[en] In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis, defined by low bone mineral density and/or prevalent vertebral fractures (VF), were randomized to placebo or raloxifene (60 or 120 mg/day). All women received daily calcium (500 mg) and vitamin D (400-600 IU) supplements. Our previous analyses found that changes in BMD and biochemical markers of bone turnover are poorly predictive of the reduction in VF risk observed with raloxifene. This present study evaluated the effects of raloxifene on type I procollagen N-terminal propeptide (PINP), a new marker of bone turnover. Logistic regression analysis models evaluated the relationships between the changes at 1 year in PINP, serum osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), and urinary excretion of type I collagen C-telopeptide fragments normalized to creatinine (CTx/Cr), and the risk of new VF at 3 years for placebo and pooled raloxifene. A subset of 967 women (mean age = 68 years) from the MORE cohort had PINP, OC, BSAP, and CTx evaluated at baseline. Both doses of raloxifene significantly decreased (P < 0.001) all biochemical markers of bone turnover from baseline. Compared to baseline, PINP levels were decreased by medians of 11.0% and 40.8% in the placebo and pooled raloxifene groups, respectively. In addition, the placebo and pooled raloxifene groups decreased serum OC by 8.5% and 31.8%, BSAP by 15.8% and 34.6%, and urinary CTx/Cr excretion by 5.6% and 46.5%, respectively, from baseline. In the pooled raloxifene group, the logistic regression relationship between 3-year VF risk and 1-year percentage change for each biochemical marker was statistically significant with PINP (slope estimate = 0.0085, P = 0.009), OC (slope estimate = 0.0068, P = 0.035), and BSAP (slope estimate = 0.0056, P = 0.039), but not with CTx/Cr (slope estimate = 0.0027, P = 0.192). Furthermore, the percent decrease in PINP at 1 year could account for 28% of the total reduction in vertebral fracture risk. In conclusion, a 1-year decrease in PINP, BSAP, or OC, but not CTx/Cr, may be predictive of the 3-year VF risk reduction with raloxifene therapy in this subset of postmenopausal women with osteoporosis.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Reginster, Jean-Yves ; Université de Liège - ULiège > Département des sciences de la santé publique > Epidémiologie et santé publique
Sarkar, S.
Zegels, Brigitte ; Université de Liège - ULiège > Département des sciences de la santé publique > Epidémiologie et santé publique
Henrotin, Yves ; Université de Liège - ULiège > Unité de recherche sur l'os et le cartillage (U.R.O.C.)
Bruyère, Olivier ; Université de Liège - ULiège > Département des sciences de la santé publique > Epidémiologie et santé publique
Agnusdei, D.
Collette, Julien ; Centre Hospitalier Universitaire de Liège - CHU > Chimie médicale
Language :
English
Title :
Reduction in PINP, a marker of bone metabolism, with raloxifene treatment and its relationship with vertebral fracture risk
Publication date :
February 2004
Journal title :
BONE
ISSN :
8756-3282
eISSN :
1873-2763
Publisher :
Elsevier Science Inc, New York, United States - New York
Ettinger B., Black D.M., Mitlak B.H., Knickerbocker R.K.et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 282:1999;637-645.
Delmas P.D., Ensrud K.E., Adachi J.D., Harper K.D.et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J. Clin. Endocrinol. Metab. 87:2002;3609-3617.
Delmas P.D. Treatment of postmenopausal osteoporosis. Lancet. 359:2002;2018-2026.
Maricic M., Adachi J.D., Sarkar S., Wu W., Wong M., Harper K.D. Early effects of raloxifene on clinical vertebral fractures at 12 months in postmenopausal women with osteoporosis. Arch. Intern. Med. 162:2002;1140-1143.
Cauley J., Norton L., Lippman M.E., Eckert S.et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Breast Cancer Res. Treat. 65:2001;125-134.
Barrett-Connor E., Grady D., Sashegyi A., Anderson P.W.et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA. 287:2002;847-857.
Cummings S.R., Karpf D.B., Harris F., Genant H.K.et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am. J. Med. 112:2002;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. J. Bone Miner. Res. 17:2002;1-10.
Watts N., Bockman R., Smith C., Li Z.et al. BMD changes explains only a fraction of the observed fracture risk reduction in risedronate-treated patients. Osteoporos. Int. 11:2000;S203.
Li Z., Meredith M.P., Hoseyni M.S. A method to assess the proportion of treatment effect explained by a surrogate endpoint. Stat. Med. 20:2001;3175-3188.
Johnell O., Oden A., De Laet C., Garnero P., Delmas P.D., Kanis J.A. Biochemical indices of bone turnover and the assessment of fracture probability. Osteoporos. Int. 13:2002;523-526.
Garnero P., Hausherr E., Chapuy M.-C., Marcelli C.et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study. J. Bone Miner. Res. 11:1996;1531-1538.
Garnero P., Sornay-Rendu E., Duboeuf F., Delmas P.D. Markers of bone turnover predict postmenopausal forearm bone loss over 4 years: the OFELY study. J. Bone Miner. Res. 14:1999;1614-1621.
Rosen C.J., Chesnut C.H. III, Mallinak N.J. The predictive value of biochemical markers of bone turnover for bone mineral density in early postmenopausal women treated with hormone replacement or calcium supplementation. J. Clin. Endocrinol. Metab. 82:1997;1904-1910.
Greenspan S.L., Parker R.A., Ferguson L., Rosen H.N., Maitland-Ramsey L., Karpf D.B. Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial. J. Bone Miner. Res. 13:1998;1431-1438.
Ravn P., Christensen J.O., Baumann M., Clemmesen B. Changes in biochemical markers and bone mass after withdrawal of ibandronate treatment: prediction of bone mass changes during treatment. Bone. 22:1998;559-564.
Ott S.M., Oleksik A., Lu Y., Harper K.D., Lips P. Bone histomorphometric and biochemical marker results of a two-year placebo controlled trial of raloxifene in postmenopausal women. J. Bone Miner. Res. 17:2002;341-348.
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. Osteoporos. Int. 12:2001;922-930.
Genant H.K., Jergas M., Palermo L.et al. Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis. J. Bone Miner. Res. 11:1996;984-996.
Efron B., Tibshirani R.J. An Introduction to the Bootstrap. Monographs on Statistics and Applied Probability. vol. 57:1993;Chapman & Hall, New York.
Bauer D.C., Sklarin P.M., Stone K.L., Black D.M.et al. Biochemical markers of bone turnover and prediction of hip bone loss in older women: the study of osteoporotic fractures. J. Bone Miner. Res. 14:1999;1404-1410.
Marcus R., Holloway L., Wells B., Greendale G.et al. The relationship of biochemical markers of bone turnover to bone density changes in postmenopausal women: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. J. Bone Miner. Res. 14:1999;1583-1595.
Melkko J., Kauppila S., Niemi S., Risteli L.et al. Immunoassay for intact amino-terminal propeptide of human type I procollagen. Clin. Chem. 42:1996;947-954.
Scariano J.K., Glew R.H., Bou-Serhal C.E., Clemens J.D., Garry P.J., Baumgartner R.N. Serum levels of cross-linked N-telopeptides and amino terminal propeptides of type I collagen indicate low bone mineral density in elderly women. Bone. 23:1998;471-477.
Scariano J.K., Garry P.J., Montoya G.D., Duran-Valdez E., Baumgartner R.N. Diagnostic efficacy of serum cross-linked N-telopeptide (NTx) and aminoterminal procollagen extension propeptide (PINP) measurements for identifying elderly women with decreased bone mineral density. Scand. J. Clin. Lab. Invest. 62:2002;237-243.
Fink E., Cormier C., Steinmetz P., Kindermans C., Le Bouc Y., Souberbielle J.C. Differences in the capacity of several biochemical bone markers to assess high bone turnover in early menopause and response to alendronate therapy. Osteoporos. Int. 11:2000;295-303.
Saarto T., Blomqvist C., Risteli J., Risteli L., Sarna S., Elomaa I. Aminoterminal propeptide of type I procollagen (PINP) correlates to bone loss and predicts the efficacy of antiresorptive therapy in pre- and post-menopausal non-metastatic breast cancer patients. Br. J. Cancer. 78:1998;240-245.
Sharp C.A., Evans S.F., Risteli L., Risteli J., Worsfold M., Davie M.W. Effects of low- and conventional-dose transcutaneous HRT over 2 years on bone metabolism in younger and older postmenopausal women. Eur. J. Clin. Invest. 26:1996;763-771.
Hannon R., Blumsohn A., Naylor K., Eastell R. Response of biochemical markers of bone turnover to hormone replacement therapy: impact of biological variability. J. Bone Miner. Res. 13:1998;1124-1133.
Bauer D.C., Black D.M., Garnero P., Hochberg M.et al. Reduction in bone turnover predicts hip, non-spine, and vertebral fracture in alendronate treated women: the Fracture Intervention Trial. Osteoporos. Int. 13:2002;521.
Fall P.M., Kennedy D., Smith J.A., Seibel M.J., Raisz L.G. Comparison of serum and urine assays for biochemical markers of bone resorption in postmenopausal women with and without hormone replacement therapy and in men. Osteoporos. Int. 11:2000;481-485.
Delmas P.D., Eastell R., Garnero P., Seibel M.J., Stepan J. The use of biochemical markers of bone turnover in osteoporosis. Committee of scientific advisors of the international osteoporosis foundation. Osteoporos. Int. 11(Suppl 6):2000;S2-S17.
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. J. Bone Miner. Res. 18:2003;1051-1056.
Greendale G.A., Espeland M., Slone S., Marcus R., Barrett-Connor E. Bone mass response to discontinuation of long-term hormone replacement therapy: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) safety follow-up study. Arch. Intern. Med. 162:2002;665-672.