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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)

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Abstract

A combined therapy with the strongly antiresorptive Alendronate and the pleiotropically acting D-hormone analogue Alfacalcidol may have additive effects on bone quality, falls and fracture risk in established osteoporosis. The aim of this study (Alfacalcidol Alendronate Combined—AAC) was to compare the efficacy and safety of a combined parallel therapy with Alendronate and Alfacalcidol to the treatment with either Alendronate in combination with plain vitamin D or Alfacalcidol alone in patients with established postmenopausal or male osteoporosis. Ninety patients were included as matched triplets to receive randomly either 1 μg Alfacalcidol daily + 500 mg calcium (group A, n = 30) or 70 mg Alendronate weekly + 1,000 mg calcium + 1,000 IU vitamin D daily (group B, n = 30) or 1 μg Alfacalcidol daily + 70 mg Alendronate weekly + 500 mg calcium daily (group C, n = 30). Patients were recruited in one centre and were followed up for 24 months. Analysis was intention-to-treat and the primary outcome was lumbar spine and total hip bone mineral density (measured observer blind). BMD was measured at the lumbar spine and at the proximal femur with dual energy X-ray absorptiometry (LUNAR Prodigy, GE, USA) at the beginning and after 12 and 24 months. During the 2-year-study we observed descriptively significant increases at the lumbar spine of 3.0% in group A compared to baseline, of 5.4% in group B and of 9.6% in group C, respectively. The superiority of the Alendronate + Alfacalcidol treatment group over Alfacalcidol alone and over Alendronate + vitamin D was of more than large relevance (both tests: MW > 0.71; CI-LB > 0.64; P < 0.001). We also observed median increases of the BMD at the total hip of 1.5% in group A, of 2.4% in group B and of 3.8% in group C, respectively. The superiority of group C over group A and over group B again was relevant and statistically significant in a descriptive sense. After 2 years there was a tendency towards higher rates of vertebral and non-vertebral fractures in group A and B as compared to C. Taking both fracture types together we observed 9, 10 and 2 “osteoporotic fractures” in groups A, B and C, respectively. The comparison of group C with pooled groups A and B and with each single group gave a relevantly lower fracture rate for the combination of Alendronate and Alfacalcidol. Furthermore a lower rate of falls was observed for the combination Alendronate plus Alfacalcidol versus Alendronate + vitamin D, but not versus Alfacalcidol alone. We found 80% of the patients in the Alendronate + Alfacalcidol group free from back pain at month 24, compared to 30% in the Alendronate + vitamin D and 43% in the Alfacalcidol monotherapy group. The superiority is relevant (both tests: MW > 0.64; CI-LB > 0.56; P < 0.003). Pain decrease also occurred more rapidly in the Alendronate + Alfacalcidol group than in the other groups. In general side effects in all groups were mild, and only four cases of moderate hypercalcuria in group A and one in group C were reported, but no case of hypercalcemia was documented. In conclusion, the combination therapy with Alendronate and Alfacalcidol exhibited superiority in terms of BMD, overall fractures, rate of falls and back pain over either Alendronate in combination with plain vitamin D or Alfacalcidol alone. The overall safety profiles of the three treatment regimens were found to be not different in this study.

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References

  1. Gambacciani M, Spinetti A, Cappagli B, Ciaponi M, Gallo R, Rovati LC, Genazzani AR (1995) Effects of low-dose monofluorophosphate and transdermal oestradiol on postmenopausal vertebral bone loss. Eur Menopause J 2:16–20

    Google Scholar 

  2. Alexandersen P, Riis BJ, Christiansen C (1999) Monofluorophosphate combined with hormone replacement therapy induces a synergistic effect on bone mass by dissociating bone formation and resorption in postmenopausal women: a randomized study. J Clin Endocriol Metab 84:3013–3020

    Article  CAS  Google Scholar 

  3. Ringe JD, Setnikar I (2002) Monofluorophosphate combined with hormone replacement therapy in postmenopausal osteoporosis. An open-label pilot efficacy and safety study. Rheumatol Int 22:27–32

    Article  PubMed  CAS  Google Scholar 

  4. Lems WF, Jacobs JWG, Bijlsma WJ, van Veen GJM, Houben HHML, Haanen HCM, Gerrits MI, van Rijn HJM (1997) Is addition of sodium fluoride to cyclical etidronate beneficial in the treatment of corticoid induced osteoporosis? Ann Rheumatol Dis 56:357–363

    CAS  Google Scholar 

  5. Ringe JD, Rovati L (2001) Treatment of osteoporosis in men with fluoride alone or in combination with bisphosphonates. Calcif Tissue Int 69:252–255

    Article  PubMed  CAS  Google Scholar 

  6. Morabito N, Gaudio A, Lasco A, Vergara C, Tallarida F, Crisafulli G, Trifiletti A, Cincotta M, Pizzoleo MA, Frisina N (2003) Three-year effectiveness of intravenous pamidronate versus pamidronate plus slow-release sodium fluoride for postmenopausal osteoporosis. Osteoporos Int 14:500–506

    Article  PubMed  CAS  Google Scholar 

  7. Ringe JD, Dorst A, Faber H, Kipshoven C, Rovati LC, Setnikar I (2005) Efficacy of etidronate and sequential monofluorophosphate in severe postmenopausal osteoporosis: a pilot study. Rheumatol Int 25:296–300

    Article  PubMed  CAS  Google Scholar 

  8. Reginster JY, Felsenberg D, Pavo I, Stepan J, Payer J, Resch H, Glüer CC, Mühlenbacher D, Quail D, Schmitt H, Nickelsen T (2003) Effect of raloxifene combined with monofluorophosphate as compared with monofluorophosphate alone in postmenopausal women with low bone mass: a randomized, controlled trial. Osteoporos Int 14:741–749

    Article  PubMed  CAS  Google Scholar 

  9. 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 16:603–610

    Article  PubMed  CAS  Google Scholar 

  10. Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ (2003) The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 349:1207–1215

    Article  PubMed  CAS  Google Scholar 

  11. Ringe JD, Schacht E (2004) Prevention and therapy of osteoporosis: the roles of plain Vitamin D and alfacalcidol. Rheumatol Int 24:189–197

    PubMed  CAS  Google Scholar 

  12. Fujita T, Fukase M, Shimada T, Yamamoto H (1992) Treatment of established osteoporosis with 1α-(OH)-Vitamin D3 and low dose intermittent Elcalcitonin (eel calcitonin derivative). JBBM 10:37–40

    Google Scholar 

  13. Ushiroyama T, Ikeda A, Sakai M, Higashiyama T, Ueki M (2001) Effects of combined use of calcitonin and 1α-hydroxycholecalciferol on vertebral bone loss and bone turnover in women with postmenopausal osteopenia and osteoporosis: a prospective study of long-term and continuous administration with low dose calcitonin. Maturitas 40:229–238

    Article  PubMed  CAS  Google Scholar 

  14. Frediani B, Allegri A, Bisogno S, Marcolongo R (1998) Effects of combined treatment with calcitriol plus alendronate on bone mass and bone turnover in postmenopausal osteoporosis. Two years of continuous treatment. Clin Drug Invest 15(3):235–244

    Article  CAS  Google Scholar 

  15. Ringe JD (2006) Alfacalcidol in prevention and treatment of all major forms of osteoporosis and renal osteopathy. Georg Thieme Verlag, Stuttgart

    Google Scholar 

  16. Schacht E, Richy F, Reginster JY (2005) The therapeutic effects of alfacalcidol on bone strength, muscle metabolism and prevention of falls and fractures. J Musculoskelet Neuronal Interact 5(3):273–284

    PubMed  CAS  Google Scholar 

  17. Fligner MA, Wolfe DA (1982) Distribution-free tests for comparing several treatments with a control. Stat Neerl 36:119–127

    Google Scholar 

  18. Lachin JM (1992) Some large-sample distribution-free estimators and tests for multivariate partially incomplete data from two populations. Stat Med 11:1151–1170

    PubMed  CAS  Google Scholar 

  19. Thall PF, Lachin JM (1988) Analysis of recurrent events: nonparametric methods for random interval count data. J Am Stat Assoc 83:339–347

    Article  Google Scholar 

  20. Wei LJ, Lachin JM (1984) Two-sample asymptotically distribution-free tests for incomplete multivariate observations. J Am Stat Assoc 79:653–661

    Article  Google Scholar 

  21. Colditz GA, Miller JN, Mosteller F (1988) Measuring gain in the evaluation of medical technology: the probability of a better outcome. Int J Technol Assessment Health Care 4:637–642

    CAS  Google Scholar 

  22. Ito M, Azuma Y, Takagi H, Komoriya K, Ohta T, Kawaguchi H (2002) Curative effect of combined treatment with Alendronate and 1α-Hydroxyvitamin D3 on bone loss by ovariectomy in aged rats. Jpn J Pharmacol 89:255–266

    Article  PubMed  CAS  Google Scholar 

  23. Erben RG, Mosekilde L, Thomsen JS, Weber K, Stahr K, Leyshon A, Smith SY, Rhipps R (2002) Prevention of bone loss in ovariectomized rats by combined treatment with risedronate and 1α,25-dihydroxyvitamin D3. J Bone Miner Res 17:1498–1511

    Article  PubMed  CAS  Google Scholar 

  24. Reszka AA, Pun S, Rodan GA, Freedman LP, Kimmel DB (2004) Bone anabolic effects of 1,25(OH)2 vitamin D3 are detected only in the presence of a powerful antiresorptive. J Bone Miner Res 19(Suppl 1):S483

    Google Scholar 

  25. Ikeda K, Ogata E (1999) The effect of vitamin D on osteoblasts and osteoclasts. Curr Opin Orthop 10:339–343

    Article  Google Scholar 

  26. Kanis JA, Gluer CC (2000) An update on the diagnosis and assessment of osteoporosis with densitometry. Committee of Scientific Advisors, International Osteoporosis Foundation. Osteoporos Int 11:192–202

    Article  PubMed  CAS  Google Scholar 

  27. Youm T, Koval KJ, Kummer FJ, Zuckerman JD (1999) Do all hip fractures result from a fall? Am J Orthop 28:190–194

    PubMed  CAS  Google Scholar 

  28. Kaptoge S, Benevolenskaya LI, Bhalla AK, Cannata JB, Boonen S, Falch JA et al (2005) Low BMD is less predictive than reported falls for future limb fractures in women across Europe: results from the European Prospective Osteoporosis Study. Bone 36:387–398

    Article  PubMed  CAS  Google Scholar 

  29. Runge M, Schacht E (2005) Multifactorial pathogenesis of falls as a basis for multifactorial interventions. J Musculoskelet Neuronal Interact 5:127–134

    PubMed  CAS  Google Scholar 

  30. Wainwright SA, Marshall LM, Ensrud KE, Cauley JA, Black DM, Hillier TA, Hochberg MC, Vogt MT, Orwoll ES, for the Study of Osteoporotic Fractures Research Group (2005) Hip fracture in women without osteoporosis. J Clin Endocrinol Metab 90:2787–2793

    Google Scholar 

  31. Nevitt MC, Cummings SR, Stone KL, Palermo L, Black DM, Bauer DC et al (2005) Risk factors for a first-incident radiographic vertebral fracture in women ≥ 65 years of age: the study of osteoporotic fractures. J Bone Miner Res 20:131–140

    Article  PubMed  Google Scholar 

  32. Bischoff HA, Borchers M, Gudat F, Duermueller U, Theiler R, Stähelin HB et al (2001) In situ detection of 1,25-dihydroxyvitamin D receptor in human skeletal muscle tissue. Histochem 33:19–24

    Article  CAS  Google Scholar 

  33. Boland R (1986) Role of vitamin D in skeletal muscle function. Endocrine Rev 784:434–448

    Google Scholar 

  34. Endo I, Inoue D, Mitsui T, Umaki Y, Akaike M, Yoshizawa T et al (2003) Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors. Endocrinology 144:5138–5144

    Article  PubMed  CAS  Google Scholar 

  35. Bischoff-Ferrari HA, Borchers M, Gudat F, Dürmüller U, Stähelin HB, Dick W (2004) Vitamin D receptor expression in human muscle tissue decreases with age. J Bone Miner Res 19:265–269

    Article  PubMed  CAS  Google Scholar 

  36. Bischoff HA, Stähelin HB, Urscheler N, Ehrsam R, Vontheim R, Perrig-Chiello P et al (1999) Muscle strength in the elderly: its relation to vitamin D metabolites. Arch Phys Med Rehabil 80:54–58

    Article  PubMed  CAS  Google Scholar 

  37. Dukas L, Schacht E, Bischoff HA (1999) Better functional mobility in community-dwelling elderly is related to D-hormone serum levels and to a daily calcium intake. J Nutr Health Aging 9:347–351

    Google Scholar 

  38. Gallagher JC (2004) The effects of calcitriol on falls and fractures and physical performance tests. J Steroid Biochem Mol Biol 89–90:497–501

    Article  PubMed  CAS  Google Scholar 

  39. Dukas L, Bischoff HA, Lindpaintner LS, Schacht E, Birkner-Binder D, Damm TN et al (2004) Alfacalcidol reduces the number of fallers in a community-dwelling elderly population with a minimum calcium intake of more than 500 mg daily. J Am Geriatr Soc 52:230–236

    Article  PubMed  Google Scholar 

  40. Dukas L, Schacht E, Mazor Z, Stähelin HB (2005) Treatment with Alfacalcidol in elderly people significantly decreases the high risk of falls associated with a low creatinine clearance of <65 ml/min. Osteoporos Int 16:198–203

    Article  PubMed  CAS  Google Scholar 

  41. Uusi-Rasi K, Kannus P, Cheng S et al (2003) Effect of alendronate and exercise on bone and physical performance of postmenopausal women: a randomized controlled trial. Bone 33:132–143

    Article  PubMed  CAS  Google Scholar 

  42. Fleisch H (1998) Bisphosphonates: mechanisms of action. Endocr Rev 19:80–100

    Article  PubMed  CAS  Google Scholar 

  43. Russell RG, Rogers MJ (1999) Bisphosphonates: from the laboratory to the clinic and back again. Bone 25:97–106

    Article  PubMed  CAS  Google Scholar 

  44. Shibata T, Shiraishi A, Masaki T, Sasaki A, Masuda Y, Hishiya A, Ishikura N, Higashi S, Uchida Y, Saito M, Ito M, Ogata E, Watanabe K, Ikeda K (2002) Vitamin D hormone inhibits osteoclastogenesis in vivo by decreasing the pool of osteoclast precursors in bone marrow. J Bone Miner Res 17:622–629

    Article  PubMed  CAS  Google Scholar 

  45. DeLuca HF, Cantorna MT (2001) Vitamin D. Its role and uses in immunology. FASEB J 15:2579–2585

    Article  PubMed  CAS  Google Scholar 

  46. Hayakawa N, Higashi S, Shiraishi A, Masaki T, Hoshino E, Matsubara S (2002) Alfacalcidol distributes to bone marrow cells in an unchanged form and converts to active forms locally. J Bone Min Res 17(Suppl 1):S276

    Google Scholar 

  47. Richy F, Ethgen O, Bruyere O, Reginster JY (2004) Efficacy of alphacalcidol and calcitriol in primary and corticosteroid-induced osteoporosis: a meta-analysis of their effects on bone mineral density and fracture rate. Osteoporos Int 15:301–310

    Article  PubMed  CAS  Google Scholar 

  48. Malavolta N, Zanardi M, Veronesi M, Ripamonti C, Gnudi S (1999) Calcitriol and alendronate combination treatment in menopausal women with low bone mass. Int J Tissue React 21:51–59

    PubMed  CAS  Google Scholar 

  49. Masud T, Mulcahy B, Thompson AV, Donnelly S, Keen RW, Doyle DV, Spector TD (1998) Effects of cyclical Etidronate combined with calcitriol versus cyclical Etidronate alone on spine and femoral neck bone mineral density in postmenopausal osteoporotic women. Ann Rheum Dis 57:346–349

    Article  PubMed  CAS  Google Scholar 

  50. Iwamoto J, Takeda T, Ichimura S, Matsu K, Uzawa M (2003) Effects of cyclical etidronate with alfacalcidol on lumbar bone mineral density, bone resorption, and back pain in postmenopausal women with osteoporosis. J Orthop Sci 8:532–537

    Article  PubMed  Google Scholar 

  51. Ones K, Schacht E (2006) Superiority of a combined treatment of Alfacalcidol and Alendronate compared to the monotherapies in postmenopausal osteoporosis. Osteoporos Int 17(1):S20(P112)

  52. Shiraishi A, Higashi S, Ohkawa H, Kubodera N, Hirasawa T, Ezawa I, et al (1999) The advantage of Alfacalcidol over vitamin D in the treatment of osteoporosis. Calcif Tissue Int 65:311–316

    Article  PubMed  CAS  Google Scholar 

  53. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY et al (2004) Effect of vitamin D on falls. A meta-analysis. JAMA 291:1999–2006

    Article  PubMed  CAS  Google Scholar 

  54. Richy F, Schacht E, Bruyere O, Ethgen O, Gourlay M, Reginster JY (2005) Vitamin D analogs versus native vitamin D in preventing bone loss and osteoporosis-related fractures: a comparative meta-analysis. Calcif Tissue Int 76:176–186

    Article  PubMed  CAS  Google Scholar 

  55. 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 randomised placebo-controlled trial. Lancet 365:1621–1628

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Medical Clinic 4, Leverkusen Clinic (University of Cologne), Leverkusen, Germany

    J. D. Ringe & P. Farahmand

  2. ZORG, Zurich Osteoporosis Research Group, Zurich, Switzerland

    E. Schacht

  3. idv Data Analysis and Study Planning, Gauting, Germany

    A. Rozehnal

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  1. J. D. Ringe
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Ringe, J.D., Farahmand, P., Schacht, E. et al. 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 (2007). https://doi.org/10.1007/s00296-006-0288-z

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