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Randomized Trial of Alendronate Plus Vitamin D3 Versus Standard Care in Osteoporotic Postmenopausal Women with Vitamin D Insufficiency

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Abstract

Vitamin D insufficiency is common in patients with osteoporosis. We conducted a randomized trial comparing alendronate 70 mg combined with vitamin D3 5,600 IU in a single tablet (ALN/D5600, n = 257) with standard care chosen by the patients’ personal physicians (n = 258) in patients with postmenopausal osteoporosis (BMD T score ≤2.5 or ≤1.5 and a prior fragility fracture) who had vitamin D insufficiency (serum 25[OH]D values 8–20 ng/ml) and who were at risk of falls. Virtually all patients randomized to standard care received bisphosphonate therapy, and in approximately 70% of cases this was combined with vitamin D supplements. However, only 24% took ≥800 IU/day of supplemental vitamin D. At 6 months the proportion of patients with vitamin D insufficiency was 8.6% in the ALN/D5600 group compared with 31.0% in the standard care group (P < 0.001). Those in the ALN/D5600 group also had a greater reduction in urinary NTX/creatinine ratio (−57% vs. −46%, P < 0.001) and bone-specific alkaline phosphatase (−47% vs. −40%, P < 0.001). In the ALN/5600 group, by 12 months the increase in BMD was greater at the lumbar spine (4.9% vs. 3.9%, P = 0.047) and the total hip (2.2% vs. 1.4%, P = 0.035), significantly fewer patients were vitamin D—insufficient (11.3% vs. 36.9%, P < 0.001), and bone turnover marker (BTM) results were similar to those at 6 months. There was no difference between groups in those who experienced falls or fractures, and adverse events were similar. Based on the finding that ALN/D5600 was more effective than standard care at correcting vitamin D insufficiency, increasing BMD, and reducing BTMs in this patient group, greater attention needs to be directed toward optimizing the treatment of osteoporosis and correcting vitamin D deficiency in postmenopausal women.

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References

  1. Gaugris S, Heaney RP, Boonen S, Kurth H, Bentkover JD, Sen SS (2005) Vitamin D inadequacy among post-menopausal women: a systematic review. QJM 98:667–676

    Article  PubMed  CAS  Google Scholar 

  2. Norman AW, Bouillon R, Whiting SJ, Vieth R, Lips P (2007) 13th Workshop consensus for vitamin D nutritional guidelines. J Steroid Biochem Mol Biol 103:204–205

    Article  PubMed  CAS  Google Scholar 

  3. Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281

    Article  PubMed  CAS  Google Scholar 

  4. Lips P, Hosking D, Lippuner K, Norquist JM, Wehren L, Maalouf G, Ragi-Eis S, Chandler J (2006) The prevalence of vitamin D inadequacy amongst women with osteoporosis: an international epidemiological investigation. J Intern Med 260:245–254

    Article  PubMed  CAS  Google Scholar 

  5. Holick MF, Siris ES, Binkley N, Beard MK, Khan A, Katzer JT, Petruschke RA, Chen E, de Papp AE (2005) Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 90:3215–3224

    Article  PubMed  CAS  Google Scholar 

  6. Kuchuk NO, van Schoor NM, Pluijm SM, Chines A, Lips P (2009) Vitamin D status, parathyroid function, bone turnover, and BMD in postmenopausal women with osteoporosis: global perspective. J Bone Miner Res 24:693–701

    Article  PubMed  CAS  Google Scholar 

  7. Binkley N, Novotny R, Krueger D, Kawahara T, Daida YG, Lensmeyer G, Hollis BW, Drezner MK (2007) Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab 92:2130–2135

    Article  PubMed  CAS  Google Scholar 

  8. Lips P, Duong T, Oleksik A, Black D, Cummings S, Cox D, Nickelsen T (2001) A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the Multiple Outcomes of Raloxifene Evaluation clinical trial. J Clin Endocrinol Metab 86:1212–1221

    Article  PubMed  CAS  Google Scholar 

  9. Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson-Hughes B (2004) Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. Am J Med 116:634–639

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  11. Kamel S, Brazier M, Rogez JC, Vincent O, Maamer M, Desmet G, Sebert JL (1996) Different responses of free and peptide-bound cross-links to vitamin D and calcium supplementation in elderly women with vitamin D insufficiency. J Clin Endocrinol Metab 81:3717–3721

    Article  PubMed  CAS  Google Scholar 

  12. 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 

  13. van Schoor NM, Visser M, Pluijm SM, Kuchuk N, Smit JH, Lips P (2008) Vitamin D deficiency as a risk factor for osteoporotic fractures. Bone 42:260–266

    Article  PubMed  Google Scholar 

  14. Ooms ME, Roos JC, Bezemer PD, van der Vijgh WJ, Bouter LM, Lips P (1995) Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial. J Clin Endocrinol Metab 80:1052–1058

    Article  PubMed  CAS  Google Scholar 

  15. Prestwood KM, Pannullo AM, Kenny AM, Pilbeam CC, Raisz LG (1996) The effect of a short course of calcium and vitamin D on bone turnover in older women. Osteoporos Int 6:314–319

    Article  PubMed  CAS  Google Scholar 

  16. von Hurst PR, Stonehouse W, Kruger MC, Coad J (2010) Vitamin D supplementation suppresses age-induced bone turnover in older women who are vitamin D deficient. J Steroid Biochem Mol Biol 121:293–296

    Article  Google Scholar 

  17. Bischoff-Ferrari H, Dawson-Hughes B, Staehelin H, Orav J, Stuck A, Theiler R, Wong J, Egli A, Kiel D, Henschkowski J (2009) Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 339:b3692

    Article  PubMed  CAS  Google Scholar 

  18. Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P (2007) Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 92:1415–1423

    Article  PubMed  CAS  Google Scholar 

  19. Segal E, Zinman C, Raz B, Ish-Shalom S (2009) Low patient compliance—a major negative factor in achieving vitamin D adequacy in elderly hip fracture patients supplemented with 800 IU of vitamin D3 daily. Arch Gerontol Geriatr 49:364–367

    Article  PubMed  CAS  Google Scholar 

  20. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, Bassford T, Beresford SA, Black HR, Blanchette P, Bonds DE, Brunner RL, Brzyski RG, Caan B, Cauley JA, Chlebowski RT, Cummings SR, Granek I, Hays J, Heiss G, Hendrix SL, Howard BV, Hsia J, Hubbell FA, Johnson KC, Judd H, Kotchen JM, Kuller LH, Langer RD, Lasser NL, Limacher MC, Ludlam S, Manson JE, Margolis KL, McGowan J, Ockene JK, O’Sullivan MJ, Phillips L, Prentice RL, Sarto GE, Stefanick ML, Van Horn L, Wactawski-Wende J, Whitlock E, Anderson GL, Assaf AR, Barad D (2006) Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 354:669–683

    Article  PubMed  CAS  Google Scholar 

  21. Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, Anderson FH, Cooper C, Francis RM, Donaldson C, Gillespie WJ, Robinson CM, Torgerson DJ, Wallace WA (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  PubMed  CAS  Google Scholar 

  22. Adami S, Giannini S, Bianchi G, Sinigaglia L, Di Munno O, Fiore CE, Minisola S, Rossini M (2009) Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int 20:239–244

    Article  PubMed  CAS  Google Scholar 

  23. Writing Committee on Behalf of the HDFP Cooperative Group (1976) The Hypertension Detection and Follow-Up Program. Prev Med 5:207–215

    Article  Google Scholar 

  24. Guralnik JM, Ferrucci L, Simonsick EM, Salive ME, Wallace RB (1995) Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability. N Engl J Med 332:556–561

    Article  PubMed  CAS  Google Scholar 

  25. Guralnik JM, Ferrucci L, Pieper CF, Leveille SG, Markides KS, Ostir GV, Studenski S, Berkman LF, Wallace RB (2000) Lower extremity function and subsequent disability: consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery. J Gerontol A Biol Sci Med Sci 55:M221–M231

    PubMed  CAS  Google Scholar 

  26. Liang K-Y, Zeger SL (2000) Longitudinal data analysis of continuous and discrete response for pre–post designs. Indian J Stat 62:134–148

    Google Scholar 

  27. Bonnick S, Saag KG, Kiel DP, McClung M, Hochberg M, Burnett SM, Sebba A, Kagan R, Chen E, Thompson DE, de Papp AE (2006) Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years. J Clin Endocrinol Metab 91:2631–2637

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Rheumatic Diseases Unit, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK

    Stuart H. Ralston

  2. University of Wisconsin, Madison, WI, USA

    Neil Binkley

  3. Center for Metabolic Bone Disease, University of Leuven, Leuven, Belgium

    Steven Boonen

  4. Institute for Aging Research, Hebrew SeniorLife and Harvard Medical School, Boston, MA, USA

    Douglas P. Kiel

  5. University of Liège, Liège, Belgium

    Jean-Yves Reginster

  6. Paris Descartes University, Paris, France

    Christian Roux

  7. Merck, Whitehouse Station, NJ, USA

    Liang Chen, Elizabeth Rosenberg & Arthur Santora

Authors
  1. Stuart H. Ralston
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  2. Neil Binkley
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  3. Steven Boonen
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  4. Douglas P. Kiel
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  5. Jean-Yves Reginster
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  6. Christian Roux
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  7. Liang Chen
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  8. Elizabeth Rosenberg
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  9. Arthur Santora
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Consortia

Investigators of FOCUS-D (FOSAVANCE vs. Standard Care—Use and Study of Vitamin D) Trial

Corresponding author

Correspondence to Stuart H. Ralston.

Additional information

This study was sponsored by Merck. S. Ralston has received consultancy fees from Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc. N. Binkley has received consultancy fees from Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc. S. Boonen has received research grants and consultancy fees from Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc. D. Kiel has received research grants and consultancy fees from Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc. J. Reginster has received consultancy fees from Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc. C. Roux received honoraria and/or lecture fees and/or research grants from Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc. L. Chen, E. Rosenberg, and A. Santora are employees of Merck & Co., Inc. and may own stock in the company.

Appendix: FOCUS-D Investigators

Appendix: FOCUS-D Investigators

Tara Coughlan, Adelaide & Meath Hospital, Dublin, Ireland; Asma Arabi, American University of Beirut Medical Center, Beirut, Lebanon; Ayse Kucukdeveci, Ankara University, Ankara, Turkey; Naren Savani, Batchworth House Mount Vernon Hospital, Middlesex, UK; Rasa Kausiene, Bendrosios terapijos skyrius, Siauliai, Lithuania; Bruno Pornel, Brussels Menopause Center, Brussels, Belgium; Tom Price, Cannock Chase Hospital, Staffordshire, UK; Claude-Laurent Benhamou, Centre Hop Porte Madeleine, Orleans, France; Maria Aguilar, Centro de Diagnostico Medicont S.A. de C.V., Nezahualcoyotl, Mexico; Mauricio Abello, Centro Integral de Reumatologia del Caribe, Barranquilla, Atlantico, Colombia; Elgardo Tobias, Centro Integral de Reumatologia e Inmunologia, Bogota, Cundinamarca, Colombia; Nadeem Rais, Chowpatty Medical Center, Mumbai, Maharashtra, India; Olga Ershova, Clinical Hospital for Emergency Care n.a. Soloviev, Yaroslavl, Russian Federation; Rene Martz, Clinical Research Hamburg, Hamburg, Germany; Sultan Linjawi, Coffs Endocrine & Diabetes Services, Coffs Harbour, NSW, Australia; Stuart Kramer, Danville Orthopedic Clinic, Danville, VA, USA; Jesus Walliser, Eentro Walliser de Osteoporosis y Metabolismo Mineral, Veracruz, Mexico; Simin Hepguler, Ege University, Bornova, Turkey; Jeffrey Gimble, Family Health Center, Baton Rouge, LA, USA; Olga Lesnyak, Family Medicine Clinic of Ural State Medical Academy, Ekaterinburg, Russian Federation; Philippe Chalem, Fundacion Instituto de Reumatologia Fernando Chalem, Bogota, Colombia; Jose Aramburu, H. de Basurto, Bilbao, Vizaya, Spain; Joseph Foldes, Hadassah Har-Hatzofim Medical Center, Jerusalem, Israel; Yasser Yaghi, Hammoud Hospital, Saida South, Lebanon; Christian Roux, Hopital Cochin, Paris, France; Carlos Abud, Hospital Central Dr. Ignacio Morones Prieto, San Luis Potosi, Mexico; Manuel Muñoz Torres, Hospital Clinico San Cecilio, Granada, Spain; Gilberto González, Hospital Clinico Universidad Catolica de Chile, Santiago, Chile; Georges Weryha, Hospital de Brabois, Vandoeuvre les Nancy, France; Emilio Martín Mola, Hospital Universitario La Paz, Madrid, Spain; Marina Shargordsky, Hypertension Clinic Wolfson Medical Center, Holon, Israel; Neeta Patel Inkosi Albert Luthuli Hospital, Durban, South Africa; Kurt Lippuner, Inselspital–Poliklinik für Osteoporose, Bern, Switzerland; Ruediger Moericke, Institut für Praventive Medizin & Klinische Forschung, Magdeburg, Germany; Basel Masri, Jordan Hospital, Amman, Jordan; Inguta Stura, Juglas Medicinas Centrs, Riga, Latvia; Robert Theiler, Klinik für Rheumatologie und Rehabilitation Stadtsp., Zurich, Switzerland; Nigar Dursun, Kocaeli University, Kocaeli, Turkey; Vincent Thompson, Libra Clinical Research Associates, Brick, NJ, USA; Dac Andersone, Liepajas Metalurga Poliklinika, Liepaja, Latvia; Mark Arya, Maroubra Medical Centre, Maroubra, NSW, Australia; Carl-Peter Anderberg, Me3Plus Clinical Trials AB, Goteborg, Sweden; Michael Pfeifer, MEDWISS Bad Pyrmont, Bad Pyrmont, Germany; Hugo Goldstraj, Multispecialty Medical Center, North Miami Beach, FL, USA; Vidmantas Alekna, Nacionalinis Osteoporozes Centras, Vilnius, Lithuania; Bram Wieskopf, North Georgia Clinical Research, Woodstock, GA, USA; Tobias De Villiers, Panorama Medi Clinic, Parow, Western Cape, South Africa; Salvatore Minisola, Policlinico Umberto I Sapienza University of Rome, Rome, Italy; Jean-Yves Reginster, Polyclinique L. Brull-Exploration de l’Os et du Cartilage, Liège, Belgium; Klaus Heil, Praxis Dr. Klaus Heil, Tuttlingen, Germany; Volkmar Herkt, Praxis Dr. Volkmar Herkt, Dresden, Germany; Jane Rohlf, Premier Research, Trenton, NJ, USA; Albert De Weerd, Pretoria East Private Hospital, Gauteng, South Africa; Sophia Ish-Shalom, Rambam Medical Center, Haifa, Israel; Loreta Bukauskiene, Reumatologijos skyrius, Klaipeda, Lithuania; Lidia Benevolenskaya, Research Institute of Rheumatology, Moscow, Russian Federation; Ruben Mantilla, Riesgo de Feractura S.A., Bogota, Cundinamarca, Colombia; Anthony Woolf, Royal Cornwall Hospitals NHS Trust, Cornwall, UK; William Otero, SERVIMED Bucaramanga, Santander, Colombia; Savithree Nayiager, St. Augustine’s Hospital, Kwazulu Natal, South Africa; Bernard Walsh, St. James’ Hospital–Robert Mayne Day Hospital, Dublin, Ireland; Stephen Newman, Brick, NJ, USA; Nitin Bagul, Synexus Lancashire Clinical Research Centre, Lancashire, UK; Essam Abdulhakim, Synexus Ltd. Merseyside Clinical Research Centre, Liverpool, UK; Shilpa Govindraj, Synexus Manchester Clinical Research Centre, Manchester, UK; Rex Sarmiento Synexus Midlands Clinical Research Centre, Birmingham, UK; Rahul Ellahbadi, Synexus Scotland Clinical Research Centre, Glasgow, UK; Hilary Shaw, Synexus Thames Valley Clinical Research, Berkshire, UK; Hawys Thomas, Synexus Wales Clinical Research Centre, Cardiff, UK; Stanley Lipschitz, The Memory Centre, Johannesburg, South Africa; Sergio Gutierrez, Torre de Especialidades–Ant Hosp. Civil de Gdl, Guadalajara, Mexico; Neil Binkley, University of Wisconsin, Madison, WI, USA; Stuart Ralston, Western General Hospital, Edinburgh, UK; Michael Davey, Westville Hospital, Durban, South Africa; Renato Lauro, Azienda Ospedaliera Universitaria, Rome, Italy; Hector Rodriguez, Central Medical & Therapy Center, Miami, FL, USA; Muataz Al-Ramahi, Jordan University Hospital, Amman, Jordan.

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Ralston, S.H., Binkley, N., Boonen, S. et al. Randomized Trial of Alendronate Plus Vitamin D3 Versus Standard Care in Osteoporotic Postmenopausal Women with Vitamin D Insufficiency. Calcif Tissue Int 88, 485–494 (2011). https://doi.org/10.1007/s00223-011-9482-4

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