Teriparatide (rhPTH 1-34) for the treatment of osteoporosis

Osteoporosis is a skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture. Osteoporosis develops through an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts resulting in increased bone loss. Numerous agents used for the prevention and treatment of osteoporosis slow bone loss by decreasing both bone resorption and formation. These include bisphosphonates, hormone replacement therapy, selective oestrogen receptor modulators and calcitonins. All reduce vertebral fracture risk and some reduce non-vertebral fracture risk, but none routinely increases bone mass and strength or restores lost bone architecture. In many respects, antiresorptive therapies halt the progression of osteoporosis. However, for patients who have osteoporosis, particularly those who have sustained their first fracture and are at high risk for subsequent fractures, there is a need to develop agents that stimulate bone formation and, thus, reverse osteoporosis. Teriparatide is the recombinant human 1-34 amino acid sequence of parathyroid hormone recently approved in the US for the treatment of men and postmenopausal women at high risk for osteoporotic fracture and in Europe for the treatment of postmenopausal women with osteoporosis. When given by once-daily injection, teriparatide increases bone mass by stimulating formation of new bone, resulting in the restoration of bone architecture.     

Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial.

Corticosteroid-induced osteoporosis is the most common secondary cause of osteoporosis. We conducted a 12-mo, randomized clinical trial of human parathyroid hormone 1-34 (hPTH 1-34) in postmenopausal women (mean age was 63 yr) with osteoporosis who were taking corticosteroids and hormone replacement therapy. Response to the treatment was assessed with bone mineral density (BMD) measurements of the lumbar spine by quantitative computed tomography (QCT); BMD measurements of the lumbar spine, hip, and forearm by dual-energy x-ray absorptiometry (DXA); and biochemical markers of bone turnover. The mean (+/-SE) changes in BMD of the lumbar spine by QCT and DXA in the PTH group were 35+/-5.5% and 11+/-1.4%, respectively, compared with a relatively small change of 1.7+/-1.8% and 0+/-0.9% in the estrogen-only group. The differences in mean percentage between the groups at 1 yr were 33.5% for the lumbar spine by QCT (P < 0.001) and 9.8% for the lumbar spine by DXA (P < 0.001). The changes in the hip and forearm were not significantly different between or within the groups. During the first 3 mo of PTH treatment, markers of bone formation increased to nearly 150%, whereas markers of bone resorption increased only 100%, suggesting an early uncoupling of bone turnover in favor of formation. These results suggest that parathyroid hormone dramatically increases bone mass in the central skeleton of postmenopausal women with corticosteroid- induced osteoporosis who are taking hormone replacement.     

Influence of glomerular filtration rate on non-(1-84) parathyroid hormone (PTH) detected by intact PTH assays

BACKGROUND: Commercial intact parathyroid hormone (I-PTH) assays detect molecular form(s) of human PTH, non-(1-84) PTH, different from the 84-amino acid native molecule. These molecular form(s) accumulate in hemodialyzed patients. We investigated the importance of non-(1-84) PTH in the interpretation of the increased I-PTH in progressive renal failure. METHODS: Five groups were studied: 26 healthy individuals, 12 hemodialyzed patients, and 31 patients with progressive renal failure subdivided according to their glomerular filtration rate (GFR) into 11 with a GFR between 60 and 100 mL. min(-1). 1.73 m(-2), 12 with a GFR between 30 and 60 mL. min(-1). 1.73 m(-2), and 8 with a GFR between 5 and 30 mL. min(-1). 1.73 m(-2). We evaluated indicators of calcium and phosphorus metabolism and creatinine clearance (CrCl) in the progressive renal failure groups, and the HPLC profile of I-PTH and C-terminal PTH in all groups. RESULTS: Only patients with a GFR <30 mL. min(-1). 1.73 m(-2) and hemodialyzed patients had decreased Ca(2+) and 1,25-dihydroxyvitamin D, and increased phosphate. In patients with progressive renal failure, I-PTH was related to Ca(2+) (r = -0.66; P <0.0001), CrCl (r = -0.61; P <0.001), 1,25-dihydroxyvitamin D (r = -0.40; P <0.05), and 25-hydroxyvitamin D (r = -0.49; P <0.01) by simple linear regression. The importance of non-(1-84) PTH in the composition of I-PTH increased with each GFR decrease, being 21% in healthy individuals, 32% in progressive renal failure patients with a GFR <30 mL. min(-1). 1.73 m(-2), and 50% in hemodialyzed patients, with PTH(1-84) making up the difference. CONCLUSIONS: As I-PTH increases progressively with GFR decrease, part of the increase is associated with the accumulation of non-(1-84) PTH, particularly when the GFR is <30 mL. min(-1). 1.73 m(-2). Concentrations of I-PTH 1.6-fold higher than in healthy individuals are necessary in hemodialyzed patients to achieve PTH(1-84) concentrations similar to those in the absence of renal failure.     

Evidence that the amino-terminal composition of non-(1-84) parathyroid hormone fragments starts before position 19

BACKGROUND: Non-(1-84) parathyroid hormone (PTH) fragments are large C-terminal fragments of PTH with a partially preserved N-terminal structure. They differ from other C-terminal PTH fragments, which do not have an N-terminal structure and do not react in intact PTH assays. We aimed to identify the minimal N-terminal structure common to all non-(1-84) PTH fragments. METHODS: Sera obtained from six healthy individuals and six patients with primary hyperparathyroidism, and six serum pools from dialysis patients with different PTH concentrations were fractionated by HPLC and analyzed by four different PTH assays. Each assay was characterized by saturation analysis of its detection antibody and capacity to react with different PTH fragments. Human PTH(1-84) [hPTH(1-84)] calibrators were normalized to an in-house hPTH(1-84) calibrator. RESULTS: The cyclase-activating PTH (CA-PTH) assay had an early (1, 2,) epitope and reacted only with hPTH(1-84). The other assays had epitopes in region (13-34). Total and intact PTH assays had epitopes proximal to position 18 and reacted equally well with hPTH(1-84) and hPTH(7-84), and the Elecsys PTH assay had an epitope distal to position 19, being saturable by hPTH(18-48) and also reacting with [Tyr(34)]hPTH(19-84). The HPLC profiles obtained with these assays showed that non-(1-84) PTH fragments did not react in the CA-PTH assay, as expected. The amount of non-(1-84) PTH detected by the other three assays was similar when the assay results were normalized to a common calibrator. CONCLUSIONS: The results suggest that the amount of non-(1-84) PTH detected by epitopes proximal or distal to position 19 of the PTH structure is identical, indicating a common minimum structure starting before position 19. This in turn points to a probable high-affinity interaction with the C-PTH receptor, as observed previously with [Tyr(34)]hPTH(19-84) in various cell lines and in mouse osteocytes with PTH/PTHrP type I receptor ablation.     

Amino-terminal form of parathyroid hormone (PTH) with immunologic similarities to hPTH(1-84) is overproduced in primary and secondary hyperparathyroidism

BACKGROUND: To separate non-(1-84)parathyroid hormone [non-(1-84)PTH] from PTH(1-84), we developed new HPLC gradients and observed that the peak coeluting with hPTH(1-84) could be separated into two entities recognized by a cyclase-activating PTH (CA-PTH) assay that reacts with the first four amino acids of the PTH structure. METHODS: Sera from six healthy individuals and five patients with primary hyperparathyroidism, and eight pools of sera from patients in renal failure were fractionated by HPLC. A total (T)-PTH assay reacting with the (15-20) region, the CA-PTH assay, and a COOH-terminal (C)-PTH assay with a (65-84) structure requirement were used to measure basal and fractionated PTH values. RESULTS: T-PTH was higher than CA-PTH in all healthy controls [mean (SD), 3.13 (0.37) vs 2.29 (0.33) pmol/L; P <0.01] and in renal failure patients [47 (35.1) vs 33.4 (26.1) pmol/L; P <0.01]. By contrast, CA-PTH concentrations were similar to or higher than T-PTH in three of five patients with primary hyperparathyroidism [25.7 (26.1) vs 23.1 (24.2) pmol/L; not significant]. The CA-PTH assay reacted with the hPTH(1-84) peak and with a minor peak different from the non-(1-84) peak recognized by the T-PTH assay. This minor peak was not recognized by the T-PTH assay. It represented 8 (2)% of CA-PTH in controls, 25 (23)% in patients with primary hyperparathyroidism, and 22 (7)% in renal failure patients, assuming equimolar reactivity to hPTH(1-84) in the CA-PTH assay. It was not oxidized hPTH(1-84), which migrated differently on HPLC and reacted similarly in the CA and T-PTH assays. CONCLUSIONS: This new molecular form of PTH has structural integrity of the (1-4) region but presumably is modified in the region (15-20), which is usually recognized by the T-PTH assay. Its clinical implications remain to be defined.     

PTH (1-34): a novel anabolic drug for the treatment of osteoporosis

The management of osteoporosis has in the past included providing patients with an adequate source of calcium and vitamin D and consideration of some type of antiresorption therapy such as hormone replacement, SERM therapy, or bisphosphonate therapy. However, patients who have very low bone density and continue to have fractures while receiving these therapies need to consider being treated with the recently approved novel anabolic drug PTH (1-34) (Forteo). The osteoblast has the receptor for parathyroid hormone (PTH). When PTH (1 -4) is given in a pulsatile fashion, for example a daily subcutaneous injection, it stimulates osteoblasts to make new bone. PTH (1-34) has been shown to markedly increase spinal bone density and increase hip bone density. In addition, the relative risk of having moderate vertebral fracture was reduced by 90%. Thus, PTH (1-34) offers an exciting new approach for the treatment of severe osteoporosis.     

Technical and clinical characterization of the Bio-PTH (1-84) immunochemiluminometric assay and comparison with a second-generation assay for parathyroid hormone

BACKGROUND: The Bio-Intact parathyroid hormone (1-84) assay (Bio-PTH), a newly developed two-site immunochemiluminometric assay, measures exclusively PTH (1-84) in contrast to second-generation "intact PTH" (I-PTH) assays. We investigated the technical performance and clinical significance of this new assay. METHODS: PTH was measured simultaneously by the Bio-PTH assay and Allegro intact PTH IRMA in sera from Japanese patients with calcium disorders. RESULTS: Measured Bio-PTH in serum was unaffected by six freeze-thaw cycles and was stable at 4 degrees C for 7 days and during storage at -20 or -80 degrees C over 28 days. The calibration curve was linear to 1800 ng/L. The detection limit was 3.9 ng/L. The intra- and interassay imprecision was <2.8% and 3.5%, respectively, for analyte concentrations spanning the range of the calibration curve. Bio-PTH was unaffected by a 1000-fold excess of PTH (7-84), although I-PTH reacted equally with PTH (7-84) and PTH (1-84). Bio-PTH was correlated with I-PTH in healthy individuals (r = 0.953; P <0.0001; n = 26) and in the full population without renal dysfunction (r = 0.994; P <0.0001; n = 62). In 72 volunteers, mean (SD) Bio-PTH was 22.2 (7.1) ng/L, or 62% of the mean I-PTH [36.1 (22.3) ng/L]. This ratio was 51% in hemodialysis patients (n = 177). Mean Bio-PTH was high in patients with primary hyperparathyroidism [121 (85) ng/L; n = 18] and hemodialysis patients [102 (104) ng/L; n = 177], low in idiopathic hypoparathyroidism [5.5 (2.8) ng/L; n = 4], and within 2 SD of the mean for healthy controls in Paget disease of the bone [34 (15) ng/L; n = 9] and bone metastasis [24 (12) ng/L; n = 8]. CONCLUSION: The Bio-PTH assay is sensitive and precise and produces expected results for patients with the studied disorders of calcium metabolism.     

Effect of Recombinant Human Parathyroid Hormone (1-84) on Resolution of Active Charcot Neuro-osteoarthropathy in Diabetes: A Randomized,Double-Blind,Placebo-Controlled Study

OBJECTIVEFractures in Charcot neuro-osteoarthropathy (CN) often fail to heal despite prolonged immobilization with below-knee casting. The aim of the study was to assess the efficacy of recombinant human parathyroid hormone (PTH) in reducing time to resolution of CN and healing of fractures.RESEARCH DESIGN AND METHODSPeople with diabetes and acute (active) Charcot foot were randomized (double-blind) to either full-length PTH (1-84) or placebo therapy, both in addition to below-knee casting and calcium and vitamin D3 supplementation. The primary outcome was resolution of CN, defined as a skin foot temperature difference >2°C at two consecutive monthly visits.RESULTSMedian time to resolution was 5 months (95% CI 4, 12) in intervention and 6 months (95% CI 2, 9) in control. There was no significant difference in time to resolution between the groups (mixed-effects logistic regression; P = 0.64). The hazard ratio of resolution was 0.84 (95% CI 0.41, 1.74; P = 0.64), and the odds ratio of resolution by 12 months was 1.22 (0.90, 1.67; P = 0.20) (intervention vs. control). On linear regression analysis, there were no significant differences in the effect of treatment on fracture scores quantitated on MRI scans (coefficient 0.13 [95% CI −0.62, 0.88]; P = 0.73) and on foot and ankle X-rays (coefficient 0.30 [95% CI −0.03, 0.63]; P = 0.07).CONCLUSIONSThis double-blind placebo-controlled trial did not reduce time to resolution or enhance fracture healing of CN. There was no added benefit of daily intervention with PTH (1-84) to below-knee casting in achieving earlier resolution of CN.     

Parathyroid hormone and calcitonin]

Parathyroid hormone (PTH) is essential for the physiologic maintenance of mineral homeostasis. PTH regulates the mineral transport in bone and kidney and through its secondary actions on mineral transport in intestine (mediated by 1.25 (OH)2D). Calcitonin, in many ways, acts as a physiologic antagonist to PTH. Recently the techniques of molecular biology have been applied to the study of these hormones and more precise mechanism of action of these hormones has been elucidated. Last year both PTH receptor and calcitonin receptor were cloned. This review briefly summarizes new informations about their biosynthesis, secretion, metabolism, action, and structures of their receptors.     

Immunochemiluminometric assays (ICMA) specific for growth hormone releasing hormone 1-44 NH2 and 1-40 OH.

We describe specific two-site immunochemiluminometric assays able to directly measure human growth hormone-releasing hormone 1–44 NH₂ and 1–40 OH concentrations in unextracted plasma. A common N-terminal antibody was purified from polyclonal rabbit antisera to growth hormone-releasing hormone 1–44 NH₂ on a growth hormone-releasing hormone 1–29 NH₂ linked affinity column and labelled with chemiluminescent acridinium ester. C-terminal specific monoclonal antibodies to growth hormone-releasing hormone 1–44 NH₂ and 1–40 OH were raised in Balb/C mice and used as solid phase antibodies. Assay of fasting specimens from normal individuals gave medians (and ranges) of 23 pg/ml (2–200) and 30 pg/ml (3–134) for growth hormone-releasing hormone 1–44 NH₂ and 1–40 OH, respectively. Samples from a series of acromegalics showed that most have values in the normal range though median values were higher, 56 pg/ml for growth hormonereleasing hormone 1–44 NH₂ (P < 0.001) and 52 pg/ml for 1–40 OH (P < 0.001). Using these assays it will be possible for the first time to directly study the physiology and pathophysiology of these two peptides.     

An N-terminal molecular form of parathyroid hormone (PTH) distinct from hPTH(1 84) is overproduced in parathyroid carcinoma

BACKGROUND: A new parathyroid hormone (PTH) species, the N-terminal PTH form (N-PTH), is distinct from intact human PTH of 84 amino acid residues [hPTH(1-84)] and is recognized in a 3rd-generation assay of "whole" PTH (wPTH; the 1-2 epitope) but not in a 2nd-generation assay of "total" PTH (tPTH; the 12-18 epitope). N-PTH usually represents <15% of wPTH but can be overproduced in severe primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism. We investigated whether N-PTH is also overproduced in parathyroid cancer and whether N-PTH concentration is influenced by calcimimetic therapy. METHODS: We studied 8 patients with parathyroid carcinoma before and at week 16 of cinacalcet therapy, 6 patients with PHPT, and 6 control individuals. We fractionated sera with HPLC and analyzed fractions with the 2 assays to quantify hPTH(1-84), N-PTH, and non-(1-84) PTH fragments. RESULTS: Half of parathyroid carcinoma patients had an increased wPTH:tPTH ratio [mean (SD), 1.35 (0.29)]; the others had a typical ratio [0.72 (0.12)]. HPLC fractionation of sera from 2 high-ratio patients confirmed N-PTH overproduction [65% (12%) of wPTH]. The N-PTH fraction was <15% of wPTH in PHPT and healthy individuals. Calcimimetic therapy appreciably reduced calcium concentrations in parathyroid carcinoma patients but had little influence on PTH concentration, the wPTH:tPTH ratio, or the PTH HPLC profile. CONCLUSION: N-PTH is overproduced in some parathyroid cancer patients, but calcimimetic therapy does not influence its production. The clinical implications of this finding in parathyroid carcinoma await additional studies with an emphasis on N-PTH's biological activity and with larger numbers of patients.     

The use of parathyroid hormone in the treatment of osteoporosis

The primary goal in the treatment of osteoporosis is to prevent skeletal fractures. Modern antiresorptive drugs reduce the number of fractures in patients with moderate osteoporosis, but they cannot repair serious damage to bone structure. Both experimental investigations and clinical trials have shown that daily injections of parathyroid hormone or its amino-terminal fragment (1-34) increase the number and activity of osteoblasts, and accelerate formation of new bone tissue. In postmenopausal women with severe osteoporosis, treatment with the amino-terminal fragment of recombinant human parathyroid hormone, given once a day as a subcutaneous injection, results in a significant increase in the bone mineral density of the spine and proximal femur, without impairing bone quality. 18-month treatment with PTH decreases the risk of both compression fractures of the spine and nonvertebral osteoporotic fractures by more than 50%. Parathyroid hormone in the recommended dose of 20 g daily has proved to be a safe and effective drug, stimulating the reconstruction of structurally damaged bone and significantly decreasing fracture risk in patients with severe osteoporosis.     

Effects of parathyroid hormone (teriparatide) on bone mass and quality in osteoporosis

Parathyroid hormone (PTH) acts as an anabolic agent and is used for the treatment for osteoporosis. Daily or once-weekly self-administered subcutaneous injection of human PTH(1-34) (teriparatide) increased bone mineral density (BMD) compared to a placebo in post-menopausal osteoporotic patients. Recently, data have accumulated that collagen cross-link formation in bone affect bone strength. In fact, impaired enzymatic cross-linking and/or an increase in non-enzymatic cross-links, pentosidine, which is a surrogate marker of advanced glycation end products(AGEs), in bone collagen have been proposed as a major cause of bone fragility in osteoporosis. Teriparatide improves bone collagen cross-link formation, microarchitecture, and bone mass, resulting in the increase of bone strength.