bone turnover markers; bone densitometry; osteocalcin; raloxifene; osteoporosis
Abstract :
[en] The change in BMD is a poor predictor of vertebral fracture risk after raloxifene treatment. One-year percent change in bone turnover and BMD was used to predict vertebral fracture risk. The percent change in osteocalcin was determined to be a better predictor of vertebral fracture risk than BMD. Introduction: The association between baseline BMD and fracture risk is well understood. However, the relationship between changes in BMD and fracture risk is not well defined. It has previously been demonstrated that BMD change was a poor predictor of vertebral fracture risk in raloxifene-treated women, whereas bone turnover markers were significantly associated with fracture risk. In the current analysis, we explore the prediction of vertebral fracture risk using changes in both BMD and bone turnover. Materials and Methods: The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, placebo-controlled trial of 7705 women with osteoporosis treated with raloxifene 60 or 120 mg/day for 3 years. Markers of bone turnover were measured in one-third of the study population (n = 2503), and the present analyses include these women. Logistic regression models were constructed using one-year percent changes in BMD and bone turnover and relevant baseline demographics to predict the risk of vertebral fracture with pooled raloxifene therapy at 3 years. All covariates were standardized before modeling to facilitate direct comparisons between changes in BMD and bone turnover. Results and Conclusion: Prevalent vertebral fracture status (p < 0.0001), baseline lumbar spine BMD (p < 0.0001), and number of years postmenopausal (p = 0.0005) were independent predictors of fracture risk in raloxifene-treated patients. Therapy-by-change in femoral neck BMD (p = 0.02) and therapy-by-change in osteocalcin (OC; p = 0.01) were also significant for all treatment groups, indicating that changes in BMD and OC have different effects on fracture risk for the placebo and pooled raloxifene groups. The final model included significant baseline variables and change in OC (p = 0.01), whereas change in femoral neck BMD was not significant. After adjustment of each significant baseline variable, the percent change in OC was better able to predict the reduction in vertebral fracture risk than the percent change in femoral neck BMD in patients treated with raloxifene.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Sarkar, S.
Reginster, Jean-Yves ; Université de Liège - ULiège > Département des sciences de la santé publique > Epidémiologie et santé publique
Crans, G. G.
Diez-Perez, A.
Pinette, K. V.
Delmas, P. D.
Language :
English
Title :
Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk
Publication date :
March 2004
Journal title :
Journal of Bone and Mineral Research
ISSN :
0884-0431
eISSN :
1523-4681
Publisher :
Amer Soc Bone & Mineral Res, Washington, United States - Washington
Kanis, J.A., Gluer, C.C., An update on the diagnosis and assessment of osteoporosis with densitometry (2000) Osteoporos Int, 11, pp. 192-202. , Committee of Scientific Advisors, International Osteoporosis Foundation
Melton III, L.J., Atkinson, E.J., O'Fallon, W.M., Wahner, H.W., Riggs, B.L., Long-term fracture prediction by bone mineral assessed at different skeletal sites (1993) J Bone Miner Res, 8, pp. 1227-1233
Ravaud, P., Reny, J.L., Giraudeau, B., Porcher, R., Dougados, M., Roux, C., Individual smallest detectable difference in bone mineral density measurements (1999) J Bone Miner Res, 14, pp. 1449-1456
Black, D.M., Cummings, S.R., Genant, H.K., Nevitt, M.C., Palermo, L., Browner, W., Axial and appendicular bone density predict fractures in older women (1992) J Bone Miner Res, 7, pp. 633-638
Hui, S.L., Slemenda, C.W., Johnston Jr., C.C., Baseline measurement of bone mass predicts fracture in white women (1989) Ann Intern Med, 111, pp. 355-361
Delmas, P.D., How does antiresorptive therapy decrease the risk of fracture in women with osteoporosis? (2000) Bone, 27, pp. 1-3
Cummings, S.R., Karpf, D.B., Harris, F., Genant, H.K., Ensrud, K., LaCroix, A.Z., Black, D.M., Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs (2002) Am J Med, 112, pp. 281-289
Sarkar, S., Mitlak, B.H., Wong, M., Stock, J.L., Black, D.M., Harper, K.D., Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy (2002) J Bone Miner Res, 17, pp. 1-10
Li, Z., Meredith, M.P., Hoseyni, M.S., A method to assess the proportion of treatment effect explained by a surrogate endpoint (2001) Stat Med, 20, pp. 3175-3188
Genant, H.K., Engelke, K., Fuerst, T., Gluer, C.C., Grampp, S., Harris, S.T., Jergas, M., Takada, M., Noninvasive assessment of bone mineral and structure: State of the art (1996) J Bone Miner Res, 11, pp. 707-730
Delmas, P.D., Eastell, R., Garnero, P., Seibel, M.J., Stepan, J., The use of biochemical markers of bone turnover in osteoporosis (2000) Osteoporos Int, 11 (SUPPL. 6), pp. S2-S17. , Committee of Scientific Advisors of the International Osteoporosis Foundation
Looker, A.C., Bauer, D.C., Chesnut III, C.H., Gundberg, C.M., Hochberg, M.C., Klee, G., Kleerekoper, M., Bell, N.H., Clinical use of biochemical markers of bone remodeling: Current status and future directions (2000) Osteoporos Int, 11, pp. 467-480
Garnero, P., Hausherr, E., Chapuy, M.-C., Marcelli, C., Grandjean, H., Muller, C., Cornier, C., Delmas, P.D., Markers of bone resorption predict hip fracture in elderly women: The EPIDOS prospective study (1996) J Bone Miner Res, 11, pp. 1531-1538
Van Daele, P.L., Seibel, M.J., Burger, H., Hofman, A., Grobbee, D.E., Van Leeuwen, J.P., Birkenhager, J.C., Pols, H.A., Case-control analysis of bone resorption markers, disability, and hip fracture risk: The Rotterdam study (1996) BMJ, 312, pp. 482-483
Ross, P.D., Kress, B.C., Parson, R.E., Wasnich, R.D., Armour, K.A., Mizrahi, I.A., Serum bone alkaline phosphatase and calcaneus bone density predict fractures: A prospective study (2000) Osteoporos Int, 11, pp. 76-82
Garnero, P., Sornay-Rendu, E., Claustrat, B., Delmas, P.D., Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: The OFELY study (2000) J Bone Miner Res, 15, pp. 1526-1536
Bjarnason, N.H., Christiansen, C., Early response in biochemical markers predicts long-term response in bone mass during hormone replacement therapy in early postmenopausal women (2000) Bone, 26, pp. 561-569
Delmas, P.D., Hardy, P., Garnero, P., Dain, M., Monitoring individual response to hormone replacement therapy with bone markers (2000) Bone, 26, pp. 553-560
Hannon, R., Blumsohn, A., Naylor, K., Eastell, R., Response of biochemical markers of bone turnover to hormone replacement therapy: Impact of biological variability (1998) J Bone Miner Res, 13, pp. 1124-1133
Garnero, P., Delmas, P.D., Variability and response of urinary resorption markers to hormone replacement therapy (1999) J Bone Miner Res, 14, pp. 470-472
Bjarnason, N.H., Sarkar, S., Duong, T., Mitlak, B., Delmas, P.D., Christiansen, C., Six and twelve month changes in bone turnover are related to reduction in vertebral fracture risk during 3 years of raloxifene treatment in postmenopausal osteoporosis (2001) Osteoporos Int, 12, pp. 922-930
Braga De Castro, M.A., Hannon, R., Eastell, R., Monitoring alendronate therapy for osteoporosis (1999) J Bone Miner Res, 14, pp. 602-608
Ravn, P., Clemmesen, B., Christiansen, C., Biochemical markers can predict the response in bone mass during alendronate treatment in early postmenopausal women (1999) Bone, 24, pp. 237-244. , Alendronate Osteoporosis Prevention Study Group
Garnero, P., Darte, C., Delmas, P.D., A model to monitor the efficacy of alendronate treatment in women with osteoporosis using a biochemical marker of bone turnover (1999) Bone, 24, pp. 603-609
Eastell, R., Blumsohn, A., The value of biochemical markers of bone turnover in osteoporosis (1997) J Rheumatol, 24, pp. 1215-1217
Miller, P.D., Baran, D.T., Bilezikian, J.P., Greenspan, S.L., Lindsay, R., Riggs, B.L., Watts, N.B., Practical clinical application of biochemical markers of bone turnover: Consensus of an expert panel (1999) J Clin Densitom, 2, pp. 323-342
Riggs, B.L., Are biochemical markers for bone turnover clinically useful for monitoring therapy in individual osteoporotic patients? (2000) Bone, 26, pp. 551-552
Eastell, R., Barton, I., Hannon, R.A., Chines, A., Garnero, P., Delmas, P.D., Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate (2003) J Bone Miner Res, 18, pp. 1051-1056
Bauer, D.C., Black, D.M., Garnero, P., Hochberg, M., Ott, S.M., Schneider, D.L., Thompson, D., Delmas, P.D., Reduction in bone turnover predicts hip, non-spine, and vertebral fracture in alendronate treated women: The Fracture Intervention Trial (2002) Osteoporos Int, 13 (SUPPL. 1), pp. S521
Delmas, P.D., Markers of bone turnover for monitoring treatment of osteoporosis with antiresorptive drugs (2000) Osteoporos Int, 11 (SUPPL. 6), pp. S66-S76
Melton, L.J., Khosla, S., Atkinson, E.J., O'Fallon, W.M., Riggs, B.L., Relationship of bone turnover to bone density and fractures (1997) J Bone Miner Res, 12, pp. 1083-1091
Johnell, O., Scheele, W.H., Lu, Y., Reginster, J.-Y., Need, A.G., Seeman, E., Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodelling in postmenopausal women with osteoporosis (2002) J Clin Endocrinol Metab, 87, pp. 985-992
Delmas, P.D., Ensrud, K.E., Adachi, J.D., Harper, K.D., Sarkar, S., Gennari, C., Reginster, J.Y., Eastell, R., Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: Four-year results from a randomized clinical trial (2002) J Clin Endocrinol Metab, 87, pp. 3609-3617
Ettinger, B., Black, D.M., Mitlak, B.H., Knickerbocker, R.K., Nickelsen, T., Genant, H.K., Christiansen, C., Cummings, S.R., Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial (1999) JAMA, 282, pp. 637-645
Genant, H.K., Jergas, M., Palermo, L., Nevitt, M., San Valentin, R., Black, D., Cummings, S.R., Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis (1996) J Bone Miner Res, 11, pp. 984-996
Lu, Y., Mathur, A.K., Blunt, B.A., Gluer, C.C., Will, A.S., Fuerst, T.P., Jergas, M.D., Genant, H.K., Dual X-ray absorptiometry quality control: Comparison of visual examination and process-control charts (1996) J Bone Miner Res, 11, pp. 626-637
Lu, Y., Ye, K., Mathur, A.K., Hui, S., Fuerst, T.P., Genant, H.K., Comparative calibration without a gold standard (1997) Stat Med, 16, pp. 1889-1905
Unnebrink, K., Windeler, J., Intention-to-treat: Methods for dealing with missing values in clinical trials of progressively deteriorating diseases (2001) Stat Med, 20, pp. 3931-3946
Efron, B., Stein, C., The jackknife estimate of variance (1981) Ann Stat, 9, pp. 586-596
Freedman, L.S., Graubard, B.I., Schatzkin, A., Statistical validation of intermediate endpoints for chronic diseases (1992) Stat Med, 11, pp. 167-178
Nevitt, M.C., Thompson, D.E., Black, D.M., Rubin, S.R., Ensrud, K., Yates, A.J., Cummings, S.R., Effect of alendronate on limited-activity days and bed-disability days caused by back pain in postmenopausal women with existing vertebral fractures (2000) Arch Intern Med, 160, pp. 77-85. , Fracture Intervention Trial Research Group
Watts, N., Bockman, R., Smith, C., Li, Z., Eastell, R., Pack, S., Lindsay, R.B., BMD changes explains only a fraction of the observed fracture risk reduction in risedronate-treated patients (2000) Osteoporos Int, 11, pp. S203
Seeman, E., Pathogenesis of bone fragility in women and men (2002) Lancet, 359, pp. 1841-1850
Boivin, G., Meunie, P.J., Changes in bone remodeling rate influence the degree of mineralization of bone which is a determinant of bone strength: Therapeutic implications (2001) Adv Exp Med Biol, 496, pp. 123-127
Stepan, J.J., Michalska, D., Zikan, V., Vokrouhlicka, J., Biochemical markers of Type I collagen synthesis and degradation in monitoring osteoporosis treatment with raloxifene and alendronate (2002) J Bone Miner Res, 17 (S1), pp. S233
Boivin, G., Lips, P., Ott, S.M., Harper, K.D., Sarkar, S., Pinette, K.V., Meunier, P.J., Contribution of raloxifene and calcium and vitamin D3 supplementation to the increase of the degree of mineralization of bone in postmenopausal women (2003) J Clin Endocrinol Metab, 88, pp. 4199-4205