Bisphosponate Fractures: Elusive but Dangerous

Krista Weiss, 2014 Gillian Lieberman, MD October 25, 2013 Bisphosponate Fractures: Elusive but Dangerous Krista Weiss, Tufts Medical School Year IV Gillian Lieberman, MD

Presentation Outline Our Patient: Clinical Presentation, Radiographs, and Diagnosis Bisphosphonate Fractures: Overview, Clinical Effects, Radiographic Findings Companion Patients Bisphosphonate Fractures: Treatment Summary 2

Presentation Outline Our Patient: Clinical Presentation, Radiographs, and Diagnosis Bisphosphonate Fractures: Overview, Clinical Effects, Radiographic Findings Companion Patients Bisphosphonate Fractures: Treatment Summary 3

Our Patient: Clinical Presentation History: 67 Asian female p/w acute left thigh pain s/p mechanical fall. Further endorses 2 mos of thigh discomfort. PMHx: HTN, HLD, osteoporosis, osteoarthritis Medications: Lisinopril, Simvastatin, Alendronate SHx: Lives in greater Boston area, works as secretary http://solomonsseal.files.wordpress.com/2011/04/legbruise.jpg 2

Now that we have reviewed the patient s history, let s consider the differential diagnosis of acute thigh pain 5

DDx: Acute Thigh Pain Fracture 2/2 osteoporosis, Vit D def, trauma, etc Ligament sprain, muscle strain DVT, thrombophlebitis Claudication Sciatica, neuropathic pain Infection abscess, osteomyelitis http://www.zcoil.com/wp-content/uploads/2013/07/leg-pain.jpg 6

In order to narrow the differential diagnosis, plain films were obtained. Let s first review the patient s previous plain films from 2 months prior to establish a comparison 7

Our Patient: Plain Film Findings Unlabeled Two months prior to acute thigh pain, pt had hip plain films for nagging leg pain Pause to review the film. Continue to view the finding Courtesy of Robert Ward, MD, Tufts Medical Center 8

Our Patient: Previous Plain Film Incomplete Atypical Fracture Two months prior to acute thigh pain, pt had hip plain films for nagging hip pain Finding: incomplete atypical fracture patient lost health insurance and was lost to follow up Courtesy of Robert Ward, MD, Tufts Medical Center 9

Now that we have reviewed the previous comparison film, let s review the current plain films 10

Our Patient: Current Plain Film Incomplete Atypical Fracture Today s film shows marked interval change Impression: acute left subtrochanteric fracture BIDMC PACS 11

Our Patient: Biopsy & Diagnosis Patient underwent surgical fixation of fracture with biopsy of fracture site Pathology: depressed bone formation, absence of double-tetracycline labeling Double-tetracycline labeling is used to assess bone growth if absent, bone growth is also absent or poor Diagnosis: Bisphosphonate fracture 12

Presentation Outline Our Patient: Clinical Presentation, Radiographs, and Diagnosis Bisphosphonate Fractures: Overview, Clinical Effects, Radiographic Findings Companion Patients Bisphosphonate Fractures: Treatment Summary 13

Bisphosphonates: MOA Examples: alendronate, zoledronic acid, pamidronate, risedronate, ibandronate MOA: Bisphosphonates (alendronate, zoledronic acid, pamidronate, risedronate, ibandronate) INHIBITED farnesyl pyrophosphate synthetase (cholesterol synthesis enzyme) Osteoclast apoptosis Bone turnover SUPPRESSED suppression of bone turnover increased bone mass w/ maintenance of microarchitecture improved structural biomechanical properties (Saleh et al 2013) 14

Bisphosphonates: Clinical Effects Clinical Effect: decrease vertebral & non-vertebral fractures w/ use < 5yrs however, recent controversy about possible increase in atypical fractures (Lo et al 2012) Typical High-energy trauma Comminuted Spiral configuration Atypical Low-energy trauma Non-comminuted Transverse or short oblique fx pattern 15

16 Atypical Femoral Fractures: Major & Minor Features From Saleh A, Hegde VV, Potty AG, Lane JM. Bisphosphonate therapy and atypical fractures. Orthop Clin N Am 2013;44:137-151.

Bisphosphonate Fractures: Clinical Presentation & Epidemiology Clinical Presentation: prodromal thigh pain acute thigh pain Epidemiology: Recent studies estimate rates of atypical femoral fractures at ~4-5 per 100,000 person-yrs & at ~55 per 100,000 person-yrs among pts taking bisphosphonates (Saleh et al 2013) Etiology: Bisphosphonates (alendronate, zoledronic acid, pamidronate, risedronate, ibandronate) INHIBITED farnesyl pyrophosphate synthetase (cholesterol synthesis enzyme) Osteoclast apoptosis Bone turnover SUPPRESSED Altered microdamage physiology, mineralization, & collagen cross-linking bone errors unable to be corrected 17

Now that we have reviewed the effects of bisphosphonate medications on bone formation, let s reexamine our patient s plain films 18

Bisphosphonate Fractures: Plain Film Findings (Unlabeled) Pause to review film. Continue to view findings. BIDMC PACS 19

Bisphosphonate Fractures: Plain Film Findings (part 1) Plain Film/CT: periosteal stress rxn simple transverse or oblique, noncomminuted fracture Callus rxn localized lateral cortical hypertrophy Medial spike Fracture angle 75-105 (Schilcher et al 2012) BIDMC PACS 20

Bisphosphonate Fractures: Plain Film Findings (part 2) Plain Film/CT: periosteal stress rxn simple transverse or oblique, noncomminuted fracture Callus rxn localized lateral cortical hypertrophy Medial spike Fracture angle 75-105 (Schilcher et al 2012) BIDMC PACS 21

Bisphosphonate Fractures: Findings on Other Modalities CT: black fracture line MRI: lateral cortical thickening or irregularity localized bone marrow edema visible fracture line Bone scan: focal lateral cortical increased activity Ward et al 2012 22

Presentation Outline Our Patient: Clinical Presentation, Radiographs, and Diagnosis Bisphosphonate Fractures: Overview, Clinical Effects, Radiographic Findings Companion Patients Bisphosphonate Fractures: Treatment Summary 23

Now that we have reviewed the key radiologic findings of bisphosphonate fractures, let s continue to view these findings in companion patients 24

Companion Pt #1: Plain Film Findings Incomplete Fx Radiolucent fx line Atypical fx w/ periosteal rxn From Saleh A, Hegde VV, Potty AG, Lane JM. Bisphosphonate therapy and atypical fractures. Orthop Clin N Am 2013;44:137-151. 25

Companion Pt #1: MRI Findings Incomplete Fx Coronal MRI T1 Coronal MRI T2 Fx line extending through cortex Bone marrow edema From Saleh A, Hegde VV, Potty AG, Lane JM. Bisphosphonate therapy and atypical fractures. Orthop Clin N Am 2013;44:137-151. 26

Companion Pt #1: Plain Film Findings Complete Fx Callus rxn localized lateral cortical hypertrophy Generalized cortical thickening Fracture angle From Saleh A, Hegde VV, Potty AG, Lane JM. Bisphosphonate therapy and atypical fractures. Orthop Clin N Am 2013;44:137-151. 27

Companion Pt #2: Plain Film Bilateral Hips Spontaneous subtrochanteric fx of left femur, s/p intramedullary fixation From Ing-Lorenzini K, Desmeules J, Plachta O, Suva D, Dayer P, Peter R. Low-energy femoral fractures associated with the long-term use of bisphosphonates. Drug Safety 2009;32(9):775-785. 28

Companion Pt #2: Plain Film Right Femur Subsequent pain in right thigh PPx intramedullary nailing & biopsy of cortex (see arrow) fx filled w/ blood, no cellular rxn or osteoclastic activity From Ing-Lorenzini K, Desmeules J, Plachta O, Suva D, Dayer P, Peter R. Low-energy femoral fractures associated with the longterm use of bisphosphonates. Drug Safety 2009;32(9):775-785. 29

Presentation Outline Our Patient: Clinical Presentation, Radiographs, and Diagnosis Bisphosphonate Fractures: Overview, Clinical Effects, Radiographic Findings Companion Patients Bisphosphonate Fractures: Treatment Summary 30

Bisphosphonate Fractures: Treatment If fracture has not yet occurred, discontinue bisphosphonates & pin femur prophylactically If fracture has occurred (our patient): Stabilize fracture may need surgical management Discontinue bisphosphonates to avoid delayed bone remodeling Ca & Vit D supplementation Teriparatide (recombinant PTH): improves bone turnover & microarchitecture, enhances fx healing Assess contralateral femur (Saleh et al 2013) http://www.rob.cs.tu-bs.de/content/03- research/01-projects/61- femur/sketch_nailing.png 31

Our Patient: Follow Up Our patient went to the operating room for internal fixation of her left femoral fracture Further, her Alendronate was discontinued and she was prescribed Ca, Vit. D & Teriparatide Importantly, her right femur was closely examined on x-ray for signs of contralateral impending fracture! 32

Presentation Outline Our Patient: Clinical Presentation, Radiographs, and Diagnosis Bisphosphonate Fractures: Overview, Clinical Effects, Radiographic Findings Companion Patients Bisphosphonate Fractures: Treatment Summary 33

Summary Bisphosphonates are associated with atypical femur fractures Highly specific radiographic features can identify at-risk pts before complete atypical fractures occur Monitor patients on bisphosphonates for symptoms of chronic thigh pain or subtle abnormalities on plain film or other imaging Future studies may help to elucidate further prevention of femoral fractures and their associated morbidity and mortality www.archwired.com 34

Acknowledgments Dr. Robert Ward Dr. Jim Wu Dr. Gillian Lieberman Claire Odom Dr. Omer Awan Dr. Justin Kung 35

References Grissom LE, Harcke HT. Radiographic features of bisphosphonate therapy in pediatric patients. Pediatric Radiol 2003;33:226-229. Ing-Lorenzini K, Desmeules J, Plachta O, Suva D, Dayer P, Peter R. Low-energy femoral fractures associated with the long-term use of bisphosphonates. Drug Safety 2009;32(9):775-785. Lo JC, Huang SY, Lee GA, Khandewal S, Provus J, Ettinger B, Gonzalez JR, Hui RL, Grimsrud CD. Clinical correlates of atypical femoral fracture. Bone 2012;51:181-184. Saleh A, Hegde VV, Potty AG, Lane JM. Bisphosphonate therapy and atypical fractures. Orthop Clin N Am 2013;44:137-151. Schilcher J, Koeppen V, Ranstan J, Skripitz R, Michaelson K, Aspenburg P. Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls. Bone 2013;52:389-392. Ward WG, Carter CJ, Wilson SC, Emory CL. Femoral stress fractures associated with long-term bisphosphonate treatment. Clin Orthop Relat Res 2012;470:759-765. 36