Calcified Tissue International

, Volume 78, Issue 3, pp 152–161 | Cite as

Calcium Supplementation Does Not Reproduce the Pharmacological Efficacy of Alfacalcidol for the Treatment of Osteoporosis in Rats

  • A. Shiraishi
  • M. Ito
  • N. Hayakawa
  • N. Kubota
  • N. Kubodera
  • E. Ogata
Article

Abstract

The purpose of this study was to assess whether a nutritional supply of calcium (Ca) could be substituted for alfacalcidol (ALF) administration in preventing bone loss due to estrogen deficiency. Female Wistar-Imamichi rats (8 months old) were ovariectomized (OVX) or sham-operated. OVX rats received ALF administration (0.025, 0.5, or 0.1 μg/kg, p.o., 5 times a week) with standard rodent chow [Ca 1.2%, phosphorus (P) 1.04%], a Ca-enriched diet containing 2%, 4%, or 6% Ca (Ca/P ratio of 2, 4, and 6, respectively), or a Ca/P-enriched diet (Ca/P ratio of 1.2). After 12 weeks of treatment, all rats were killed to harvest the spine, serum, and urine samples. Neither the ALF treatment nor the Ca supplement caused hypercalcemia. In the spine, ALF prevented decreases in bone mineral density (BMD) and compressive strength of lumbar spine induced by OVX. Micro-computed tomographic analysis confirmed that ALF significantly improved the trabecular bone pattern factor and the structure model index and suppressed bone destruction. In contrast, of particular interest, high-dose Ca administration did not have marked effects on bone fragility. Also, when both Ca and P were administered in high doses, BMD and mechanical strength decreased dose-dependently, urinary P excretion significantly increased, and serum parathyroid hormone level increased. Together, it is difficult to adjust the Ca supply through diet alone without disrupting the balance between serum Ca and P levels. Consequently, we conclude that ALF is beneficial for the treatment of osteoporosis, which is not achieved by the use of a Ca supplement.

Keywords

Osteoporosis Alfacalcidol Calcium Ovariectomy 

References

  1. 1.
    Aaron JE, Makins NB, Sagreiya K (1987) The microanatomy of trabecular bone loss in normal aging men and women. Clin Orthop 215:260–271PubMedGoogle Scholar
  2. 2.
    Ebeling PR, Sandgren ME, DiMagno EP, Lane AW, DeLuca HF, Riggs BL (1992) Evidence of an age-related decrease in intestinal responsiveness to vitamin D: relationship between serum 1,25-dihydroxyvitamin D3 and intestinal vitamin D receptor concentrations in normal women. J Clin Endocrinol Metab 75:176–182PubMedGoogle Scholar
  3. 3.
    Chapuy MC, Arlot ME, Duboeuf 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
  4. 4.
    Chevally T, Rizzoli R, Nydegger V, Slosman D, Rapin CH, Michel JP, Vasey H, Bonjour JP (1994) Effects of calcium supplements on femoral bone mineral density and vertebral fracture rate in vitamin D-replete elderly patients. Osteoporos Int 4:245–252Google Scholar
  5. 5.
    Recker RR, Hinders S, Davies KM, Heaney RP, Stegman MR, Kimmel DB, Lappe JM (1996) Correcting calcium nutritional deficiency prevents spine fractures in elderly women. J Bone Miner Res 11:1961–1966PubMedGoogle Scholar
  6. 6.
    Dawson-Huges B, Harris SS, Krall EA, Dallal GE (1997) Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 337:670–676Google Scholar
  7. 7.
    Reichel H, Koeffler HP, Norman AW (1989) The role of the vitamin D endocrine system in health and disease. N Engl J Med 320:980–981PubMedGoogle Scholar
  8. 8.
    Brommage R, DeLuca HF (1985) Evidence that 1,25-dihydroxyvitamin D3 in the physiologically active metabolite of vitamin D3. Endocr Rev 6:491–511PubMedGoogle Scholar
  9. 9.
    Orimo H, Shiraki M, Hayashi Y, Hoshino T, Onaya T, Miyazaki S, Kurosawa H, Nakamura T, Ogawa N (1994) Effects of 1αhydroxy-vitamin D3 on lumbar bone mineral density and vertebral fractures in patients with postmenopausal osteoporosis. Calcif Tissue Int 54:370–376CrossRefPubMedGoogle Scholar
  10. 10.
    Reid IR (1996) Vitamin D and its metabolites in the management of osteoporosis. In: Marcus R, Feldman D, Kelsey J (eds) Osteoporosis. Academic Press, New York, pp 1169–1190 Google Scholar
  11. 11.
    Shiraishi A, Takeda S, Masaki T, Higuchi Y, Uchiyama Y, Kubodera N, Sato K, Ikeda K, Nakamura T, Matsumoto T, Ogata E (2000) Alfacalcidol inhibits bone resorption and stimulates formation in an ovariectomized rat model of osteoporosis: distinct actions from estrogen. J Bone Miner Res 15:770–779PubMedGoogle Scholar
  12. 12.
    Shiraishi A, Higashi S, Ohkawa H, Kubodera N, Hirasawa T, Ezawa I, Ikeda K, Ogata E (1999) The advantage of alfacalcidol over vitamin D in the treatment of osteoporosis. Calcif Tissue Int 65:311–316CrossRefPubMedGoogle Scholar
  13. 13.
    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 51:1359–1364PubMedGoogle Scholar
  14. 14.
    Riggs BL (2000) Estrogen/progestins and bone. Osteoporos Int 11(suppl 2):S44Google Scholar
  15. 15.
    Dawson-Hughes B, Dallal GE, Krall EA, Sadowski L, Sahyoun N, Tannenbaum S (1990) A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. N Engl J Med 323:878–883PubMedGoogle Scholar
  16. 16.
    Elders PJ, Lips P, Netelenbos JC, van Ginkel FC, Khoe E, van der Vijgh WJ, van der Stelt PF (1994) Long-term effect of calcium supplementation on bone loss in perimenopausal women. J Bone Miner Res 9:963–970PubMedGoogle Scholar
  17. 17.
    Reid IR, Ames RW, Evans MC, Gamble GD, Sharpe SJ (1995) Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: a randomized controlled trial. Am J Med 98:331–335CrossRefPubMedGoogle Scholar
  18. 18.
    Aloia JF, Vaswani A, Yeh JK, Ross PL, Flaster E, Dilmanian FA (1994) Calcium supplementation with and without hormone replacement therapy to prevent postmenopausal bone loss. Ann Intern Med 15:97–103Google Scholar
  19. 19.
    Standing Committee on the Scientific Evaluation of Dietary References Intake (1997) Calcium. In: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. National Academy Press, Washington DC, pp 71–145 Google Scholar
  20. 20.
    Fukushima M, Suzuki Y, Tohira Y, Matsunaga I, Ochi K, Nagano H, Nishii Y, Suda T (1975) Metabolism of 1α-hydroxyvitamin D3 to 1α,25-dihydroxyvitamin D3 in perfused rat liver. Biochem Biophys Res Commun 66:632–638CrossRefPubMedGoogle Scholar
  21. 21.
    Mosekilde L, Danielsen CC, Knudsen UB (1993) The effects of aging and ovariectomy on the vertebral bone mass and biomechanical properties of mature rats. Bone 14:1–6PubMedGoogle Scholar
  22. 22.
    Ruegsegger P, Koller B, Mullar R (1996) A microtomographic system for the non-destructive evaluation of bone architecture. Calcif Tissue Int 58:24–29PubMedGoogle Scholar
  23. 23.
    Ito M, Nakamura T, Matsumoto T, Tsurusaki K, Hayashi K (1998) Analysis of trabecular microarchitecture of human iliac bone using microcomputed tomography in patients with hip arthrosis with or without vertebral fracture. Bone 23:163–169CrossRefPubMedGoogle Scholar
  24. 24.
    Hildebrand T, Laib A, Muller R, Dequeker J, Ruegsegger P (1999) Direct three-dimensional morphometric analysis of human cancellous bone: microstructural data from spine, femur, iliac crest, and calcaneous. J Bone Miner Res 14:1167–1174PubMedGoogle Scholar
  25. 25.
    Hahn M, Vogel M, Pompesious-Kempa M, Delling G (1992) Trabecular bone pattern factor – a new parameter for simple quantification of bone microarchitecture. Bone 13:327–330CrossRefPubMedGoogle Scholar
  26. 26.
    Hildebrand T, Ruegsegger P (1997) Quantification of bone microarchitecture with the structure model index. Comp Methods Biochem Biomed Eng 1:15–23Google Scholar
  27. 27.
    Baylink D, Stauffer M, Wergedal J, Rich C (1970) Formation, mineralization and resorption of bone in vitamin D-deficient rats. J Clin Invest 49:1122–1134PubMedGoogle Scholar
  28. 28.
    Tanaka Y, DeLuca HF (1971) Bone mineral mobilization activity of 1,25-dihydroxycholecalciferol, a metabolite of vitamin D. Arch Biochem Biophys 146:574–578CrossRefPubMedGoogle Scholar
  29. 29.
    Weinstein RS, Underwood JL, Hutson MS, DeLuca HF (1984) Bone histomorphometry in vitamin D-deficient rats infused with calcium and phosphorus. Am J Physiol 246:E499–E505PubMedGoogle Scholar
  30. 30.
    Kimmel DB, Recker RR, Gallagher JC, Vaswani AS, Aloia JF (1990) A comparison of iliac bone histomorphometric data in post-menopausal osteoporotic and normal subjects. Bone Miner 11:217–235CrossRefPubMedGoogle Scholar
  31. 31.
    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 208:137–145CrossRefPubMedGoogle Scholar
  32. 32.
    Heaney RP, Nordin BEC (2002) Calcium effects on phosphorus absorption: implications for the prevention and co-therapy of osteoporosis. J Am Coll Nutr 21:239–244PubMedGoogle Scholar
  33. 33.
    Heaney RP (2002) The importance of calcium intake for lifelong skeletal health. Calcif Tissue Int 70:70–73CrossRefPubMedGoogle Scholar
  34. 34.
    Leichsenring JM, Norris LM, Lamison SA, Wilson ED, Patton MB (1951) The effect of level of intake on calcium and phosphorus metabolism in college women. J Nutr 45:407–418PubMedGoogle Scholar
  35. 35.
    Draper HH, Sie Tl, Bergan JG (1972) Osteoporosis in aging rats induced by high phosphorus diets. J Nutr 102:1133–1141PubMedGoogle Scholar
  36. 36.
    Anderson GH, Draper HH (1972) Effect of dietary phosphorus on calcium metabolism in intact and parathyroidectomized adult rats. J Nutr 102:1123–1132PubMedGoogle Scholar
  37. 37.
    Laflamme GH, Jowsey J (1972) Bone and soft tissue changes with oral phosphate supplements. J Clin Invest 51:2834–2840PubMedGoogle Scholar
  38. 38.
    Hayakawa N, Higashi S, Shiraishi A, Masaki T, Uchida Y, Hoshino E (2001) The distribution and metabolism of alfacalcidol in bone and bone marrow cells after oral administration. J Bone Miner Res 16(suppl 1):S554Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • A. Shiraishi
    • 1
  • M. Ito
    • 2
  • N. Hayakawa
    • 1
  • N. Kubota
    • 1
  • N. Kubodera
    • 1
  • E. Ogata
    • 3
  1. 1.Product Research DepartmentChugai Pharmacological Co.GotembaJapan
  2. 2.Department of RadiologyNagasaki University School of MedicineNagasakiJapan
  3. 3.Cancer Institute Hospital, Japanese Foundation for Cancer ResearchKoto-wardJapan

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