Skip to main content

Advertisement

SpringerLink
Log in

Inadequate responders to osteoporosis treatment: proposal for an operational definition

  • Special Feature
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

The concept of inadequate response to osteoporosis treatment is not clear. In the literature several criteria have been used. We propose an operational definition of an inadequate responder based on the changes observed in bone mineral density and incident fractures while on therapy.

Introduction

Fractures may occur in compliant patients even while on active treatment. These cases have been defined as inadequate responders (IR).

Methods

We reviewed the basis for this concept and propose an operational definition for IR.

Results

Good compliance and adequate calcium and vitamin D supplementation are the first requirement. The second requirement is a treatment period of at least 1 year, since before that time treatment may not have been fully effective. Fractures are the gold standard for measuring efficacy and changes in bone density and turnover markers may be surrogates. We propose classifying patient response as: Inadequate—incident fracture and a decrease in BMD greater than a significant change (Trend Assessment Margin or TAM); Possibly inadequate—incident fracture or a decrease in BMD greater than a significant change (TAM); and Appropriate—no fracture and no decrease in BMD greater than a significant change (TAM). Additional criteria (biochemical markers, bone quality parameters) may be taken into account.

Conclusion

A wide consensus on the IR concept is required given its clinical, regulatory, and reimbursement implications.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Cramer JA, Gold DT, Silverman SL et al (2007) A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int 18:1023–1031

    Article  CAS  PubMed  Google Scholar 

  2. Caro JJ, Ishak KJ, Huybrechts KF et al (2004) The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int 15:1003–1008

    Article  PubMed  Google Scholar 

  3. Siris ES, Harris ST, Rosen CJ et al (2006) Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc 81:1013–1022

    Article  PubMed  Google Scholar 

  4. Black DM, Cummings SR, Karpf DB et al (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348:1535–1541

    Article  CAS  PubMed  Google Scholar 

  5. Harris ST, Watts NB, Genant HK et al (1999) 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 282:1344–1352

    Article  CAS  PubMed  Google Scholar 

  6. Ettinger B, Black DM, Mitlak BH et al (1999) 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 282:637–645

    Article  CAS  PubMed  Google Scholar 

  7. Chesnut CH III, Silverman S, Andriano K et al (2000) 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 109:267–276

    Article  CAS  PubMed  Google Scholar 

  8. Meunier PJ, Roux C, Seeman E et al (2004) The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 350:459–468

    Article  CAS  PubMed  Google Scholar 

  9. Neer RM, Arnaud CD, Zanchetta JR et al (2001) Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441

    Article  CAS  PubMed  Google Scholar 

  10. Adami S, Isaia G, Luisetto G et al (2006) Fracture incidence and characterization in patients on osteoporosis treatment: the ICARO study. J Bone Miner Res 21:1565–1570

    Article  CAS  PubMed  Google Scholar 

  11. Hugen PW, Langebeek N, Burger DM et al (2002) Assessment of adherence to HIV protease inhibitors: comparison and combination of various methods, including MEMS (electronic monitoring), patient and nurse report, and therapeutic drug monitoring. J Acquir Immune Defic Syndr 30:324–334

    Article  CAS  PubMed  Google Scholar 

  12. Nieuwkerk PT, Oort FJ (2005) Self-reported adherence to antiretroviral therapy for HIV-1 infection and virologic treatment response: a meta-analysis. J Acquir Immune Defic Syndr 38:445–448

    Article  PubMed  Google Scholar 

  13. Walsh JC, Mandalia S, Gazzard BG (2002) Responses to a 1 month self-report on adherence to antiretroviral therapy are consistent with electronic data and virological treatment outcome. AIDS 16:269–277

    Article  PubMed  Google Scholar 

  14. Arnsten JH, Demas PA, Farzadegan H et al (2001) Antiretroviral therapy adherence and viral suppression in HIV-infected drug users: comparison of self-report and electronic monitoring. Clin Infect Dis 33:1417–1423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fletcher CV, Testa MA, Brundage RC et al (2005) Four measures of antiretroviral medication adherence and virologic response in AIDS clinical trials group study 359. J Acquir Immune Defic Syndr 40:301–306

    Article  PubMed  Google Scholar 

  16. Harrington JT, Ste-Marie LG, Brandi ML et al (2004) Risedronate rapidly reduces the risk for nonvertebral fractures in women with postmenopausal osteoporosis. Calcif Tissue Int 74:129–135

    Article  CAS  PubMed  Google Scholar 

  17. Pols HA, Felsenberg D, Hanley DA et al (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. Fosamax International Trial Study Group. Osteoporos Int 9:461–468

    Article  CAS  PubMed  Google Scholar 

  18. Seeman E (2007) Is a change in bone mineral density a sensitive and specific surrogate of anti-fracture efficacy. Bone 41:308–317

    Article  CAS  PubMed  Google Scholar 

  19. Dempster DW (2002) Bone remodeling. In: Coe FL, Favus MJ (eds) (2002) Disorders of bone and mineral metabolism, 2nd edn. Lippincott Williams and Wilkins, Baltimore, pp 315–343

    Google Scholar 

  20. Diez-Perez A, Gonzalez-Macias J, Marin F et al (2007) Prediction of absolute risk of non-spinal fractures using clinical risk factors and heel quantitative ultrasound. Osteoporos Int 18:629–639

    Article  CAS  PubMed  Google Scholar 

  21. Baim S, Wilson CR, Lewiecki EM et al (2005) Precision assessment and radiation safety for dual-energy X-ray absorptiometry: position paper of the International Society for Clinical Densitometry. J Clin Densitom 8:371–378

    Article  PubMed  Google Scholar 

  22. Gluer CC (1999) Monitoring skeletal changes by radiological techniques. J Bone Miner Res 14:1952–1962

    Article  CAS  PubMed  Google Scholar 

  23. Lodder MC, Lems WF, Ader HJ et al (2004) Reproducibility of bone mineral density measurement in daily practice. Ann Rheum Dis 63:285–289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sarkar S, Reginster JY, Crans GG et al (2004) Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Min Res 19:394–401

    Article  Google Scholar 

  25. Chapurlat RD, Palermo L, Ramsay P, Cummings SR (2005) Risk of fracture among women who lose bone density during treatment with alendronate: the Fracture Intervention Trial. Osteoporos Int 16:842–848

    Article  CAS  PubMed  Google Scholar 

  26. Lenchik L, Kiebzak GM, Blunt BA (2002) International Society for Clinical Densitometry Position Development Panel and Scientific Advisory Committee. What is the role of serial bone mineral density measurements in patient management. J Clin Densitom 5 [Suppl]:S29–S38

    Article  PubMed  Google Scholar 

  27. Bauer DC, Black DM, Garnero P et al (2004) Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the Fracture Intervention Trial. J Bone Miner Res 19:1250–1258

    Article  PubMed  Google Scholar 

  28. Barrett-Connor E (1991) Nutrition epidemiology: how do we know what they ate. Am J Clin Nutr 54 [Suppl 1]:182S–187S

    CAS  PubMed  Google Scholar 

  29. Gaugris S, Heaney RP, Boonen S et al (2005) Vitamin D inadequacy among post-menopausal women: a systematic review. QJM 98:667–676

    Article  CAS  PubMed  Google Scholar 

  30. Dixon T, Mitchell P, Beringer T et al (2006) An overview of the prevalence of 25-hydroxy-vitamin D inadequacy amongst elderly patients with or without fragility fracture in the United Kingdom. Curr Med Res Opin 22:405–415

    Article  CAS  PubMed  Google Scholar 

  31. Wilkins CH, Birge SJ (2005) Prevention of osteoporotic fractures in the elderly. Am J Med 118:1190–1195

    Article  PubMed  Google Scholar 

  32. Jackson C, Gaugris S, Sen SS et al (2007) The effect of cholecalciferol (vitamin D3) on the risk of fall and fracture: a meta-analysis. QJM 100:185–192

    Article  CAS  PubMed  Google Scholar 

  33. Del Puente A, Scognamiglio A, Itto E et al (2000) Intramuscular clodronate in nonresponders to oral alendronate therapy for osteoporosis. J Rheumatol 27:1980–1983

    CAS  PubMed  Google Scholar 

  34. Heckman GA, Papaioannou A, Sebaldt RJ et al (2002) Effect of vitamin D on bone mineral density of elderly patients with osteoporosis responding poorly to bisphosphonates. BMC Musculoskelet Disord 3:6

    Article  PubMed  PubMed Central  Google Scholar 

  35. Sawka AM, Adachi JD, Ioannidis G et al (2003) What predicts early fracture or bone loss on bisphosphonate therapy. J Clin Densitom 6:315–322

    Article  PubMed  Google Scholar 

  36. Lewiecki EM (2003) Nonresponders to osteoporosis therapy. J Clin Densitom 6:307–314

    Article  PubMed  Google Scholar 

  37. National Institute for Clinical Excellence (2004) Final appraisal determination—secondary prevention of osteoporotic fragility fractures in postmenopausal women. http://www.nice.org.uk/page.aspx?o=115560

  38. Jakob F, Marin F, Martin-Mola E et al (2006) Characterization of patients with an inadequate clinical outcome from osteoporosis therapy: the Observational Study of Severe Osteoporosis (OSSO). QJM 99:531–543

    Article  CAS  PubMed  Google Scholar 

  39. Obermayer-Pietsch BM, Nickelsen T, Marin F et al (2006) Response of BMD to 24 months of teriparatide (rhPTH 1–34) in patients with and without prior antiresorptive treatment: final results from the EUROFORS Study. J Bone Miner Res 21 [Suppl 1]:S43

    Google Scholar 

  40. Sarkar S, Mitlak BH, Wong M et al (2002) Relationship between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Min Res 17:1–10

    Article  CAS  Google Scholar 

  41. Khosla S (2003) Surrogates for fracture endpoints in clinical trials. J Bone Min Res 18:1146–1149

    Article  Google Scholar 

  42. Sebba AI, Bonnick SL, Kagan R et al (2004) Response to therapy with once-weekly alendronate 70 mg compared to once-weekly risedronate 35 mg in the treatment of postmenopausal osteoporosis. Curr Med Res Opin 20:2031–2041

    Article  CAS  PubMed  Google Scholar 

  43. Ferrar L, Jiang G, Armbrecht G et al (2007) Is short vertebral height always an osteoporotic fracture? The Osteoporosis and Ultrasound Study (OPUS). Bone 41:5–12

    Article  CAS  PubMed  Google Scholar 

  44. Ohlendorff SD, Tofteng CL, Jensen JE et al (2007) Single nucleotide polymorphisms in the P2X7 gene are associated to fracture risk and to effect of estrogen treatment. Pharmacogenet Genomics 17:555–567

    Article  CAS  PubMed  Google Scholar 

  45. Rapuri PB, Gallagher JC, Knezetic JA et al (2006) Estrogen receptor alpha gene polymorphisms are associated with changes in bone remodeling markers and treatment response to estrogen. Maturitas 53:371–379

    Article  CAS  PubMed  Google Scholar 

  46. Yahata T, Quan J, Tamura N et al (2005) Association between single nucleotide polymorphisms of estrogen receptor alpha gene and efficacy of HRT on bone mineral density in post-menopausal Japanese women. Hum Reprod 20:1860–1866

    Article  CAS  PubMed  Google Scholar 

  47. Tofteng CL, Abrahamsen B, Jensen JE et al (2004) Two single nucleotide polymorphisms in the CYP17 and COMT Genes—relation to bone mass and longitudinal bone changes in postmenopausal women with or without hormone replacement therapy. The Danish Osteoporosis Prevention Study. Calcif Tissue Int 75:123–132

    Article  CAS  PubMed  Google Scholar 

  48. Morrison NA, George PM, Vaughan T et al (2005) Vitamin D receptor genotypes influence the success of calcitriol therapy for recurrent vertebral fracture in osteoporosis. Pharmacogenet Genomics 15:127–135

    Article  CAS  PubMed  Google Scholar 

  49. Steines D, Arnaud C, Liew S et al (2005) Predicting hip fracture in a sub-group of subjects from the study of osteoporotic fractures using automated structural measurements of proximal femur in pelvic radiographs. J Bone Miner Res 20 [Suppl 1]:F090

    Google Scholar 

  50. Rivadeneira F, Zillikens MC, De Laet CE et al (2007) Femoral neck BMD is a strong predictor of hip fracture susceptibility in elderly men and women because it detects cortical bone instability: the Rotterdam Study. J Bone Miner Res 22:1781–1790

    Article  PubMed  Google Scholar 

  51. Hernandez CJ, Gupta A, Keaveny TM (2006) A biomechanical analysis of the effects of resorption cavities on cancellous bone strength. J Bone Miner Res 21:1248–1255

    Article  PubMed  PubMed Central  Google Scholar 

  52. Ladinsky GA, Vasilic B, Popescu AM et al (2008) Trabecular structure quantified with the MRI-based virtual bone biopsy in postmenopausal women contributes to vertebral deformity burden independent of areal vertebral BMD. J Bone Miner Res 23:64–74

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Fernando Marin, M.D. for useful comments and Christine O’Hara for invaluable help with the English version of the manuscript. The study was supported in part by an official grant from the Spanish Ministry of Health (Fondo de Investigaciones Sanitarias [FIS] number PI052233).

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Hospital del Mar, Autonomous University of Barcelona, URFOA-IMIM, RETICEF, Barcelona, Spain

    A. Díez-Pérez

  2. Hospital Marqués de Valdecilla, University of Cantabria, RETICEF, Santander, Spain

    J. González-Macías

  3. Department of Internal Medicine, Hospital del Mar, Passeig Maritim 25–29, 08003, Barcelona, Spain

    A. Díez-Pérez

Authors
  1. A. Díez-Pérez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. González-Macías
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Díez-Pérez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Díez-Pérez, A., González-Macías, J. Inadequate responders to osteoporosis treatment: proposal for an operational definition. Osteoporos Int 19, 1511–1516 (2008). https://doi.org/10.1007/s00198-008-0659-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-008-0659-2

Keywords

Search

Navigation