in aging multiparous and virgin rats.

In humans, the progressive loss in skeletal bone mass with aging increases the risk of osteoporosis and bone fractures in the elderly. As parathyroid hormone (PTH) and growth hormone (GH) may both be anabolic in bone, we tested if the combination of these hormones would increase bone mass more than either agent alone in aging multiparous and virgin female rats. In four separate studies, female rats (15-18 months old) were treated for 12 or 15 days with synthetic human parathyroid hormone (hPTH 1-34) at 80 micrograms/kg per day given once daily, alone or combined with ovine GH at 1 mg/kg per day given twice daily. Bone of distal femurs, proximal tibias and lumbar vertebrae, dietary mineral (Ca, P, Mg) excretion and balance and serum chemistry were assessed. PTH alone stimulated bone formation and increased bone mass in three of four experiments and consistently increased serum 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and mineral retention. GH alone did not change either bone formation or bone mass, but combined with PTH increased mineral retention and serum 1,25-(OH)2D3), more than either hormone alone. Despite this stimulatory effect on Ca retention, GH did not further enhance the anabolic effect of hPTH 1-34 on bone mass of aging multiparous and virgin female rats.

Aging↗
PubMed1990

Fluoride therapy and parathyroid hormone activity in osteoporosis.

1. To determine the relationships between parathyroid hormone activity and long-term sodium fluoride therapy in osteoporosis, cytochemical bioassays (for biologically active parathyroid hormone) were performed in 22 osteoporotic control patients and in 18 patients after 15 +/- 10 months of treatment (60 mg of sodium fluoride daily). Ten patients were studied longitudinally by repeated metabolic balances and were therefore common to both groups. All patients were receiving mineral supplements. 2. Cross-sectional data showed a fourfold mean increase in biologically active parathyroid hormone on fluoride treatment (P less than 0.005) together with a 51% increase in serum alkaline phosphatase (P less than 0.005). Longitudinal data showed, in addition, a significant increase in the calcium balance of 2.4 +/- 1.2 (SEM) mmol daily (P less than 0.05) and the development of a positive phosphorus balance (P less than 0.02). 3. Fluoride-treated patients were then analysed in two groups according to the level of biologically active parathyroid hormone. Thirty-two per cent of values were above the upper limit of normal (18 pg/ml). The mean serum alkaline phosphatase level in this group showed no elevation above that of the control patients, the overall rise being accounted for entirely by patients with normal levels of biologically active parathyroid hormone. High levels of biologically active parathyroid hormone were also associated with relative hypophosphataemia (P less than 0.01), relative hypercalciuria (P less than 0.05) and an increased urine/faecal calcium ratio (P less than 0.025). 4. Results show that long-term fluoride and calcium therapy increase biologically active parathyroid hormone in osteoporosis and that excessive parathyroid hormone activity may account for certain features of the refractory state.

Adult↗
PubMed1991

Intact parathyroid hormone levels during pregnancy, in healthy term neonates and in hypocalcemic preterm infants.

We measured parathyroid hormone levels in pregnant and nonpregnant women and at 1, 2 and 5 days of life in healthy term neonates and in hypocalcemic preterm infants using a new immunoradiometric assay which measures only biologically active intact parathyroid hormone and by a mid-molecule parathyroid hormone radioimmunoassay. During pregnancy intact and mid-molecule parathyroid hormone levels did not show any modification and were not different from parathyroid hormone levels of nonpregnant age-matched controls. Serum calcium and phosphorus levels did not vary during each trimester of pregnancy. In cord serum intact and mid-molecule parathyroid hormone values were low in both term and preterm infants. In term neonates intact and mid-molecule parathyroid hormone levels peaked on day 1; in preterm infants intact parathyroid hormone levels peaked on day 1 while mid-molecule parathyroid hormone values peaked on day 2. Intact parathyroid hormone levels showed a more marked increase in preterm (19-fold) than in term neonates (7.5-fold) on day 1. Our data do not confirm the previously reported "physiologic" hyperparathyroidism in pregnancy. Moreover we found a normal parathyroid gland responsiveness to decreasing serum calcium levels in the first days of life in term and preterm infants. Our results suggest that measurement of intact parathyroid hormone 1-84 by immunoradiometric assay in the first days of life is a more sensitive index of parathyroid gland secretory function than the measurement of middle or carboxyl-terminal parathyroid hormone fragments allowing the detection of the dynamic changes of parathyroid hormone which occur in hypocalcemic preterm infants.

Adult↗
PubMed2001

The early phase of calcipenia-induced parathyroid hormone secretion is blunted in vasculary perfused parathyroid glands of streptozotocin-diabetic rats.

OBJECTIVES: To study effects of diabetes mellitus on parathyroid hormone (PTH) secretion, the rat parathyroid glands were perfused via the bilateral carotic arteries. MATERIAL AND METHODS: Diabetic rats showed plasma glucose levels above 30 mmol/l, but no change in plasma PTH concentration, 14 days after an administration of 70 mg/kg of streptozotocin. Krebs-Ringer bicarbonate buffer containing 0.1% bovine serum albumin was used for perfusate. Perfusate calcium was lowered from 2.5 mmol/l to 0.5 mmol/l. RESULTS: In the normal rat parathyroid glands, PTH secretion was promptly evoked by calcipenia (from below 0.25 ng for 2.5 min in the perfusion with normal calcium to 0.73 +/- 0.17 ng during calcipenia time 0-2.5 min), and slightly decreased (0.51 +/- 0.12 ng during calcipenia time 2.5-5 min), and then increased (0.75 +/- 0.16 ng during calcipenia time 7.5-10 min). Diabetes abolished the early phase of PTH secretion (below 0.25 ng during calcipenia time 0-2.5 min), but did not affect the late phase of PTH secretion (0.64 +/- 0.14 ng during calcipenia time 7.5-10 min). Insulin treatment with 25 U/kg daily for 14 days completely normalized the early phase of PTH secretion. CONCLUSION: It is suggested that an insulin-deficient diabetes, not quantitatively but qualitatively, impaires the PTH secretion.

Animals↗
PubMed1987

Immunological properties of synthetic human parathyroid hormone: effect of deamidation at position 76.

Synthetic human parathyroid hormone with asparagine at residue 76 (hPTH 1-84 (Asn 76], as seen in the native peptide, was labelled with 125I and used as radioligand in radioimmunoassays. It was found to give better binding to antibodies raised against extracted human parathyroid hormone (hPTH 1-84) than 125I-labelled native hPTH 1-84. It was also superior in the study of the antigenic determinants of these antisera by the use of calibration curves with synthetic fragments of the human parathyroid hormone. The immunological properties of synthetic hPTH 1-84 (Asn 76) were examined in four region-specific labelled antibody assays and compared with those of native hPTH 1-84 and with an analogue of parathyroid hormone 1-84 with aspartic acid at residue 76 (hPTH 1-84 (Asp 76]. The synthetic hPTH 1-84 (Asn 76) and the native hormone behaved similarly in all four assays which were specific to the amino-, mid- and carboxy-regions of human parathyroid hormone. The synthetic hPTH 1-84 (Asp 76) also behaved similarly in the amino- and both mid-region-specific assays but was markedly less reactive in the carboxy-region-specific assay. This demonstrated that deamidation at residue 76 of human parathyroid hormone affects the immunological properties of the molecule. This also provides an explanation for a previous observation that in a carboxy-terminal-specific assay the native 53-84 peptide (hPTH 53-84) was more reactive than a synthetic preparation of 53-84 with aspartic acid at residue 76. It is concluded that synthetic hPTH 1-84 (Asn 76) is a satisfactory standard for the immunoassay of human parathyroid hormone and is useful as a radioligand when labelled with 125I.

Antibodies↗
PubMed2005

Daily and cyclic parathyroid hormone in women receiving alendronate.

BACKGROUND: We evaluated whether patients with osteoporosis treated with long-term alendronate have a response to parathyroid hormone treatment and whether short, three-month cycles of parathyroid hormone therapy could be as effective as daily administration. METHODS: We randomly assigned 126 women with osteoporosis who had been taking alendronate for at least 1 year to continued alendronate plus parathyroid hormone (1-34) subcutaneously daily, continued alendronate plus parathyroid hormone (1-34) subcutaneously daily for three 3-month cycles alternating with 3-month periods without parathyroid hormone, or alendronate alone for 15 months. RESULTS: In both parathyroid hormone groups, bone formation indexes rose swiftly. Among the women who were receiving cyclic parathyroid hormone, bone formation declined during cycles without parathyroid hormone and increased again during cycles with parathyroid hormone. Bone resorption increased in both parathyroid hormone groups but increased progressively more in the daily-treatment group than in the cyclic-therapy group. Spinal bone mineral density rose 6.1 percent in the daily-treatment group and 5.4 percent in the cyclic-therapy group (P<0.001 for each parathyroid hormone group as compared with the alendronate group and no significant difference between parathyroid hormone groups). One woman in the daily-treatment group, two in the cyclic-therapy group, and four in the alendronate group had new or worsening vertebral deformities. CONCLUSIONS: This study suggests that a regimen of three-month cycles of parathyroid hormone alternating with three-month cycles without parathyroid hormone causes the early phase of action of parathyroid hormone (characterized by pure stimulation of bone formation) to be dissociated from the later phase (activation of bone remodeling). The early phase may be more important to the increase in spinal bone mineral density. In patients with persistent osteoporosis after prior alendronate treatment, both daily treatment and cyclic treatment with parathyroid hormone increase spinal bone mineral density.

Aged↗
PubMed1991

Preexisting bone loss associated with ovariectomy in rats is reversed by parathyroid hormone.

Previous studies have demonstrated that when parathyroid hormone (PTH) administration to rats is started immediately following ovariectomy, it prevents bone loss due to ovarian hormone deficiency. In this study, we examined whether bone loss induced by ovariectomy could be reversed by parathyroid hormone if hormone therapy is started after the bone loss had already occurred. In the first experiment, two groups of animals were ovariectomized or sham operated, killed after 40 days, and their bones examined to ensure that bone loss occurred. In the second experiment, three groups of rats were studied. Group 1 rats were sham operated, and rats in groups 2 and 3 were ovariectomized. Each rat in group 3 received a single subcutaneous injection of 8 micrograms parathyroid hormone [hPTH-(1-34); Bachem, CA] per 100 g body weight per day, starting 40 days following ovariectomy. Rats in groups 1 and 2 received solvent vehicle, and all animals were sacrificed on day 60. Ovariectomized rats had lost an appreciable amount of bone 40 days after surgery, as indicated by a significant decrease in femoral and vertebral densities and calcium and an over 55% loss of cancellous bone in the tibial metaphysis. The loss of bone was reversed by intermittent PTH administration. Increased cancellous bone in the parathyroid hormone-treated ovariectomized rats was associated with increased trabecular osteoblasts, decreased trabecular osteoclasts, and increased serum osteocalcin and urinary hydroxyproline. Our findings indicate that parathyroid hormone can substantially augment bone mass after the loss due to ovarian hormone deficiency has already occurred. The hormone caused positive bone balance in vivo in ovarian hormone-deficient animals by increasing bone formation and decreasing bone resorption.

Animals↗