title: Bisphosphonate treatment of type I diabetic mice prevents early bone loss but accentuates suppression of bone formation.
abstract: Type I (T1) diabetes is an autoimmune and metabolic disease associated with bone loss. Previous studies demonstrate that T1-diabetes decreases osteoblast activity and viability. Bisphosphonate therapy, commonly used to treat osteoporosis, is demonstrated to inhibit osteoclast activity as well as osteoblast apoptosis. Therefore, we examined the effect of weekly alendronate treatments on T1-diabetes induced osteoblast apoptosis and bone loss. Bone TUNEL assays identified that alendronate therapy prevents the diabetes-induced osteoblast death observed during early stages of diabetes development. Consistent with this, alendronate treatment for 40 days was able to prevent diabetes-induced trabecular bone loss. Alendronate was also able to reduce marrow adiposity in both control diabetic mice compared to untreated mice. Mechanical testing indicated that 40 days of alendronate treatment increased bone stiffness but decreased the work required for fracture in T1-diabetic and alendronate treated mice. Of concern at this later time point, bone formation rate and osteoblast markers, which were already decreased in diabetic mice, were further suppressed in alendronate-treated diabetic mice. Taken together, our results suggest that short-term alendronate treatment can prevent T1-diabetes-induced bone loss in mice, possibly in part by inhibiting diabetes onset associated osteoblast death, while longer treatment enhanced bone density but at the cost of further suppressing bone formation in diabetic mice.
authors: Department of Physiology, Biomedical Imaging Research Center, Michigan State University, East Lansing, Michigan.
authors: Lindsay M
authors: LM
authors: Coe
authors: Srinivasan Arjun
authors: SA
authors: Tekalur
authors: Yutian
authors: Y
authors: Shu
authors: Melissa J
authors: MJ
authors: Baumann
authors: Laura R
authors: LR
authors: McCabe
mesh_terms: D019386:Alendronate / Q000633:toxicity*; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000633:toxicity*; D001862:Bone Resorption; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D004164:Diphosphonates / Q000633:toxicity; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D055114:X-Ray Microtomography
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D019386:Alendronate
references: J Diabetes Complications. 2012 Jan-Feb;26(1):1-9
references: 22257906
references: J Cell Biochem. 2007 Dec 15;102(6):1343-57
references: 17975793
references: Acta Histochem. 2013 Sep;115(7):649-57
references: 23465485
references: J Bone Miner Res. 2010 Jul;25(7):1604-15
references: 20200974
references: J Biomech. 2005 Mar;38(3):467-75
references: 15652544
references: Bone. 1996 Feb;18(2):141-50
references: 8833208
references: J Bone Miner Res. 2008 Nov;23(11):1815-24
references: 18597625
references: Endocrinology. 2005 Aug;146(8):3622-31
references: 15905321
references: Endocrinology. 1988 Jul;123(1):290-5
references: 3133194
references: Ann N Y Acad Sci. 2009 Sep;1173 Suppl 1:E64-7
references: 19751417
references: Osteoporos Int. 2011 May;22(5):1547-53
references: 20661545
references: N Engl J Med. 1998 Jul 30;339(5):292-9
references: 9682041
references: FEBS Lett. 2010 Jul 16;584(14):3095-100
references: 20621835
references: Bone. 1998 Aug;23(2):155-61
references: 9701475
references: Diabetologia. 1999 Aug;42(8):920-5
references: 10491750
references: Histochem Cell Biol. 2007 Aug;128(2):125-33
references: 17609971
references: Diabetes Metab Res Rev. 2004 Nov-Dec;20 Suppl 2:S1-8
references: 15551299
references: J Cell Physiol. 2009 Mar;218(3):575-83
references: 19006181
references: Can J Physiol Pharmacol. 2007 Jan;85(1):113-32
references: 17487251
references: N Engl J Med. 1995 Nov 30;333(22):1437-43
references: 7477143
references: J Cell Physiol. 2013 Apr;228(4):689-95
references: 22886636
references: N Engl J Med. 2000 Aug 31;343(9):604-10
references: 10979796
references: Endocrinology. 2004 Jan;145(1):447-52
references: 14525917
references: JAMA. 1999 Oct 13;282(14):1344-52
references: 10527181
references: Calcif Tissue Int. 1997 May;60(5):397-400
references: 9115153
references: J Cell Physiol. 2009 Feb;218(2):376-84
references: 18932203
references: Am J Physiol Gastrointest Liver Physiol. 2009 May;296(5):G1020-9
references: 19299577
references: Diabetes Care. 2005 Dec;28(12):2850-5
references: 16306544
references: Am J Health Syst Pharm. 2004 Jan 15;61(2):160-73; quiz 175-6
references: 14750401
references: J Clin Invest. 1989 Jun;83(6):1930-5
references: 2524504
references: J Clin Invest. 1999 Nov;104(10):1363-74
references: 10562298
references: Biochem Biophys Res Commun. 1999 Aug 2;261(2):456-8
references: 10425206
references: Matrix Biol. 2008 Sep;27(7):609-18
references: 18619537
references: Ann Intern Med. 1998 Feb 15;128(4):253-61
references: 9471927
references: J Physiol Pharmacol. 1999 Jun;50(2):155-67
references: 10424714
references: Adv Ther. 2007 Nov-Dec;24(6):1314-20
references: 18165214
references: Diabetes Metab. 2006 Nov;32(5 Pt 1):453-8
references: 17110900
references: JAAPA. 2006 Dec;19(12):25-30
references: 17243258
references: N Engl J Med. 1998 Feb 19;338(8):485-92
references: 9443925
references: Endocrinol Metab Clin North Am. 2003 Mar;32(1):253-71
references: 12699302
references: Am J Med Sci. 2010 Jun;339(6):519-24
references: 20400887
references: Diabetes Res Clin Pract. 1998 May;40(2):75-9
references: 9681272
references: Diabet Med. 2009 Jan;26(1):45-52
references: 19125760
references: Exp Gerontol. 2009 Nov;44(11):708-17
references: 19706321
references: Curr Opin Rheumatol. 1996 Jul;8(4):384-91
references: 8864593
references: Bone. 1993 Mar-Apr;14(2):137-41
references: 8334031
references: J Clin Endocrinol Metab. 2001 Jan;86(1):32-8
references: 11231974
references: Eur J Pharmacol. 2008 Dec 14;600(1-3):140-7
references: 18973752
references: Bone. 1999 Jul;25(1):97-106
references: 10423031
references: Calcif Tissue Int. 1996 May;58(5):316-9
references: 8661964
references: J Clin Invest. 1993 May;91(5):2004-11
references: 8486770
references: Diabetes. 2005 Nov;54(11):3274-81
references: 16249455
references: Diabetes. 2006 Jan;55(1):225-33
references: 16380497
references: Curr Osteoporos Rep. 2003 Dec;1(3):116-22
references: 16036074
references: Am J Epidemiol. 1993 Jun 1;137(11):1203-11
references: 8322761
references: J Bone Miner Res. 2011 May;26(5):993-1001
references: 21542002
references: J Cell Physiol. 2006 Dec;209(3):967-76
references: 16972249
references: Endocrinology. 2007 Jan;148(1):198-205
references: 17053023
references: Curr Osteoporos Rep. 2014 Jun;12(2):181-8
references: 24623537
references: J Bone Miner Res. 2007 Dec;22(12):1924-32
references: 17708715
references: Bone. 1998 May;22(5):455-61
references: 9600778
references: J Cell Physiol. 2012 Apr;227(4):1326-34
references: 21604269
references: Calcif Tissue Int. 2009 Sep;85(3):247-56
references: 19641838
references: Crit Rev Eukaryot Gene Expr. 2011;21(2):187-206
references: 22077156
references: J Clin Endocrinol Metab. 2007 Mar;92(3):1172-5
references: 17179196
references: Cancer Res. 2000 Nov 1;60(21):6001-7
references: 11085520
references: Bone. 1997 Aug;21(2):147-53
references: 9267690
references: J Cell Physiol. 2011 Feb;226(2):477-83
references: 20677222
references: J Clin Endocrinol Metab. 1995 Apr;80(4):1194-202
references: 7714089
references: J Endocrinol Invest. 2000 May;23(5):295-303
references: 10882147
references: Am J Pathol. 2009 Oct;175(4):1574-85
references: 19745063
references: Br Med Bull. 2008;86:129-43
references: 18477578
references: Diabetes Care. 2004 Jul;27(7):1547-53
references: 15220226
references: Br J Obstet Gynaecol. 1996 May;103 Suppl 13:2-7; discussion 7-8
references: 8624337
references: Biol Proced Online. 2009 Mar 06;11:296-315
references: 19495918
references: Bone. 2006 Sep;39(3):443-52
references: 16627025
references: N Engl J Med. 2010 May 13;362(19):1761-71
references: 20335571
references: J Clin Invest. 1991 Dec;88(6):2095-105
references: 1661297