Biomarkers of Bisphosphonate Failure in Osteoporosis

  • Elisa CairoliEmail author
  • Iacopo ChiodiniEmail author
Reference work entry
Part of the Biomarkers in Disease: Methods, Discoveries and Applications book series (BDMDA)


Bisphosphonates are the first-line agents for the management of osteoporosis. Through the suppression of bone turnover, they are able to significantly reduce fracture risk in patients with an adequate calcium and vitamin D supplementation. Bisphosphonate failure can be assumed when two or more fragility fractures occur in the course of treatment, but surrogate markers of the efficacy of bisphosphonate treatment are the variations of bone mineral density (BMD) and of bone turnover markers (BTM). Indeed, the demonstration of a significant decrease in BMD and the absence of a significant decrease in BTM while on therapy are considered as indicators of treatment failure. Moreover, other biochemical, clinical, and genetic parameters can be predictive of an inadequate response to bisphosphonate treatment.


Osteoporosis Fracture Bisphosphonate Treatment failure Bone turnover Bone mineral density 

List of Abbreviations


Atypical femoral fracture


Alkaline phosphatase


Bone-specific alkaline phosphatase


Bone mineral density


Bone sialoprotein


Bone turnover marker


Carboxy-terminal cross-linking telopeptide of type I collagen




Squalene synthase


Farnesyl pyrophosphate synthase


Geranylgeranyl diphosphate synthase


International Federation of Clinical Chemistry and Laboratory Medicine


International Osteoporosis Foundation


Low-density lipoprotein receptor-related protein


Least significant change


Mevalonate kinase


Amino-terminal cross-linking telopeptide of type I collagen




Osteonecrosis of the jaw


Amino-terminal propeptide of type I procollagen


Vitamin D receptor


  1. Adler RA, El-Hajj Fuleihan G, Bauer DC, 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;31:16–35.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Allen MR, Burr DB. The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg. 2009;67:61–70.CrossRefPubMedGoogle Scholar
  3. Baim S, Miller PD. Assessing the clinical utility of serum CTX in postmenopausal osteoporosis and its use in predicting risk of osteonecrosis of the jaw. J Bone Miner Res. 2009;24:561–74.CrossRefPubMedGoogle Scholar
  4. Bauer DC, Black DM, Garnero P, 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;19:1250–8.CrossRefPubMedGoogle Scholar
  5. Bauer DC, Garnero P, Hochberg MC, et al. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res. 2006;21:292–9.CrossRefPubMedGoogle Scholar
  6. Baxter I, Rogers A, Eastell R, et al. Evaluation of urinary N-telopeptide of type I collagen measurements in the management of osteoporosis in clinical practice. Osteoporos Int. 2013;24:941–7.CrossRefPubMedGoogle Scholar
  7. Bergmann P, Body JJ, Boonen S, et al. Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club. Int J Clin Pract. 2009;63:19–26.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab. 2000;85:4118–24.CrossRefPubMedGoogle Scholar
  9. Black DM, Delmas PD, Eastell R, et al. HORIZON pivotal fracture trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809–22.CrossRefPubMedGoogle Scholar
  10. Brazier JE, Harper R, Jones NM, et al. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ. 1992;305:160–4.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Cairoli E, Eller-Vainicher C, Ulivieri FM, et al. Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis. Osteoporos Int. 2014;25:1401–10.CrossRefPubMedGoogle Scholar
  12. Chapurlat RD, Palermo L, Ramsay P, et al. Risk of fracture among women who lose bone density during treatment with alendronate. The Fracture Intervention Trial. Osteoporos Int. 2005;16:842–8.CrossRefPubMedGoogle Scholar
  13. Choi HJ, Choi JY, Cho SW, et al. Genetic polymorphism of geranylgeranyl diphosphate synthase (GGSP1) predicts bone density response to bisphosphonate therapy in Korean women. Yonsei Med J. 2010;51:231–8.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Compston J. Monitoring osteoporosis treatment. Best Pract Res Clin Rheumatol. 2009;23:781–8.CrossRefPubMedGoogle Scholar
  15. Conti V, Russomanno G, Corbi G, et al. A polymorphism at the translation start site of the vitamin D receptor gene is associated with the response to anti-osteoporotic therapy in postmenopausal women from southern Italy. Int J Mol Sci. 2015;16:5452–66.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Dell RM, Adams AL, Greene DF, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res. 2012;27:2544–50.CrossRefPubMedGoogle Scholar
  17. Delmas PD, Vrijens B, Eastell R, et al. Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2007;92:1296–304.CrossRefPubMedGoogle Scholar
  18. Delmas PD, Munoz F, Black DM, et al. Effects of yearly zoledronic acid 5 mg on bone turnover markers and relation of PINP with fracture reduction in postmenopausal women with osteoporosis. J Bone Miner Res. 2009;24:1544–51.CrossRefPubMedGoogle Scholar
  19. Díez-Pérez A, Adachi JD, Adami S, et al. Risk factors for treatment failure with antiosteoporosis medication: the global longitudinal study of osteoporosis in women (GLOW). J Bone Miner Res. 2014;29:260–7.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Díez-Pérez A, González-Macías J. Inadequate responders to osteoporosis treatment: proposal for an operational definition. Osteoporos Int. 2008;19:1511–6.CrossRefPubMedGoogle Scholar
  21. Díez-Pérez A, Adachi JD, Agnusdei D, et al. Treatment failure in osteoporosis. Osteoporos Int. 2012a;23:2769–74.CrossRefPubMedGoogle Scholar
  22. Díez-Pérez A, Olmos JM, Nogués X, et al. Risk factors for prediction of inadequate response to antiresorptives. J Bone Miner Res. 2012b;27:817–24.CrossRefPubMedGoogle Scholar
  23. Eastell R, Barton I, Hannon RA, et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res. 2003;18:1051–6.CrossRefPubMedGoogle Scholar
  24. Eastell R, Hannon RA, Garnero P, et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate: review of statistical analysis. J Bone Miner Res. 2007;22:1656–60.CrossRefPubMedGoogle Scholar
  25. Eastell R, Vrijens B, Cahall DL, et al. Bone turnover markers and bone mineral density response with risedronate therapy: relationship with fracture risk and patient adherence. J Bone Miner Res. 2011;26:1662–9.CrossRefPubMedGoogle Scholar
  26. Eller-Vainicher C, Cairoli E, Zhukouskaya VV, Morelli V, Palmieri S, Scillitani A, Beck-Peccoz P, Chiodini I. Prevalence of subclinical contributors to low bone mineral density and/or fragility fracture. Eur J Endocrinol. 2013;169:225–37.CrossRefPubMedGoogle Scholar
  27. Favus MJ. Bisphosphonates for osteoporosis. N Engl J Med. 2010;363:2027–35.CrossRefPubMedGoogle Scholar
  28. Fink E, Cormier C, Steinmetz P, et al. Differences in the capacity of several biochemical bone markers to assess high bone turnover in early menopause and response to alendronate therapy. Osteoporos Int. 2000;11:295–303.CrossRefPubMedGoogle Scholar
  29. Fitzpatrick LA. Secondary causes of osteoporosis. Mayo Clin Proc. 2002;77:453–68.CrossRefPubMedGoogle Scholar
  30. Garnero P, Darte C, Delmas PD. A model to monitor the efficacy of alendronate treatment in women with osteoporosis using a biochemical marker of bone turnover. Bone. 1999;24:603–9.CrossRefPubMedGoogle Scholar
  31. Gennari L, Merlotti D, De Paola V, et al. Update on the pharmacogenetics of the vitamin D receptor and osteoporosis. Pharmacogenomics. 2009;10:417–33.CrossRefPubMedGoogle Scholar
  32. Greenspan SL, Parker RA, Ferguson L, et al. 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. 1998;13:1431–8.CrossRefPubMedGoogle Scholar
  33. Harris ST, Watts NB, Genant HK, 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;282:1344–52.CrossRefPubMedGoogle Scholar
  34. Hawley S, Javaid MK, Rubin KH, et al. Incidence and predictors of multiple fractures despite high adherence to oral bisphosphonates: a binational population-based cohort study. J Bone Miner Res. 2016;31:234–44.CrossRefPubMedGoogle Scholar
  35. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet. 2002;359:1929–36.CrossRefPubMedGoogle Scholar
  36. Khosla S, Burr D, Cauley J, 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;22:1479–91.CrossRefPubMedGoogle Scholar
  37. Kruk M, Ralston SH, Albagha OM. LRP5 Polymorphisms and response to risedronate treatment in osteoporotic men. Calcif Tissue Int. 2009;84:171–9.CrossRefPubMedGoogle Scholar
  38. Lee J, Vasikaran S. Current recommendations for laboratory testing and use of bone turnover markers in management of osteoporosis. Ann Lab Med. 2012;32:105–12.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Lewiecki EM. Nonresponders to osteoporosis therapy. J Clin Densitom. 2003;6:307–14.CrossRefPubMedGoogle Scholar
  40. López-Delgado L, Riancho-Zarrabeitia L, Riancho JA. Genetic and acquired factors influencing the effectiveness and toxicity of drug therapy in osteoporosis. Expert Opin Drug Metab Toxicol. 2016;12:389–98.CrossRefPubMedGoogle Scholar
  41. Marini F, Falchetti A, Silvestri S, et al. Modulatory effect of farnesyl pyrophosphate synthase (FDPS) rs2297480 polymorphism on the response to long-term amino-bisphosphonate treatment in postmenopausal osteoporosis. Curr Med Res Opin. 2008;24:2609–15.CrossRefPubMedGoogle Scholar
  42. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312:1254–9.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Marx RE, Cillo Jr JE, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg. 2007;65:2397–410.CrossRefPubMedGoogle Scholar
  44. Morales-Santana S, Díez-Pérez A, Olmos JM, et al. Circulating sclerostin and estradiol levels are associated with inadequate response to bisphosphonates in postmenopausal women with osteoporosis. Maturitas. 2015;82:402–10.CrossRefPubMedGoogle Scholar
  45. Naylor KE, Jacques RM, Paggiosi M, et al. Response of bone turnover markers to three oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO study. Osteoporos Int. 2016;27:21–31.CrossRefPubMedGoogle Scholar
  46. NIH consensus development panel on osteoporosis prevention, diagnosis, and therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785–95.Google Scholar
  47. Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90:1294–301.CrossRefPubMedGoogle Scholar
  48. Palomba S, Orio Jr F, Russo T, et al. BsmI vitamin D receptor genotypes influence the efficacy of antiresorptive treatments in postmenopausal osteoporotic women. A 1-year multicenter, randomized and controlled trial. Osteoporos Int. 2005;16:943–52.CrossRefPubMedGoogle Scholar
  49. Ravn P, Hosking D, Thompson D, et al. Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal intervention cohort study. J Clin Endocrinol Metab. 1999;84:2363–8.PubMedGoogle Scholar
  50. Seeman E. Is a change in bone mineral density a sensitive and specific surrogate of anti-fracture efficacy? Bone. 2007;41:308–17.CrossRefPubMedGoogle Scholar
  51. Seibel MJ. Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev. 2005;26:97–122.PubMedPubMedCentralGoogle Scholar
  52. Seibel MJ, Naganathan V, Barton I, et al. Relationship between pretreatment bone resorption and vertebral fracture incidence in postmenopausal osteoporotic women treated with risedronate. J Bone Miner Res. 2004;19:323–9.CrossRefPubMedGoogle Scholar
  53. Vasikaran S, Eastell R, Bruyère O, et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011;22:391–420.CrossRefPubMedGoogle Scholar
  54. Visekruna M, Wilson D, McKiernan FE. Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab. 2008;93:2948–52.CrossRefPubMedGoogle Scholar
  55. Wang C, Zheng H, He JW, et al. Genetic polymorphisms in the mevalonate pathway affect the therapeutic response to alendronate treatment in postmenopausal Chinese women with low bone mineral density. Pharmacogenomics J. 2015;15:158–64.CrossRefPubMedGoogle Scholar
  56. Zhou PR, Liu HJ, Liao EY, et al. LRP5 polymorphisms and response to alendronate treatment in Chinese postmenopausal women with osteoporosis. Pharmacogenomics. 2014;15:821–31.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  1. 1.Unit of Endocrinology and Metabolic DiseasesFondazione IRCCS Ca’ Granda – Ospedale Maggiore PoliclinicoMilanItaly
  2. 2.Department of Clinical Sciences and Community HealthUniversity of MilanMilanItaly

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