Skip to main content
SpringerLink
Log in

Bisphosphonates: Mechanisms of Action and Role in Osteoporosis Therapy

  • Chapter
  • First Online:
Osteoporosis

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

Bisphosphonates are the most commonly prescribed treatments for osteoporosis in both postmenopausal women and men. They inhibit bone resorption by osteoclasts and indirectly reduce bone formation coupled to resorption without direct effects on bone formation by osteoblasts. Several of the nitrogen-containing bisphosphonates (N-BP) have been shown to reduce the risk of fractures of the spine, proximal femur and non-vertebral fractures in prospective placebo-controlled studies up to 4 years long. While fracture risk reduction implies improved bone strength and bone strength cannot be measured in individual patients, current models indicate that decreased bone resorption results in both improved bone microarchitecture and greater bone mass, and that both effects contribute to bone strength. All bisphosphonates share the “bisphosphonate” P-C-P structure responsible for their affinity for hydroxyapatite on bone surfaces, while the chemistry of the moiety linked to the central carbon results in their inhibition of osteoclast-mediated bone resorption. The pharmacokinetic profiles of all N-BPs are similar and differ substantially from most other drugs. Oral bioavailability is <1% and they must be administered fasting or via intravenous (IV) infusion. BPs in blood distribute quickly to bone surfaces or are eliminated in urine. The half-life of BPs on bone surfaces is 3–5 weeks, where they inhibit osteoclasts that form resorption lacunae on BP-coated surface. Their long bone-surface half-life allows weekly, monthly and even yearly treatment regimens. BPs are not metabolized and may be incorporated into new bone, where they are not pharmacologically active unless a subsequent round of bone remodeling results in their resorption. When BP treatment is stopped, bone resorption increases in two phases. The first phase occurs over weeks to months as the concentration on the surface of bone decreases. If enough BP has been incorporated into new bone formed during prior treatment, that bisphosphonate may be released and again inhibit bone resorption. The second phase of post-treatment resorption increase occurs gradually as BP within bone decreases (estimated half-life with bone is approximately 5 years). Upper gastrointestinal symptoms are the only common side effects of oral bisphosphonates and may require use of an intravenous formulation. Less common side effects include musculoskeletal pain that begins several months after the start of treatment and resolves when treatment is interrupted. Two rare potential side effects (osteonecrosis of the jaw and atypical femoral fractures) limit broader patient acceptance and lead to the use of a “drug holiday” after 3–5 years of treatment to reduce side effect risk. Controlled clinical trials are required to determine the persistence of both fracture risk reduction and risk of adverse events (including atypical femoral fractures) after long-term (3–5 years) treatment with bisphosphonates is either discontinued, continued at the same dose or continued at a lower dose, to develop an evidence-based approach to the use of drug holidays.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Consensus development conference: prophylaxis and treatment of osteoporosis. Am J Med. 1991;90(1):107–10.

    Google Scholar 

  2. Fleisch H. Bisphosphonates in bone disease: from the laboratory to the patient. 4th ed. San Diego: Academic Press; 2000. xii, 212 p. p.

    Google Scholar 

  3. Lewiecki EM. Bisphosphonates for the treatment of osteoporosis: insights for clinicians. Ther Adv Chronic Dis. 2010;1(3):115–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Francis MD, Briner WW. The effect of phosphonates on dental enamel in vitro and calculus formation in vivo. Calcif Tissue Res. 1973;11(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  5. Ebetino FH, Hogan AM, Sun S, Tsoumpra MK, Duan X, Triffitt JT, et al. The relationship between the chemistry and biological activity of the bisphosphonates. Bone. 2011;49(1):20–33.

    Article  CAS  PubMed  Google Scholar 

  6. O’Neil MJ, Heckelman PE, Dobbelaar PH, Roman KJ, Kenny CM, Karaffa LS, et al. The Merck index: an encyclopedia of chemicals, drugs, and biologicals. 15th ed. Cambridge, UK: Royal Society of Chemistry; 2013.

    Google Scholar 

  7. Leu CT, Luegmayr E, Freedman LP, Rodan GA, Reszka AA. Relative binding affinities of bisphosphonates for human bone and relationship to antiresorptive efficacy. Bone. 2006;38(5):628–36.

    Article  CAS  PubMed  Google Scholar 

  8. Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006;38(5):617–27.

    Article  CAS  PubMed  Google Scholar 

  9. Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev. 1998;19(1):80–100.

    Article  CAS  PubMed  Google Scholar 

  10. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010;1192:190–200.

    Article  CAS  PubMed  Google Scholar 

  11. Russell RG. Bisphosphonates: the first 40 years. Bone. 2011;49(1):2–19.

    Article  CAS  PubMed  Google Scholar 

  12. Fleisch H, Russell RG, Francis MD. Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science. 1969;165(3899):1262–4.

    Article  CAS  PubMed  Google Scholar 

  13. Fleisch H, Russell RG, Simpson B, Muhlbauer RC. Prevention by a diphosphonate of immobilization “osteoporosis” in rats. Nature. 1969;223(5202):211–2.

    Article  CAS  PubMed  Google Scholar 

  14. Shinoda H, Adamek G, Felix R, Fleisch H, Schenk R, Hagan P. Structure-activity relationships of various bisphosphonates. Calcif Tissue Int. 1983;35(1):87–99.

    Article  CAS  PubMed  Google Scholar 

  15. Schenk R, Eggli P, Fleisch H, Rosini S. Quantitative morphometric evaluation of the inhibitory activity of new aminobisphosphonates on bone resorption in the rat. Calcif Tissue Int. 1986;38(6):342–9.

    Article  CAS  PubMed  Google Scholar 

  16. Schenk R, Merz WA, Muhlbauer R, Russell RG, Fleisch H. Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl 2 MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats. Calcif Tissue Res. 1973;11(3):196–214.

    Article  CAS  PubMed  Google Scholar 

  17. Rogers MJ, Russell RG, Blackburn GM, Williamson MP, Watts DJ. Metabolism of halogenated bisphosphonates by the cellular slime mould Dictyostelium discoideum. Biochem Biophys Res Commun. 1992;189(1):414–23.

    Article  CAS  PubMed  Google Scholar 

  18. Rogers MJ, Ji X, Russell RG, Blackburn GM, Williamson MP, Bayless AV, et al. Incorporation of bisphosphonates into adenine nucleotides by amoebae of the cellular slime mould Dictyostelium discoideum. Biochem J. 1994;303(Pt 1):303–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Frith JC, Monkkonen J, Blackburn GM, Russell RG, Rogers MJ. Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5′-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro. J Bone Miner Res. 1997;12(9):1358–67.

    Article  CAS  PubMed  Google Scholar 

  20. Frith JC, Monkkonen J, Auriola S, Monkkonen H, Rogers MJ. The molecular mechanism of action of the antiresorptive and antiinflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum. 2001;44(9):2201–10.

    Article  CAS  PubMed  Google Scholar 

  21. Rogers MJ, Crockett JC, Coxon FP, Monkkonen J. Biochemical and molecular mechanisms of action of bisphosphonates. Bone. 2011;49(1):34–41.

    Article  CAS  PubMed  Google Scholar 

  22. Schmidt A, Rutledge SJ, Endo N, Opas EE, Tanaka H, Wesolowski G, et al. Protein-tyrosine phosphatase activity regulates osteoclast formation and function: inhibition by alendronate. Proc Natl Acad Sci U S A. 1996;93(7):3068–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S A. 1999;96(1):133–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res. 1998;13(4):581–9.

    Article  CAS  PubMed  Google Scholar 

  25. van Beek E, Pieterman E, Cohen L, Lowik C, Papapoulos S. Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun. 1999;264(1):108–11.

    Article  PubMed  Google Scholar 

  26. Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G. Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys. 2000;373(1):231–41.

    Article  CAS  PubMed  Google Scholar 

  27. Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001;296(2):235–42.

    CAS  PubMed  Google Scholar 

  28. Amin D, Cornell SA, Gustafson SK, Needle SJ, Ullrich JW, Bilder GE, et al. Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. J Lipid Res. 1992;33(11):1657–63.

    CAS  PubMed  Google Scholar 

  29. Glantschnig H, Fisher JE, Wesolowski G, Rodan GA, Reszka AA. M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death Differ. 2003;10(10):1165–77.

    Article  CAS  PubMed  Google Scholar 

  30. Sugatani T, Hruska KA. Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem. 2005;280(5):3583–9.

    Article  CAS  PubMed  Google Scholar 

  31. Reszka AA, Halasy-Nagy JM, Masarachia PJ, Rodan GA. Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1 kinase during apoptosis. A link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase. J Biol Chem. 1999;274(49):34967–73.

    Article  CAS  PubMed  Google Scholar 

  32. Fisher JE, Rosenberg E, Santora AC, Reszka AA. In vitro and in vivo responses to high and low doses of nitrogen-containing bisphosphonates suggest engagement of different mechanisms for inhibition of osteoclastic bone resorption. Calcif Tissue Int. 2013;92(6):531–8.

    Article  CAS  PubMed  Google Scholar 

  33. Merck & Co. I. FOSAMAX® (alendronte sodium) tablets and oral solution Prescribing Information. In: Merck & Co. I, editor. Retrieved from: http://www.merck.com/product/usa/pi_circulars/f/fosamax/fosamax_pi.pdf: Merck & Co., Inc; 2016.

  34. Chilcott W. ACTONEL® (risedronate sodium) tablets Prescribing Information. Retrieved from: https://www.allergan.com/assets/pdf/actonel_pi: Warner Chilcott (US), LLC; 2015.

  35. Genentech. BONIVA® (ibandronate sodium) Tablets. In: Genentech, editor.: Genentech; 2016.

    Google Scholar 

  36. Reginster JY, Wilson KM, Dumont E, Bonvoisin B, Barrett J. Monthly oral ibandronate is well tolerated and efficacious in postmenopausal women: results from the monthly oral pilot study. J Clin Endocrinol Metab. 2005;90(9):5018–24.

    Article  CAS  PubMed  Google Scholar 

  37. Recker RR, Saville PD. Intestinal absorption of disodium ethane-1-hydroxy-1,1-diphosphonate (disodium etidronate) using a deconvolution technique. Toxicol Appl Pharmacol. 1973;24(4):580–9.

    Article  CAS  PubMed  Google Scholar 

  38. Yakatan GJ, Poynor WJ, Talbert RL, Floyd BF, Slough CL, Ampulski RS, et al. Clodronate kinetics and bioavailability. Clin Pharmacol Ther. 1982;31(3):402–10.

    Article  CAS  PubMed  Google Scholar 

  39. Warner Chilcott (US) L. ATELVIA® (risedronate sodium) delayed-release tablets Prescribing Information. In: Warner Chilcott (US) L, editor. Retrieved from: https://www.allergan.com/assets/pdf/atelvia_pi2015.

  40. Khan SA, Kanis JA, Vasikaran S, Kline WF, Matuszewski BK, McCloskey EV, et al. Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res. 1997;12(10):1700–7.

    Article  CAS  PubMed  Google Scholar 

  41. Cocquyt V, Kline WF, Gertz BJ, Van Belle SJ, Holland SD, DeSmet M, et al. Pharmacokinetics of intravenous alendronate. J Clin Pharmacol. 1999;39(4):385–93.

    Article  CAS  PubMed  Google Scholar 

  42. Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone. 1996;18(2):75–85.

    Article  CAS  PubMed  Google Scholar 

  43. Lin JH, Duggan DE, Chen IW, Ellsworth RL. Physiological disposition of alendronate, a potent anti-osteolytic bisphosphonate, in laboratory animals. Drug Metab Dispos. 1991;19(5):926–32.

    CAS  PubMed  Google Scholar 

  44. Masarachia P, Weinreb M, Balena R, Rodan GA. Comparison of the distribution of 3H-alendronate and 3H-etidronate in rat and mouse bones. Bone. 1996;19(3):281–90.

    Article  CAS  PubMed  Google Scholar 

  45. Porras AG, Holland SD, Gertz BJ. Pharmacokinetics of alendronate. Clin Pharmacokinet. 1999;36(5):315–28.

    Article  CAS  PubMed  Google Scholar 

  46. Lin JH, Russell G, Gertz B. Pharmacokinetics of alendronate: an overview. Int J Clin Pract Suppl. 1999;101:18–26.

    CAS  PubMed  Google Scholar 

  47. Bone HG, Downs RW Jr, Tucci JR, Harris ST, Weinstein RS, Licata AA, et al. Dose-response relationships for alendronate treatment in osteoporotic elderly women. Alendronate Elderly Osteoporosis Study Centers. J Clin Endocrinol Metab. 1997;82(1):265–74.

    CAS  PubMed  Google Scholar 

  48. Bone HG, Adami S, Rizzoli R, Favus M, Ross PD, Santora A, et al. Weekly administration of alendronate: rationale and plan for clinical assessment. Clin Ther. 2000;22(1):15–28.

    Article  CAS  PubMed  Google Scholar 

  49. Mitchell DY, Eusebio RA, Sacco-Gibson NA, Pallone KA, Kelly SC, Nesbitt JD, et al. Dose-proportional pharmacokinetics of risedronate on single-dose oral administration to healthy volunteers. J Clin Pharmacol. 2000;40(3):258–65.

    Article  CAS  PubMed  Google Scholar 

  50. Schnitzer T, Bone HG, Crepaldi G, Adami S, McClung M, Kiel D, et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group. Aging (Milano). 2000;12(1):1–12.

    CAS  Google Scholar 

  51. Rizzoli R, Greenspan SL, Bone G 3rd, Schnitzer TJ, Watts NB, Adami S, et al. Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis. J Bone Miner Res. 2002;17(11):1988–96.

    Article  CAS  PubMed  Google Scholar 

  52. Harris ST, Watts NB, Li Z, Chines AA, Hanley DA, Brown JP. Two-year efficacy and tolerability of risedronate once a week for the treatment of women with postmenopausal osteoporosis. Curr Med Res Opin. 2004;20(5):757–64.

    Article  CAS  PubMed  Google Scholar 

  53. Miller PD, McClung MR, Macovei L, Stakkestad JA, Luckey M, Bonvoisin B, et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res. 2005;20(8):1315–22.

    Article  CAS  PubMed  Google Scholar 

  54. Reginster JY, Adami S, Lakatos P, Greenwald M, Stepan JJ, Silverman SL, et al. Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study. Ann Rheum Dis. 2006;65(5):654–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Chen T, Berenson J, Vescio R, Swift R, Gilchick A, Goodin S, et al. Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol. 2002;42(11):1228–36.

    Article  CAS  PubMed  Google Scholar 

  56. Cosman F, Gilchrist N, McClung M, Foldes J, de Villiers T, Santora A, et al. A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates. Osteoporos Int. 2016;27(1):377–86.

    Article  CAS  PubMed  Google Scholar 

  57. Saag K, Lindsay R, Kriegman A, Beamer E, Zhou W. A single zoledronic acid infusion reduces bone resorption markers more rapidly than weekly oral alendronate in postmenopausal women with low bone mineral density. Bone. 2007;40(5):1238–43.

    Article  CAS  PubMed  Google Scholar 

  58. McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol. 2009;114(5):999–1007.

    Article  CAS  PubMed  Google Scholar 

  59. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):1809–22.

    Article  CAS  PubMed  Google Scholar 

  60. Grey A, Bolland MJ, Horne A, Mihov B, Gamble G, Reid IR. Duration of antiresorptive activity of zoledronate in postmenopausal women with osteopenia: a randomized, controlled multidose trial. CMAJ. 2017;189(36):E1130–E6.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Bouxsein ML. Bone quality: and old concept revisited. Osteoporos Int. 2003;14 Suppl 5:S1–3.

    Article  Google Scholar 

  62. Cranney A, Wells G, Willan A, Griffith L, Zytaruk N, Robinson V, et al. Meta-analyses of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev. 2002;23(4):508–16.

    Article  CAS  PubMed  Google Scholar 

  63. Cummings SR, Karpf DB, Harris F, Genant HK, Ensrud K, LaCroix AZ, et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med. 2002;112(4):281–9.

    Article  CAS  PubMed  Google Scholar 

  64. Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab. 2000;85(11):4118–24.

    Article  CAS  PubMed  Google Scholar 

  65. Pols HA, Felsenberg D, Hanley DA, Stepan J, Munoz-Torres M, Wilkin TJ, et al. 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. Fosamax International Trial Study Group. Osteoporos Int. 1999;9(5):461–8.

    Article  CAS  PubMed  Google Scholar 

  66. Cummings SR. How drugs decrease fracture risk: lessons from trials. J Musculoskelet Neuronal Interact. 2002;2(3):198–200.

    CAS  PubMed  Google Scholar 

  67. Dempster DW. Bone microarchitecture and strength. Osteoporos Int. 2003;14 Suppl 5:S54–6.

    Article  PubMed  Google Scholar 

  68. Thomsen JS, Ebbesen EN, Mosekilde L. Predicting human vertebral bone strength by vertebral static histomorphometry. Bone. 2002;30(3):502–8.

    Article  CAS  PubMed  Google Scholar 

  69. Recker R, Lappe J, Davies KM, Heaney R. Bone remodeling increases substantially in the years after menopause and remains increased in older osteoporosis patients. J Bone Miner Res. 2004;19(10):1628–33.

    Article  PubMed  Google Scholar 

  70. Heaney RP. Remodeling and skeletal fragility. Osteoporos Int. 2003;14 Suppl 5:S12–5.

    Google Scholar 

  71. Parfitt AM. High bone turnover is intrinsically harmful: two paths to a similar conclusion. The Parfitt view. J Bone Miner Res. 2002;17(8):1558–9.. author reply 60

    Article  PubMed  Google Scholar 

  72. Heaney RP. The bone-remodeling transient: implications for the interpretation of clinical studies of bone mass change. J Bone Miner Res. 1994;9(10):1515–23.

    Article  CAS  PubMed  Google Scholar 

  73. Heaney RP, Yates AJ, Santora AC 2nd. Bisphosphonate effects and the bone remodeling transient. J Bone Miner Res. 1997;12(8):1143–51.

    Article  CAS  PubMed  Google Scholar 

  74. Watts NB, Harris ST, Genant HK, Wasnich RD, Miller PD, Jackson RD, et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med. 1990;323(2):73–9.

    Article  CAS  PubMed  Google Scholar 

  75. Harris ST, Watts NB, Jackson RD, Genant HK, Wasnich RD, Ross P, et al. Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded therapy followed by one year of open therapy. Am J Med. 1993;95(6):557–67.

    Article  CAS  PubMed  Google Scholar 

  76. Cranney A, Welch V, Adachi JD, Guyatt G, Krolicki N, Griffith L, et al. Etidronate for treating and preventing postmenopausal osteoporosis. Cochrane Database Syst Rev. 2001;(4):Cd003376.

    Google Scholar 

  77. Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, et al. Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD003376.

    Google Scholar 

  78. Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):2359–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995;333(22):1437–43.

    Article  CAS  PubMed  Google Scholar 

  80. Karpf DB, Shapiro DR, Seeman E, Ensrud KE, Johnston CC Jr, Adami S, et al. Prevention of nonvertebral fractures by alendronate. A meta-analysis. Alendronate Osteoporosis Treatment Study Groups. JAMA. 1997;277(14):1159–64.

    Article  CAS  PubMed  Google Scholar 

  81. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996;348(9041):1535–41.

    Article  CAS  PubMed  Google Scholar 

  82. Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280(24):2077–82.

    Article  CAS  PubMed  Google Scholar 

  83. Looker AC, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP, et al. Updated data on proximal femur bone mineral levels of US adults. Osteoporos Int. 1998;8(5):468–89.

    Article  CAS  PubMed  Google Scholar 

  84. Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350(12):1189–99.

    Article  CAS  PubMed  Google Scholar 

  85. Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296(24):2927–38.

    Article  CAS  PubMed  Google Scholar 

  86. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999;282(14):1344–52.

    Article  CAS  PubMed  Google Scholar 

  87. Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int. 2000;11(1):83–91.

    Article  CAS  PubMed  Google Scholar 

  88. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344(5):333–40.

    Article  CAS  PubMed  Google Scholar 

  89. Qaseem A, Forciea MA, McLean RM, Denberg TD. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(11):818–39.

    Article  PubMed  Google Scholar 

  90. Cranney A, Tugwell P, Adachi J, Weaver B, Zytaruk N, Papaioannou A, et al. Meta-analyses of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis. Endocr Rev. 2002;23(4):517–23.

    Article  CAS  PubMed  Google Scholar 

  91. Chesnut CH 3rd, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19(8):1241–9.

    Article  CAS  PubMed  Google Scholar 

  92. Recker RR, Ste-Marie LG, Langdahl B, Czerwinski E, Bonvoisin B, Masanauskaite D, et al. Effects of intermittent intravenous ibandronate injections on bone quality and micro-architecture in women with postmenopausal osteoporosis: the DIVA study. Bone. 2010;46(3):660–5.

    Article  CAS  PubMed  Google Scholar 

  93. Eisman JA, Civitelli R, Adami S, Czerwinski E, Recknor C, Prince R, et al. Efficacy and tolerability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study. J Rheumatol. 2008;35(3):488–97.

    CAS  PubMed  Google Scholar 

  94. Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357(18):1799–809.

    Article  CAS  PubMed  Google Scholar 

  95. Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012;27(2):243–54.

    Article  CAS  PubMed  Google Scholar 

  96. Black DM, Reid IR, Cauley JA, Cosman F, Leung PC, Lakatos P, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2015;30(5):934–44.

    Article  CAS  PubMed  Google Scholar 

  97. Sakai A, Ikeda S, Okimoto N, Matsumoto H, Teshima K, Okazaki Y, et al. Clinical efficacy and treatment persistence of monthly minodronate for osteoporotic patients unsatisfied with, and shifted from, daily or weekly bisphosphonates: the BP-MUSASHI study. Osteoporos Int. 2014;25(9):2245–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kubo T, Shimose S, Matsuo T, Fujimori J, Ochi M. Minodronate for the treatment of osteoporosis. Drugs Today (Barc). 2010;46(1):33–7.

    Article  Google Scholar 

  99. Matsumoto T, Hagino H, Shiraki M, Fukunaga M, Nakano T, Takaoka K, et al. Effect of daily oral minodronate on vertebral fractures in Japanese postmenopausal women with established osteoporosis: a randomized placebo-controlled double-blind study. Osteoporos Int. 2009;20(8):1429–37.

    Article  CAS  PubMed  Google Scholar 

  100. Hagino H, Shiraki M, Fukunaga M, Nakano T, Takaoka K, Ohashi Y, et al. Three years of treatment with minodronate in patients with postmenopausal osteoporosis. J Bone Miner Metab. 2012;30(4):439–46.

    Article  CAS  PubMed  Google Scholar 

  101. McCloskey EV, Dunn JA, Kanis JA, MacLennan IC, Drayson MT. Long-term follow-up of a prospective, double-blind, placebo-controlled randomized trial of clodronate in multiple myeloma. Br J Haematol. 2001;113(4):1035–43.

    Article  CAS  PubMed  Google Scholar 

  102. McCloskey EV, Beneton M, Charlesworth D, Kayan K, deTakats D, Dey A, et al. Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res. 2007;22(1):135–41.

    Article  CAS  PubMed  Google Scholar 

  103. Rosen CJ, Hochberg MC, Bonnick SL, McClung M, Miller P, Broy S, et al. 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. 2005;20(1):141–51.

    Article  CAS  PubMed  Google Scholar 

  104. Reid DM, Hosking D, Kendler D, Brandi ML, Wark JD, Weryha G, et al. Alendronic acid produces greater effects than risedronic acid on bone density and turnover in postmenopausal women with osteoporosis: results of FACTS -international. Clin Drug Investig. 2006;26(2):63–74.

    Article  CAS  PubMed  Google Scholar 

  105. Reid DM, Hosking D, Kendler D, Brandi ML, Wark JD, Marques-Neto JF, et al. 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. 2008;62(4):575–84.

    Article  CAS  PubMed  Google Scholar 

  106. Bonnick S, Saag KG, Kiel DP, McClung M, Hochberg M, Burnett SM, et al. Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years. J Clin Endocrinol Metab. 2006;91(7):2631–7.

    Article  CAS  PubMed  Google Scholar 

  107. Hagino H, Nishizawa Y, Sone T, Morii H, Taketani Y, Nakamura T, et al. A double-blinded head-to-head trial of minodronate and alendronate in women with postmenopausal osteoporosis. Bone. 2009;44(6):1078–84.

    Article  CAS  PubMed  Google Scholar 

  108. Sambrook PN, Geusens P, Ribot C, Solimano JA, Ferrer-Barriendos J, Gaines K, et al. Alendronate produces greater effects than raloxifene on bone density and bone turnover in postmenopausal women with low bone density: results of EFFECT (Efficacy of FOSAMAX versus EVISTA Comparison Trial) International. J Intern Med. 2004;255(4):503–11.

    Article  CAS  PubMed  Google Scholar 

  109. Zhang L, Pang Y, Shi Y, Xu M, Xu X, Zhang J, et al. Indirect comparison of teriparatide, denosumab, and oral bisphosphonates for the prevention of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. Menopause. 2015;22(9):1021–5.

    Article  PubMed  Google Scholar 

  110. Liu CL, Lee HC, Chen CC, Cho DY. Head-to-head comparisons of bisphosphonates and teriparatide in osteoporosis: a meta-analysis. Clin Invest Med. 2017;40(3):E146–e57.

    Article  PubMed  Google Scholar 

  111. Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003;349(13):1207–15.

    Article  CAS  PubMed  Google Scholar 

  112. Black DM, Bilezikian JP, Ensrud KE, Greenspan SL, Palermo L, Hue T, et al. One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med. 2005;353(6):555–65.

    Article  CAS  PubMed  Google Scholar 

  113. Cosman F, Miller PD, Williams GC, Hattersley G, Hu MY, Valter I, et al. Eighteen months of treatment with subcutaneous abaloparatide followed by 6 months of treatment with alendronate in postmenopausal women with osteoporosis: Results of the ACTIVExtend Trial. Mayo Clin Proc. 2017;92(2):200–10.

    Article  CAS  PubMed  Google Scholar 

  114. Saag KG, Petersen J, Brandi ML, Karaplis AC, Lorentzon M, Thomas T, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377(15):1417–27.

    Article  CAS  PubMed  Google Scholar 

  115. Bauer DC, Black DM, Garnero P, Hochberg M, Ott S, Orloff J, et al. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial. J Bone Miner Res. 2004;19(8):1250–8.

    Article  PubMed  Google Scholar 

  116. Hassager C, Risteli J, Risteli L, Jensen SB, Christiansen C. Diurnal variation in serum markers of type I collagen synthesis and degradation in healthy premenopausal women. J Bone Miner Res. 1992;7(11):1307–11.

    Article  CAS  PubMed  Google Scholar 

  117. Lewiecki EM, Watts NB. Assessing response to osteoporosis therapy. Osteoporos Int. 2008;19(10):1363–8.

    Article  CAS  PubMed  Google Scholar 

  118. Silverman S, Christiansen C. Individualizing osteoporosis therapy. Osteoporos Int. 2012;23(3):797–809.

    Article  CAS  PubMed  Google Scholar 

  119. Wells G, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, et al. Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):Cd004523.

    Google Scholar 

  120. Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):Cd001155.

    Google Scholar 

  121. Adler RA, El-Hajj Fuleihan G, Bauer DC, Camacho PM, Clarke BL, Clines GA, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016;31(1):16–35.

    Article  CAS  PubMed  Google Scholar 

  122. Camacho PM, Petak SM, Binkley N, Clarke BL, Harris ST, Hurley DL, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016--executive summary. Endocr Pract. 2016;22(9):1111–8.

    Article  PubMed  Google Scholar 

  123. Adami S, Zamberlan N. Adverse effects of bisphosphonates. A comparative review. Drug Saf. 1996;14(3):158–70.

    Article  CAS  PubMed  Google Scholar 

  124. Adami S, Bhalla AK, Dorizzi R, Montesanti F, Rosini S, Salvagno G, et al. The acute-phase response after bisphosphonate administration. Calcif Tissue Int. 1987;41(6):326–31.

    Article  CAS  PubMed  Google Scholar 

  125. Khan M, Cheung AM, Khan AA. Drug-related adverse events of osteoporosis therapy. Endocrinol Metab Clin N Am. 2017;46(1):181–92.

    Article  Google Scholar 

  126. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25(11):2267–94.

    Article  PubMed  Google Scholar 

  127. Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014;29(1):1–23.

    Article  PubMed  Google Scholar 

  128. Schilcher J, Koeppen V, Ranstam J, Skripitz R, Michaelsson K, Aspenberg P. Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls. Bone. 2013;52(1):389–92.

    Article  PubMed  Google Scholar 

  129. Schilcher J, Koeppen V, Aspenberg P, Michaelsson K. Risk of atypical femoral fracture during and after bisphosphonate use. Acta Orthop. 2015;86(1):100–7.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Schilcher J, Michaelsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364(18):1728–37.

    Article  CAS  PubMed  Google Scholar 

  131. Mahjoub Z, Jean S, Leclerc JT, Brown JP, Boulet D, Pelet S, et al. Incidence and characteristics of atypical femoral fractures: clinical and geometrical data. J Bone Miner Res. 2016;31(4):767–76.

    Article  CAS  PubMed  Google Scholar 

  132. Marcano A, Taormina D, Egol KA, Peck V, Tejwani NC. Are race and sex associated with the occurrence of atypical femoral fractures? Clin Orthop Relat Res. 2014;472(3):1020–7.

    Article  PubMed  Google Scholar 

  133. Khan A, Morrison A, Cheung A, Hashem W, Compston J. Osteonecrosis of the jaw (ONJ): diagnosis and management in 2015. Osteoporos Int. 2016;27(3):853–9.

    Article  CAS  PubMed  Google Scholar 

  134. Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O’Ryan F, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015;30(1):3–23.

    Article  PubMed  Google Scholar 

  135. Khan AA, Morrison A, Kendler DL, Rizzoli R, Hanley DA, Felsenberg D, et al. Case-based review of osteonecrosis of the jaw (ONJ) and application of the international recommendations for management from the international task force on ONJ. J Clin Densitom. 2017;20(1):8–24.

    Article  PubMed  Google Scholar 

  136. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61(9):1115–7.

    Article  PubMed  Google Scholar 

  137. Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol. 2003;21(22):4253–4.

    Article  PubMed  Google Scholar 

  138. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22(10):1479–91.

    Article  PubMed  Google Scholar 

  139. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws – 2009 update. J Oral Maxillofac Surg. 2009;67(5 Suppl):2–12.

    PubMed  Google Scholar 

  140. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw – 2014 update. J Oral Maxillofac Surg. 2014;72(10):1938–56.

    Article  PubMed  Google Scholar 

  141. Scagliotti GV, Hirsh V, Siena S, Henry DH, Woll PJ, Manegold C, et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol. 2012;7(12):1823–9.

    Article  CAS  PubMed  Google Scholar 

  142. Grbic JT, Landesberg R, Lin SQ, Mesenbrink P, Reid IR, Leung PC, et al. Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial. J Am Dent Assoc. 2008;139(1):32–40.

    Article  CAS  PubMed  Google Scholar 

  143. Barrett-Connor E, Swern AS, Hustad CM, Bone HG, Liberman UA, Papapoulos S, et al. Alendronate and atrial fibrillation: a meta-analysis of randomized placebo-controlled clinical trials. Osteoporos Int. 2012;23(1):233–45.

    Article  CAS  PubMed  Google Scholar 

  144. Patel DV, Bolland M, Nisa Z, Al-Abuwsi F, Singh M, Horne A, et al. Incidence of ocular side effects with intravenous zoledronate: secondary analysis of a randomized controlled trial. Osteoporos Int. 2015;26(2):499–503.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Arthur C. Santora II & Anupa Sharma

Authors
  1. Arthur C. Santora II
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anupa Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anupa Sharma .

Editor information

Editors and Affiliations

  1. Massachusetts General Hospital, Boston, MA, USA

    Benjamin Z. Leder

  2. Massachusetts General Hospital, Boston, MA, USA

    Marc N. Wein

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Santora, A.C., Sharma, A. (2020). Bisphosphonates: Mechanisms of Action and Role in Osteoporosis Therapy. In: Leder, B., Wein, M. (eds) Osteoporosis. Contemporary Endocrinology. Humana, Cham. https://doi.org/10.1007/978-3-319-69287-6_14

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-69287-6_14

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-319-69286-9

  • Online ISBN: 978-3-319-69287-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation