Osteoporosis International

, Volume 24, Issue 1, pp 253–262 | Cite as

A meta-analysis characterizing the dose–response relationships for three oral nitrogen-containing bisphosphonates in postmenopausal women

  • J. Yates
Original Article



A meta-analysis of spine BMD dose–response relationships for alendronate, risedronate, and ibandronate was performed. Data from all three oral bisphosphonates conform to a log–linear relationship between dose and change in spine BMD relative to placebo at 1 year, with an incremental gain of about 1 % for each doubling of dose.


Animal data suggesting differences in potency and differences in approved oral dosage strengths for alendronate, risedronate, and ibandronate in the treatment of osteoporosis raise questions about their dose–response relationships and relative potencies in humans.


A meta-analysis of dose–response relationships for spine BMD increases for these three bisphosphonates was performed using data from 21 placebo-controlled trials that collectively included over 13,000 patients on active treatment and over 8,000 on placebo.


For alendronate over the range of 1 to 20 mg/day, there was a strong log–linear relationship between dose and the increase in spine BMD relative to placebo at 1 year (R 2 = 0.994 using sample-weighted means). For each doubling in alendronate dose, there was an incremental gain of about 1 % in spine BMD. On the same scale, risedronate and ibandronate are approximately equipotent to alendronate on a weight-for-weight basis. The increases in BMD efficacy with each doubling of dose are parallel for all three nitrogen-containing bisphosphonates (NCBPs).


All three NCBPs are approximately equipotent and exhibit a log–linear relationship between dose and the increase in spine BMD. Differences in efficacy between the available oral bisphosphonate regimens appear to be a function of dose rather than inherent differences in therapeutic potential.


Alendronate Dose response Ibandronate Meta-analysis Risedronate 


Conflicts of interest



  1. 1.
    Mühlbauer R, Bauss F, Scheenk R, Janner M, Bosies E, Strein K, Fleisch H (1991) BM 21.0955, a potent new bisphosphonate to inhibit bone resorption. J Bone Miner Res 6(9):1003–1011PubMedCrossRefGoogle Scholar
  2. 2.
    Green JR, Muller K, Jaeggi KA (1994) Preclinical pharmacology of CGP 42,446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 9(5):745–751PubMedCrossRefGoogle Scholar
  3. 3.
    Eastell R, Devogelaer J-P, Peel NFA, Chines AA, Bax DE, Sacco-Gibson N, Nagant de Deuxchaisnes C, Russell RGG (2000) Prevention of bone loss with risedronate in glucocorticoid-treated rheumatoid arthritis patients. Osteoporos Int 11:331–337PubMedCrossRefGoogle Scholar
  4. 4.
    Delmas PD, Balena R, Confavreux E, Hardouin C, Hardy P, Bremond A (1997) Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study. J Clin Oncol 15:955–962PubMedGoogle Scholar
  5. 5.
    Chesnut CH III, McClung MR, Ensrud KE, Bell NH, Genant HK, Harris ST, Singer FR, Stock JL, Yood RA, Delmas PD, Kher U, Pryor-Tillotson S, Santora AC II (1995) Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling. Am J Med 99:144–152.6PubMedCrossRefGoogle Scholar
  6. 6.
    Gertz BJ, Holland SD, Kline WF, Matuszewski BK, Freeman A, Quan H, Lasseter KC, Mucklow JC, Porras AG (1995) Studies of the oral bioavailability of alendronate. Clinical Pharmacol Ther 58(3):288–298CrossRefGoogle Scholar
  7. 7.
    Mitchell DY, Heise MA, Pallone KA, Clay ME, Nesbitt JD, Russell DA, Melson CW (1999) The effects of dosing regimen on the pharmacokinetics of risedronate. J Clinical Pharm 48:536–542Google Scholar
  8. 8.
    Bonnick S, Broy S, Kaiser F, Teutsch C, Rosenberg E, DeLucca P, Melton M (2007) Treatment with alendronate plus calcium, alendronate alone, or calcium alone for postmenopausal low bone mineral density. Current Med Res Opin 23(6):1341–1349CrossRefGoogle Scholar
  9. 9.
    Adami S, Passeri M, Ortolani S, Broggini M, Carratelli L, Caruso I, Gandolini G, Gnessi L, Laurenzi M, Lombardi A, Norbiato G, Pryor-Tillotson S, Reda C, Romanini L, Subrizi D, Wei L, Yates J (1995) Effects of oral alendronate and intranasal salmon calcitonin on bone mass and biochemical markers of bone turnover in postmenopausal women with osteoporosis. Bone 4:383–390CrossRefGoogle Scholar
  10. 10.
    Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW, Dequecker J, Favus M, Seeman E, Recker RR, Capizzi T, Santora AC, Lombardi A, Shah RV, Hirsch LJ, Karpf DB (1995) Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. NEJM 333(22):1437–1443PubMedCrossRefGoogle Scholar
  11. 11.
    Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348(9041):1535–1541PubMedCrossRefGoogle Scholar
  12. 12.
    Bone HG, Downs RW, Tucci JR, Harris ST, Weinstein RS, Licata AA, McClung MR, Kimmel DB, Gertz BJ, Hale E, Polvino WJ (1997) Dose–response relationships for alendronate treatment in osteoporotic elderly women. J Clin Endocrinol Metab 82(1):265–274PubMedCrossRefGoogle Scholar
  13. 13.
    Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the fracture intervention trial. JAMA 280(24):2077–2082PubMedCrossRefGoogle Scholar
  14. 14.
    McClung M, Clemmesen B, Daifotis A, Gilchrist NL, Eisman J, Weinstein RS, Fuleihan GE-H, Reda C, Yates AJ, Ravn P (1998) Alendronate prevents postmenopausal bone loss in women without osteoporosis: a double-blind, randomized, controlled trial. Annals Int Med l 128(4):253–261Google Scholar
  15. 15.
    Hosking D, Chilvers C, Christiansen C, Ravn P, Wasnich R, Ross P, McClung M, Balske A, Thompson D, Daley M, Yates AJ (1998) Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. NEJM 338(8):485–492PubMedCrossRefGoogle Scholar
  16. 16.
    Greenspan S, Parker RA, Ferguson L, Rosen HN, Maitland-Ramsey L, Karpf DB (1998) Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial. J Bone Miner Res 13:1431–1438PubMedCrossRefGoogle Scholar
  17. 17.
    Pols HAP, Felsenberg D, Hanley DA, Stepan J, Munoz-Torres M, Wilkin TJ, Qin-sheng G, Galich AM, Vandormael K, Yates AJ, Stych B (1999) Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Osteoporos Int 9:461–468PubMedCrossRefGoogle Scholar
  18. 18.
    Bone HG, Greenspan SL, McKeever C, Bell N, Davidson M, Downs RW, Emkey R, Meunier PJ, Miller SS, Mulloy AL, Recker RR, Weiss SR, Heyden N, Musliner T, Suryawanshi S, Yates AJ, Lombardi A (2000) Alendronate and estrogen effects in postmenopausal women with low bone mineral density. J Clin Endocrinol Metab 85(2):720–726PubMedCrossRefGoogle Scholar
  19. 19.
    Hosking D, Adami S, Felsenberg D, Cannata Andia J, Välimäki M, Benhamou L, Reginster J-Y, Yacik C, Rybak-Feglin A, Petruschke RA, Zaru L, Santora AC (2003) Comparison of change in bone resorption and bone mineral density with once-weekly alendronate and daily risedronate: a randomised, placebo-controlled study. Curr Med Res Opin 19(5):383–394PubMedCrossRefGoogle Scholar
  20. 20.
    Mortensen L, Charles P, Bekker P, DiGennaro J, Johnston CC (1998) Risedronate increases bone mass in an early postmenopausal population: two years of treatmentplus one year of follow-up*. J Clin Endocrinol Metab 83(2):396–402PubMedCrossRefGoogle Scholar
  21. 21.
    Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH III, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD (1999) Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA 282(14):1344–1352PubMedCrossRefGoogle Scholar
  22. 22.
    Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, Lund B, Ethgen D, Pack S, Roumagnac I, Eastell R (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 11:83–91PubMedCrossRefGoogle Scholar
  23. 23.
    Fogelman I, Ribot C, Smith R, Ethgen D, Sod E, Reginster J-Y (2000) Risedronate reverses bone loss in postmenopausal women with low bone mass: results from a multinational, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 85:1895–1900PubMedCrossRefGoogle Scholar
  24. 24.
    Hooper M, Ebeling PR, Roberts AP, Graham JJ, Nicholson GC, D’Emden M, Ernst TF, Wenderoth D (2005) Risedronate prevents bone loss in early postmenopausal women: a prospective randomized, placebo-controlled trial. Climacteric 8:251–262PubMedCrossRefGoogle Scholar
  25. 25.
    Ravn P, Clemmesen B, Riis BJ, Christiansen C (1996) The effect on bone mass and bone markers of different doses of ibandronate: a new bisphosphonate for prevention and treatment of postmenopausal osteoporosis: a 1-year, randomized, double-blind, placebo-controlled dose-finding study. Bone 19(5):527–533PubMedCrossRefGoogle Scholar
  26. 26.
    Riis BJ, Ise J, Von Stein T, Bagger Y, Christiansen C (2001) Ibandronate: a comparison of oral daily dosing versus intermittent dosing in postmenopausal osteoporosis. J Bone Miner Res 16(10):1871–1878PubMedCrossRefGoogle Scholar
  27. 27.
    Chesnut CH, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, Felsenberg D, Huss H, Gilbride J, Schimmer R, Delmas P (2004) Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 19:1241–1249CrossRefGoogle Scholar
  28. 28.
    McClung MR, Wasnich RD, Recker R, Cauley JA, Chesnut CH, Ensrud KE, Burdeska A, Mills T (2004) Oral daily ibandronate prevents bone loss in early postmenopausal women without osteoporosis. J Bone Miner Res 19(1):11–18PubMedCrossRefGoogle Scholar
  29. 29.
  30. 30.
    Cranney A, Wells G, Willan A, Griffith L, Zytaruk N, Robinson V, Black D, Adachi J, Shea B, Tugwell P, Guyatt G (2002) Meta-analyses of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev 23:508–516PubMedCrossRefGoogle Scholar
  31. 31.
    Tanko LB, McClung MR, Schimmer RC, Mahoney P, Christiansen C (2003) The efficacy of 48-week oral ibandronate treatment in postmenopausal ostteoporosis when taken 30 versus 60 minutes before breakfast. Bone 32:421–426PubMedCrossRefGoogle Scholar
  32. 32.
    Cranney A, Tugwell P, Adachi J, Weaver B, Zytaruk N, Papaioannou A, Robinson V, Shea B, Wells G, Guyatt G (2002) Meta-analyses of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis. Endocr Rev 23:517–523PubMedCrossRefGoogle Scholar
  33. 33.
    Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C (2002) Meta-analyses of therapies for postmenopausal osteoporosis. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 23:570–577PubMedCrossRefGoogle Scholar
  34. 34.
    Rosen CJ, Hochberg MC, Bonnick SL, McClung M, Miller P, Broy S, Kagan R, Chen E, Petruschke RA, Thompson DE, de Papp AE (2005) Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res 20:141–151PubMedCrossRefGoogle Scholar
  35. 35.
    Bonnick S, Saag KG, Kiel DP, McClung M, Hochberg M, Burnett S-AM, 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 91:2631–2637PubMedCrossRefGoogle Scholar
  36. 36.
    Reid DM, Hosking D, Kendler D, Brandi ML, Wark JD, Marques-Neto JF, Weryha G, Verbruggen N, Hustad CM, Mahlis EM, Melton ME (2008) A comparison of the effect of alendronate and risedronate on bone mineral density in postmenopausal women with osteoporosis: 24-month results from FACTS-International. Int J Clin Pract 62(4):575–584PubMedCrossRefGoogle Scholar
  37. 37.
    Reid DM, Hosking D, Kendler D, Brandi ML, Wark JD, Weryha G, Marques-Neto JF, Gaines KA, Verbruggen N, Melton ME (2006) Alendronic acid produces greater effects than risedronic acid on bone density and turnover in postmenopausal women with osteoporosis: results of FACTS1 fosamax actonel comparison trials. Int Clin Drug Invest 26(2):63–74CrossRefGoogle Scholar
  38. 38.
    Miller PD, Epstein S, Sedarati F, Reginster JY (2008) Once-monthly oral ibandronate compared with weekly oral alendronate in postmenopausal osteoporosis: results from the head-to-head MOTION study. Curr Med Res Opin 24:207–213PubMedGoogle Scholar
  39. 39.
    Hochberg MC, Greenspan S, Wasnich RD, Miller P, Thompson DE, Ross PD (2002) Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab 87:1586–1592PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2012

Authors and Affiliations

  1. 1.BoulderUSA

Personalised recommendations