Bone turnover matters:​ the raloxifene treatment paradox of dramatic decreases in vertebral fractures without commensurate increases in bone density

Riggs, B. Lawrence<sup>1</sup>; Melton, III, L. Joseph<sup>2</sup>

Affiliations

¹Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA

²Section of Clinical Epidemiology, Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA.

Links

DOI: 10.1359/jbmr.2002.17.1.11

PubMed: 11771656

WoS: 000172730400002

Cited Works (18)

Year	Entry
1983	Parfitt AM, Mathews CH, Villanueva AR, Kleerekoper M, Frame B, Rao DS. Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis: implications for the microanatomic and cellular mechanisms of bone loss. J Clin Invest. October 1983;72(4):1396-1409.
1996	Garnero P, Hausherr E, Chapuy M, Marcelli C, Grandjean H, Muller C, Cormier C, Bréart G, Meunier PJ, Delmas PD. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study. J Bone Miner Res. October 1996;11(10):1531-1538.
1999	Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH III, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD; Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA. October 13, 1999;282(14):1344-1352.
2001	McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, Adami S, Fogelman I, Diamond T, Eastell R, Meunier PJ, Wasnich RD, Greenwald M, Kaufman J-M, Chesnut CH, Reginster J-Y; Hip Intervention Program Study Group. Effect of risedronate on the risk of hip fracture in elderly women: Hip Intervention Program Study Group. NEJM. February 1, 2001;344(5):333-340.
1990	Riggs BL, Hodgson SF, O'Fallon WM, Chao EYS, Wahner HW, Muhs JM, Cedel SL, Melton LJ III. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. NEJM. March 22, 1990;322(12):802-809.
2002	Sarkar S, Mitlak BH, Wong M, Stock JL, Black DM, Harper KD. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res. January 2002;17(1):1-10.
2000	Chesnut CH, Silverman S, Andriano K, Genant H, Gimona A, Harris S, Kiel D, LeBoff M, Maricic M, Miller P, Moniz C, Peacock M, Richardson P, Watts N, Baylink D; PROOF Study Group. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. Am J Med. September 2000;109(4):267-276.
1996	Müller R, Hildebrand T, Häuselmann HJ, Rüegsegger P. In vivo reproducibility of three‐dimensional structural properties of noninvasive bone biopsies using 3D‐pQCT. J Bone Miner Res. November 1996;11(11):1745-1750.
1995	Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M, Seeman E, Recker RR, Capizzi T, Santora AC, Lombardi A, Shah RV, Hirsch LJ, Karpf DB; Group, Alendronate Phase III Osteoporosis Treatment Study. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. NEJM. November 30, 1995;333(22):1437-1443.
1996	Riggs BL, Melton LJ III, O'Fallon WM. Drug therapy for vertebral fractures in osteoporosis: evidence that decreases in bone turnover and increases in bone mass both determine antifracture efficacy. Bone. March 1996;18(3)(suppl 1):197S-201S.
1999	Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Glüer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR; Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. August 18, 1999;282(7):637-645.
1989	Turner CH. Yield behavior of bovine cancellous bone [published correction appears in J Biomech Eng. 1989;111(4):335]. J Biomech Eng. August 1989;111(3):256-260.
2000	Faulkner KG. Bone matters: are density increases necessary to reduce fracture risk? J Bone Miner Res. February 2000;15(2):183-187.
1992	Lufkin EG, Wahner HW, O'Fallon WM, Hodgson SF, Kotowicz MA, Lane AW, Judd HL, Caplan RH, Riggs BL. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med. July 1, 1992;117(1):1-9.
2001	Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster J-Y, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mellström D, Oefjord ES, Marcinowska-Suchowierska E, Salmi J, Mulder H, Halse J, Sawicki AZ, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. NEJM. May 10, 2001;344(19):1434-1441.
1998	Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ; Fracture Intervention Trial Research Group. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. December 23, 1998;280(24):2077-2082.
1996	Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. May 18, 1996;312(7041):1254-1259.
1997	Melton LJ III, Khosla S, Atkinson EJ, O'Fallon WM, Riggs BL. Relationship of bone turnover to bone density and fractures. J Bone Miner Res. July 1997;12(7):1083-1091.

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2002	Wehrli F, Saha P, Gomberg B, Song H, Snyder P, Benito M, Wright A, Weening R. Role of magnetic resonance for assessing structure and function of trabecular bone. Top Magn Reson Imaging. October 2002;13(5):335-355.
2003	Heaney RP. Is the paradigm shifting? Bone. October 2003;33(4):457-465.
2004	Borah B, Dufresne TE, Chmielewski PA, Johnson TD, Chines A, Manhart MD. Risedronate preserves bone architecture in postmenopausal women with osteoporosis as measured by three-dimensional microcomputed tomography. Bone. April 2004;34(4):736-746.
2005	Borah B, Ritman EL, Dufresne TE, Jorgensen SM, Liu S, Sacha J, Phipps RJ, Turner RT. The effect of risedronate on bone mineralization as measured by micro-computed tomography with synchrotron radiation: correlation to histomorphometric indices of turnover. Bone. July 2005;37(1):1-9.
2006	Bevill G, Eswaran SK, Gupta A, Papadopoulos P, Keaveny TM. Influence of bone volume fraction and architecture on computed large-deformation failure mechanisms in human trabecular bone. Bone. December 2006;39(6):1218-1225.
2022	Ozasa R, Matsugaki A, Ishimoto T, Kamura S, Yoshida H, Magi M, Matsumoto Y, Sakuraba K, Fujimura K, Miyahara H, Nakano T. Bone fragility via degradation of bone quality featured by collagen/apatite micro-arrangement in human rheumatic arthritis. Bone. February 2022;155:116261.
2023	Surowiec RK, Saldivar R, Rai RK, Metzger CE, Jacobson AM, Allen MR, Wallace JM. Ex vivo exposure to calcitonin or raloxifene improves mechanical properties of diseased bone through non-cell mediated mechanisms. Bone. August 2023;173:116805.
2007	Nazarian A, Muller J, Zurakowski D, Müller R, Snyder BD. Densitometric, morphometric and mechanical distributions in the human proximal femur. J Biomech. 2007;40(11):2573-2579.
2007	Eswaran SK, Allen MR, Burr DB, Keaveny TM. A computational assessment of the independent contribution of changes in canine trabecular bone volume fraction and microarchitecture to increased bone strength with suppression of bone turnover. J Biomech. 2007;40(15):3424-3431.
2010	Cory E, Nazarian A, Entezari V, Vartanians V, Müller R, Snyder BD. Compressive axial mechanical properties of rat bone as functions of bone volume fraction, apparent density and micro-CT based mineral density. J Biomech. March 22, 2010;43(5):953-960.
2011	Nazarian A, Arroyo FJA, Rosso C, Aran S, Snyder BD. Tensile properties of rat femoral bone as functions of bone volume fraction, apparent density and volumetric bone mineral density. J Biomech. September 2, 2011;44(13):2482-2488.
2002	Parfitt AM. High bone turnover is intrinsically harmful: two paths to a similar conclusion: the Parfitt view. J Bone Miner Res. August 2002;17(8):1558-1559.
2003	Paschalis EP, Boskey AL, Kassem M, Eriksen EF. Effect of hormone replacement therapy on bone quality in early postmenopausal women. J Bone Miner Res. June 2003;18(6):955-959.
2003	Eastell R, Barton I, Hannon R, Chines A, Garnero P, Delmas P. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res. June 2003;18(6):1051-1056.
2004	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. October 2004;19(10):1628-1633.
2005	Ito M, Ikeda K, Nishiguchi M, Shindo H, Uetani M, Hosoi T, Orimo H. Multi‐detector row CT imaging of vertebral microstructure for evaluation of fracture risk. J Bone Miner Res. October 2005;20(10):1828-1836.
2006	Hernandez CJ, Gupta A, Keaveny TM. A biomechanical analysis of the effects of resorption cavities on cancellous bone strength. J Bone Miner Res. August 2006;21(8):1248-1255.
2008	Kazakia GJ, Hyun B, Burghardt AJ, Krug R, Newitt DC, de Papp AE, Link TM, Majumdar S. In vivo determination of bone structure in postmenopausal women: a comparison of MR‐pQCT and high‐field MR imaging. J Bone Miner Res. 2008;23(4):463-474.
2010	Burghardt AJ, Kazakia GJ, Sode M, de Papp AE, Link TM, Majumdar S. A longitudinal HR-pQCT study of alendronate treatment in postmenopausal women with low bone density: relations among density, cortical and trabecular microarchitecture, biomechanics, and bone turnover. J Bone Miner Res. December 2010;25(12):2558-2571.
2006	Sambrook P, Cooper C. Osteoporosis. Lancet. June 17, 2006;367(9527):2010-2018.
2008	Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. September 2008;83(9):1032-1045.
2008	Kazakia GJ, Burghardt AJ, Cheung S, Majumdar S. Assessment of bone tissue mineralization by conventional x-ray microcomputed tomography: comparison with synchrotron radiation microcomputed tomography and ash measurements. Med Phys. 2008;35(7):3170-3179.
2009	Vasilić B, Rajapakse CS, Wehrli FW. Classification of trabeculae into three‐dimensional rodlike and platelike structures via local inertial anisotropy. Med Phys. July 2009;36(7):3280-3291.
2003	Ammann P, Rizzoli R. Bone strength and its determinants. Osteoporos Int. March 2003;14(suppl 3):S13-S18.
2003	Bouxsein ML. Bone quality: where do we go from here? Osteoporos Int. September 2003;14(suppl 5):S118-S127.
2008	Ruppel ME, Miller LM, Burr DB. The effect of the microscopic and nanoscale structure on bone fragility. Osteoporos Int. September 2008;19(9):1251-1265.
2007	Sievänen H, Kannus P, Järvinen TLN. Bone quality: an empty term. PLoS Med. March 2007;4(3):e27.
2009	Slyfield CR Jr. Automated Sub-Micron Resolution Serial Block Face Imaging of Cancellous Bone Using Epifluorescence Microscopy [Master's thesis]. Cleveland, OH: Case Western Reserve University; January 2009.
2011	Kummari SR. Experimental and Computational Evaluation of Microscopic Tissue Damage and Remodeling Cavities in Trabecular Bone [PhD thesis]. Cleveland, OH: Case Western Reserve University; May 2011.
2012	Slyfield CR Jr. The Biomechanics of Bone Turnover [PhD thesis]. Ithaca, NY: Cornell University; January 2012.
2017	Matheny JB. Interactions Between Bone Remodeling and Microdamage in Cancellous Bone [PhD thesis]. Ithaca, NY: Cornell University; August 2017.
2008	Nazarian A. Relative Interaction of Material and Structure in Normal and Pathologic Bone [PhD thesis]. Swiss Federal Institute of Technology Zürich; 2008.
2010	Wang JL. Effects of Aging and Remodeling on Bone Microdamage Formation [Master's thesis]. Atlanta, GA: Georgia Institute of Technology; December 2010.
2012	Brennan MA. Close to the Bone: Investigations Into Bone Tissue Mineralisation and Mechanobiology of Osteoporosis [PhD thesis]. University of Southampton; January 2012.
2008	Kennedy OD. The Effect of Bone Turnover on Bone Quality and Material Properties [PhD thesis]. Trinity College Dublin; 2008.
2008	Bevill GR. Micromechanical Modeling of Failure in Trabecular Bone [PhD thesis]. Berkeley, CA: Berkeley, University of California; 2008.
2018	Oweis R. Associations Between Fluoride Intakes, Bone Outcomes and Dental Fluorosis [PhD thesis]. University of Iowa; May 2018.
2022	Zhang X. Development of an Image-Based System for Assessment of Bone Density, Geometry, and Micro-Architecture Suitable for Human Studies [PhD thesis]. University of Iowa; August 2022.
2010	Kyle KA. Differential Effects of PPAR-Γ Activation Vs. Chemical or Genetic Reduction of DPP-4 Activity on Murine Bone Quality [Master's thesis]. University of Toronto; 2010.
2013	Liu CC. Effects of a New Conjugate Drug in a Rat Model of Postmenopausal Osteoporosis [Master's thesis]. University of Toronto; 2013.