Femoral insufficiency fractures associated with prolonged bisphosphonate therapy.
BACKGROUND
Emerging evidence has linked the long-term use of bisphosphonates with femoral insufficiency fractures. It has been suggested that the prolonged effect on bone remodeling leads to the accumulation of microfractures and weakening of bone.


OBJECTIVE
We investigated the association between bisphosphonate use and femoral insufficiency fractures.


METHODS
We evaluated 100 patients with low-energy femoral shaft fractures before and after bisphosphonates became available for use. Twenty-one consecutive patients who presented between January 1995 and February 1997 were compared with 79 consecutive patients who presented between January 2007 and February 2009. The radiographs of all 100 patients were examined for evidence of preexisting insufficiency fractures. We identified insufficiency fractures by a transverse fracture line on the tension side of the femur with lateral cortical thickening immediately adjacent to the fracture. Relevant details from the history were recorded.


RESULTS
Forty-one patients had an underlying femoral insufficiency fracture, all of whom had been receiving bisphosphonate therapy. Among the 21 patients with low-energy femoral fractures before the availability of bisphosphonates, none had insufficiency fractures. Of the 41 patients with insufficiency fractures, 29 (71%) had prodromal pain and 18 (44%) had bilateral insufficiency fractures. Bisphosphonate use was associated (odds ratio greater than 1000) with insufficiency fracture. The mean duration of bisphosphonate use in patients with insufficiency fractures was longer than in patients without fractures (7.1 versus 3.2 years).


CONCLUSIONS
Long-term bisphosphonate use is associated with insufficiency fractures of the femoral shaft, which commonly present with prodromal thigh pain and may be bilateral. These fractures were not seen before bisphosphonates became available for use.
Isaacs
Joseph D
JD
The St George and Sutherland Hospital Orthopaedic Departments, Sydney, NSW, Australia. eyezaks@yahoo.com.au
Shidiak
Louis
L
Harris
Ian A
IA
Szomor
Zoltan L
ZL
D000368:Aged; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects*; D016723:Bone Remodeling / Q000187:drug effects*; D016009:Chi-Square Distribution; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D004334:Drug Administration Schedule; D005260:Female; D005264:Femoral Fractures / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000503:physiopathology; D015775:Fractures, Stress / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000503:physiopathology; D006801:Humans; D008297:Male; D009517:New South Wales; D016017:Odds Ratio; D010146:Pain / Q000139:chemically induced; D011859:Radiography; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
D050071:Bone Density Conservation Agents; D004164:Diphosphonates
Bone. 2001 May;28(5):524-31
11344052
J Bone Miner Res. 2003 Jun;18(6):1012-9
12817753
Osteoporos Int. 1993;3 Suppl 3:S29-39
8298200
Osteoporos Int. 2009 Aug;20(8):1353-62
19066707
JAMA. 1998 Dec 23-30;280(24):2077-82
9875874
Osteoporos Int. 2010 Apr;21(4):701-3
19562241
Bone. 2000 Jul;27(1):13-20
10865204
N Engl J Med. 2003 Jul 31;349(5):457-63
12890844
J Bone Miner Res. 1994 Nov;9(11):1833-7
7863833
J Clin Endocrinol Metab. 2000 Sep;85(9):3109-15
10999794
N Engl J Med. 2008 Mar 20;358(12):1304-6
18354114
Connect Tissue Res. 2002;43(2-3):535-7
12489211
J Clin Endocrinol Metab. 2005 Mar;90(3):1897-9
15758064
Expert Opin Drug Metab Toxicol. 2008 Nov;4(11):1371-8
18950279
J Bone Joint Surg Br. 2007 Mar;89(3):349-53
17356148
J Clin Endocrinol Metab. 2005 Mar;90(3):1294-301
15598694
Bone. 2000 Nov;27(5):687-94
11062357
J Bone Miner Res. 2003 Mar;18(3):512-20
12619936
Geriatrics. 2006 Jan;61(1):31-3
16405362
Acta Orthop. 2008 Aug;79(4):459-60
18766476
N Engl J Med. 2000 Aug 31;343(9):604-10
10979796
Ann Intern Med. 1995 Sep 15;123(6):401-8
7639438
Osteoporos Int. 2009 Jun;20(6):1023-6
19340504
Acta Orthop. 2008 Aug;79(4):565-7
18766492
N Engl J Med. 2001 Feb 1;344(5):333-40
11172164
J Clin Endocrinol Metab. 1994 Dec;79(6):1693-700
7989477
N Engl J Med. 2004 Mar 18;350(12):1189-99
15028823
J Clin Endocrinol Metab. 2000 Nov;85(11):4118-24
11095442
Rheumatol Int. 2011 Jul;31(7):973-5
20383511
Osteoporos Int. 2009 Jun;20(6):887-94
18850239
J Bone Miner Res. 2000 Apr;15(4):613-20
10780852
Osteoporos Int. 2008 Nov;19(11):1613-20
18483689
Calcif Tissue Int. 2001 Nov;69(5):281-6
11768198
J Bone Miner Res. 2007 Nov;22(11):1759-65
17663638
N Engl J Med. 1995 Nov 30;333(22):1437-43
7477143
J Clin Endocrinol Metab. 2008 Aug;93(8):2948-52
18522980
JAMA. 2006 Dec 27;296(24):2927-38
17190893
Philos Trans R Soc Lond B Biol Sci. 1984 Feb 13;304(1121):509-18
6142490
J Bone Miner Res. 2009 Dec;24(12):1998-2006
19453263
Osteoporos Int. 2010 Apr;21(4):705-8
19669853
Orthopedics. 2010 Jul;33(7):468
20608597
Geriatrics. 2009 Jan;64(1):18-23
19256578
J Orthop Trauma. 2010 Feb;24(2):75-81
20101130
Osteoporos Int. 2005 May;16(5):468-74
15448985
J Pediatr Endocrinol Metab. 2006 Apr;19(4):523-8
16759038
J Orthop Trauma. 2008 May-Jun;22(5):346-50
18448990
Injury. 2008 Feb;39(2):224-31
18222447
J Bone Joint Surg Am. 2009 Nov;91(11):2556-61
19884427
N Engl J Med. 1990 Jul 12;323(2):73-9
2113611
Endocr Rev. 2007 Apr;28(2):151-64
17200084
Am J Med. 1997 Oct;103(4):291-7
9382121
Bone. 2010 Aug;47(2):235-40
20580684
Arch Intern Med. 2000 Feb 28;160(4):517-25
10695692
Lancet. 1996 Dec 7;348(9041):1535-41
8950879
J Bone Miner Res. 2004 Aug;19(8):1259-69
15231012
J Bone Miner Res. 2004 Jun;19(6):999-1005
15125797
Curr Med Res Opin. 2006 May;22(5):919-28
16709313
Bone. 2001 Aug;29(2):185-91
11502482
Clin Orthop Relat Res. 2009 Jul;467(7):1921-6
19198962
Am J Gastroenterol. 2002 Jan;97(1):58-64
11808969
Connect Tissue Res. 2009;50(1):46-54
19212852
Bone. 2006 Oct;39(4):872-9
16765660
Bone. 2003 Mar;32(3):311-5
12667559
Ann Intern Med. 1992 Jul 1;117(1):1-9
1534476
Osteoporos Int. 1999;9(5):461-8
10550467
Orthopedics. 2010 Apr;33(4):
20415309
J Bone Miner Res. 1998 Apr;13(4):581-9
9556058
Osteoporos Int. 2010 Feb;21(2):195-214
19760059