Osteoporosis International

, Volume 20, Issue 2, pp 187–195 | Cite as

To stop or not to stop, that is the question

  • Ego Seeman
Hot Stuff


Treatment aimed at preventing fractures should be stopped if evidence of continued antifracture efficacy is lacking, if continued treatment increases bone fragility by adversely affecting matrix properties, and if stopping does not increased bone fragility. Credible evidence of antifracture efficacy beyond 5 years is lacking because of attrition of the cohort originally allocated to treatment or placebo and lack of controls. Prolonged suppression of remodeling is associated with accumulation of microdamage, advanced glycation products and increased tissue mineral density in animal studies but the structural benefits appear to out weight these adverse effects. Atypical minimal trauma subtrochanteric fractures are associated with prolonged treatment in human subjects but these are exceedingly rare. Stopping treatment does result in the reemergence of remodeling, rapidly with some drugs, more slowly with others while fracture rates are increased in poor compliers to treatment. Thus, within the constraints of limited evidence, I infer that stopping therapy is more likely to do net harm than continuing therapy - treatment should be continued in the majority of individuals.


Benefit Harm Osteoporosis Stopping Treatment 



The author would like to acknowledge the constructive criticisms by the Editors-in-Chief, Drs John Kanis and Robert Lindsay.


  1. 1.
    Kanis JA, Oden A, Johnell O, De Laet C, Jonsson B, Oglesby AK (2003) The components of excess mortality after hip fracture. Bone 32:468–473PubMedCrossRefGoogle Scholar
  2. 2.
    Kanis JA, Johnell O, Oden A, De Laet C, Jonsson B, Dawson A (2002) Ten year risk of osteoporotic fracture and the effect of risk factors on screening strategies. Bone 30:251–258PubMedCrossRefGoogle Scholar
  3. 3.
    Delmas PD (2002) Treatment of postmenopausal osteoporosis. Lancet 359:2018–2026PubMedCrossRefGoogle Scholar
  4. 4.
    Parfitt AM (1996) Skeletal heterogeneity and the purposes of bone remodelling: Implications for the understanding of osteoporosis. In: Marcus R, Feldman D, Kelsey J (eds) Osteoporosis. Academic, San Diego, pp 315–339Google Scholar
  5. 5.
    Lips P, Courpron P, Meunier PJ (1978) Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age. Calcif Tissue Res 10:13–17CrossRefGoogle Scholar
  6. 6.
    Seeman E, Delmas PD (2006) Bone quality: the material and structural basis of bone strength. N Engl J Med 354:2250–2261PubMedCrossRefGoogle Scholar
  7. 7.
    Seeman E (2007) Is a change in bone mineral density a sensitive and specific surrogate of anti-fracture efficacy. Bone 41:308–317PubMedCrossRefGoogle Scholar
  8. 8.
    Parfitt AM (1980) Morphological basis of bone mineral measurements: transient and steady state effects of treatment in osteoporosis. Mineral Electrolyte Metab 4:273–287Google Scholar
  9. 9.
    Hernandez CJ, Gupt A, Keaveny TM (2006) A biomechanical analysis of the effects of resorption cavities on cancellous bone strength. J Bone Miner Res 21:1248–1255PubMedCrossRefGoogle Scholar
  10. 10.
    Boivin G, Meunier PJ (2002) Changes in bone remodeling rate influence the degree of mineralization of bone. Connect Tissue Res 43:535–537PubMedCrossRefGoogle Scholar
  11. 11.
    Akkus O, Polyakova-Akkus A, Adar F, Schaffler MB (2003) Aging of microstructural compartments in human compact bone. J Bone Miner Res 18:1012–1019PubMedCrossRefGoogle Scholar
  12. 12.
    Bone HG, Hosking D, Devogelaer J-P, Emkey RD, Yonino RP, RodriguezPortales JA, Downs RW, Gupta J, Santora AC, Liberman UA (2004) Ten years experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350:1189–1199PubMedCrossRefGoogle Scholar
  13. 13.
    Rosen CJ, Hochberg MC, Bonnick SL, McClung M, Miller P, Broy S, Kagan R, Chen E, Petruschke RA, Thompson DE, de Papp AE (2005) Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res 20:141–151PubMedCrossRefGoogle Scholar
  14. 14.
    Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J (2008) Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43:222–229PubMedCrossRefGoogle Scholar
  15. 15.
    Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, Luiz H de Gregorio LH, Hadji P Lorenz C, Hofbauer LC, Álvaro-Gracia JM, Wang H, Austin M, Wagman RB, Newmark R, Libanati C, San Martin J, Bone HG. Comparison of the effect of denosumab and alendronate on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res. OnlineGoogle Scholar
  16. 16.
    Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P, Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR, Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H, Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G, Verbruggen L, Meunier PJ (2002) Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 346:653–661PubMedCrossRefGoogle Scholar
  17. 17.
    Compston JE, Yamaguchi K, Croucher PI, Garrahan NJ, Lindsay PE, Shaw RW (1995) The effects of gonadotrophin releasing hormone agonists on iliac crest cancellous bone structure in women with endometriosis. Bone 16:261–267PubMedCrossRefGoogle Scholar
  18. 18.
    Eriksen EF, Langdahl B, Vesterby A, Rungby J, Kassem M (1999) Hormone replacement therapy prevents osteoclastic hyperactivity: a histomorphometric study in early postmenopausal women. J Bone Miner Res 14:1217–1221PubMedCrossRefGoogle Scholar
  19. 19.
    Reginster JY, Felsenberg D, Boonen S et al (2008) Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis: results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum 58:1687–1695PubMedCrossRefGoogle Scholar
  20. 20.
    Mellstrom DD, Sorensen OH, Goemaere S, Roux C, Johnson TD, Chines AA (2004) Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int 75:462–468PubMedCrossRefGoogle Scholar
  21. 21.
    Jackson RD, LaCroix AZ, Gass M et al (2006) Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 354:669–683PubMedCrossRefGoogle Scholar
  22. 22.
    Prince RL, Devine A, Dhaliwal SS, Dick IM (2006) Effects of calcium supplementation on clinical fracture and bone structure results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med 166:869–875PubMedCrossRefGoogle Scholar
  23. 23.
    Reid IR, Mason B, Horne A, Ames R, Reid HE, Bava U, Bolland MJ, Gamble GD (2006) Randomized controlled trial of calcium in healthy older women. Amer J Med 119:777–785PubMedCrossRefGoogle Scholar
  24. 24.
    Seeman E, Compston J, Adachi J, Brandi ML, Cooper C, Dawson-Hughes B, Jönsson B, Pols BH, Cramer JA (2007) Non-compliance: the Achilles’ heel of anti-fracture efficacy. Osteoporos Int 18:711–719PubMedCrossRefGoogle Scholar
  25. 25.
    Reid IR, Bolland MJ, Grey A (2008) Effect of calcium supplementation on hip fractures. Osteoporos Int 19:1119–1123. doi: 10.1007/s00198-008-0563-9 PubMedCrossRefGoogle Scholar
  26. 26.
    Bolland MJ, P Barber A, Doughty RN, Mason B, Horne A, Ames R, Gamble GD, Grey A, Reid IR. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. doi: 10.1136/bmj.39440.525752.BE
  27. 27.
    Sarkar S, Mitlak BH, Wong M, Stock JL, Black DM, Harper KD (2002) Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res 17:1–10PubMedCrossRefGoogle Scholar
  28. 28.
    Watts NB, Geusens P, Barton P, Felsenberg D (2005) Relationship between changes in BMD and nonvertebral fracture incidence associated with risedronate: reduction in risk of nonvertebral fracture is not related to change in BMD. J Bone Miner Res 20:2097–2104PubMedCrossRefGoogle Scholar
  29. 29.
    Chapurlat RD, Palermo L, Ramsay P, Cummings SR (2005) Risk of fracture among women who lose bone density during treatment with alendronate. The fracture intevention trial. Osteoporos Int 16:842–848PubMedCrossRefGoogle Scholar
  30. 30.
    Lindsay R, Miller P, Pohl G, Emmett V. Glass EV, Chen P, Krege JH (2008) Relationship between duration of teriparatide therapy and clinical outcomes in postmenopausal women with osteoporosis. Osteoporos Int. doi: 10.1007/s00198-008-0766-0
  31. 31.
    Allen M, Iwata K, Phipps R, Burr DB (2006) Alterations in canine vertebral bone turnover, microdamage accumulation, and biochemical properties following 1 year treatment with clinical treatment doses of risedronate or alendronate. Bone 39:872–879PubMedCrossRefGoogle Scholar
  32. 32.
    Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 15:613–620PubMedCrossRefGoogle Scholar
  33. 33.
    Saito M, Mori S, Mashiba T, Komatsubara S, Marumo K (2008) Calcium, phosphorus, and pentosidine contents and the ratio of mature to immature crosslinks increased pentosidine content correlated inversely with cortical activation frequency. Osteoporos Int 19:1343–1354Google Scholar
  34. 34.
    Allen MR Iwata K, Sato M, Burr DB (2006) Raloxifene enhances vertebral mechanical properties independent of bone density. Bone 39:1130–1135CrossRefGoogle Scholar
  35. 35.
    Stepan JJ, Burr DB, Pavo I, Sipos A, Michalska D, Li J, Fahrleitner-Pammer A, Petto H, Westmore M, Michalsky D, Sato M, Dobnig H (2007) Low bone mineral density is associated with bone microdamage accumulation in postmenopausal women with osteoporosis. Bone 41:378–385PubMedCrossRefGoogle Scholar
  36. 36.
    Goh SK, Yang KY, Koh JSB, Wong MK, Chua SY, Chua DTC, Howe TS (2007) Subtrochanteric insufficiency fractures in patients on alendronate therapy. J Bone Joint Surg (Br) 89-B:349–353Google Scholar
  37. 37.
    Lenart B, Nevasier A, Peterson MG, Edobor-Osula F, Schreck B, Chang C, Lorich DG, Lane JM (2007) Low energy diaphyseal fractures associated with alendronate use. J Bone Miner Res 22(Suppl 1):S430Google Scholar
  38. 38.
    Odvina CV, Zerwekh JE, Rao DS, Maaloof N, Gottschalk FA, Pak CYC (2005) Severly suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 1294–1301Google Scholar
  39. 39.
    Bilezikian JP (2006) Osteonecrosis of the jaw–do bisphosphonates pose a risk? N Engl J Med 30;355:2278–2281Google Scholar
  40. 40.
    Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S (2003) Brief report: Bisphosphonare-dinduced osteopetrosis. New Engl J Med 349:457–463PubMedCrossRefGoogle Scholar
  41. 41.
    Whyte MP, McAlister WH, Novack DV, Clements KL, Schoenecker PL, Wenkert D (2008) Bisphosphonate-induced osteopetrosis: novel bone modeling defects, metaphyseal osteopenia, and osteosclerosis fractures after drug exposure ceases. J Bone Miner Res 23:1698–1707PubMedCrossRefGoogle Scholar
  42. 42.
    Watts NB, Chines AW, Olszynski P, McKeever CD, McClung MR, Zhou X, Grauer A (2008) Fracture risk remains reduced one year after discontinuation. Osteoporos Int 19:365–372PubMedCrossRefGoogle Scholar
  43. 43.
    Fuchs RK, Phipps R, Burr DB (2008) Reestablishment of normal cancellous bone turnover differs following the withdrawal of alendronate and risedronate treatment in ovarectomized rats. J Bone Miner Res 23:1689–1697PubMedCrossRefGoogle Scholar
  44. 44.
    Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, Mangood A, Russell RG, Ebetino FH (2006) Novel insights into actions of bisphosphonates on bone: Differences in interactions with hydroxyapatite. Bone 38:617–627PubMedCrossRefGoogle Scholar
  45. 45.
    Coxon FP (2008) An update on the pharmacology of bisphosphonates and analogues with lower bone affinity. IBMS Bonekey 5:357–369CrossRefGoogle Scholar
  46. 46.
    Russell RG, Watts NB, Ebetino FH, Rogers MJ (2008) Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19:733–759PubMedCrossRefGoogle Scholar
  47. 47.
    Roux C, Seeman E, Eastell R, Adachi J, Jackson RD, Felsenberg D, Songcharoen S, Rizzoli R, Di Munno O, Horlait S, Valent D, Watts NB (2004) Efficacy of risedronate on clinical vertebral fractures within six months. Curr Med Res Opin 20:433–439. 23PubMedCrossRefGoogle Scholar
  48. 48.
    Szulc P, Seeman E, Duboeuf F, Sornay-Rendu E, Delmas PD (2006) Bone fragility: failure of periosteal apposition to compensate for increased endocortical resorption in postmenopausal women. J Bone Miner Res 21:1856–1863PubMedCrossRefGoogle Scholar
  49. 49.
    Heiss G, Wallace R, Garnet L, Anderson GL, Aragaki A, Beresford SAA, Brzyski R, Chlebowski RT, Gass M, LaCroix A, Manson JE, Prentice RL, Rossouw J, Stefanick ML (2008) Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 299:1036–1045PubMedCrossRefGoogle Scholar
  50. 50.
    Lindsay R, Scheele WH Neer R et al (2004) Sustained vertebral fracture risk reduction after withderawal of teriparatide in postmenopausal women with osteoporosis. Arch Intern Med 2024–2030Google Scholar
  51. 51.
    Prince R, Sipos A, Hossain A, Syversen A et al (2005) Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment. J Bone Miner Res 20:1507–1513PubMedCrossRefGoogle Scholar
  52. 52.
    Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR, FLEX Research Group (2006) Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 296:2927–2938PubMedCrossRefGoogle Scholar
  53. 53.
    Black D, Thompson DE, Bauer D, Ensrud K et al (2000) Fracture risk reduction with alendronate in women with osteoporosis; The Fracture Intervention Trial. J Clin Endocrionol Metab 85:4118–4124CrossRefGoogle Scholar
  54. 54.
    Gallagher AM, Rietbrock S, Olson M, van Staa TP (2008) Fracture outcomes related to persistence and compliance with oral bisphosphonates. J Bone Miner Res 23:1569–1575PubMedCrossRefGoogle Scholar
  55. 55.
    Curtis JR, Westfall AO, Cheng H, Delzell E, Saag KG (2008) Risk of hip fracture after bisphosphonate discontinuation: implications for a drug holiday. Osteoporos Int 19:1613–1620PubMedCrossRefGoogle Scholar
  56. 56.
    Bolland MJ, Grey AB, Horne AM, Briggs SE, Thomas MG, Ellis-Pegler RB, Callon KE, Gamble GD, Reid IR (2008) Effects of intravenous zoledronate on bone turnover and BMD persist for at least 24 months. J Bone Miner Res 23:1304–1308PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2008

Authors and Affiliations

  1. 1.Department of Endocrinology, Austin HealthUniversity of MelbourneMelbourneAustralia

Personalised recommendations