Skip to main content
SpringerLink
Log in

Effects of combined and separate intermittent administration of low-dose human parathyroid hormone fragment (1–34) and 17β-estradiol on bone histomorphometry in ovariectomized rats with established osteopenia

  • Laboratory Investigations
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Summary

To evaluate the potential use of a combination of parathyroid hormone (PTH) and estrogen as therapy for osteoporosis, we examined the effects of combined and separate administration of low-dose PTH and estradiol in ovariectomized rats with established osteopenia. Ovariectomized rats were untreated for 5 weeks after surgery and then injected s.c. with vehicle (Ovx+V), 1–34 hPTH (2.5 μg/kg/day) (Ovx+P), 17β-estradiol (50 μg/kg/day) (Ovx+E), or a combination of these (Ovx+P+E), for a further 4 weeks. We found no differences in serum calcium, tubular reabsorption of phosphate, or 25OHD. 1,25(OH)2D levels were significantly higher in Ovx+P and lower in Ovx+E, when compared with Ovx+V. Though there was no change in bone mineral density (BMD) in the diaphysis region of femurs, reduction of BMD in the distal region of the femurs in Ovx+V was reversed in Ovx+E and Ovx+P+E. Compared with Ovx+V, Ovx+P and Ovx+P+E had significantly higher cancellous bone volume (Cn-BV/TV) whereas Ovx+E showed a nonsignificant increase. When indices of bone turnover were examined, PTH alone showed a small but not significant improvement in bone formation rate (BFR). Increased osteoclast surface (OCS), as the result of ovariectomy, was inhibited in Ovx+E and Ovx+P+E. Estrogen alone (Ovx+E) severely inhibited BFR, but co-administration of PTH and estrogen (Ovx+P+E) showed an impressive reversal of such inhibition. The changes in BFR were mainly derived from changes in double-labeled surface (dLS), except a small increase in mineral apposition rate was also observed in Ovx+P+E. These results suggest that, after extensive cancellous bone loss in the rat tibia, low doses of PTH function anabolically, especially in situations where the bone formation rate is low. A combination of both estrogen and PTH may provide the best treatment for improving bone mass by decreasing resorption and maintaining a high bone formation rate.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Lindsay R, Hart DM, Aitken JM, MacDonald EB, Anderson JB, Clarke AC (1976) Long-term prevention of postmenopausal osteoporosis by estrogen. Lancet 1:1038–1040

    Google Scholar 

  2. Lindsay R, Hart DM, Forrest C, Baird C (1980) Prevention of spinal osteoporosis in oophorectomized women. Lancet 2:1151–1154

    Google Scholar 

  3. Reeve J, Meunier PJ, Parsons JA, Bernat M, Bijvoet OLM, Courpron P, Edouard C, Klenerman L, Neer RM, Renier JC, Slovik D, Vismans EJFE, Potts JT (1980) Anabolic effect of human PTH on trabecular bone in involutional osteoporosis: a multicenter trial. Br Med J 280:1340

    Google Scholar 

  4. Slovik D, Rosenthal DI, Doppelt SH, Potts JT, Daly MA, Cambell JA, Neer RM (1986) Restoration of spinal bone in osteoporotic men by treatment with human PTH (1–34) and 1,25-dihydroxvitamin D. J Bone Miner Res 1:377–382

    Google Scholar 

  5. Reeve J, Davies UM, Hesp R, McNally E, Katz D (1990) Treatment of osteoporosis with human parathyroid peptide and observations on effect of sodium fluoride. Br Med J 301:314–318

    Google Scholar 

  6. Parisien M, Silverberg SJ, Shane E, Cruz LDA, Lindsay R, Bilezikian JP, Dempster DW (1990) The histomorphometry of bone in primary hyperparathyroidism: preservation of cancellous bone structure. J Clin Endocrinol Metab 70:930–938

    Google Scholar 

  7. Meunier PJ, Bressot C (1982) Endocrine influences on bone cells and bone remodeling evaluated by clinical histomorphometry. In: Parson JA (ed) Endocrinology of calcium metabolism. Raven Press, New York, pp 445–458

    Google Scholar 

  8. Saville PD (1969) Changes in skeletal mass and fragility with castration in the rat: a model of osteoporosis. J Am Geriatr Soc 17:155–169

    Google Scholar 

  9. Aitken JM, Armstrong E, Armstrong JB (1972) Osteoporosis after oophorectomy in the mature female rat and the effect of estrogen and/or progestogen replacement therapy in its prevention. J Endocrinol 55:79–87

    Google Scholar 

  10. Lindgren JU, Lindholm TS (1979) Effect of I-alphahydroxyvitamin D on osteoporosis in rat induced by oophorectomy. Calcif Tissue Int 27:161–164

    Google Scholar 

  11. Kalu DN, Hardin RR, Cockerham R (1984) Evaluation of the pathogenesis of skeletal changes in ovariectomized rats. Endocrinology 115:507–512

    Google Scholar 

  12. Wronski TJ, Lowry PL, Walsh CC, Ignaszewski LA (1985) Skeletal alterations in ovariectomized rats. Calcif Tissue Int 37:324–328

    Google Scholar 

  13. Wronski TJ, Walsh CC, Ignaszewski LA (1986) Histologic evidence for osteopenia and increased bone turnover in ovariectomized rats. Bone 7:119–123

    Google Scholar 

  14. Wronski TJ, Cintron M, Dann LM (1988) Temporal relationship between bone loss and increased bone turnover in ovariectomized rats. Calcif Tissue Int 43:179–183

    Google Scholar 

  15. Wronski TJ, Dann LM, Scott KS, Cintron M (1989) Long-term effects of ovariectomy and aging on the rat skeleton. Calcif Tissue Int 45:360–366

    Google Scholar 

  16. Cruess RL, Hong KC (1979) The effect of long-term estrogen administration on bone metabolism in the female rat. Endocrinology 104:1188–1193

    Google Scholar 

  17. Lindquist B, Budy AM, McLean FC, Howard JL (1960) Skeletal metabolism in estrogen-treated rats studied by means of 45Ca. Endocrinology 66:100–111

    Google Scholar 

  18. Takano-Yamamoto T, Rodan GA (1990) Direct effects of 17β-estradiol on trabecular bone in ovariectomized rats. Proc Natl Acad Sci 87:2172–2176

    Google Scholar 

  19. Wronski TJ, Cintron M, Doherty AL, Dann LM (1988) Estrogen treatment prevents osteopenia and depresses bone turnover in ovariectomized rats. Endocrinology 123:681–686

    Google Scholar 

  20. Turner RT, Vandersteenhoven JJ, Bell NH (1987) The effects of ovariectomy and 17β-estradiol on cortical bone histomorphometry in growing rats. J Bone Miner Res 2:115–122

    Google Scholar 

  21. Turner RT, Wakley GK, Hannon KS, Bell NH (1980) Tamoxifen inhibits osteoclast-mediated resorption of trabecular bone in ovarian hormone-deficient rats. Endocrinology 122:1146–1150

    Google Scholar 

  22. Tam CS, Heersche JNM, Murray TM, Parsons JA (1982) PTH stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration. Endocrinology 110:506–512

    Google Scholar 

  23. Gera I, Dobrolet N, Hock JM (1989) Intermittent, but not continuous, PTH increases bone mass independently of resorption (abstract). J Bone Miner Res 4 (suppl 1):S744

    Google Scholar 

  24. Gunness-Hey M, Hock JM (1984) Increased trabecular bone mass in rats treated with synthetic human PTH. Metab Bone Dis Rel Res 5:177–181

    Google Scholar 

  25. Hock JM, Gera I, Fonseca J, Raisz LG (1988) Human PTH (1–34) increases bone in ovariectomized and orchidectomized rats. Endocrinology 122:2899–2903

    Google Scholar 

  26. Hock JM, Hummert J, Boyce R, Fonseca J, Raisz LG (1989) Resorption is not essential for the stimulation of bone growth by human PTH 1–34 in rats in vivo. J Bone Miner Res 4:449–458

    Google Scholar 

  27. Liu CC, Kalu DN (1990) Human PTH prevents bone loss and augments bone formation in sexually mature ovariectomized rats. J Bone Miner Res 3:973–982

    Google Scholar 

  28. Hefti E, Trechsel U, Bonjour JP, Fleisch H, Schenk R (1982) Increase of whole body calcium and skeletal mass in normal and osteoporotic adult rats treated with PTH. Clin Sci 62:389–396

    Google Scholar 

  29. Tada K, Yamauro T, Okumura H, Kasai R, Takahashi H (1990) Restoration of axial and appendicular bone volumes by h-PTH (1–34) in parathyroidectomized and osteopenic rats. Bone 11:163–169

    Google Scholar 

  30. Kalu DN, Echon R, Hollis BW (1991) Modulation of ovariectomy-related bone loss by parathyroid hormone in rats. Mech Ageing Dev 56:49–62

    Google Scholar 

  31. Parfitt AM, Mathews CHE, Villanueva AR, Kleerekoper M, Frame B, Rao DS (1983) Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the microanatomic and cellular mechanisms of bone loss. J Clin Invest 72:1396–1409

    Google Scholar 

  32. Okumura H, Yamamuro T, Kasai R, Hayashi T, Tada K, Nishii Y (1988) Effect of 1α-hydroxyvitamin D3 on osteoporosis induced by immobilization combined with ovariectomy in rats. Bone 8:351–355

    Google Scholar 

  33. Reinhardt TA, Horst RL, Orf JW, Hollis BW (1984) A microassay for 1,25-dihydroxyvitamin D not requiring HPLC: application to clinical studies. J Clin Endocrinol Metab 58:91–98

    Google Scholar 

  34. Preece MA, O'Riordan JLH, Lawson DEM, Kodicek E (1974) A competitive protein-binding assay for 25-hydroxycholecalciferol and 25-hydroxyergocalciferol in serum. Clin Chim Acta 54:235–242

    Google Scholar 

  35. Wronski TJ, Yen CF, Scott KS (1990) Estrogen and diphosphonate treatment provide long-term protection against vertebral osteopenia in ovx rats (abstract). J Bone Miner Res 5 (suppl 2): S445

  36. Baron R, Tross R, Vignery A (1984) Evidence of sequential remodeling in rat trabecular bone: morphology, dynamic, histomorphometry and changes during skeletal maturation. Anat Rec 208:137–145

    Google Scholar 

  37. Heaney RP, Recker RR, Saville PD (1978) Menopausal changes in bone remodeling. J Lab Clin Med 92:964–970

    Google Scholar 

  38. Riggs BL, Melton LJ (1986) Involutional osteoporosis. N Engl J Med 314:1676–1686

    Google Scholar 

  39. Delmas PD, Wahner HW, Mann KG, Riggs BL (1983) Assessment of bone turnover in postmenopausal osteoporosis by measurement of serum bone Gla-protein. J Lab Clin Med 102:470–476

    Google Scholar 

  40. Stepan JJ, Pospichal J, Presl J, Pacovsky V (1987) Bone loss and biochemical indices of bone remodeling in surgically induced postmenopausal women. Bone 8:279–284

    Google Scholar 

  41. Fogelman I, Poser JW, Smith ML, Hart DM, Bevan JA (1984) Alterations in skeletal metabolism following oophorectomy. In: Christiansen C, Arnaud CD, Nordin BEC, Parfitt AM, Peck WA, Riggs BL (eds) Osteoporosis I. Glostrup Hospital, Copenhagen, pp 519

    Google Scholar 

  42. Steiniche T, Hasling C, Charles P, Eriksen EF, Mosekilde L, Melsen F (1989) A randomized study on the effects of estrogen/ gestagen or high dose oral calcium on trabecular bone remodeling in postmenopausal osteoporosis. Bone 10:313–320

    Google Scholar 

  43. Recker RR, Saville PD, Heaney RP (1977) Effect of estrogens and calcium carbonate on bone loss in postmenopausal women. Ann Intern Med 87:649–655

    Google Scholar 

  44. Christiansen C, Christiansen MS, Larsen NE, Transbol I (1982) Pathophysiological mechanisms of estrogen effect on bone metabolism. J Clin Endocrinol Metab 55:1124–1130

    Google Scholar 

  45. Riggs BL, Hamstra A, DeLuca HF (1981) Assessment of 25-hydroxyvitamin D 1-hydroxylase reserve in postmenopausal osteoporosis by administration of parathyroid extract. J Clin Endocrinol Metab 53:633–635

    Google Scholar 

  46. Gallagher JC, Riggs BL, DeLuca HF (1980) Effect of estrogen on calcium absorption and serum vitamin D metabolites in postmenopausal osteoporosis. J Clin Endocrinol Metab 51:1359–1364

    Google Scholar 

  47. Nordin BEC, Peacock M, Crilly RG, Marshall DH (1979) Calcium absorption and plasma 1,25-(OH)2-D levels in postmenopausal osteoporosis. In: Vitamin D. Basic research and its clinical application. Walter de Gruyter, New York, p 99

    Google Scholar 

  48. Lindgren JU, DeLuca HF (1982) Role of PTH and 1,25-dihydroxyvitamin D in the development of osteopenia in oophorectomized rats. Calcif Tissue Int 34:510–514

    Google Scholar 

  49. Okamoto S, DeLuca HF, Nagataki S (1982) Low serum 1,25(OH)2 vitamin D3 in oophorectomy osteoporosis model rats: weight-matched control study (abstract). 4th Annual Scientific Meeting of the American Society for Bone and Mineral Research, San Francisco, CA S57

  50. Falch JA, Oftebro H, Hang E (1980) Early postmenopausal bone loss is not associated with a decrease in circulating levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D or vitamin D binding proteins in female rats. J Endocrinol 86:419–423

    Google Scholar 

  51. Pavlovitch H, Clemens TL, Laouari D, O'Riordan JLH, Balsans (1980) Lack of effect of Ovx on the metabolism of vitamin D and intestinal calcium-binding proteins in female rats. J Endocrinol 86:419–424

    Google Scholar 

  52. Ismail F, Epstein S, Fallon MD, Thomas SB, Reinhardt TA (1988) Serum bone gla protein and the vitamin D endocrine system in the oophorectomized rat. Endocrinology 1221:624–630

    Google Scholar 

  53. Thomas ML, Hope WG, Ibarra M (1988) The relationship between long bone growth rate and duodenal calcium transport in female rats. J Bone Miner Res 3:503–507

    Google Scholar 

  54. Baski SN, Kenny AD (1977) Estradiol stimulation of 1,25-dihydroxyvitamin D production in normal rats. Pharmacology 19:186–190

    Google Scholar 

  55. Mawer EB, Clements MR, Hickey CD (1990) Estrogen enhances metabolic clearance of 25-hydroxyvitamin D in rats (abstract). J Bone Miner Res 5 (suppl 2):S131

    Google Scholar 

  56. Lemann J, Gray RW, Maierhofer WJ, Adams ND (1984) Effects of weight loss on serum 1,25-(OH)2-vitamin D concentrations in adults: a preliminary report. Calcif Tissue Int 36:139–144

    Google Scholar 

  57. Ebeling PR, Sandgren ME, DiMagno EP, DeLuca HF, Riggs BL (1990) Relationship between serum 1,25-dihydroxyvitamin D and intestinal vitamin D receptor concentrations in normal women: evidence for age-related decrease in intestinal responsiveness (abstract). J Bone Miner Res 5 (suppl 2):S274

    Google Scholar 

  58. Chan SDH, Chiu DKH, Atkins D (1984) Oophorectomy leads to a selective decrease in 1,25-dihydroxycholecalciferol receptors in rat jejunal villous cells. Clin Sci 66:745–748

    Google Scholar 

  59. Faugere MC, Okamoto S, DeLuca HF, Malluche HH (1986) Calcitriol corrects bone loss induced by oophorectomy in rats. Am J Physiol 250:E35-E38

    Google Scholar 

  60. Gunness-Hey M, Gera I, Fonseca J, Raisz LG, Hock JM (1988) 1,25 dihydroxyvitamin D3 alone or in combination with PTH does not increase bone mass in young rats. Calcif Tissue Int 43:284–288

    Google Scholar 

  61. Bradbeer JN, Arlot M, Reeve J, Meunier PJ (1988) Human parathyroid peptide (hPTH 1–34) treatment increases the mean wall thickness of iliac trabecular packets of new bone in patients with crush fracture osteoporosis. J Bone Miner Res 3:S160

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Regional Bone Center, Helen Hayes Hospital, Rt. 9W, 10993, W. Haverstraw, New York

    V. Shen, D. W. Dempster, R. W. E. Mellish, R. Birchman, W. Horbert & R. Lindsay

  2. Department of Medicine, Columbia University, New York, New York

    D. W. Dempster & R. Lindsay

  3. Department of Pathology, Columbia University, New York, New York

    D. W. Dempster & R. Lindsay

Authors
  1. V. Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. W. Dempster
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. W. E. Mellish
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Birchman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W. Horbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R. Lindsay
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shen, V., Dempster, D.W., Mellish, R.W.E. et al. Effects of combined and separate intermittent administration of low-dose human parathyroid hormone fragment (1–34) and 17β-estradiol on bone histomorphometry in ovariectomized rats with established osteopenia. Calcif Tissue Int 50, 214–220 (1992). https://doi.org/10.1007/BF00296285

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00296285

Key words

Search

Navigation