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• W1988156746 abstract "The parathyroid polyhormone hypothesis holds that peptides derived from the metabolism of parathyroid hormone (PTH) (so-called C-terminal fragments) are themselves biologically active and that their effects are mediated by a novel ‘C-terminal receptor.’ The evidence supporting these assertions is extensive but remains inconclusive. This Commentary focuses on in vivo pharmacology studies that provide information relevant to understanding the physiological significance of C-terminal fragments. The more recent studies of this sort provide compelling evidence that the bioactivity of C-terminal fragments is likely to become physiologically relevant in settings of secondary hyperparathyroidism. In this condition, circulating levels of C-terminal fragments greatly exceed those of PTH. There is convincing evidence that the hypocalcemic effect of C-terminal fragments results from direct actions on the skeleton that inhibit bone resorption. On the other hand, there are few if any results of in vivo studies suggesting a role for C-terminal fragments in more physiological settings, at least when parameters associated with systemic calcium homeostasis are assessed. The parathyroid polyhormone hypothesis holds that peptides derived from the metabolism of parathyroid hormone (PTH) (so-called C-terminal fragments) are themselves biologically active and that their effects are mediated by a novel ‘C-terminal receptor.’ The evidence supporting these assertions is extensive but remains inconclusive. This Commentary focuses on in vivo pharmacology studies that provide information relevant to understanding the physiological significance of C-terminal fragments. The more recent studies of this sort provide compelling evidence that the bioactivity of C-terminal fragments is likely to become physiologically relevant in settings of secondary hyperparathyroidism. In this condition, circulating levels of C-terminal fragments greatly exceed those of PTH. There is convincing evidence that the hypocalcemic effect of C-terminal fragments results from direct actions on the skeleton that inhibit bone resorption. On the other hand, there are few if any results of in vivo studies suggesting a role for C-terminal fragments in more physiological settings, at least when parameters associated with systemic calcium homeostasis are assessed. The physiological significance of peptides derived from proteolysis of parathyroid hormone (PTH) has remained controversial ever since they were first detected in 1971,1.Habener J.F. Powell D. Murray T.M. et al.Parathyroid hormone: secretion and metabolism in vivo.Proc Natl Acad Sci USA. 1971; 68: 2986-2991Crossref PubMed Scopus (94) Google Scholar and it continues to be an aspect of parathyroid physiology that periodically captures general interest. This field of research merited two chapters of review in the first edition of The Parathyroids2.Mallette L.E. Parathyroid hormone and parathyroid hormone-related protein as polyhormones.in: Bilezikian J.P. Marcus R. Levine M.A. The Parathyroids. 1st edn. Raven Press, Ltd., New York1994: 171-184Google Scholar, 3.Murray T.M. Rao L.G. Rizzoli R. Interactions of parathyroid hormone, parathyroid hormone-related protein, and their fragments with conventional and non conventional receptor sites.in: Bilezikian J.P. Marcus R. Levine M.A. The Parathyroids. 1st edn. Raven Press, Ltd., New York1994: 185-211Google Scholar but not a one in the second edition. In fact, the biological activity of PTH peptide fragments receives little mention in the latter edition (‘Scant mention’ is more accurate. Of 863 pages of text (including pages listing references), the biological activity of C-terminal fragments receives passing mention on three. There are four separate references to this topic in the 2nd edition of The Parathyroids. The interested reader with time on their hands can challenge these figures, but I believe they are correct.), an omission that might have signaled a resolution to this long-standing controversy by simply dropping it in the dustbin. However, this topical research has been plucked from the trash, dusted off, and presented anew. It cleans up nicely – and there is renewed interest in the biological activity of PTH-derived peptides. Three quite disparate experimental approaches have provided the results that drew general attention: improvements in immunoassays for PTH, engineered cell lines that lack the classical PTH receptor, and an animal model showing a robust effect of PTH peptide fragments. These recent findings were covered in the presentations of Drs Pierre D'Amour and Harald Jüppner in the second session of the Symposium entitled ‘Control and Action of PTH.’ The written version of Dr D'Amour's presentation appears in this Issue.4.D'Amour P. Circulating PTH molecular forms. What we know and what we don't.Kidney Int. 2006Abstract Full Text Full Text PDF Scopus (42) Google Scholar With initial resistance that finally yielded to constant prodding, I agreed to author some text in lieu of Dr Jüppner and was tasked with providing a general overview of the field. General reviews and commentaries on this topic are recent and plentiful;5.Goodman W.G. Juppner H. Salusky I.B. Sherrard D.J. Parathyroid hormone (PTH), PTH-derived peptides, and new PTH assays in renal osteodystrophy.Kidney Int. 2003; 63: 1-11Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 6.Goodman W.G. Salusky I.B. Juppner H. New lessons from old assays: parathyroid hormone (PTH), its receptors, and the potential biological relevance of PTH fragments.Nephrol Dial Transplant. 2002; 17: 1731-1736Crossref PubMed Scopus (29) Google Scholar, 7.Brossard J.H. Yamamoto L.N. D'Amour P. Parathyroid hormone metabolites in renal failure: bioactivity and clinical implications.Semin Dial. 2002; 15: 196-201Crossref PubMed Scopus (29) Google Scholar, 8.D'Amour P. Brossard J.H. Carboxyl-terminal parathyroid hormone fragments: role in parathyroid hormone physiopathology.Curr Opin Nephrol Hypertens. 2005; 14: 330-336Crossref PubMed Scopus (35) Google Scholar, 9.Martin K.J. Akhtar I. Gonzalez E.A. Parathyroid hormone: new assays, new receptors.Semin Nephrol. 2004; 24: 3-9Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar the most comprehensive is that by Murray et al.10.Murray T.M. Rao L.G. Divieti P. Bringhurst F.R. Parathyroid hormone secretion and action: evidence for discrete receptors for the carboxyl-terminal region and related biological actions of carboxyl-terminal ligands.Endocr Rev. 2005; 26: 78-113Crossref PubMed Scopus (240) Google Scholar This Commentary differs from these overviews by viewing the controversy regarding bioactive PTH peptides through the lens of pharmacology. The view is admittedly narrow, but it brings into focus some studies that have previously escaped attention yet contain results that address the significance of these bioactive peptides in physiological or pathophysiological settings. As one who has watched the action in this field from the sidelines, I take some risk in commenting about it. However, the task of doing so has fallen on many in the past who accept to chair a session and they have left some guidance. That left by Roy Greep at the Third Parathyroid Conference in1967 is some of the best, and I use it now as my safe harbor statement:First, I must make it clear that my overview of this highly competitive area of research will be that of an interested observer and not a contestant. That position affords me the advantage of emotional detachment and of a no-iron-in-the fire point of view. The disadvantage is that an observer cannot gain the deep insight that comes with daily involvement with the thorny aspects of problems in research.11.Greep R.O. Bulls and bears in calcium homeostasis.in: Talmage R.V. Belanger L.F. Parathyroid Hormone and Thyrocalcitonin (Calcitonin). Excerpta Medica Fdn., Amsterdam1968: 11-17Google Scholar Like Greep, I too will ‘…look for soft spots in this total effort…’ and play the devil's advocate, mostly because it is an open position. However, I start angelically by reintroducing a term that is conceptually useful and perhaps physiologically meaningful. The moniker ‘parathyroid polyhormone’ appears to have originated in a review by Lawrence Mallette12.Mallette L.E. The parathyroid polyhormones: new concepts in the spectrum of peptide hormone action.Endocr Rev. 1991; 12: 110-117Crossref PubMed Scopus (54) Google Scholar and it is a term that has been used rarely since. When the phrase does appear, it is in reference to PTH-related peptide (PTHrP).13.Rizzoli R. Ferrari S. Parathyroid hormone-related protein: a polyhormone involved in growth, development and gestation.Eur J Endocrinol. 1995; 133: 272-274Crossref PubMed Scopus (4) Google Scholar, 14.Strewler G.J. The parathyroid hormone-related protein.Endocrinol Metab Clin North Am. 2000; 29: 629-645Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar However, it is a term that succinctly and accurately describes the subject matter presented at the Symposium. And it remains a heuristic term – one that should prompt further experimental investigation in order to accept it into or exclude it from our lexicon but mostly to push back or eliminate this frontier of parathyroid physiology. The version of the parathyroid polyhormone hypothesis offered here refers specifically to PTH and consists of two distinct assertions. The first is that peptides derived from the metabolism of PTH are biologically active. The second is that the biological effects of these fragments result from actions on a novel receptor – one that is not the PTH/PTHrP receptor (PTH-R1). Although the validity of the second assertion requires that of the first, PTH peptide fragments could express their biological activity without acting on a new receptor. The validity of both assertions has rather profound implications: nothing less than a previously unrecognized ligand(s) and receptor system that contributes to parathyroid physiology. There is certainly no lack of peptide ligand candidates. The proteolytic breakdown of PTH both within parathyroid glands and at peripheral sites (mostly within Kupffer cells of the liver) gives rise to many structurally distinct N-terminally truncated peptides with intact C-terminals (collectively: C-terminal fragments).10.Murray T.M. Rao L.G. Divieti P. Bringhurst F.R. Parathyroid hormone secretion and action: evidence for discrete receptors for the carboxyl-terminal region and related biological actions of carboxyl-terminal ligands.Endocr Rev. 2005; 26: 78-113Crossref PubMed Scopus (240) Google Scholar These peptide fragments circulate at levels that normally surpass and, in end-stage renal disease, greatly exceed that of PTH.4.D'Amour P. Circulating PTH molecular forms. What we know and what we don't.Kidney Int. 2006Abstract Full Text Full Text PDF Scopus (42) Google Scholar, 15.John M.R. Goodman W.G. Gao P. et al.A novel immunoradiometric assay detects full-length human PTH but not amino-terminally truncated fragments: implications for PTH measurements in renal disease.J Clin Endo Metab. 1999; 84: 4287-4290Crossref PubMed Google Scholar, 16.Reichel H. Esser A. Roth H.J. Schmidt-Gayk H. Influence of PTH assay methodology on differential diagnosis of renal bone disease.Nephrol Dial Transplant. 2003; 18: 759-768Crossref PubMed Scopus (77) Google Scholar Although there is a general agreement that the quantitatively major peptide fragments have N-terminals originally within the mid-molecule region of the parent hormone (positions 39–53) and end at position 84,10.Murray T.M. Rao L.G. Divieti P. Bringhurst F.R. Parathyroid hormone secretion and action: evidence for discrete receptors for the carboxyl-terminal region and related biological actions of carboxyl-terminal ligands.Endocr Rev. 2005; 26: 78-113Crossref PubMed Scopus (240) Google Scholar the unambiguous sequence identification of the quantitatively dominant species has just recently been reported.17.Zhang C.X. Weber B.V. Thammavong J. et al.Identification of carboxyl-terminal peptide fragments of parathyroid hormone in human plasma at low-picomolar levels by mass spectrometry.Anal Chem. 2006; 78: 1451Google Scholar In contrast, N-terminally intact PTH peptides, like the 1–34 fragment teriparatide, are generally believed to be absent.9.Martin K.J. Akhtar I. Gonzalez E.A. Parathyroid hormone: new assays, new receptors.Semin Nephrol. 2004; 24: 3-9Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 10.Murray T.M. Rao L.G. Divieti P. Bringhurst F.R. Parathyroid hormone secretion and action: evidence for discrete receptors for the carboxyl-terminal region and related biological actions of carboxyl-terminal ligands.Endocr Rev. 2005; 26: 78-113Crossref PubMed Scopus (240) Google Scholar Only one report describes the detection and characterization of an endogenous N-terminally intact peptide fragment of PTH (PTH(1–37)18.Hock D. Magerlein M. Heine G. et al.Isolation and characterization of the bioactive circulating human parathyroid hormone hPTH-1–37.FEBS Lett. 1997; 400: 221-225Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar); if this fragment does normally circulate, its contribution to the total pool of PTH peptide fragments is quantitatively minor. In any event, the major ligand candidates at present are mid-molecule C-terminal fragments that include ‘non-1–84 PTH,’ generally thought to be PTH(7–84). Moreover, new peptide ligand candidates continue to be identified.4.D'Amour P. Circulating PTH molecular forms. What we know and what we don't.Kidney Int. 2006Abstract Full Text Full Text PDF Scopus (42) Google Scholar Most of the evidence demonstrating biological effects of C-terminal fragments derives from in vitro studies and the sheer volume of such reports is staggering.10.Murray T.M. Rao L.G. Divieti P. Bringhurst F.R. Parathyroid hormone secretion and action: evidence for discrete receptors for the carboxyl-terminal region and related biological actions of carboxyl-terminal ligands.Endocr Rev. 2005; 26: 78-113Crossref PubMed Scopus (240) Google Scholar Typically, concentrations of C-terminal fragments several orders of magnitude higher than those that appear in the circulation are required to elicit a cellular response, but there are plenty of reports showing quite dramatic effects at peptide concentrations that are likely within the physiological range, probably within the therapeutic, and certainly correspond to the much higher levels that occur in patients with severe secondary hyperparathyroidism. The remaining uncertainties about the precise structure of C-terminal fragments will likely soon vanish when improved bioanalytical methods are combined with those of immunoassay. And there are no early indications that unambiguous structural identification of peptide fragments derived from PTH will greatly alter the conclusions drawn from in vitro studies. Many of the responses affected by very low concentrations of C-terminal fragments, however, are in transformed cell lines and the limitations inherent in these cellular systems are well known. This is not to deny the insights that can be gained from in vitro experiments. Indeed, it can be argued that Tim Murray's observations using a rat osteosarcoma cell line19.Murray T.M. Rao L.G. Muzaffar S.A. Ly H. Human parathyroid hormone carboxylterminal peptide (53–84) stimulates alkaline phosphatase activity in dexamethasone-treatred rat osteosarcoma cells in vitro.Endocrinology. 1989; 124: 1097-1099Crossref PubMed Scopus (76) Google Scholar were the spark that ignited real interest in this field. In addition, in vitro studies in a transformed cell remains one of the few practical ways to tease out the molecular mechanisms underlying physiological phenomenon. However, a physiological phenomenon is what seems to be lacking when trying to make sense of the in vitro results. The literature is replete with reports showing that all kinds of cellular responses, in a wide variety of functionally distinct tissues, can be elicited or modulated by exposure to C-terminal fragments. The in vivo corollary and the physiological context to place the diverse effects observed in vitro is either entirely lacking or too speculative. The literature is becoming awash with cellular and molecular mechanisms that need something to explain. Gathered here for consideration are results of in vivo studies that might clarify this complexity. One approach of determining the physiological significance of PTH C-terminal fragments is to perform head-to-head comparisons of PTH and teriparatide in vivo. The logic of this approach is simple: the exogenous administration of PTH gives rise to C-terminal fragments, but teriparatide does not; any differential effects can reasonably be assumed to result from C-terminal fragments. Another approach is to administer C-terminal fragments to either normal or surgically compromised animals. This experimental approach provided the data showing that PTH and teriparatide have nearly identical effects on all the physiologically and clinically relevant parameters of systemic calcium homeostasis. It is the experimental model that gives us confidence using the more practical peptide in place of PTH. When a C-terminal fragment mimics or blocks both or either of their effects, it is time to pay attention; this explains the importance of three recent studies using the thyroparathyroidectomized rat model to demonstrate a hypocalcemic effect of C-terminal fragments. Thyroparathyroidectomized rats rapidly become hypocalcemic but can be made normo- or hypercalcemic by the administration of PTH or teriparatide. The calcemic effects of PTH or teriparatide are blocked by the simultaneous administration of a C-terminal fragment-like PTH(7–84) or by a mixture of several different C-terminal fragments.20.Langub M.C. Monier-Faugere M.C. Wang G. et al.Administration of PTH-(7–84) antagonizes the effects of PTH-(1–84) on bone in rats with moderate renal failure.Endocrinology. 2003; 144: 1135-1138Crossref PubMed Scopus (98) Google Scholar, 21.Nguyen-Yamamoto L. Rousseau L. Brossard J.H. et al.Synthetic carboxyl-terminal fragments of parathyroid hormone (PTH) decrease ionized calcium concentration in rats by acting on a receptor different from the PTH/PTH-related peptide receptor.Endocrinology. 2001; 142: 1386-1392Crossref PubMed Scopus (149) Google Scholar, 22.Slatopolsky E. Finch J. Clay P. et al.A novel mechanism for skeletal resistance in uremia.Kidney Int. 2000; 58: 753-761Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar By themselves, the mixture of C-terminal fragments or PTH(7–84) further reduce serum calcium levels. Significantly, the hypocalcemic effect of PTH(7–84) occurs even in nephrectomized animals, so it seems to result from a direct action of C-terminal fragments on the skeleton. Indeed, the hypocalcemic effect of PTH(7–84) is associated with significantly lowered numbers of osteoclasts and osteoblasts; new bone formation elicited by PTH is likewise depressed by co-administration of PTH(7–84).20.Langub M.C. Monier-Faugere M.C. Wang G. et al.Administration of PTH-(7–84) antagonizes the effects of PTH-(1–84) on bone in rats with moderate renal failure.Endocrinology. 2003; 144: 1135-1138Crossref PubMed Scopus (98) Google Scholar There are, of course, some apparent discrepancies in the overall data to resolve. Why, for instance, do PTH and teriparatide elicit hypercalcemic responses of similar magnitude? As noted, PTH, but not teriparatide, comes ready-made with C-terminal fragments that will be generated endogenously following exogenous administration. None of the in vivo studies cited above have measured the levels of C-terminal fragments produced by exogenously administered PTH (although P D'Amour has recently done so). Given the molar ratio of C-terminal fragments to PTH used in two of the studies,20.Langub M.C. Monier-Faugere M.C. Wang G. et al.Administration of PTH-(7–84) antagonizes the effects of PTH-(1–84) on bone in rats with moderate renal failure.Endocrinology. 2003; 144: 1135-1138Crossref PubMed Scopus (98) Google Scholar, 21.Nguyen-Yamamoto L. Rousseau L. Brossard J.H. et al.Synthetic carboxyl-terminal fragments of parathyroid hormone (PTH) decrease ionized calcium concentration in rats by acting on a receptor different from the PTH/PTH-related peptide receptor.Endocrinology. 2001; 142: 1386-1392Crossref PubMed Scopus (149) Google Scholar the explanation might be trivial and simply reflect the relatively large excess of C-terminal fragments required to demonstrate a hypocalcemic effect in vivo. It is uncertain how the results of the Slatopolsky et al.22.Slatopolsky E. Finch J. Clay P. et al.A novel mechanism for skeletal resistance in uremia.Kidney Int. 2000; 58: 753-761Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar study, in which a 1:1 molar ratio of peptides nearly ablated the hypocalcemic response to PTH, because the peptides were administered by multiple intraperitoneal injections and injections of PTH(7–84) occurred before those of PTH. This route of administration will add a pharmacokinetic dimension, absent in the other two studies, that makes it unlikely that a 1:1 molar ratio of peptides was present in the circulation for any sustained period of time. Based on the pharmacokinetic profile of PTH in the rat following subcutaneous injection, it is likely that there was a progressive increase in the C-terminal fragment to PTH ratio during the course of the experiment. It is also puzzling why a mixture of C-terminal fragments blocks the hypercalcemic effect of teriparatide but not PTH, particularly because PTH(7–84) blocks the hypercalcemic effect of both, bearing in mind that only one of the three studies tested both PTH and teriparatide.21.Nguyen-Yamamoto L. Rousseau L. Brossard J.H. et al.Synthetic carboxyl-terminal fragments of parathyroid hormone (PTH) decrease ionized calcium concentration in rats by acting on a receptor different from the PTH/PTH-related peptide receptor.Endocrinology. 2001; 142: 1386-1392Crossref PubMed Scopus (149) Google Scholar Moreover, the model at present is still heterologous (human PTH and human C-terminal fragments tested in rats). Pierre D'Amour has shared with me some of his most recent results using rat PTH and rat teriparatide – there are some differences when compared to the results obtained using the human versions of these peptides. Whether rat versions of C-terminal fragments will behave differently from their human counterparts must still be determined. Misleading information might start accumulating if this model fails to go homologous. Finally, only a single dose of PTH or teriparatide and a single molar ratio was examined in each study and full-dose–response curves to the hypercalcemic peptides will have to be established in the presence and absence of different levels of C-terminal fragments. Laborious and technically challenging work lies ahead but the potential insights to be gained justify the effort. The findings in the thyroparathyroidectomized rat model are remarkable in three respects. First, they are robust and the hypocalcemic effect of C-terminal fragments has been demonstrated in three independent laboratories using three different experimental designs. The test peptides can be infused acutely or chronically or administered by intraperitoneal injection. The absolute amount of peptides administered and the molar ratios of C-terminal fragment(s) to PTH differ among these studies, but the hypocalcemic effect persists. Second, they define an in vivo phenomenon that causally links to an in vitro mechanism at the tissue level and the ability of PTH(7–84) to inhibit calcium release from isolated rat calvaria.23.Divieti P. John M.R. Juppner H. Binghurst F.R. Human PTH-(7–84) inhibits bone resorption in vitro via actions independent of the type 1 PTH/PTHrP receptor.Endocrinology. 2002; 143: 171-176Crossref PubMed Scopus (160) Google Scholar This is one of the few instances in this field is a causal link between in vitro and in vivo is compelling. Finally, they provide an in vivo phenomenon that is probably of clinical and possibly of physiological significance. The biological effect(s) of C-terminal fragments are most likely to be clinically relevant in the settings of chronic renal failure and end-stage renal disease where serum levels of C-terminal fragments can overwhelm those of PTH.5.Goodman W.G. Juppner H. Salusky I.B. Sherrard D.J. Parathyroid hormone (PTH), PTH-derived peptides, and new PTH assays in renal osteodystrophy.Kidney Int. 2003; 63: 1-11Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar In these conditions, the large molar excess of C-terminal fragment corresponds to those used in two20.Langub M.C. Monier-Faugere M.C. Wang G. et al.Administration of PTH-(7–84) antagonizes the effects of PTH-(1–84) on bone in rats with moderate renal failure.Endocrinology. 2003; 144: 1135-1138Crossref PubMed Scopus (98) Google Scholar, 21.Nguyen-Yamamoto L. Rousseau L. Brossard J.H. et al.Synthetic carboxyl-terminal fragments of parathyroid hormone (PTH) decrease ionized calcium concentration in rats by acting on a receptor different from the PTH/PTH-related peptide receptor.Endocrinology. 2001; 142: 1386-1392Crossref PubMed Scopus (149) Google Scholar and probably all the rodent studies. The precise role(s) played by C-terminal fragments is uncertain, but Slatopolsky et al.22.Slatopolsky E. Finch J. Clay P. et al.A novel mechanism for skeletal resistance in uremia.Kidney Int. 2000; 58: 753-761Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar have suggested that they antagonize the action of PTH at PTH-R1s and that this explains or contributes to skeletal resistance in chronic renal failure and end-stage renal disease. A simple and thus appealing hypothesis supported not only by the findings in the rodent model but additionally consistent with lowered expression levels of PTH-R1s at skeletal (and renal) sites. The available data make a compelling argument that the bioactivity of C-terminal receptors becomes clinically important in secondary hyperparathyroidism associated with chronic renal failure and end-stage renal disease. The hypocalcemic effect of C-terminal fragments seems to result from actions of these peptides on the skeleton, and some role for these peptides in the pathophysiology of renal osteodystrophy is easy to conceive. Drugs that regulate the absolute levels of C-terminal fragments and/or their levels relative to PTH, or the peptides themsleves, might provide new treatments for some or all types of skeletal abnormalities that contribute to renal osteodystrophy. The biological role of C-terminal fragments in other pathophysiological settings that result from or are associated with abnormal levels of serum PTH remains uncertain as does their role in normal physiology. Since changes in the level of serum calcium regulate the ratio of PTH to C-terminal fragments secreted from the parathyroid glands in normal individuals, it is reasonable to suppose that this is indicative of some physiological role for C-terminal fragments. Although this might well be true, there is at least one set of in vivo studies that challenge this view. The data derive from studies using ovariectomized (OVX) rodent models and they are based on head-to-head comparisons of teriparatide and PTH. When administered daily by subcutaneous injection at equimolar doses, the effects of PTH and teriparatide on various readouts of skeletal metabolism are nearly identical. The only consistent difference between various histomorphometric and bone mineral parameters is the somewhat lower magnitude of effect of PTH than that of teriparatide.24.Kimmel D.B. Bozzato R.P. Kronis K.A. et al.The effect of recombinant human (1–84) or synthetic human (1–34) parathyroid hormone on the skeleton of adult osteopenic ovariectomized rats.Endocrinology. 1993; 132: 1577-1584Crossref PubMed Scopus (0) Google Scholar, 25.Mosekilde L. Sogaard C.H. Danielsen C.C. Torring O. The anabolic affects of human parathyroid hormone (hPTH) on rat vertebral body mass are also reflected in the quality of bone, assessed by biomechanical testing: a comparison study between hPTH-(1–34) and hPTH-(1–84).Endocrinology. 1991; 129: 421-428Crossref PubMed Scopus (171) Google Scholar, 26.Oxlund H. Ejersted C. Andreassen T.T. et al.Parathyroid hormone (1–34) and (1–84) stimulate cortical bone formation both from periosteum and endosteum.Calcif Tissue Int. 1993; 53: 394-399PubMed Google Scholar Similarly, there were no differences between the effects of teriparatide and PTH on mechanical strength of various bones.27.Ejersted C. Andreassen T.T. Oxlund H. et al.Human parathyroid hormone (1–34) and (1–84) increase the mechanical strength and thickness of cortical bone in rats.J Bone Miner Res. 1993; 8: 1097-1101Crossref PubMed Scopus (144) Google Scholar Nearly all these studies tested examined the two peptides at a number of different equimolar doses and did not detect any differences worth mentioning. Another head-to-head comparative study, this time using 5-week-old male mice, assessed the expression of various activated protein-1 genes in the distal femoral metaphysis of mice 30 min after administering different doses of PTH or teriparatide.28.Stanislaus D. Devanarayan V. Hock J.M. In vivo comparison of activated protein-1 gene activation in response to human parathyroid hormone (hPTH)(1–34) and hPTH(1–84) in the distal femur metaphyses of young mice.Bone. 2000; 27: 819-826Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar The efficacies of teriparatide and PTH were similar for any one of these five responses, and their potencies differed significantly for only two of the five activated protein-1 genes examined. In the aggregate, the results" @default.
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• W1988156746 title "The parathyroid polyhormone hypothesis revisited" @default.
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