Considerations for Development of Surrogate Endpoints for Antifracture Efficacy of New Treatments in Osteoporosis: a Perspective

Overview

Journal J Bone Miner Res

Publisher Oxford University Press

Date 2008 Mar 6

PMID 18318643

Citations 23

Authors

Mary L Bouxsein

Pierre D Delmas

Affiliations

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Abstract

Because of the broad availability of efficacious osteoporosis therapies, conduct of placebo-controlled trials in subjects at high risk for fracture is becoming increasing difficult. Alternative trial designs include placebo-controlled trials in patients at low risk for fracture or active comparator studies, both of which would require enormous sample sizes and associated financial resources. Another more attractive alternative is to develop and validate surrogate endpoints for fracture. In this perspective, we review the concept of surrogate endpoints as it has been developed in other fields of medicine and discuss how it could be applied in clinical trials of osteoporosis. We outline a stepwise approach and possible study designs to qualify a biomarker as a surrogate endpoint in osteoporosis and review the existing data for several potential surrogate endpoints to assess their success in meeting the proposed criteria. Finally, we suggest a research agenda needed to advance the development of biomarkers as surrogate endpoints for fracture in osteoporosis trials. To ensure optimal development and best use of biomarkers to accelerate drug development, continuous dialog among the health professionals, industry, and regulators is of paramount importance.

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References

Chen P, Satterwhite J, Licata A, Lewiecki E, Sipos A, Misurski D . Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis. J Bone Miner Res. 2005; 20(6):962-70. DOI: 10.1359/JBMR.050105. View

Bouxsein M . Determinants of skeletal fragility. Best Pract Res Clin Rheumatol. 2005; 19(6):897-911. DOI: 10.1016/j.berh.2005.07.004. View

Keyak J, Kaneko T, Tehranzadeh J, Skinner H . Predicting proximal femoral strength using structural engineering models. Clin Orthop Relat Res. 2005; (437):219-28. DOI: 10.1097/01.blo.0000164400.37905.22. View

Rossini M, Gatti D, Zamberlan N, Braga V, Dorizzi R, Adami S . Long-term effects of a treatment course with oral alendronate of postmenopausal osteoporosis. J Bone Miner Res. 1994; 9(11):1833-7. DOI: 10.1002/jbmr.5650091121. View

Eckstein F, Lochmuller E, Lill C, Kuhn V, Schneider E, Delling G . Bone strength at clinically relevant sites displays substantial heterogeneity and is best predicted from site-specific bone densitometry. J Bone Miner Res. 2002; 17(1):162-71. DOI: 10.1359/jbmr.2002.17.1.162. View

Ravn P, Clemmesen B, Riis B, Christiansen C . The effect on bone mass and bone markers of different doses of ibandronate: a new bisphosphonate for prevention and treatment of postmenopausal osteoporosis: a 1-year, randomized, double-blind, placebo-controlled dose-finding study. Bone. 1996; 19(5):527-33. DOI: 10.1016/s8756-3282(96)00229-3. View

Wehrli F, Hilaire L, Fernandez-Seara M, Gomberg B, Song H, Zemel B . Quantitative magnetic resonance imaging in the calcaneus and femur of women with varying degrees of osteopenia and vertebral deformity status. J Bone Miner Res. 2002; 17(12):2265-73. DOI: 10.1359/jbmr.2002.17.12.2265. View

Neer R, Arnaud C, Zanchetta J, Prince R, Gaich G, Reginster J . 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. DOI: 10.1056/NEJM200105103441904. View

Cheng X, Li J, Lu Y, Keyak J, Lang T . Proximal femoral density and geometry measurements by quantitative computed tomography: association with hip fracture. Bone. 2006; 40(1):169-74. DOI: 10.1016/j.bone.2006.06.018. View

10.

Cooper C, Stakkestad J, Radowicki S, Hardy P, Pilate C, Dain M . Matrix delivery transdermal 17beta-estradiol for the prevention of bone loss in postmenopausal women. The International Study Group. Osteoporos Int. 1999; 9(4):358-66. DOI: 10.1007/s001980050159. View

11.

Alonso A, Molenberghs G, Burzykowski T, Renard D, Geys H, Shkedy Z . Prentice's approach and the meta-analytic paradigm: a reflection on the role of statistics in the evaluation of surrogate endpoints. Biometrics. 2004; 60(3):724-8. DOI: 10.1111/j.0006-341X.2004.00222.x. View

12.

Chen P, Miller P, Delmas P, Misurski D, Krege J . Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatide-treated postmenopausal women with osteoporosis. J Bone Miner Res. 2006; 21(11):1785-90. DOI: 10.1359/jbmr.060802. View

13.

Bouxsein M, Palermo L, Yeung C, Black D . Digital X-ray radiogrammetry predicts hip, wrist and vertebral fracture risk in elderly women: a prospective analysis from the study of osteoporotic fractures. Osteoporos Int. 2002; 13(5):358-65. DOI: 10.1007/s001980200040. View

14.

Finkelstein J, Hayes A, Hunzelman J, Wyland J, Lee H, Neer R . The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med. 2003; 349(13):1216-26. DOI: 10.1056/NEJMoa035725. View

15.

Lang T, Guglielmi G, van Kuijk C, DE SERIO A, Cammisa M, Genant H . Measurement of bone mineral density at the spine and proximal femur by volumetric quantitative computed tomography and dual-energy X-ray absorptiometry in elderly women with and without vertebral fractures. Bone. 2002; 30(1):247-50. DOI: 10.1016/s8756-3282(01)00647-0. View

16.

. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69(3):89-95. DOI: 10.1067/mcp.2001.113989. View

17.

Ettinger B . Use of low-dosage 17 beta-estradiol for the prevention of osteoporosis. Clin Ther. 1993; 15(6):950-62; discussion 949. View

18.

Prentice R . Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989; 8(4):431-40. DOI: 10.1002/sim.4780080407. View

19.

Meunier P, Roux C, Seeman E, Ortolani S, Badurski J, Spector T . 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. DOI: 10.1056/NEJMoa022436. View

20.

Prestwood K, Kenny A, Unson C, Kulldorff M . The effect of low dose micronized 17ss-estradiol on bone turnover, sex hormone levels, and side effects in older women: a randomized, double blind, placebo-controlled study. J Clin Endocrinol Metab. 2001; 85(12):4462-9. DOI: 10.1210/jcem.85.12.7001. View