Differential Effects of PPAR-Γ Activation Vs. Chemical or Genetic Reduction of DPP-4 Activity on Murine Bone Quality

This study characterized the effects of two anti-diabetic drugs, a thiazolidinedione (TZD) and a Dipeptidyl Peptidase-4 (DPP-4) inhibitor on bone quality in a glucose intolerant mouse model. Bone quality in a DPP-4 -/- mouse model was also examined. Bone quality was evaluated through densitometry, mechanical testing and techniques to assess remodeling, structural and mineral properties.

TZD treatment negatively affected trabecular mechanical properties in male, female and ovariectomized female (OVX) mice. Male mice exhibited the greatest effect due to TZD treatment with reduced vertebral vBMD, trabecular structure and bone formation. DPP-4 inhibitor treatment improved vertebral vBMD and trabecular architecture in female mice but improvements were lost in females following OVX. Male, female and OVX mice experienced increased trabecular mineralization due to DPP-4 inhibitor treatment. Genetic inactivation of DPP-4 did not produce a major bone phenotype in male and female mice but lead to reduced femoral geometry and mechanics in OVX mice.

Year	Entry
1995	Borchers RE, Gibson LJ, Burchardt H, Hayes WC. Effects of selected thermal variables on the mechanical properties of trabecular bone. Biomaterials. May 1995;16(7):545-551.
2000	Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. January 21, 2000;100(2):197-207.
2000	Wang X, Bank RA, TeKoppele JM, Hubbard GB, Althanasiou KA, Agrawal CM. Effect of collagen denaturation on the toughness of bone. Clin Orthop Relat Res. February 2000;371:228-239.
2002	Thomsen JS, Ebbesen EN, Mosekilde L. Predicting human vertebral bone strength by vertebral static histomorphometry. Bone. March 2002;30(3):502-508.
1998	Riggs BL, Khosla S, Melton LJ III. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res. May 1998;13(5):763-773.
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.
1993	Grynpas M. Age and disease-related changes in the mineral of bone. Calcif Tiss Int. February 1993;53(suppl 1):S57-S64.
2001	Turner CH, Burr DB. Experimental techniques for bone mechanics. In: Cowin SC, ed. Bone Mechanics Handbook. 2nd ed. Boca Raton, FL: CRC Press; 2001:7-1–7-35.
2002	Hochberg MC, Greenspan S, Wasnich RD, Miller P, Thompson DE, Ross PD. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab. April 2002;87(4):1586-1592.
1980	Hansson T, Roos B, Nachemson A. The bone mineral content and ultimate compressive strength of lumbar vertebrae. Spine. January–February 1980;5(1):46-55.
2001	Majeska RJ. Cell biology of bone. In: Cowin SC, ed. Bone Mechanics Handbook. 2nd ed. Boca Raton, FL: CRC Press; 2001:2-1–2-24.
2005	Strotmeyer ES, Cauley JA, Schwartz AV, Nevitt MC, Resnick HE, Bauer DC, Tylavsky FA, Rekeneire Nd, Harris TB, Newman AB. Nontraumatic fracture risk with diabetes mellitus and impaired fasting glucose in older white and black adults: the health, aging, and body composition study. Arch Intern Med. July 25, 2005;165(14):1612-1617.
1982	Leichter I, Margulies JY, Weinreb A, Mizrahi J, Robin GC, Conforty B, Makin M, Bloch B. The relationship between bone density, mineral content, and mechanical strength in the femoral neck. Clin Orthop Relat Res. March 1982;163:272-281.
1998	Wang XD, Masilamani NS, Mabrey JD, Alder ME, Agrawal CM. Changes in the fracture toughness of bone may not be reflected in its mineral density, porosity, and tensile properties. Bone. July 1998;23(1):67-72.
2002	Cummings SR, Melton LJ III. Epidemiology and outcomes of osteoporotic fractures. Lancet. May 18, 2002;359(9319):1761-1767.
2002	Wang X, Shen X, Li X, Agrawal CM. Age-related changes in the collagen network and toughness of bone [published correction appears in Bone. 2003;32(1):107]. Bone. 2002;31(1):1-7.
2002	Burr DB. The contribution of the organic matrix to bone's material properties. Bone. July 2002;31(1):8-11.
1996	Garnero P, Sornay‐Rendu E, Chapuy M, Delmas PD. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res. 1996;11(3):337-349.
2000	Garner P, Sornay-Rendu E, Claustrat B, Delmas PD. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res. August 2000;15(8):1526-1536.
2006	Saito M, Fujii K, Mori Y, Marumo K. Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats. Osteoporos Int. October 2006;17(10):1514-1523.
2006	Rosen CJ, Bouxsein ML. Mechanisms of disease: is osteoporosis the obesity of bone? Nat Clin Pract Rheumatol. January 2006;2(1):35-43.
2005	Tommasini SM, Morgan TG, van der Meulen MCH, Jepsen KJ. Genetic variation in structure‐function relationships for the inbred mouse lumbar vertebral body. J Bone Miner Res. May 2005;20(5):817-827.
1993	Balena R, Toolan BC, Shea M, Markatos A, Myers ER, Lee SC, Opas EE, Seedor JG, Klein H, Frankenfield D, Quartuccio H, Fioravanti C, Clair J, Brown E, Hayes WC, Rodan GA. The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates. J Clin Invest. December 1993;92(6):2577-2586.
1987	Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR. Bone histomorphometry: standardization of nomenclature, symbols, and units: report of the ASBMR histomorphometry nomenclature committee. J Bone Miner Res. December 1987;2(6):595-610.
1993	Turner CH, Burr DB. Basic biomechanical measurements of bone: a tutorial. Bone. 1993;14(4):595-608.
2001	Boskey AL. Bone mineralization. In: Cowin SC, ed. Bone Mechanics Handbook. 2nd ed. Boca Raton, FL: CRC Press; 2001:5-1–5-33.
2007	Buckley JM, Loo K, Motherway J. Comparison of quantitative computed tomography-based measures in predicting vertebral compressive strength. Bone. March 2007;40(3):767-774.
1995	Oxlund H, Barckman M, Ørtoft G, Andreassen TT. Reduced concentrations of collagen cross-links are associated with reduced strength of bone. Bone. October 1995;17(4)(suppl):S365-S371.
1987	Turner RT, Vandersteenhoven JJ, Bell NH. The effects of ovariectomy and 17β-estradiol on cortical bone histomorphometry in growing rats. J Bone Miner Res. 1987;2(2):115-122.
1993	Crolet JM, Aoubiza B, Meunier A. Compact bone: numerical simulation of mechanical characteristics. J Biomech. June 1993;26(6):677-687.
2006	Viguet-Carrin S, Garnero P, Delmas PD. The role of collagen in bone strength. Osteoporos Int. March 2006;17(3):319-336.
2001	Jee WSS, Yao W. Overview: animal models of osteopenia and osteoporosis. J Musculoskel Neuron Interact. March 2001;1(3):193-207.
2001	Jee WSS. Integrated bone tissue physiology: anatomy and physiology. In: Cowin SC, ed. Bone Mechanics Handbook. 2nd ed. Boca Raton, FL: CRC Press; 2001:1-1–1-68.
2002	Seeman E. Pathogenesis of bone fragility in women and men. Lancet. May 25, 2002;359(9320):1841-1850.
2005	Felsenberg D, Boonen S. The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management. Clin Ther. January 2005;27(1):1-11.
2002	Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet. June 1, 2002;359(9321):1929-1936.
2001	Vashishth D, Gibson GJ, Khoury JI, Schaffler MB, Kimura J, Fyhrie DP. Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone. February 2001;28(2):195-201.
2001	Cowin SC. Mechanics of materials. In: Cowin SC, ed. Bone Mechanics Handbook. 2nd ed. Boca Raton, FL: CRC Press; 2001:6-1–6-24.
1997	McCalden RW, McGeough JA, Court-Brown CM. Age-related changes in the compressive strength of cancellous bone: the relative importance of changes in density and trabecular architecture. J Bone Joint Surg. March 1997;79A(3):421-427.
2002	Riggs BL, Melton LJ III. Bone turnover matters: the raloxifene treatment paradox of dramatic decreases in vertebral fractures without commensurate increases in bone density. J Bone Miner Res. January 2002;17(1):11-14.
1984	Pelker RR, Friedlaender GE, Markham TC, Panjabi MM, Moen CJ. Effects of freezing and freeze‐drying on the biomechanical properties of rat bone. J Orthop Res. 1984;1(4):405-411.
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.
2000	Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. April 2000;21(2):115-137.
1998	Rho J-Y, Kuhn-Spearing L, Zioupos P. Mechanical properties and the hierarchical structure of bone. Med Eng Phys. 1998;20(2):92-102.

Year

Entry

1995

Borchers RE, Gibson LJ, Burchardt H, Hayes WC. Effects of selected thermal variables on the mechanical properties of trabecular bone. Biomaterials. May 1995;16(7):545-551.

2000

Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. January 21, 2000;100(2):197-207.

2000

Wang X, Bank RA, TeKoppele JM, Hubbard GB, Althanasiou KA, Agrawal CM. Effect of collagen denaturation on the toughness of bone. Clin Orthop Relat Res. February 2000;371:228-239.

2002

Thomsen JS, Ebbesen EN, Mosekilde L. Predicting human vertebral bone strength by vertebral static histomorphometry. Bone. March 2002;30(3):502-508.

1998

Riggs BL, Khosla S, Melton LJ III. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res. May 1998;13(5):763-773.