Treatment Failure

  • Elisa Torres del Pliego
  • Daniel Prieto-Alhambra
  • Adolfo Díez-Perez


A number of drugs for the treatment of osteoporosis have been developed in the last four decades. Calcitonin was the first available agent specifically developed for osteoporosis treatment and widely employed. Other options like hormone replacement therapy (both estrogens and androgens) had been used before but sporadically and in isolated trials. The effects on bone mineral density, as the first radiological and isotopic methods became available, were used for monitoring drug response. However, as research in the field progressed and new drugs were incorporated into the clinical armamentarium, the evaluation of the efficacy of these treatments became increasingly complex.

A hallmark in the evaluation of the efficacy of the treatments for osteoporosis was the design of the trials with alendronate, and Gideon Rodan was the key figure that settled up what still today are the standard criteria for measuring the effect of drug interventions in osteoporosis. The design of the FIT trial established the reduction of fracture incidence as the main outcome for the first time. This criterion required a large sample size and a long period of follow-up to achieve enough statistical power for detecting differences between arms. Moreover, like in other areas of medicine, FIT focused on a final endpoint representing the pathological event in clinics, fracture; additionally, intermediate endpoints, basically bone mineral density (BMD) variation and bone turnover markers (BTM), were used as surrogates of the efficacy. This scheme has been persisting, and therefore, efficacy estimates have relied in these three pillars.

Regulatory agencies and evidence evaluation have been working on these grounds. Pivotal trials have been carried out in a highly controlled setting, with excellent follow-up and adherence, in populations with selected clinical profile where strict inclusion and exclusion criteria were applied. However, for the practicing clinician using these drugs, two problems immediately came out. First, patients attending clinics in real-life environment often do not match with the ideal patients included in clinical trials, raising potential issues of applicability (external validity) of the results to the “common patient.” It has been estimated that up to 80 % of patients attending an osteoporosis clinics would have been excluded from participation in the pivotal trials. Second, adherence to osteoporosis medications is poor, and this is associated with a reduction in effectiveness. Therefore, a gap between evidence gathered under ideal conditions and daily practice was an element of uncertainty for the clinician.

Furthermore, even under ideal controlled conditions, some patients in the pivotal trials still suffered fractures in the treatment arm. The consequence for the clinician is the lack of firm basis for making decisions in the individual patient.


Osteoporosis treatment Treatment failure Drugs inappropriate response Drug efficacy Risk factors Treatment adherence Fracture while on treatment 


  1. 1.
    Bloch-Michel H, Milhaud G, Coutris G, Waltzing P, Charret A, Morin Y, et al. [Long term treatment of osteoporosis with thyrocalcitonin. Apropos of 7 cases]. Revue du rhumatisme et des maladies osteo-articulaires. 1970;37(10):629–38.PubMedGoogle Scholar
  2. 2.
    Dambacher MA, Olah AJ, Guncaga J, Lentner C, Haas HG. [Metabolic rates and histological-morphometrical investigations in bones of patients with osteoporosis subjected to long-term application of calcitonin]. Acta endocrinologica Supplementum. 1971;152:87.PubMedGoogle Scholar
  3. 3.
    Jowsey J, Riggs BL, Goldsmith RS, Kelly PJ, Arnaud CD. Effects of prolonged administration of porcine calcitonin in postmenopausal osteoporosis. J Clin Endocrinol Metab. 1971;33(5):752–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Wallach S, Aloia J, Cohn S. Treatment of osteoporosis with calcitonin. Semin Drug Treat. 1972;2(1):21–5.PubMedGoogle Scholar
  5. 5.
    Black DM, Reiss TF, Nevitt MC, Cauley J, Karpf D, Cummings SR. Design of the fracture intervention trial. Osteoporos Int. 1993;3 Suppl 3:S29–39.PubMedCrossRefGoogle Scholar
  6. 6.
    *Dowd R, Recker RR, Heaney RP. Study subjects and ordinary patients. Osteoporos Int. 2000;11(6):533–6. *This paper shows how ordinary patients in everyday’s practice do not fulfill inclusion criteria or have major exclusion criteria when compared with the cases included in the pivotal trials for osteoporosis treatment.PubMedCrossRefGoogle Scholar
  7. 7.
    Cramer JA, Gold DT, Silverman SL, Lewiecki EM. A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int. 2007;18(8):1023–31.PubMedCrossRefGoogle Scholar
  8. 8.
    Caro JJ, Ishak KJ, Huybrechts KF, Raggio G, Naujoks C. The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int. 2004;15(12):1003–8.PubMedCrossRefGoogle Scholar
  9. 9.
    *Siris ES, Harris ST, Rosen CJ, Barr CE, Arvesen JN, Abbott TA, et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc. 2006;81(8):1013–22. *When adherence to treatment decreases, so does the antifracture efficacy. Below 80% adherence efficacy declines and for adherence rates of 50% & or less, the treatment efficacy totally vanishes.PubMedCrossRefGoogle Scholar
  10. 10.
    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.PubMedCrossRefGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    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.PubMedCrossRefGoogle Scholar
  13. 13.
    Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282(7):637–45.PubMedCrossRefGoogle Scholar
  14. 14.
    Chesnut 3rd CH, Silverman S, Andriano K, Genant H, Gimona A, Harris S, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med. 2000;109(4):267–76.PubMedCrossRefGoogle Scholar
  15. 15.
    Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350(5):459–68.PubMedCrossRefGoogle Scholar
  16. 16.
    Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434–41.PubMedCrossRefGoogle Scholar
  17. 17.
    Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–65.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312(7041):1254–9.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Johnell O, Kanis JA, Oden A, Johansson H, De Laet C, Delmas P, et al. Predictive value of BMD for hip and other fractures. J Bone Miner Res. 2005;20(7):1185–94.PubMedCrossRefGoogle Scholar
  21. 21.
    *Delmas PD, Li Z, Cooper C. Relationship between changes in bone mineral density and fracture risk reduction with antiresorptive drugs: some issues with meta-analyses. J Bone Miner Res. 2004;19(2):330–7. *Methodological approach to discuss the caveats in the relationship established between BMD variations in response to treatment and fracture risk reduction.PubMedCrossRefGoogle Scholar
  22. 22.
    Delmas PD, Seeman E. Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy. Bone. 2004;34(4):599–604.PubMedCrossRefGoogle Scholar
  23. 23.
    *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. *Analysis of the fracture risk reduction proportion that is explained by the modifications in bone density in response to treatment.PubMedCrossRefGoogle Scholar
  24. 24.
    Bell KJ, Hayen A, Macaskill P, Irwig L, Craig JC, Ensrud K, et al. Value of routine monitoring of bone mineral density after starting bisphosphonate treatment: secondary analysis of trial data. BMJ. 2009;338:b2266.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    *Austin M, Yang YC, Vittinghoff E, Adami S, Boonen S, Bauer DC, et al. Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures. J Bone Miner Res. 2012;27(3):687–93. *Analysis of the fracture risk reduction proportion that is explained by the modifications in bone density in response to treatment with osumab, the drug where this relationship is the strongest among the currently available drugs.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Khosla S. Surrogates for fracture endpoints in clinical trials. J Bone Miner Res. 2003;18(6):1146–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Compston J. Monitoring bone mineral density during antiresorptive treatment for osteoporosis. BMJ. 2009;338:b1276.PubMedCrossRefGoogle Scholar
  28. 28.
    Lenchik L, Kiebzak GM, Blunt BA. What is the role of serial bone mineral density measurements in patient management? J Clin Densitom. 2002;5(Suppl):S29–38.PubMedCrossRefGoogle Scholar
  29. 29.
    Baim S, Wilson CR, Lewiecki EM, Luckey MM, Downs Jr RW, Lentle BC. Precision assessment and radiation safety for dual-energy X-ray absorptiometry: position paper of the International Society for Clinical Densitometry. J Clin Densitom. 2005;8(4):371–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Gluer CC. Monitoring skeletal changes by radiological techniques. J Bone Miner Res. 1999;14(11):1952–62.PubMedCrossRefGoogle Scholar
  31. 31.
    Lodder MC, Lems WF, Ader HJ, Marthinsen AE, van Coeverden SC, Lips P, et al. Reproducibility of bone mineral density measurement in daily practice. Ann Rheum Dis. 2004;63(3):285–9.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    *Chapurlat RD, Palermo L, Ramsay P, Cummings SR. Risk of fracture among women who lose bone density during treatment with alendronate. The Fracture Intervention Trial. Osteoporos Int. 2005;16(7):842–8. *Demonstration of the anti fracture benefit even in patients that loose BMD on treatment when compared with not-treated individuals in the placebo arm.PubMedCrossRefGoogle Scholar
  33. 33.
    Sarkar S, Mitlak BH, Wong M, Stock JL, Black DM, Harper KD. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res. 2002;17(1):1–10.PubMedCrossRefGoogle Scholar
  34. 34.
    Eastell R, Barton I, Hannon RA, Chines A, Garnero P, Delmas PD. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res. 2003;18(6):1051–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Eastell R, Hannon RA, Garnero P, Campbell MJ, Delmas PD. 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(11):1656–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Sarkar S, Reginster JY, Crans GG, Diez-Perez A, Pinette KV, Delmas PD. Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res. 2004;19(3):394–401.PubMedCrossRefGoogle Scholar
  37. 37.
    Reginster JY, Sarkar S, Zegels B, Henrotin Y, Bruyere O, Agnusdei D, et al. Reduction in PINP, a marker of bone metabolism, with raloxifene treatment and its relationship with vertebral fracture risk. Bone. 2004;34(2):344–51.PubMedCrossRefGoogle Scholar
  38. 38.
    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.PubMedCrossRefGoogle Scholar
  39. 39.
    Delmas PD, Munoz F, Black DM, Cosman F, Boonen S, Watts NB, 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(9):1544–51.PubMedCrossRefGoogle Scholar
  40. 40.
    *Meier C, Seibel MJ, Kraenzlin ME. Use of bone turnover markers in the real world: are we there yet? J Bone Miner Res. 2009;24(3):386–8. *Review of the strengths and weakness of the bone turnover markers, in special with respect to their use in clinical practice.PubMedCrossRefGoogle Scholar
  41. 41.
    Glover SJ, Gall M, Schoenborn-Kellenberger O, Wagener M, Garnero P, Boonen S, et al. Establishing a reference interval for bone turnover markers in 637 healthy, young, premenopausal women from the United Kingdom, France, Belgium, and the United States. J Bone Miner Res. 2009;24(3):389–97.PubMedCrossRefGoogle Scholar
  42. 42.
    *Vasikaran S, Eastell R, Bruyere O, Foldes AJ, Garnero P, Griesmacher A, 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(2):391–420. *Position paper on the practical use of bone turnover markers.PubMedCrossRefGoogle Scholar
  43. 43.
    Diez-Perez A, Gonzalez-Macias J, Marin F, Abizanda M, Alvarez R, Gimeno A, et al. Prediction of absolute risk of non-spinal fractures using clinical risk factors and heel quantitative ultrasound. Osteoporos Int. 2007;18(5):629–39.PubMedCrossRefGoogle Scholar
  44. 44.
    Johnell O, Oden A, Caulin F, Kanis JA. Acute and long-term increase in fracture risk after hospitalization for vertebral fracture. Osteoporos Int. 2001;12(3):207–14.PubMedCrossRefGoogle Scholar
  45. 45.
    Johnell O, Kanis JA, Oden A, Sernbo I, Redlund-Johnell I, Petterson C, et al. Fracture risk following an osteoporotic fracture. Osteoporos Int. 2004;15(3):175–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Levis S, Quandt SA, Thompson D, Scott J, Schneider DL, Ross PD, et al. Alendronate reduces the risk of multiple symptomatic fractures: results from the fracture intervention trial. J Am Geriatr Soc. 2002;50(3):409–15.PubMedCrossRefGoogle Scholar
  47. 47.
    Watts NB, Josse RG, Hamdy RC, Hughes RA, Manhart MD, Barton I, et al. Risedronate prevents new vertebral fractures in postmenopausal women at high risk. J Clin Endocrinol Metab. 2003;88(2):542–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Barrett-Connor E, Nielson CM, Orwoll E, Bauer DC, Cauley JA. Epidemiology of rib fractures in older men: osteoporotic fractures in men (MrOS) prospective cohort study. BMJ. 2010;340:c1069.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    *van Staa TP, Leufkens HG, Cooper C. Does a fracture at one site predict later fractures at other sites? A British cohort study. Osteoporos Int. 2002;13(8):624–9. *Analysis of how much a previous fracture predicts the occurrence of new fragility fractures in other anatomical locations.PubMedCrossRefGoogle Scholar
  50. 50.
    Harrington JT, Ste-Marie LG, Brandi ML, Civitelli R, Fardellone P, Grauer A, et al. Risedronate rapidly reduces the risk for nonvertebral fractures in women with postmenopausal osteoporosis. Calcif Tissue Int. 2004;74(2):129–35.PubMedCrossRefGoogle Scholar
  51. 51.
    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.PubMedCrossRefGoogle Scholar
  52. 52.
    Seeley DG, Browner WS, Nevitt MC, Genant HK, Scott JC, Cummings SR. Which fractures are associated with low appendicular bone mass in elderly women? The Study of Osteoporotic Fractures Research Group. Ann Intern Med. 1991;115(11):837–42.PubMedCrossRefGoogle Scholar
  53. 53.
    Mackey DC, Black DM, Bauer DC, McCloskey EV, Eastell R, Mesenbrink P, et al. Effects of antiresorptive treatment on nonvertebral fracture outcomes. J Bone Miner Res. 2011;26(10):2411–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Adami S, Isaia G, Luisetto G, Minisola S, Sinigaglia L, Gentilella R, et al. Fracture incidence and characterization in patients on osteoporosis treatment: the ICARO study. J Bone Miner Res. 2006;21(10):1565–70.PubMedCrossRefGoogle Scholar
  55. 55.
    del Puente A, Scognamiglio A, Itto E, Ferrara G, Oriente P. Intramuscular clodronate in nonresponders to oral alendronate therapy for osteoporosis. J Rheumatol. 2000;27(8):1980–3.PubMedGoogle Scholar
  56. 56.
    Heckman GA, Papaioannou A, Sebaldt RJ, Ioannidis G, Petrie A, Goldsmith C, et al. Effect of vitamin D on bone mineral density of elderly patients with osteoporosis responding poorly to bisphosphonates. BMC Musculoskelet Disord. 2002;3:6.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Sawka AM, Adachi JD, Ioannidis G, Olszynski WP, Brown JP, Hanley DA, et al. What predicts early fracture or bone loss on bisphosphonate therapy? J Clin Densitom. 2003;6(4):315–22.PubMedCrossRefGoogle Scholar
  58. 58.
    Lewiecki EM. Nonresponders to osteoporosis therapy. J Clin Densitom. 2003;6(4):307–14.PubMedCrossRefGoogle Scholar
  59. 59.
    Jakob F, Marin F, Martin-Mola E, Torgerson D, Fardellone P, Adami S, et al. Characterization of patients with an inadequate clinical outcome from osteoporosis therapy: the Observational Study of Severe Osteoporosis (OSSO). QJM. 2006;99(8):531–43.PubMedCrossRefGoogle Scholar
  60. 60.
    Obermayer-Pietsch BM, Marin F, McCloskey EV, Hadji P, Farrerons J, Boonen S, et al. Effects of two years of daily teriparatide treatment on BMD in postmenopausal women with severe osteoporosis with and without prior antiresorptive treatment. J Bone Miner Res. 2008;23(10):1591–600.PubMedCrossRefGoogle Scholar
  61. 61.
    Diez-Perez A, Gonzalez-Macias J. Inadequate responders to osteoporosis treatment: proposal for an operational definition. Osteoporos Int. 2008;19(11):1511–6.PubMedCrossRefGoogle Scholar
  62. 62.
    *Diez-Perez A, Adachi JD, Agnusdei D, Bilezikian JP, Compston JE, Cummings SR, et al. Treatment failure in osteoporosis. Osteoporos Int. 2012;23(12):2769–74. *Position paper establishing the criteria for considering failure in patients receiving antiosteoporosis medications.PubMedCrossRefGoogle Scholar
  63. 63.
    Diez-Perez A, Olmos JM, Nogues X, Sosa M, Diaz-Curiel M, Perez-Castrillon JL, et al. Risk factors for prediction of inadequate response to antiresorptives. J Bone Miner Res. 2012;27(4):817–24.PubMedCrossRefGoogle Scholar
  64. 64.
    Diez-Perez A, Adachi JD, Adami S, Anderson Jr FA, Boonen S, Chapurlat R, 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(1):260–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Prieto-Alhambra D, Pages-Castella A, Wallace G, Javaid MK, Judge A, Nogues X, et al. Predictors of fracture while on treatment with oral bisphosphonates: a population-based cohort study. J Bone Miner Res. 2014;29(1):268–74.PubMedCrossRefGoogle Scholar
  66. 66.
    *Lewiecki EM, Cummings SR, Cosman F. Treat-to-target for osteoporosis: is now the time? J Clin Endocrinol Metab. 2013;98(3):946–53. *Article on the importance and future prospects for setting standard targets to be achieved when treating patients with osteoporosis.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Elisa Torres del Pliego
    • 1
  • Daniel Prieto-Alhambra
    • 2
  • Adolfo Díez-Perez
    • 1
  1. 1.Department of Internal MedicineHospital del Mar-IMIM, Autonomous University of Barcelona and RETICEF, Instituto Carlos IIIBarcelonaSpain
  2. 2.Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS)University of OxfordOxfordUK

Personalised recommendations