Calcified Tissue International

, Volume 83, Issue 6, pp 393–403 | Cite as

Bone Parameters are Improved with Intermittent Dosing of Vitamin D3 and Calcitonin

  • C. J. Andresen
  • M. Moalli
  • C. H. Turner
  • E. Berryman
  • R. Pero
  • C. M. BagiEmail author


Intermittent combination of an anabolic agent to promote bone formation and an antiresorptive agent that would prevent further bone loss is a theoretically attractive approach for restoring bone mass. We tested the potential of intermittently dosed calcitriol and calcitonin (CT) to restore bone properties in ovariectomized (Ovx) rats. Rats had Ovx or sham surgery at 8 weeks old and 4 weeks later were assigned to experimental groups: (1) sham vehicle, (2) Ovx vehicle, (3) Ovx + parathyroid hormone (PTH, 40 μg/kg), and (4) Ovx + calcitriol (2 μg/kg) + CT (2 μg/kg). Group 3 received PTH every week throughout the study, and group 4 received calcitriol at weeks 1, 3, 5, and 7 and CT at weeks 2, 4, 6, and 8. Dosing was carried out for 8 weeks with serum, and micro-computed tomographic analysis was done at 0, 4, and 8 weeks. Femurs and tibias were used for radiological analyses and for mechanical testing. Dosing with PTH improved bone mass and structure of cancellous bone at metaphyses of tibias and femurs as well as properties of cortical bone including geometry and strength. Intermittent dosing with calcitriol and CT was less potent in correcting loss of cancellous bone relative to treatment with PTH and had no effect on cortical bone parameters. However, intermittent dosing with calcitriol and CT was robust enough to improve cancellous bone mass and structure through bone formation without causing deleterious side effects. Our data provide additional evidence that therapies can be devised to ameliorate the skeletal defects associated with established osteoporosis.


Vitamin D3 Calcitonin Parathyroid hormone Bone biomarker Bone quality Bone strength Ovariectomized rat 


  1. 1.
    Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R (1993) Anabolic actions of parathyroid hormone on bone. Endocr Rev 14:690–709PubMedCrossRefGoogle Scholar
  2. 2.
    Kimmel DB, Bozzato RP, Kronis KA, Coble T, Sindrey D, Kwong P, Recker RR (1993) The effect of recombinant human (1–84) or synthetic human (1–34) parathyroid hormone on the skeleton of adult osteopenic ovariectomized rats. Endocrinology 132:1577–1584PubMedCrossRefGoogle Scholar
  3. 3.
    Crandall C (2002) Parathyroid hormone for treatment of osteoporosis. Arch Intern Med 16:2297–2309CrossRefGoogle Scholar
  4. 4.
    Black DM, Bilezikian JP, Ensrud KE, Greenspan SL, Palermo L, Hue T, Lang TF, McGowan JA, Rosen CJ (2005) One year of alendronate after one year of parathyroid hormone (1–84) for osteoporosis. N Engl J Med 353:555–565PubMedCrossRefGoogle Scholar
  5. 5.
    Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowen JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ (2003) The effects of parathyroid hormone and alendronate alone or in combination in postemenopausal osteoporosis. N Engl J Med 25:1207–1215CrossRefGoogle Scholar
  6. 6.
    Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM (2003) The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 25:1216–1226CrossRefGoogle Scholar
  7. 7.
    Delmas PD, Vergnaud P, Arlot ME, Pastoureau P, Meunier PJ, Nilssen MH (1995) The anabolic effect of human PTH (1–34) on bone formation is blunted when bone resorption is inhibited by the bisphosphonate tiludronate—is activated resorption a prerequisite for the in vivo effect of PTH on formation in a remodeling system? Bone 16:603–610PubMedCrossRefGoogle Scholar
  8. 8.
    Li M, Li Mosekilde, Søgaard CH, Thomsen JS, Wronski TJ (1995) Parathyroid hormone monotherapy and cotherapy with antiresorptive agents restore vertebral bone mass and strength in aged ovariectomized rats. Bone 16:629–635PubMedCrossRefGoogle Scholar
  9. 9.
    Baumann BD, Wronski TJ (1995) Response of cortical bone to antiresorptive agents and parathyroid hormone in aged ovariectomized rats. Bone 16:247–253PubMedCrossRefGoogle Scholar
  10. 10.
    Rizzoli R, Boonen S, Brandi ML, Burlet N, Delmas P, Reginster JY (2008) The role of calcium and vitamin D in the management of osteoporosis. Bone 42:246–249PubMedCrossRefGoogle Scholar
  11. 11.
    Holick MF (2006) Resurrection of vitamin D deficiency and rickets. J Clin Invest 116:2062–2072PubMedCrossRefGoogle Scholar
  12. 12.
    Narbaitz R, Stumpf WE, Sar M, Huang S, DeLuca HF (1983) Autoradiographic localization of target cells for 1α,25-dihydroxyvitamin D3 in bones from fetal rats. Calcif Tissue Int 35:177–182PubMedCrossRefGoogle Scholar
  13. 13.
    Erben RG, Bromm S, Stangassinger M (1998) Therapeutic efficacy of 1α,25-dihydroxyvitamin D3 and calcium in osteopenic ovariectomized rats: evidence for a direct anabolic effect of 1α,25-dihydroxyvitamin D3 on bone. Endocrinology 139:4319–4328PubMedCrossRefGoogle Scholar
  14. 14.
    Montero-Odasso M, Duque G (2005) Vitamin D in the aging musculoskeletal system: an authentic strength preserving hormone. Mol Aspects Med 26:203–219PubMedCrossRefGoogle Scholar
  15. 15.
    Pike WJ (2006) New steroidal vitamin D receptor modulators: are these ligands the real deal? BoneKEy Osteovision 3:14–18Google Scholar
  16. 16.
    Zaidi M, Inzerillo AM, Moonga BS, Bevis PJR, Huang CL-H (2002) Forty years of calcitonin—where are we now? A tribute to the work of Iain Macintyre, FRS. Bone 30:655–663PubMedCrossRefGoogle Scholar
  17. 17.
    Martin TJ (1999) Calcitonin, an update. Bone 24(Suppl):63S–65SPubMedCrossRefGoogle Scholar
  18. 18.
    Davey RA, Morris HA (2005) The effects of salmon calcitonin-induced hypocalcemia on bone metabolism in ovariectomized rats. J Bone Miner Metab 23:359–365PubMedCrossRefGoogle Scholar
  19. 19.
    Wada S, Udagawa N, Nagata N et al (1996) Calcitonin receptor down-regulation relates to calcitonin resistance in mature mouse osteoclasts. Endocrinology 137:1042–1048PubMedCrossRefGoogle Scholar
  20. 20.
    Frost HM (1983) Bone histomorphometry: analysis of trabecular bone dynamics. In: Recker R (ed) Bone histomorphometry, techniques and interpretation. CRC Press, Boca Raton, FL, pp 109–131Google Scholar
  21. 21.
    Parfitt AM, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry nomenclature, symbols and units. J Bone Miner Res 2:595–610PubMedCrossRefGoogle Scholar
  22. 22.
    Francis RM, Peacock M, Barkworth SA (1984) Renal impairment and its effects on calcium metabolism in elderly women. Age Aging 13:14–20CrossRefGoogle Scholar
  23. 23.
    Cannigia A, Nuti R, Lore F, Martini G, Turchetti V, Righi G (1990) Long-term treatment with calcitriol in postmenopausal osteoporosis. Metabolism 39(Suppl 1):43–49CrossRefGoogle Scholar
  24. 24.
    Ooms ME, Roos JC, Bezemer PD, Van der Vijfh WJF, Bouther LM, Lips P (1995) Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial. J Clin Endocrinol Metab 80:1052–1058PubMedCrossRefGoogle Scholar
  25. 25.
    Gallagher JC, Jerpbak CM, Jee WSS, Johnson KA, DeLuca HF, Riggs BL (1982) 1,25-Dihydroxyvitamin D3: short- and long-term effects on bone and calcium metabolism in patients with postmenopausal osteoporosis. Proc Natl Acad Sci USA 79:3325–3329PubMedCrossRefGoogle Scholar
  26. 26.
    Gallagher JC, Riggs BL, Recker RR, Goldgar D (1989) The effect of calcitriol on patients with postmenopausal osteoporosis with special reference to fracture frequency. Proc Soc Exp Biol Med 191:287–292PubMedGoogle Scholar
  27. 27.
    Tilyard M, Spears G, Thomson J, Dovey S (1992) Treatment of postmenopausal osteoporosis with calcitriol or calcium. N Engl J Med 326:357–362PubMedGoogle Scholar
  28. 28.
    Shiraki M, Itoh H, Orimo H (1993) The ultra long-term treatment of senile osteoporosis with 1 alpha-hydroxyvitamin D3. Bone Miner 20:223–234PubMedCrossRefGoogle Scholar
  29. 29.
    Chapuy MC, Arlot ME, Dubeuf F, Brun J, Crouzet B, Arnaud S, Delmas PD, Meunier PJ (1992) Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 327:1637–1642PubMedGoogle Scholar
  30. 30.
    Vahle JL, Sato M, Long GG, Young JK, Francis PC, Engelhardt JA, Westmore MS, Linda Y, Nold JB (2002) Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1–34) for 2 years and relevance to human safety. Toxicol Pathol 30:312–321PubMedCrossRefGoogle Scholar
  31. 31.
    Sato M, Ma YL, Hock JM, Westmore MS, Vahle J, Villanueva A, Turner CH (2002) Skeletal efficacy with parathyroid hormone in rats was not entirely beneficial with long-term treatment. J Pharmacol Exp Ther 302:304–313PubMedCrossRefGoogle Scholar
  32. 32.
    Allen MR, Burr DB (2007) Mineralization, microdamage, and matrix: how bisphosphonates influence material properties of bone. BoneKEy Osteovision 4:49–60Google Scholar
  33. 33.
    Lau KHW, Baylink D (1999) Vitamin D therapy of osteoporosis: plain vitamin D therapy versus active vitamin D analog (D-hormone) therapy. Calcif Tissue Int 65:295–306PubMedCrossRefGoogle Scholar
  34. 34.
    Devlin H, Lumb G, Ferguson MWJ (1992) Serum parathyroid hormone and calcitonin levels following ovariectomy in the adult rat. Exp Clin Endocrinol 99:84–86PubMedGoogle Scholar
  35. 35.
    Chesnut CHIII, Silverman S, Andriano K, Genant H, Gimona A, Harris S, Kiel D, LeBoff M, Maricic M, Miller P, Moniz C, Peacock M, Richardson P, Watts N, Baylink D (2000) A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med 109:267–276Google Scholar
  36. 36.
    McDermott MT, Kidd GS (1987) The role of calcitonin in the development and treatment of osteoporosis. Endocr Rev 8:377–3390PubMedCrossRefGoogle Scholar
  37. 37.
    Body J-J (2002) Calcitonin for the long-term prevention and treatment of postmenopausal osteoporosis. Bone 30:75S–79SPubMedCrossRefGoogle Scholar
  38. 38.
    Kanis JA (2002) Calcitonin in osteoporosis. Bone 30:65S–66SPubMedCrossRefGoogle Scholar
  39. 39.
    Wallach S, Roussau G, Martin L, Azria M (1999) Effects of calcitonin on animal and in vitro models of skeletal metabolism. Bone 25:509–516PubMedCrossRefGoogle Scholar
  40. 40.
    Kronenberg HM (1997) Parathyroid hormone and osteocalcin—when friends become strangers. Endocrinology 138:3083–3084PubMedCrossRefGoogle Scholar
  41. 41.
    Raisz LG, Wener JA, Trummel CL et al (1972) Induction, inhibition and escape as phenomenon in bone resorption. Excerpta Medica Int Cong Ser 243:446–453Google Scholar
  42. 42.
    Messer HH, Copp DH (1974) Changes in response to calcitonin following prolonged administration to intact rats. Proc Soc Exp Biol Med 146:643–647PubMedGoogle Scholar
  43. 43.
    Tada K, Yamamuro T, Okumura H, Kasai R, Takahashi H (1990) Restoration of axial and apendicular bone volumes by h-PTH (1–34) in parathyreoidectomized and osteopenic rats. Bone 11:163–169PubMedCrossRefGoogle Scholar
  44. 44.
    Chappard D, Retailleau-Gaborit N, Legrand E, Felix Basle M, Audran M (2005) Comparison insight bone measurements by histomorphometry and mCT. J Bone Miner Res 20:1177–1184PubMedCrossRefGoogle Scholar
  45. 45.
    Miller MA, Bare SP, Recker RR, Smith SY, Fox J (2008) Intratrabecular tunneling increases trabecular number throughout the skeleton of ovariectomized rhesus monkeys treated with parathyroid hormone 1–84. Bone 42:1175–1183PubMedCrossRefGoogle Scholar
  46. 46.
    Nishida S, Yamaguchi A, Tanizawa T, Endo N, Mashiba T, Uchiyama Y, Suda T, Yoshiki S, Takahashi HE (1994) Increased bone formation by intermittent PTH administration is due to the simulation of proliferation and differentiation of osteoprogenitor cells in bone marrow. Bone 15:717–723PubMedCrossRefGoogle Scholar
  47. 47.
    Wronski TJ, Ratkus AM, Thomsen JS, Vulcan Q, Mosekilde L (2001) Sequential treatment with basic fibroblast growth factor and parathyroid hormone restores lost cancellous bone mass and strength in the proximal tibia of aged ovariectomized rats. J Bone Miner Res 16:1399–1407PubMedCrossRefGoogle Scholar
  48. 48.
    Iida-Klein A, Hughes C, Lu SS, Moreno A, Shen V, Dempster DW, Cosman F, Lindsay R (2006) Effects of cyclic versus daily hPTH (1–34) regimens on bone strength in association with BMD, biochemical markers, and bone structure in mice. J Bone Miner Res 21:274–282PubMedCrossRefGoogle Scholar
  49. 49.
    Andresen CJ, Olson E, Nduaka CI, Pero R, Bagi CM (2006) Action of calciotropic hormones on bone metabolism—role of vitamin D3 in bone remodeling events. Am J Immunol 2:40–51CrossRefGoogle Scholar
  50. 50.
    Frost HM (1990) Structural adaptation to mechanical usage (SATMU). 1. Redefining Wolff’s law: the bone remodeling problem. Anat Rec 226:414–422PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • C. J. Andresen
    • 1
  • M. Moalli
    • 1
  • C. H. Turner
    • 2
  • E. Berryman
    • 1
  • R. Pero
    • 1
  • C. M. Bagi
    • 1
    Email author
  1. 1.World Wide Comparative Medicine, Pfizer Global Research and DevelopmentPfizer Inc.GrotonUSA
  2. 2.Orthopedic ResearchIndiana University-Purdue UniversityIndianapolisUSA

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