Bisphosphonates: mechanism of action and role in clinical practice.
Bisphosphonates are primary agents in the current pharmacological arsenal against osteoclast-mediated bone loss due to osteoporosis, Paget disease of bone, malignancies metastatic to bone, multiple myeloma, and hypercalcemia of malignancy. In addition to currently approved uses, bisphosphonates are commonly prescribed for prevention and treatment of a variety of other skeletal conditions, such as low bone density and osteogenesis imperfecta. However, the recent recognition that bisphosphonate use is associated with pathologic conditions including osteonecrosis of the jaw has sharpened the level of scrutiny of the current widespread use of bisphosphonate therapy. Using the key words bisphosphonate and clinical practice in a PubMed literature search from January 1, 1998, to May 1, 2008, we review current understanding of the mechanisms by which bisphosphonates exert their effects on osteoclasts, discuss the role of bisphosphonates in clinical practice, and highlight some areas of concern associated with bisphosphonate use.
Drake
Matthew T
MT
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN 55905, USA. drake.matthew@mayo.edu
Clarke
Bart L
BL
Khosla
Suneep
S
D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001862:Bone Resorption / Q000188:drug therapy; D001842:Bone and Bones / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy; D010001:Osteitis Deformans / Q000188:drug therapy*; D010010:Osteoclasts / Q000187:drug effects*; D010024:Osteoporosis / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy
D050071:Bone Density Conservation Agents; D004164:Diphosphonates
N Engl J Med. 2001 Sep 27;345(13):948-55
11575286
J Am Geriatr Soc. 2007 May;55(5):752-7
17493196
Clin Ther. 2006 Feb;28(2):236-42
16678644
J Natl Cancer Inst. 2002 Oct 2;94(19):1458-68
12359855
J Urol. 2003 Jun;169(6):2008-12
12771706
J Clin Endocrinol Metab. 2000 Jun;85(6):2129-34
10852440
J Am Soc Nephrol. 2003 Oct;14(10):2669-76
14514747
J Clin Endocrinol Metab. 2007 Apr;92(4):1385-90
17227802
N Engl J Med. 2001 May 10;344(19):1434-41
11346808
Bone. 2007 Jul;41(1):122-8
17468062
J Clin Endocrinol Metab. 2005 Mar;90(3):1294-301
15598694
N Engl J Med. 2003 Sep 25;349(13):1216-26
14500805
Clin Endocrinol (Oxf). 2002 May;56(5):565-9
12030903
Br J Cancer. 2000 Feb;82(4):858-64
10732759
Bone. 2000 Nov;27(5):687-94
11062357
Clin Exp Immunol. 2005 Jan;139(1):101-11
15606619
J Clin Oncol. 2006 Oct 20;24(30):4895-900
17001071
N Engl J Med. 2007 Aug 16;357(7):712-3; author reply 714-5
17703529
N Engl J Med. 2000 Aug 31;343(9):604-10
10979796
J Clin Oncol. 1998 Jun;16(6):2038-44
9626201
N Engl J Med. 2007 May 3;356(18):1809-22
17476007
Blood. 2006 Dec 1;108(12):3951-2
17114572
J Clin Oncol. 2007 Mar 20;25(9):1038-42
17369566
J Bone Miner Res. 2004 Aug;19(8):1241-9
15231010
N Engl J Med. 2001 Feb 1;344(5):333-40
11172164
J Bone Miner Res. 2007 Oct;22(10):1502-9
17824840
J Oral Maxillofac Surg. 2003 Sep;61(9):1115-7
12966493
N Engl J Med. 2004 Mar 18;350(12):1189-99
15028823
Arch Phys Med Rehabil. 1999 Mar;80(3):243-51
10084430
J Bone Miner Res. 2006 Jan;21(1):132-40
16355282
N Engl J Med. 2007 Mar 8;356(10):1075-6
17347467
J Clin Invest. 1999 Nov;104(10):1363-74
10562298
N Engl J Med. 2007 Nov 15;357(20):2028-39
18003959
Endocr Pract. 2006 Jan-Feb;12(1):48-53
16524863
N Engl J Med. 2003 Oct 23;349(17):1676-9; discussion 1676-9
14573746
J Oral Maxillofac Surg. 2005 Nov;63(11):1567-75
16243172
JAMA. 2002 Jul 17;288(3):321-33
12117397
N Engl J Med. 2006 Nov 9;355(19):2048-50
17093260
N Engl J Med. 2002 Feb 28;346(9):653-61
11870242
Mayo Clin Proc. 2006 Aug;81(8):1013-22
16901023
Nature. 1966 Nov 26;212(5065):901-3
4306793
J Bone Miner Res. 2001 Nov;16(11):2126-31
11697810
Mayo Clin Proc. 2007 Apr;82(4):516-7; author reply 517-8
17418085
J Clin Invest. 2002 Nov;110(9):1293-9
12417568
Ann N Y Acad Sci. 2006 Apr;1068:367-401
16831938
J Bone Miner Res. 1998 Jun;13(6):1032-8
9626635
Pediatrics. 2007 Mar;119 Suppl 2:S163-5
17332237
Osteoporos Int. 2004 Dec;15(12):992-7
15175844
N Engl J Med. 2003 Sep 25;349(13):1207-15
14500804
Rheumatology (Oxford). 2007 Mar;46(3):460-6
16899499
N Engl J Med. 1995 Nov 30;333(22):1437-43
7477143
Cancer. 2000 Mar 1;88(5):1082-90
10699899
J Bone Miner Res. 2007 Oct;22(10):1479-91
17663640
N Engl J Med. 2006 Aug 10;355(6):593-600
16899779
Osteoporos Int. 2003 Dec;14(12):965-8
14504697
JAMA. 2006 Dec 27;296(24):2927-38
17190893
J Clin Endocrinol Metab. 2005 Feb;90(2):627-34
15546907
J Bone Miner Res. 1997 Oct;12(10):1700-7
9333131
Haematologica. 2006 Jul;91(7):968-71
16757414
Osteoporos Int. 2006;17(11):1638-44
16896510
N Engl J Med. 2006 Nov 30;355(22):2278-81
17135582
J Pediatr Orthop B. 2003 Mar;12(2):77-87
12584489
JAMA. 1999 Oct 13;282(14):1344-52
10527181
N Engl J Med. 2005 Aug 11;353(6):555-65
16093464
Indian Pediatr. 2008 Feb;45(2):105-9
18310788
N Engl J Med. 2007 May 3;356(18):1895-6
17476024
J Pediatr Orthop. 2005 Sep-Oct;25(5):607-12
16199940
J Clin Endocrinol Metab. 1996 Mar;81(3):961-7
8772558
J Am Soc Nephrol. 2001 Jul;12(7):1530-1537
11423583
N Engl J Med. 2005 Sep 1;353(9):898-908
16135834
Clin Nephrol. 2004 Jan;61(1):63-7
14964460
Osteoporos Int. 2007 Jul;18(7):1009-15
17554581
Cancer J. 2001 Sep-Oct;7(5):377-87
11693896
N Engl J Med. 2006 Aug 17;355(7):675-84
16914703
Pain. 2004 Oct;111(3):306-312
15363874
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7829-34
16684881
N Engl J Med. 2007 Jul 19;357(3):266-81
17634462
Arch Intern Med. 2008 Apr 28;168(8):826-31
18443257
Calcif Tissue Int. 2002 Aug;71(2):103-11
12085156
Clin Pharmacokinet. 2005;44(6):551-70
15932344
Intern Med J. 2006 Sep;36(9):600-3
16911552
Int J Urol. 2007 Dec;14(12):1071-5
18036042
J Bone Miner Res. 2002 Jan;17(1):11-4
11771656
J Biol Chem. 2005 Feb 25;280(8):7317-25
15590626
Endocrine. 2001 Mar;14(2):159-64
11394632
Science. 1998 Jan 23;279(5350):509-14
9438836
Calcif Tissue Res. 1970;6(3):183-96
5500673
Osteoporos Int. 2004 Oct;15(10):792-8
15071723
Bone. 2008 Jan;42(1):36-42
17920005
J Bone Miner Res. 2004 Oct;19(10):1742-5
15355570
Br J Haematol. 2002 Nov;119(2):576-7
12406106
Bone. 1996 Feb;18(2):75-85
8833200
J Clin Endocrinol Metab. 2006 Aug;91(8):2882-7
16684825
N Engl J Med. 1996 Feb 22;334(8):488-93
8559201
N Engl J Med. 1996 Dec 12;335(24):1785-91
8965890
Cancer. 2001 Apr 1;91(7):1191-200
11283917
Mayo Clin Proc. 2006 Aug;81(8):1047-53
16901028
Ann Oncol. 2003 Sep;14(9):1399-405
12954579
Bone. 2007 Sep;41(3):346-52
17618847
Bone Marrow Transplant. 2008 Feb;41(4):393-8
17994116
J Clin Oncol. 2007 Mar 1;25(7):820-8
17159195
Osteoporos Int. 2001;12(2):112-6
11303710
Lancet. 1996 Dec 7;348(9041):1535-41
8950879
Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005324
17943849
BMJ. 2008 Apr 12;336(7648):813-6
18334527
J Pharmacol Exp Ther. 2001 Feb;296(2):235-42
11160603
J Clin Oncol. 2002 Aug 1;20(15):3219-24
12149294
Osteoporos Int. 2005 Dec;16(12):1989-98
16133643
Cancer. 2004 Jun 15;100(12):2613-21
15197804
NIH Consens Statement. 1994 Jun 6-8;12(4):1-31
7599655
JAMA. 1998 Dec 23-30;280(24):2077-82
9875874
N Engl J Med. 2007 Nov 1;357(18):1799-809
17878149
J Natl Cancer Inst. 2004 Jun 2;96(11):879-82
15173273
Arch Intern Med. 2005 Feb 14;165(3):346-7
15710802
J Bone Miner Res. 1994 Mar;9(3):303-4
8191921
J Bone Miner Res. 2001 Nov;16(11):2111-7
11697808
Osteoporos Int. 2003 Oct;14(10):801-7
14610641
Calcif Tissue Int. 1997 Oct;61(4):266-71
9312195
J Clin Oncol. 2002 Sep 1;20(17):3719-36
12202673
Arch Intern Med. 2007 Mar 26;167(6):591-6
17389291
Br J Cancer. 2004 Mar 22;90(6):1133-7
15026791
Cancer. 2003 Sep 1;98(5):962-9
12942563
Ann Intern Med. 2002 Dec 3;137(11):875-83
12458987
Curr Oncol. 2008 Jan;15(Suppl 1):S30-40
18231646
J Clin Endocrinol Metab. 2006 Oct;91(10):3835-43
16835281
J Bone Miner Res. 2002 Nov;17(11):1988-96
12412806
Bone. 2006 Oct;39(4):954-8
16769264
Ann Intern Med. 2006 May 16;144(10):753-61
16702591
J Bone Miner Res. 2005 Jul;20(7):1235-43
15940378
Leukemia. 2007 Jul;21(7):1545-8
17410188
Endocr Pract. 2007 Sep;13(5):513-20
17872354
Bone. 2003 Dec;33(6):960-9
14678856
Osteoporos Int. 2006;17(6):914-21
16538553
Am J Respir Crit Care Med. 2000 Sep;162(3 Pt 1):941-6
10988110
J Clin Oncol. 2005 Dec 1;23(34):8580-7
16314620
J Bone Miner Res. 1998 Apr;13(4):581-9
9556058
N Engl J Med. 1994 Dec 15;331(24):1618-23
7969342
N Engl J Med. 2005 Aug 11;353(6):566-75
16093465