Skip to main content
SpringerLink
Log in

Alfacalcidol-supplemented raloxifene therapy has greater bone-sparing effect than raloxifene-alone therapy in postmenopausal Japanese women with osteoporosis or osteopenia

Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Cite this article

Abstract

Vitamin D insufficiency is prevalent in osteopenic and osteoporotic postmenopausal women. The persistent increase in circulating parathyroid hormone (PTH) caused by vitamin D insufficiency reduces bone density response to antiresorptive agents in these postmenopausal women. It is not well known whether administration of raloxifene might increase serum PTH secondary to the suppression of serum calcium in postmenopausal women with osteopenia or osteoporosis. We tried to assess whether raloxifene might affect serum PTH and whether the addition of alfacalcidol to raloxifene therapy could have favorable effects on bone mineral density (BMD) and bone turnover as compared to raloxifene-alone therapy in postmenopausal Japanese women with osteoporosis or osteopenia (≤2.0 SD based on young Japanese women). A total of 169 subjects were randomly assigned to groups receiving 60 mg raloxifene (R), or 1 μg alfacalcidol (D), or a combination of both (R + D) for 2 years. Serum levels of 25-hydroxyvitamin D [25(OH)D] were measured at randomization. The modified ‘intention to treat’ method was used. We compared the groups using a Tukey–Kramer test for changes in L- and TH-BMD and calcium metabolism when significant differences were found using one-way ANOVA. The parameters in each group during the experimental period were analyzed by means of paired t tests. Baseline 25(OH)D and i-PTH were 23.7 ng/ml and 38.4 pg/ml, respectively. At 6 months, i-PTH demonstrated a significant increase (+21.0%) in the R-group whereas significant decreases in i-PTH were observed in the D-group and combination-group (−15.9 and −8.9%, respectively). There were significant increases in L-BMD in the R + D-group (+4.1% at 1 year and +4.7% at 2 years, P < 0.0001) and in the R-group (+2.9% at 1 year and +2.8% at 2 years, P < 0.001), but the difference between the groups did not reach a significant level. Vitamin D status at randomization did not affect the subsequent BMD response in coadministration of alfacalcidol with raloxifene. Supplementation with alfacalcidol to raloxifene therapy demonstrates a greater bone-sparing effect by suppressing the secondary increment of serum PTH than when raloxifene is used alone.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Hagenau T, Vest R, Gissel TN et al (2009) Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: an ecologic meta-analysis. Osteoporos Int 20:133–140

    Article  PubMed  CAS  Google Scholar 

  2. Dawson-Hughes BN, Heaney RP, Holick MF et al (2005) Estimates of optimal vitamin D status. Osteoporos Int 16:713–716

    Article  PubMed  CAS  Google Scholar 

  3. Steingrimsdottir L, Gunnarsson O, Indridason O et al (2005) Relationship between serum parathyroid hormone levels, vitamin D sufficiency and calcium intake. JAMA 294:2336–2341

    Article  PubMed  CAS  Google Scholar 

  4. The RECORD trial group (2005) Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomized placebo-controlled trial. Lancet 365:1621–1628

    Article  Google Scholar 

  5. Jackson RD, LaCroix AZ, Gass M et al (2006) Calcium plus vitamin D and the risk of fracture. N Engl J Med 354:669–683

    Article  PubMed  CAS  Google Scholar 

  6. Adams JS, Hewison M (2010) Update in vitamin D. J Clin Endocrinol Metab 95:471–478

    Article  PubMed  Google Scholar 

  7. Gallagher JC, Sai A (2010) Vitamin D insufficiency, deficiency, and bone health. J Clin Endcrinol Metab 95:2630–2633

    Article  CAS  Google Scholar 

  8. Heaney RP, Davies KM, Chen TC et al (2003) Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77:204–210

    PubMed  CAS  Google Scholar 

  9. Hollis BW, Wagner CL (2004) Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr 79:717–726

    PubMed  CAS  Google Scholar 

  10. Vieth R, Chan PC, MacFarlane GD (2001) Efficacy and safety of vitamin D intake exceeding the lowest observed adverse effect level. Am J Clin Nutr 73:288–298

    PubMed  CAS  Google Scholar 

  11. Hoeck HC, Li B, Qvist P (2009) Changes in 25-hydroxyvitamin D3 to oral treatment with vitamin D3 in postmenopausal females with osteoporosis. Osteoporos Int 20:1329–1335

    Article  PubMed  CAS  Google Scholar 

  12. Reginster JY (2005) The high prevalence of inadequate serum vitamin D levels and implications for bone health. Curr Med Res Opin 21:579–585

    Article  PubMed  CAS  Google Scholar 

  13. Lips P (2001) Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev 22:477–501

    Article  PubMed  CAS  Google Scholar 

  14. Sakuma M, Endo N, Oinuma T et al (2006) Vitamin D and intact PTH status in patients with hip fracture. Osteoporos Int 17:1608–1614

    Article  PubMed  CAS  Google Scholar 

  15. Sakuma M, Endo N, Oinuma T (2007) Serum 25-OHD insufficiency as a risk factor for hip fracture. J Bone Miner Metab 25:147–150

    Article  PubMed  CAS  Google Scholar 

  16. Gorai I, Chaki O, Taguchi Y et al (1999) Early postmenopausal bone loss is prevented by estrogen and partially by 1-alpha-OH-vitamin D3: therapeutic effects of estrogen and/or 1-alpha-OH-vitamin D3. Calcif Tissue Int 65:16–22

    Article  PubMed  CAS  Google Scholar 

  17. Orimo H, Shiraki M, Hayashi Y et al (1994) Effects of 1 alpha-hydroxyvitamin D3 on lumbar bone mineral density and vertebral fractures in patients with postmenopausal osteoporosis. Calcif Tissue Int 54:370–376

    Article  PubMed  CAS  Google Scholar 

  18. Ringe JD, Farahmand P, Schacht E, Rozehnal A (2007) A superiority of a combined treatment of alendronate and alfacalcidol compared to the combination of alendronate and plain vitamin D or alfacalcidol alone in established postmenopausal or male osteoporosis (AAC-Trial). Rheumatol Int 27:425–434

    Article  PubMed  CAS  Google Scholar 

  19. Adami S, Giannini S, Bianchi G et al (2009) Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int 20:239–244

    Article  PubMed  CAS  Google Scholar 

  20. Barone A, Pioli G, Girasole G et al (2007) Secondary hyperparathyroidism due to hypovitaminosis D affects bone mineral density response to alendronate in elderly women with osteoporosis: a randomized controlled trail. J Am Geriatr Soc 55:752–757

    Article  PubMed  Google Scholar 

  21. Geller JL, Hu B, Reed S et al (2008) Increase in bone mass after correction of vitamin D insufficiency in bisphosphonate-treated patients. Endocr Pract 14:293–297

    PubMed  Google Scholar 

  22. Orimo H, Hayashi Y, Fukunaga M et al (2001) Diagnostic criteria for primary osteoporosis: year (2000) revision. J Bone Miner Metab 19:331–337

    Article  PubMed  CAS  Google Scholar 

  23. Slemenda CW, Longcope CL, Peacock M et al (1996) Sex steroids, bone mass, and bone loss. A prospective study of pre-, peri- and postmenopausal women. J Clin Invest 97:14–21

    Article  PubMed  CAS  Google Scholar 

  24. Gorai I, Chaki O, Nakayama M et al (1995) Urinary biochemical markers for bone resorption during the menstrual cycle. Calcif Tissue Int 57:100–104

    Article  PubMed  CAS  Google Scholar 

  25. Blackburn GF, Shah HP, Kenten JH et al (1991) Electrochemiluminescence detection for development of immunoassays and DNA probe assays for clinical diagnosis. Clin Chem 37:1534–1539

    PubMed  CAS  Google Scholar 

  26. Garnero P, Borel O, Delmas PD (2001) Evaluation of a fully automated serum assay for C-terminal cross-linking telopeptide of type I collagen in osteoporosis. Clin Chem 47:694–702

    PubMed  CAS  Google Scholar 

  27. Hollis BW, Kamerud JQ, Selvaag SR et al. (1993) Determination of vitamin D status by radioimmunoassay with an 125I-labeled tracer. Clin Chem 39:529–533

    Google Scholar 

  28. Fillee C et al (2008) Validation of the Beckman Coulter Unicel® DxI 800 for intra-operative and routine intact parathyroid hormone assay: A073. Clin Chem Lab Med 46:A168

    Google Scholar 

  29. Abraha I, Montedori A (2010) Modified intention to treat reporting in randomized controlled trials: systemic review. BMJ 340:c2697

    Article  PubMed  Google Scholar 

  30. Heaney RP (2004) Functional indices of vitamin D status and ramifications of vitamin D deficiency. Am J Clin Nutr 80 (suppl):1706S–1709S

    Google Scholar 

  31. Gorai I, Tanaka Y, Hattori S, Iwaoki Y (2010) Assessment of adherence to treatment of postmenopausal osteoporosis with raloxifene and/or alfacalcidol in postmenopausal Japanese women. J Bone Miner Metab 28:176–184

    Article  PubMed  CAS  Google Scholar 

  32. Thomas MK, Lloyd-Jones DM, Thadhani RI et al (1998) Hypovitaminosis D in medical inpatients. N Engl J Med 338:777–783

    Article  PubMed  CAS  Google Scholar 

  33. Chapuy MC, Preziosi P, Maamer M et al (1997) Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 7:439–444

    Article  PubMed  CAS  Google Scholar 

  34. Kinyamu HK, Gallagher JC, Rafferty KA et al (1998) Dietary calcium and vitamin D intake in elderly women: effect on serum parathyroid hormone and vitamin D metabolites. Am J Clin Nutr 67:342–348

    PubMed  CAS  Google Scholar 

  35. Lips P, Duong TU, Oleksir A (2001) A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcome of raloxifene evaluation clinical trail. J Clin Endocrinol Metab 86:1212–1221

    Article  PubMed  CAS  Google Scholar 

  36. Oleksik A, Doung T, Popp-Snijders C et al (2001) Effects of the selective oestrogen receptor modulator-raloxifene-on calcium and PTH secretory dynamics in women with osteoporosis. Clin Endocrinol 54:575–582

    Article  CAS  Google Scholar 

  37. Rubin MR, Lee KH, McMahon DJ, Silverbery S (2003) Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 88:1174–1178

    Article  PubMed  CAS  Google Scholar 

  38. Carrillo-Lopez N, Roman-Garcia P, Rodriguez-Rebolar A et al (2009) Indirect regulation of PTH by estrogen may require FGF23. J Am Soc Nephrol 20:2009–2017

    Article  PubMed  CAS  Google Scholar 

  39. Heaney RP, Draper MW (1997) Raloxifene and estrogen: comparative bone-remodeling kinetics. J Clin Endocrinol Metab 82:3425–3429

    Article  PubMed  CAS  Google Scholar 

  40. Brown EM, Pollak M, Seidman CE et al. (1995) Calcium-ion-sensing cell-surface receptors. N Engl J Med 333:234–240

    Google Scholar 

  41. Garnero P, Munoz F, Somay-Rendu E, Delmas PD (2007) Associations of vitamin D status with bone mineral density, bone turnover, bone loss and fracture risk in healthy postmenopausal women. The OFELY study. Bone (NY) 40:716–722

    CAS  Google Scholar 

  42. Antoniucci DM, Vittinghoff E, Blackwell T, Black DM, Sellmeyer DE (2005) Vitamin D insufficiency does not affect bone mineral density response to raloxifene. J Clin Endocrinol Metab 90:4566–4572

    Article  PubMed  CAS  Google Scholar 

  43. Papadimitropoulos E, Wells G, Shea B et al (2002) Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocr Rev 23:560–569

    Article  PubMed  CAS  Google Scholar 

  44. Need AG, Nordin BEC (2008) Misconceptions: Vitamin D insufficiency causes malabsorption of calcium. Bone (NY) 42:1021–1024

    Google Scholar 

  45. Biswas P, Zanello LP (2009) 1α,25(OH)3 vitamin D induction of ATP secretion in osteoblasts. J Bone Miner Res 24:1450–1460

    Article  PubMed  CAS  Google Scholar 

  46. Watts NB, Lewiecki EM, Bonnick SL et al (2009) Clinical value of monitoring BMD in patients treated with bisphosphonates for osteoporosis. J Bone Miner Res 24:1643–1646

    Article  PubMed  CAS  Google Scholar 

  47. Antoniucci DM, Vittinghoff E, Palermo L, Black DM, Sellmeyer DE (2009) Vitamin D insufficiency does not affect response of bone mineral density to alendronate. Osteoporos Int 20:1259–1266

    Article  PubMed  CAS  Google Scholar 

  48. Majima T, Komatsu Y, Shimatsu A et al (2008) Efficacy of combined treatment with raloxifene and alfacalcidol on bone density and biochemical markers of bone turnover in postmenopausal osteoporosis. Endocr J 55:127–134

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

I.G. has received honoraria for lectures from Chugai Pharmaceutical Co., Ltd, Tokyo, Japan.

Author information

Author notes

  1. Itsuo Gorai & Yaku Tanaka

    Present address: Department of Obstetrics and Gynecology, Hori Hospital, 292 Futatsubashi-cho, Seya-ku, Yokohama, Kanagawa, 246-0021, Japan

  2. Shin Hattori

    Present address: Department of Obstetrics and Gynecology, Odawara Municipal Hospital, Odawara, Kanagawa, 250-8558, Japan

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, International University of Health and Welfare Atami Hospital, Atami, Shizuoka, 413-0012, Japan

    Itsuo Gorai, Shin Hattori & Yaku Tanaka

  2. Department of Obstetrics and Gynecology, JA Yoshida General Hospital, Yoshida-cho, Hiroshima, 731-0595, Japan

    Yasuhisa Iwaoki

Authors
  1. Itsuo Gorai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shin Hattori
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yaku Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuhisa Iwaoki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Itsuo Gorai.

About this article

Cite this article

Gorai, I., Hattori, S., Tanaka, Y. et al. Alfacalcidol-supplemented raloxifene therapy has greater bone-sparing effect than raloxifene-alone therapy in postmenopausal Japanese women with osteoporosis or osteopenia. J Bone Miner Metab 30, 349–358 (2012). https://doi.org/10.1007/s00774-011-0325-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-011-0325-1

Keywords

search

Navigation