The Effects of Zoledronate and Raloxifene Combination Therapy on Diseased Mouse Bone

Links

URL: https://scholarworks.iupui.edu/handle/1805/18922

Abstract

Current interventions used to reduce skeletal fragility are insufficient at enhancing bone across multiple hierarchical levels. Bisphosphonates, such as Zoledronate (ZOL), treat a variety of bone disorders by increasing bone mass and bone mineral density to decrease fracture risk. Despite the mass-based improvements, bisphosphonate use has been shown to compromise bone quality. Alternatively, Raloxifene (RAL) has recently been demonstrated to improve tissue quality and overall mechanical properties by binding to collagen and increasing tissue hydration in a cell-independent manner. We hypothesized that a combination of RAL and ZOL would improve mechanical and material properties of bone more than either monotherapy alone by enhancing both quantity and quality of bone. In this study, wildtype (WT) and heterozygous (OIM+/-) male mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL, ZOL, or RAL and ZOL from 8 weeks to 16 weeks of age. Combination treatment resulted in higher trabecular architecture, cortical mechanical properties, and cortical fracture toughness in diseased mouse bone. Two fracture toughness properties, direct measures of the tissues ability to resist the initiation and propagation of a crack, were significantly improved with combination treatment in OIM+/- compared to control. There was no significant effect on fracture toughness with either monotherapy alone in either genotype. Following the mass-based effects of ZOL, bone volume fraction was significantly higher with combination treatment in both genotypes. Similar results were seen in trabecular number. Combination treatment resulted in higher ultimate stress in both genotypes, with RAL additionally increasing ultimate stress in OIM+/-. RAL and combination treatment in OIM+/- also produced a higher resilience compared to the control. Given no significant changes in cortical geometry, these mechanical alterations were likely driven by the qualitybased effects of RAL. In conclusion, this study demonstrates the beneficial effects of using combination therapy to increase bone mass while simultaneously improving tissue quality, especially to enhance the mechanical integrity of diseased bone. Combination therapies could be a future mechanism to improve bone health and combat skeletal fragility on multiple hierarchal levels.

Cited Works (18)

Year	Entry
2017	Lloyd AA, Gludovatz B, Riedel C, Luengo EA, Saiyed R, Marty E, Lorich DG, Lane JM, Ritchie RO, Busse B, Donnelly E. Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance. Proc Natl Acad Sci USA. August 15, 2017;114(33):8722-8727.
2009	Tang SY, Allen MR, Phipps R, Burr DB, Vashishth D. Changes in non-enzymatic glycation and its association with altered mechanical properties following 1-year treatment with risedronate or alendronate. Osteoporos Int. July 2009;20(6):887-894.
2011	Russell RGG. Bisphosphonates: the first 40 years. Bone. July 2011;49(1):2-19.
2006	Seeman E, Delmas PD. Bone quality: the material and structural basis of bone strength and fragility. NEJM. May 25, 2006;354(21):2250-2261.
2011	Donnelly E. Methods for assessing bone quality: a review. Clin Orthop Relat Res. August 2011;469:2128-2138.
2001	van der Meulen MCH, Jepsen KJ, Mikić B. Understanding bone strength: size isn’t everything. Bone. July 2001;29(1):101-104.
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.
2008	Russell RGG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. June 2008;19(6):733-759.
2008	Ritchie RO, Koester KJ, Ionova S, Yao W, Lane NE, Ager JW III. Measurement of the toughness of bone: a tutorial with special reference to small animal studies. Bone. November 2008;43(5):798-812.
2011	Allen MR, Burr DB. Bisphosphonate effects on bone turnover, microdamage, and mechanical properties: what we think we know and what we know that we don't know. Bone. July 2011;49(1):56-65.
2008	Allen MR, Gineyts E, Leeming DJ, Burr DB, Delmas PD. Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra. Osteoporos Int. March 2008;19(3):329-337.
2001	NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. February 14, 2001;285(6):785-795.
2010	Launey ME, Buehler MJ, Ritchie RO. On the mechanistic origins of toughness in bone. Ann Rev Mater Sci. 2010;40:25-53.
2009	Wallace JM, Golcuk K, Morris MD, Kohn DH. Inbred strain-specific response to biglycan deficiency in the cortical bone of C57BL6/129 and C3H/He mice. J Bone Miner Res. June 2009;24(6):1002-1012.
2003	Judex S, Boyd S, Qin Y-X, Miller L, Müller R, Rubin C. Combining high-resolution micro-computed tomography with material composition to define the quality of bone tissue. Curr Osteoporos Rep. June 2003;1(1):11-19.
2014	Carriero A, Zimmermann EA, Paluszny A, Tang SY, Bale H, Busse B, Alliston T, Kazakia G, Ritchie RO, Shefelbine SJ. How tough is brittle bone? investigating osteogenesis imperfecta in mouse bone. J Bone Miner Res. June 2014;29(6):1392-1401.
2010	Saito M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int. 2010;21(2):195-214.
2014	Gallant MA, Brown DM, Hammond M, Wallace JM, Du J, Deymier-Black AC, Almer JD, Stock SR, Allen MR, Burr DB. Bone cell-independent benefits of raloxifene on the skeleton: a novel mechanism for improving bone material properties. Bone. April 2014;61:191-200.