Abstract
Surrogate markers in clinical medicine provide a useful means to assess therapeutic response to pharmacologic therapy in a wide range of chronic disease states. In the area of osteoporosis, the surrogate markers of change in bone mineral density (BMD) and bone turnover markers (BTM) provide the clinician with a means of assessing the biologic response to osteoporosis-specific pharmacologic agents. Increases in BMD and/or reductions in BTM can independently be correlated to reductions in vertebral and nonvertebral fracture risk. In managing osteoporosis patients, the BTM change at an earlier point of time after initiation of therapy and a change in BTM can provide earlier feed-back to the patient and clinician regarding issues such as compliance and a bone biologic response. An increase in BMD at 12 or 24 months after initiation of therapy is also evidence of an improvement in bone strength though with antiresorptive agents no change in BMD may also be associated with risk reduction within clinical trial sets. In this regard, changes in BMD and BTM are complimentary in their application to patient management.
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References and Recommended Reading
Kanis J: Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. Osteoporos Int 1994, 4:368–381.
Miller PD, Hochberg M, Wehren LE, et al.: How useful are measures of BMD and bone turnover? Curr Med Res Opin 2005, 21:545–553. This review examines why surrogate markers are valid indicators of therapeutic response in managing postmenopausal osteoporosis therapies; and, analyzes the strengths and weaknesses of the statistical methodologies used to assess changes in bone strength with the use of antiresorptive agents.
Khosla S: Surrogates for fracture end-points in clinical trials. J Bone Miner Res 2003, 18:1146–1149.
Watts NB, Cooper C, Linday R, et al.: Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom 2004, 7:255–261.
Kanis J, Oden A, Johnell O, et al.: Uncertain future of trials in osteoporosis. Osteoporos Int 2002, 13:443–449.
FDA position on end-points in osteoporosis clinical trials. http://www.FDA.gov/cder.guidance/osteo.pdf
US Department of Health and Services: Bone health and osteoporosis: a report of the US Surgeon General. Rockville, Maryland. Department of Health and Human Services, Office of The Surgeon General. 2004.
Schnitzer T, Bone H, Crepasldi G, et al.: Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Aging Clin Exp Res 2000, 12:1–12.
Brown JP, Kendler DL, McClung MR, et al.: The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcif Tissue Int 2002, 71:103–111.
Miller PD, McClung M, Macovei L, et al.: Monthly oral ibandronate therapy in postmenopausal osteoporosis: one year results from the MOBILE study. J Bone Miner Res 2005, In press. This pivotal paper describes the comparator trial of monthly versus daily oral ibandronate that led to the FDA registration of this first intermittent bisphosphonate dosing.
Sarkar S, Reginster J-Y, Crans CG, et al.: Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res 2004, 19:394–401.
Delman P, Seeman E: Changes in bone mineral density explain little of the reduction in vertebral or non-vertebral fracture risk with anti-resorptive therapy. Bone 2004, 34:599–604.
Faulkner KG: Bone matters: are density increases necessary to reduce fracture risk? J Bone Miner Res 2000, 15:183–187. This editorial examined the relationship between antiresorptive induced changes in BMD and fracture risk reduction that suggested that (in non-head-to-head studies) antiresorptive agents may reduce fracture risk similarly with little differences in BMD changes.
Watts NB: Therapies to improve bone mineral density and reduce the risk of fracture: clinical trial results. J Reprod Med 2002, 47(Suppl 1):82–92.
Miller PD: Osteoporosis treatment outcomes: the factors that lead to the ultimate end point of osteoporosis therapies: fracture risk reduction. Endocrinologist 2003, 13(Suppl 2):S4-S9.
Miller PD: The treatment of osteoporosis: antiresorptive therapy. Clin Lab Med 2000, 20:603–622.
Miller PD: Optimizing the management of postmenopausal osteoporosis with bisphosphonates: the emerging role of intermittent therapy. Clin Ther 2005, 27:1–16. A review of the different bisphosphonate(s) and their different effects on bone remodeling and risk reduction and the data that has led to concepts of intermittent dosing.
Russell RGG, Croucher PI, Rogers MJ: Bisphosphonates: pharmacology, mechanisms of action and clinical uses. Osteoporos Int 1999, 5(Suppl 2):S66-S80.
Borah B, Dufrense TE, Chmielewski PA, et al.: Risedronate preserves trabecular architecture and increases bone strength in vertebrae of oophorectomized minipigs as measured by 3- dimensional microcomputed tomography. J Bone Miner Res 2002, 17:1139–1147. The first evidence suggesting that bisphosphonates increase bone strength by architectural changes that, in part, are independent of changes in bone mineral content.
Jarvinen TLN, Sievanen H, Jokihaara J, et al.: Revival of bone strength: the bottom line. J Bone Miner Res 2005, 20:717–720.
Turner CH, Burr DB: Basic biomechanical measurements of bone: a tutorial. Bone 1993, 14:595–608.
Burr DB, Turner CH: Biomechanics of bone. In Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Edited by Favus M. Washington DC: American Society for Bone and Mineral Research. 2003:58–64.
Burr DB: Bone material properties and mineral matrix contributions to fracture risk or age in women and men. J Musculoskelet Neuronal Interact 2002, 2:201–204.
Misof BM, Roschger P, Cosman F, et al.: Effects of intermittent parathyroid hormone administration on bone mineralization density in iliac crest biopsies from patients with osteoporosis: a paired study before and after treatment. J Clin Endocrinol Metab 2003, 88:1150–1156.
Boivin G, Vedi S, Purdie DW, et al.: Influence of estrogen therapy at conventional and high doses on the degree of mineralization of iliac bone tissue: a quantitative microradiographic analysis in postmenopausal women. Bone 2005, 36:562–567.
Roschger P, Gupta HS, Berzlanovich A, et al.: Constant mineralization density distribution in cancellous human bone. Bone 2003, 32:316–323.
Borah B, Ritman EL, Dufresne TE, et al.: The effect of risedronate on bone mineralization as measured by micro-computed tomography with synchrotron radiation: correlation to histomorphometric indices of turnover. Bone 2005, 37:1–9.
Paschalis EP, Glass EV, Donley DW, Eriksen EF: Bone mineral and collagen quality in iliac crest biopsies of patients given teriparatide: new results from the fracture prevention trial. J Clin Endocrinol Metab 2005, [Epub ahead of print].
Paschalis EP, Shane E, Lyritis G, et al.: Bone fragility and collagen cross-links. J Bone Miner Res 2004, 19:2000–2004.
Wasnich RD, Miller PD: Antifracture efficacy of antiresportive agents are related to changes in bone density. J Clin Endocrinol Metab 2000, 85:1–6.
Cummings SR, Karpf DB, Harris F, et al.: Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with anti-resorptive drugs. Am J Med 2002, 112:281–289.
Hochberg MC, Greenspan SL, Wasnich RD, et al.: Changes in bone density and turnover explain the reductions in incidence of non-vertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab 2002, 87:1586–1592.
Freedman LS, Graubard BI, Schatzkin A: Statistical validation of intermediate endpoints for chronic diseases. Stat Med 1992, 11:167–178.
Shih J, Bauer DC, Orloff J, et al.: Proportion of fracture risk reduction explained by BMD changes using Freeman’s analysis depends on choice of predictors. Osteoporos Int 2002, 13(Suppl 3):538–539.
Rosen CJ, Hochberg M, Bonnick S, et al.: Treatment with onceweekly alendronate 70 mg compared to once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized, double-blind study. J Bone Miner Res 2005, 20:141–151. The head-to-head clinical trial comparing changes in BMD and BTM in postmenopausal women given weekly alendronate or risedronate.
McClung M, Miller PD, Civetelli R, San Martin J: Teriparatide and alendronate increase bone mass by opposite effects on bone remodeling. Arch Int Med 2005, In press. The head-to-head clinical trial comparing the effects of daily (20 ώg/ day) subcutaneous teriparatide to daily (10 mg/day) alendronate on BMD and BTM in postmenopausal women.
Sackett DL, Straus SE, Richardson WS, et al.: Evidence Based Medicine. London: Churchill Livingstone; 2000.
Bonnick SL, Johnston CC Jr, Kleerekoper M, et al.: Importance of precision in bone density measurements. J Clin Densitom 2001, 4:105–110.
Lenchick L, Leib ES, Hamdy RC, et al.: Executive summary International Society for Clinical Densitometry position development conference Denver, Colorado July 20–22, 2001. J Clin Densitom 2002, 5(Suppl 1):S1-S3.
Dowd R, Recker RR, Heaney RP: Study subjects and ordinary patients. Osteoporos Int, 11:533–536.
Lewiecki M: Non-responders to osteoporosis therapies. J Clin Densit 2003, 6:307–314.
Chapuy MC, Arlot ME, Duboeuf F, et al.: Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992, 327:1637–1642.
Delmas P, Eastell R: Percentage of 3 year vertebral and nonvertebral fracture effect explained by changes in bone resorption and BMD in postmenopausal women treated with risedronate. European Economic Congress on Osteoporosis and Osteoarthritis 2004, 5:S42.
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, 18:1051–1056. The effect of reducing bone turnover as assessed by urinary N-telopeptide on incident vertebral fracture risk reduction in postmenopausal women treated with risedronate.
Bauer DC, Black D, Garnero P, et al.: Reduction in bone turnover predicts hip, non-spine,and vertebral fracture in alendronate treated women: the Fracture Intervention Trial. J Bone Miner Res 2004, 19:1250–1258. The effect of reducing bone turnover as assessed by bone specific alkaline phosphatase on incident vertebral fracture risk reduction in postmenopausal women treated with alendronate.
Recker R, Lappe J, Davies KM, Heaney R: Bone remodeling increases substantially in the years after menopause and remains increased in older osteoporosis patients. J Bone Miner Res 2004, 19:1628–1633.
Rittmaster RS, Bolognese M, Ettinger MP, et al.: Enhancement in bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab 2000, 85:2129–2134.
Neer RM, Arnaud CD, Zanchetta JR, et al.: Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001, 344:1434–1441.
Finkelstein JS, Hayes A, Hunzelman JL, et al.: The effects of parathyroid hormone, alendronate or both in mean with osteoporosis. N Engl J Med 2003, 349:1216–1226.
Black DM, Greenspan SL, Ensrud KE, et al.: The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003, 349:1207–1215.
Kurland ES, Cosman F, McMahon DJ, et al.: Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J Clin Endocrinol Metab 2000, 85:3069–3076.
Orwoll ES, Scheele WH, Paul S, et al.: The effect of teriparatide man parathyroid hormone (1-34)therapy on bone density in men with osteoporosis. J Bone Miner Res 2003, 18:9–17.
Hodsman AB, Kisiel M, Adachi JD, et al.: Histomorphometric evidence for increased bone turnover and cortical thickness without increased cortical porosity after 2 years of cyclical hPTH (1-34) therapy in women with severe osteoporosis. Bone 2000, 27:311- 318.
Dempster DW, Cosman F, Kurland ES, et al.: Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner Res 2001, 16:1846–1853.
Zanchetta JR, Bogado CE, Ferretti JL, et al.: Effects of teriparatide combinant human 1–34 parathyroid hormoneon cortical bone in postmenopausal women with osteoporosis. J Bone Miner Res 2003, 18:539–543.
Uusi-Rasi K, Semanick LM, Zanchetta JR, et al.: Effects of teriparatide [rhPTH (1-34)] treatment on structural geometry of the proximal femur in elderly osteoporotic women. Bone 2005, 36:948–958. The data showing that teriparatide (rh 1–34 PTH) increases the crosssectional area of the femoral neck as measured by DXA.
Burr DB, Hirano T, Turner CH: Intermittently administered human parathyroid hormone(1-34) treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys. J Bone Miner Res 2001, 16:157–165.
Cehn P, Satterwhite JH, Licata AA, et al.: Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis. J Bone Miner Res 2005, 20:962–970. The first study to show that in groups of patient’s early changes in bone formation markers induced by teriparatide are correlated with improvements in BMD.
Arlot M, Meunier PJ, Boivin G, et al.: Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters. J Bone Miner Res 2005, 20:1244–1253.
Ettinger B, San Martin JA, Crans CG, et al.: Differential effects of teriparatide after treatment with raloxifene or alendronate. J Bone Miner Res 2004, 19:745–751.
Deal C, Omizo M, Schwartz E, et al.: Raloxifene in combination with teriparatide reduces teriparatide-induced stimulation of bone resorption but not formation in postmenopausal women with osteoporosis. J Bone Miner Res 2004, 19(Suppl 1):S44.
Lindsay R, Scheele WH, Neer R, et al.: Sustained vertebral fracture risk reduction after withdrawal of teriparatide in postmenopausal women with osteoporosis. Arch Intern Med 2004, 164:2024–2030.
Prince R, Sipos A, Hossain A, et al.: Non-vertebral fractures after PTH discontinuation. J Bone Miner Res 2005, In press.
van Staa TP, Geusens P, Pols HA, et al.: A simple score for estimating the long-term risk of fracture in patients using oral glucocorticoids. QJM 2005, 98:191–198.
Van Staa TP, Laan RF, Barton IP, et al.: Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy. Arthritis Rheum 2003, 48:3224–3229.
Maricic M, Gluck O: Densitometry in glucocorticoid-induced osteoporosis. J Clin Densitom 2004, 7:359–363.
Miller PD, Shane E: Management of transplantation renal bone disease: interplay of bone mineral density and decisions regarding bisphosphonate use. In Medical Mangement of Kidney Transplantation. Edited by Weir MR. Philadelphia: Lippincott Williams & Wilkins; 2004:359–375.
Rehman Q, Lane N: Effect of glucocorticoids on bone density. Med Pediatr Oncol 2003, 41:212–216.
Lane N: An update on glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am 2001, 27:235–253.
Sambrook P, Lane N: Corticosteroid osteoporosis. Best Pract Res Clin Rheumatol 2001, 15:401–413.
Miller PD: Bisphosphonates for the prevention and treatment of corticosteroid-induced osteoporosis. Osteoporos Int 2001, 12(Suppl 3):S3-S10.
Weinstein RS, Chen JR, Powers CC, et al.: Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest 2002, 109:1041–1048.
American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis: Recommendation for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheum 2001, 44:1496–1503. The position of the American College of Rheumatology on the prevention and treatment of GIOP.
Maricic M: Glucocorticoid-induced osteoporosis-treatment options and guidelines. Curr Osteo Rep 2005, 3:25–29. An excellent, accurate, and current review on treatment of GIOP.
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Miller, P.D. Bone density and markers of bone turnover in predicting fracture risk and how changes in these measures predict fracture risk reduction. Curr Osteoporos Rep 3, 103–110 (2005). https://doi.org/10.1007/s11914-005-0018-6
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DOI: https://doi.org/10.1007/s11914-005-0018-6