Subscribe to RSS
DOI: 10.1055/s-2002-33257
Anabolic Effects of Recombinant Human Parathyroid Hormone (1 - 84) and Synthetic Human Parathyroid Hormone (1 - 34) on the Mandibles of Osteopenic Ovariectomized Rats with Maxillary Molar Extraction
Publication History
Received 18 June 2001
Accepted after Revision 25 February 2002
Publication Date:
12 August 2002 (online)
![](https://www.thieme-connect.de/media/hmr/200206/lookinside/thumbnails/10.1055-s-2002-33257-1.jpg)
Abstract
In rodent osteoporosis models such as ovariectomized (OVX) rats, intermittently administered human parathyroid hormone (hPTH) has an anabolic effect in vertebrae and long bones. In the present experiments, subcutaneously injected hPTH(1 - 34) or hPTH(1 - 84) dose- and time-dependently increased bone mineral density (BMD) as measured by dual energy X-ray absorptiometry in mandibles, L2 to L4 vertebrae and femurs of such rats. The highest dose (15.9 nmol/kg, s. c.) of either peptide given four times weekly for 10 weeks completely reversed the effects of overiectomy on BMD. Significant elevation in lumbar BMD after 10 weeks was observed with hPTH(1 - 34) or hPTH(1 - 84) at 1.1 nmol/kg, whereas hPTH(1 - 34) at 1.1 and 4.2 nmol/kg significantly increased BMD of the whole bone and the metaphysis of the femur and the diaphysis of the bone, respectively. In contrast, significant effects of hPTH(1 - 84) administration on BMD increase in the femur were observed at 4.2 and 15.9 nmol/kg in the whole bone and the metaphysis, and in the diaphysis, respectively. Maxillary molar extraction left mandibular BMD in rats with intact ovaries unchanged, but significantly decreased mandibular BMD in OVX rats. Administration of hPTH(1 - 84) for 10 weeks in OVX rats without or with extraction significantly increased BMD in the mandibular molar region at doses of 15.9 and 4.2 nmol/kg, respectively, indicating that efficacy was increased by extraction. A significant BMD increase in the molar region in OVX rats with extraction occurred at only 1.1 nmol/kg of hPTH(1 - 34) and 4.2 nmol/kg of hPTH(1 - 84). Also, BMD of the ramus region was increased by administration of both peptides to a lesser extent than that of the molar region in these rats. Thus, intermittent administration of hPTH, especially hPTH(1 - 34), has an anabolic effect on bone, particularly alveolar bone. Such treatment may increase alveolar bone mass in postmenopausal women with osteoporosis.
Key words
Intermittent Administration - Bone Mineral Density - Bone Formation - Osteoporosis
References
- 1 Chrischilles E, Shireman T, Wallace R. Costs and health effects of osteoporotic fractures. Bone. 1994; 15 377-386
- 2 Christiansen C. Prevention and treatment of osteoporosis: a review of current modalities. Bone. 1992; 13 Suppl. 1 S35-S39
- 3 Lane N E, Thompson J M, Strewler G J, Kinney J H. Intermittent treatment with human parathyroid hormone (hPTH 1 - 34) increased trabecular bone volume but not connectivity in osteopenic rats. J Bone Miner Res. 1995; 10 1470-1477
- 4 Kimmel D B, Recker R R, Gallagher J C, Vaswani A S, Aloia J F. A comparison of iliac bone histomorphometric data in post-menopausal osteoporotic and normal subjects. Bone Miner. 1990; 11 217-235
- 5 Weinstein R S, Hutson M S. Decreased trabecular width and increased trabecular spacing contribute to bone loss with aging. Bone. 1987; 8 137-142
- 6 Christiansen C, Lindsay R. Estrogens, bone loss and preservation. Osteoporosis International. 1990; 1 7-13
- 7 Margolis R N, Canalis E, Partridge N C. Invited review of a workshop: anabolic hormones in bone: basic research and therapeutic potential. J Clin Endocrinol Metab. 1996; 81 872-877
- 8 Reeve J, Davies U M, Hesp R, McNally E, Katz D. Treatment of osteoporosis with human parathyroid peptide and observations on effect of sodium fluoride. British Medical Journal. 1990; 301 314-318
- 9 Reeve J, Meunier P J, Parsons J A, Bernat M, Bijvoet O L, Courpron P, Edouard C, Klenerman L, Neer R M, Renier J C, Slovik D, Vismans F J, Potts Jr. J T. Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. Br Med J. 1980; 280 1340-1344
- 10 Slovik D M, Rosenthal D I, Doppelt S H, Potts Jr. J T, Daly M A, Campbell J A, Neer R M. Restoration of spinal bone in osteoporotic men by treatment with human parathyroid hormone (1 - 34) and 1,25-dihydroxyvitamin D. J Bone Miner Res. 1986; 1 377-381
- 11 Frost H M, Jee W SS. On the rat model of human osteopenias and osteoporoses. Bone Miner. 1992; 18 227-236
- 12 Kalu D N. The ovariectomized rat model of postmenopausal bone loss. Bone Miner. 1991; 15 175-191
- 13 Dempster D W, Cosman F, Parisien M, Shen V, Lindsay R. Anabolic actions of parathyroid hormone on bone. Endocrine Rev. 1993; 14 690-709
- 14 Baumann B D, Wronski T J. Response of cortical bone to antiresorptive agents and parathyroid hormone in aged ovariectomized rats. Bone. 1995; 16 247-253
- 15 Meng X W, Liang X G, Birchman R, Wu D D, Dempster D W, Lindsay R, Shen V. Temporal expression of the anabolic action of PTH in cancellous bone of ovariectomized rats. J Bone Miner Res. 1996; 11 421-429
- 16 Mitlak B H, Burdette-Miller P, Schoenfeld D, Neer R M. Sequential effects of chronic human PTH (1 - 84) treatment of estrogen-deficiency osteopenia in the rat. J Bone Miner Res. 1996; 11 430-439
- 17 Dobnig H, Turner R T. Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology. 1995; 136 3632-3638
- 18 Tam C S, Heersche J NM, Murray T M, Parsons J A. Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration. Endocrinology. 1982; 110 506-512
- 19 Miller S C, Bowman B M, Miller M A, Bagi C M. Calcium absorption and osseous organ-, tissue-, and envelope-specific changes following ovariectomy in rats. Bone. 1991; 12 439-446
- 20 Elovic R P, Hipp J A, Hayes W C. Ovariectomy decreases the bone area fraction of the rat mandible. Calcified Tissue Int. 1995; 56 305-310
- 21 Miller S C, Hunziker J, Mecham M, Wronski T J. Intermittent parathyroid hormone administration stimulates bone formation in the mandibles of aged ovariectomized rats. J Dent Res. 1997; 76 1471-1476
- 22 Bonofiglio D, Maggiolini M, Catalano S, Marsico S, Aquila S, Ando S. Bone mineral density is inversely related to parathyroid hormone in adolescent girls. Horm Metab Res. 2001; 33 170-174
- 23 Kanzawa M, Sugimoto T, Kobayashi T, Kobayashi A, Chihara K. Association between parathyroid hormone (PTH)/PTH-related peptide receptor gene polymorphism and the extent of bone mass reduction in primary hyperparathyroidism. Horm Metab Res. 2000; 32 355-358
- 24 Gomez J M, Gomez N, Fiter J, Soler J. Effects of long-term treatment with GH in the bone mineral density of adults with hypopituitarism and GH deficiency and after discontinuation of GH replacement. Horm Metab Res. 2000; 32 66-70
- 25 D’Erasmo E, Pisani D, Ragno A, Raejntroph N, Letizia C, Acca M. Relationship between serum albumin and bone mineral density in postmenopausal women and in patients with hypoalbuminemia. Horm Metab Res. 1999; 31 385-388
- 26 Elovic R P, Hipp J A, Hayes W C. Maxillary molar extraction causes increased bone loss in the mandible of ovariectomized rats. J Bone Miner Res. 1995; 10 1087-1093
- 27 Gardella T J, Rubin D, Abou-Samra A-B, Keutmann H T, Potts J T , Kronenberg H M, Nussbaum S R. Expression of human parathyroid hormone-(1 - 84) in Escherichia coli as a factor X-cleavable fusion protein. J Biol Chem. 1990; 265 15 854-15 859
- 28 Torres R, de la Piedra C, Rapado A. Clinical usefulness of serum tartrate-resistant acid phosphatase in Paget’s disease of bone: correlation with other biochemical markers of bone remodelling. Calcified Tissue Int. 1991; 49 14-16
- 29 Frolik C A, Cain R L, Sato M, Harvey A K, Chandrasekhar S, Black E C, Tashjian A H, Hock J M. Comparison of recombinant human PTH(1 - 34) (LY333334) with a C-terminally substituted analog of human PTH-related protein(1 - 34) (RS-66 271): In vitro activity and in vivo pharmacological effects in rats. J Bone Miner Res. 1999; 14 163-172
- 30 Kimmel D B, Bozzato R P, Kronis K A, Coble T, Sindrey D, Kwong P, Recker R R. 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 1577-1584
- 31 Lane N E, Sanchez S, Modin G W, Genant H K, Pierini E, Arnaud C D. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest. 1998; 102 1627-1633
- 32 Mosekilde L, Søgaard C H, Danielsen C C, Tørring O, Nilsson M HL. The anabolic effects 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; 129 421-428
- 33 Rittmaster R S, Bolognese M, Ettinger M P, Hanley D A, Hodsman A B, Kendler D L, Rosen C J. Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab. 2000; 85 2129-2134
- 34 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; 27 819-826
- 35 Wronski T J, Yen C-F, Qi H, Dann L M. Parathyroid hormone is more effective than estrogen or bisphosphonates for restoration of lost bone mass in ovariectomized rats. Endocrinology. 1993; 132 823-831
- 36 Nguyen-Yamamoto L, Rousseau L, Brossard J-H, Lepage R, D’Amour P. 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 1386-1392
- 37 Kalu D N, Liu C-C, Hardin R R, Hollis B W. The aged rat model of ovarian hormone deficiency bone loss. Endocrinology. 1989; 124 7-16
- 38 Toolan B C, Shea M, Myers E R, Borchers R E, Seedor J G, Quartuccio H, Rodan G, Hayes W C. Effects of 4-amino-1-hydroxybutylidene bisphosphonate on bone biomechanics in rats. J Bone Miner Res. 1992; 7 1399-1406
- 39 Andersson N, Lindberg M K, Ohlsson C, Andersson K, Ryberg B. Repeated in vivo determinations of bone mineral density during parathyroid hormone treatment in ovariectomized mice. J Endocrinol. 2001; 170 529-537
- 40 Harter L V, Hruska K A, Duncan R L. Human osteoblast-like cells respond to mechanical strain with increased bone matrix protein production independent of hormonal regulation. Endocrinology. 1995; 136 528-535
- 41 Toma C D, Ashkar S, Gray M L, Schaffer J L, Gerstenfeld L C. Signal transduction of mechanical stimuli is dependent on microfilament integrity: identification of osteopontin as a mechanically induced gene in osteoblasts. J Bone Miner Res. 1997; 12 1626-1636
- 42 Salter D M, Robb J E, Wright M O. Electrophysiological responses of human bone cells to mechanical stimulation: evidence for specific integrin function in mechanotransduction. J Bone Miner Res. 1997; 12 1133-1141
- 43 Wozniak M, Fausto A, Carron C P, Meyer D M, Hruska K A. Mechanically strained cells of the osteoblast lineage organize their extracellular matrix through unique sites of alphavbeta3-integrin expression. J Bone Miner Res. 2000; 15 1731-1745
- 44 Dobnig H, Turner R T. Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology. 1995; 136 3632-3638
- 45 LaFlamme S E, Auer K L. Integrin signaling. Semin Cancer Biol. 1996; 7 111-118
- 46 Hunziker J, Wronski T J, Miller S C. Mandibular bone formation rates in aged ovariectomized rats treated with anti-resorptive agents alone and in combination with intermittent parathyroid hormone. J Dent Res. 2000; 79 1431-1438
- 47 Nakajima M, Ejiri S, Tanaka M, Toyooka E, Kohno S, Ozawa H. Effect of intermittent administration of human parathyroid hormone (1 - 34) on the mandibular condyle of ovariectomized rats. J Bone Miner Metab. 2000; 18 9-17
- 48 Hodsman A B, Steer B M, Fraher L J, Drost D J. Bone densitometric and histomorphometric responses to sequential human parathyroid hormone (1 - 38) and salmon calcitonin in osteoporotic patients. Bone Miner. 1991; 14 67-83
- 49 Inomata N, Akiyama M, Kubota N, Jüppner H. Characterization of a novel parathyroid hormone (PTH) receptor with specificity for the carboxyl-terminal region of PTH-(1 - 84). Endocrinology. 1995; 136 4732-4740
- 50 Kaji H, Sugimoto T, Kanatani M, Miyauchi A, Kimura T, Sakakibara S, Fukase M, Chihara K. Carboxyl-terminal parathyroid hormone fragments stimulate osteoclast-like cell formation and osteoclastic activity. Endocrinology. 1994; 134 1897-1904
- 51 Divieti P, Inomata N, Chapin K, Singh R, Jüppner H, Bringhurst F R. Receptors for the carboxyl-terminal region of pth(1 - 84) are highly expressed in osteocytic cells. Endocrinology. 2001; 142 916-925
- 52 Jüppner H, Abou-Samra A B, Freeman M, Kong X F, Schipani E, Richards J, Kolakowski L F, Hock J, Potts J T, Kronenberg H M, Segre G V. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991; 254 1024-1026
N. Horiuchi, D.D.S., Ph.D.
Department of Biochemistry,
Ohu University School of Dentistry
Koriyama 963-8611 · Japan
Fax: + 81 (249) 38-91 92
Email: fwga 4746@mb.infoweb.ne.jp