Atypical Femoral FracturesAtypical Femoral FracturesInsights and EnigmasInsights and Enigmas
MadhuMadhu Mehta, M.D.Mehta, M.D.Clinical Asst. Prof. of MedicineClinical Asst. Prof. of Medicine
Department ofDepartment ofImmunology/RheumatologyImmunology/RheumatologyThe Ohio State UniversityThe Ohio State University
AbreviationsAbreviations usedused
TFFTFF-- Typical femoral fracturesTypical femoral fractures AFFAFF-- Atypical femoral fracturesAtypical femoral fractures BPOBPO-- BisphosphonateBisphosphonate PMOPMO-- Postmenopausal osteoporosisPostmenopausal osteoporosis FXFX-- FractureFracture BxBx-- BiopsyBiopsy HRHR-- Hazard RatioHazard Ratio
Need for discussionNeed for discussion Widespread use of BPO ,millions of patient years of Widespread use of BPO ,millions of patient years of
exposure over 4 decadesexposure over 4 decades Substantial reduction (30 Substantial reduction (30 –– 50 percent) in 50 percent) in ““ Typical Typical
osteoporotic fracturesosteoporotic fractures”” Long standing concern about diminished bone Long standing concern about diminished bone
turnover/diminished bone strength. turnover/diminished bone strength. ““frozen bone frozen bone conceptconcept””—— ONJ, ONJ, microcracksmicrocracks
Reports only since 2005 on Reports only since 2005 on ““ Atypical Femoral FXAtypical Femoral FX”” Is it a new entity or rare osteoporotic fracture, should we Is it a new entity or rare osteoporotic fracture, should we
be concerned?be concerned?
Sites of Femur fractureSites of Femur fracture
Fractures in PMOFractures in PMO--Differential featuresDifferential featuresTypical femoral fractureTypical femoral fracture Atypical femoral fractureAtypical femoral fracture
Associated with fallAssociated with fall-- 95 %95 % No fallNo fall
No No prodromeprodrome ProdromalProdromal thigh painthigh pain
Reduction( 30Reduction( 30--50% ) with effective BPO 50% ) with effective BPO therapytherapy
Often Often assosciatedassosciated with BPO/Steroid usewith BPO/Steroid use
Located at or above the Located at or above the trochantertrochanter --95 %, 95 %, Can be Can be communitedcommunited, 5% , 5% diaphysealdiaphyseal
Below the Below the intertrochantericintertrochanteric line,proxline,prox. . Shaft of the femur, nonShaft of the femur, non--comminutedcomminuted
Generally spiral, could be transverseGenerally spiral, could be transverse Transverse with a medial spikeTransverse with a medial spike
Generally unilateralGenerally unilateral U/L or B/LU/L or B/L
Increased femoral cortical thicknessIncreased femoral cortical thickness
Typical Typical intertrochantericintertrochantericfracturefracture
Typical Femoral neck fractureTypical Femoral neck fracture
Typical Typical CommunitedCommunited femoral shaft femoral shaft fracturefracture
Atypical B/L Transverse Femoral fracture with cortical hypertrophy
Atypical Transverse Femoral Atypical Transverse Femoral midshaftmidshaft fracturefracture
focal cortical thickening
diffuse periosteal new boneformation
AFFAFFDiagnosticDiagnostic ModalitiesModalities
Plain x‐ray Radionuclide scanning
MRI Dexa Scan
Body of evidence for AFFBody of evidence for AFF Small, not based on prospective Small, not based on prospective
randomized clinical trialsrandomized clinical trials HistomorphometricHistomorphometric datadata Retrospective Analysis from BPO Retrospective Analysis from BPO
clinical trialsclinical trials Analysis from register based national Analysis from register based national
Cohort studyCohort study
HistomorphometryHistomorphometry
Iliac crest bone biopsiesIliac crest bone biopsies No significant biopsy data available from No significant biopsy data available from
actual fracture siteactual fracture site Conflicting bone biopsy reportsConflicting bone biopsy reports
HistomorphometryHistomorphometry
OdvinaOdvina etaletal--2005, 2005, Bone Bone bxbx reports on 9 pts with unusual fracturereports on 9 pts with unusual fracture FosamaxFosamax for 3for 3--8 yrs8 yrs Delayed healing in 5Delayed healing in 5 3 on concomitant estrogen and 2 on steroids3 on concomitant estrogen and 2 on steroids Predominant feature of marked decrease of bone Predominant feature of marked decrease of bone
formation with reduced or absent formation with reduced or absent osteoblasticosteoblasticsurfacesurface
Supported Supported ““ frozen bone conceptfrozen bone concept””
HistomorphometryHistomorphometry VisekrunaVisekruna etaletal--20082008
BxBx reports on 2 ptsreports on 2 pts 5, 10 yrs of 5, 10 yrs of fosamaxfosamax exposure respectivelyexposure respectively Both also on steroidsBoth also on steroids Both had increased Both had increased osteoclastosteoclast nos. One had nos. One had
decreased decreased osteoblastsosteoblasts, other increased, other increased No definite conclusionsNo definite conclusions
HistomorphometryHistomorphometry
SomfordSomford et alet al-- 20092009 1 1 Pt. With RAPt. With RA Multiple DMARDS, SteroidsMultiple DMARDS, Steroids Left AFF, 9 months later Left AFF, 9 months later --RtRt AFFAFF
BxBx from iliac crest and from iliac crest and RtRt femur 1 cm above femur 1 cm above FxFx OsteoblastOsteoblast suppression at Crest/suppression at Crest/cancellouscancellous bonebone OsteoclastOsteoclast induction at Shaft/ cortical bone induction at Shaft/ cortical bone ? Diff. mechanisms at 2 sites perhaps due to ? Diff. mechanisms at 2 sites perhaps due to
genetic and morphological differencesgenetic and morphological differences
HistomorphometryHistomorphometry, , DenosumabDenosumabdatadata
Inhibitor of RANK Inhibitor of RANK ligandligand, inhibits , inhibits osteoclastosteoclast differentiation and function differentiation and function
Most potent Most potent antiresorptiveantiresorptive agentagent Recently approved for use of Recently approved for use of
postmenopausal osteoporosispostmenopausal osteoporosis Effects on bone Effects on bone histomorphometryhistomorphometry ,and ,and
relationship with AFF analyzed by relationship with AFF analyzed by Reid Reid etaletal in 2010,in 2010, with hypothesis it should with hypothesis it should increase risk of AFF by severe increase risk of AFF by severe suppression of bone turnoversuppression of bone turnover
HistomorphometryHistomorphometry, , DenosumabDenosumabdatadata
Iliac crest biopsies in subset of placebo and Iliac crest biopsies in subset of placebo and DenosumabDenosumab treated women at 24 and 36 months in treated women at 24 and 36 months in Freedom studyFreedom study
Double labeling present only in 19% of Double labeling present only in 19% of denosumabdenosumabversus 94% of placebo bones indicating significantly versus 94% of placebo bones indicating significantly lower bone turnover with druglower bone turnover with drug
Bone markers did not distinguish Bone markers did not distinguish denosumabdenosumab treated treated patients with double patients with double labels(highlabels(high turn over) from those turn over) from those with absent labels (low turnover)with absent labels (low turnover)
OsteoclastsOsteoclasts absent in more than 50% of absent in more than 50% of DenosumabDenosumab treated patientstreated patients
HistomorphometryHistomorphometry, , DenosumabDenosumabdatadata
STAND study.STAND study. Biopsies performed at 24 and 36 months on patients continuallyBiopsies performed at 24 and 36 months on patients continually
treated with treated with FosamaxFosamax versus switch to versus switch to DenosumabDenosumab after 24 months of after 24 months of FosamaxFosamax treatmenttreatment
Absent or single labeling in 80% of Absent or single labeling in 80% of DenosumabDenosumab biopsies biopsies versus 10% of the versus 10% of the FosamaxFosamax biopsies biopsies ----confirms strong confirms strong inhibition of bone turnover by inhibition of bone turnover by DenosumabDenosumab
Surprisingly markedly reduced fracture incidence Over 3 years Surprisingly markedly reduced fracture incidence Over 3 years and the absence of any AFF in and the absence of any AFF in DenosumabDenosumab treated patients treated patients Does not support Does not support ““frozen bonefrozen bone”” conceptconcept
Could future data from longer duration of treatment be Could future data from longer duration of treatment be different?different?
Data from clinical trialsData from clinical trials Black etalBlack etal--2010.2010.
Secondary analysis of results of 3 large RCT Of Secondary analysis of results of 3 large RCT Of BPO, 14,000 PTSBPO, 14,000 PTS
2 ON 2 ON FosamaxFosamax-- (FIT and FLEX), 1 On (FIT and FLEX), 1 On ReclastReclast(HORIZON PFT)(HORIZON PFT)
284 Femur FX records reviewed284 Femur FX records reviewed Only 12 AFF, rate of 2.3 per 10,000 pt yrs. Hazard Only 12 AFF, rate of 2.3 per 10,000 pt yrs. Hazard
ratio of 1.03 on BPO compared with placeboratio of 1.03 on BPO compared with placebo*Increase in risk was not significant, *Increase in risk was not significant, butbut patients on patients on
low dose of low dose of FosamaxFosamax and on less than 4 years of and on less than 4 years of treatmenttreatment
Data from registriesData from registries Possible coding mistakes constitute inherent Possible coding mistakes constitute inherent
limitation, can confound datalimitation, can confound data Relative infrequency of AFFRelative infrequency of AFF
10% of all femoral fractures are 10% of all femoral fractures are subtrochantericsubtrochantericand and diaphysealdiaphyseal andand
out of those only 10% atypicalout of those only 10% atypical Danish registryDanish registry , cross section exam of , cross section exam of
hospital discharge records of 12000 patients hospital discharge records of 12000 patients between 1997 through 2005 period between 1997 through 2005 period compared compared AFF AFF vsvs TFFTFF
Data Data fromDanishfromDanish registryregistry Only 7% of patients with AFF exposed to Only 7% of patients with AFF exposed to FosamaxFosamax, 15% , 15%
exposed to exposed to glucocorticoidsglucocorticoids Hazard ratio between Hazard ratio between FosamaxFosamax users versus nonusers versus non--FosamaxFosamax
users only 1.46users only 1.46 BPO Exposure BPO Exposure
HR for AFF was 1.46HR for AFF was 1.46 HR for TFF was 1.45 HR for TFF was 1.45 No sig. diff. between two types of No sig. diff. between two types of FxFx, after adjustment for , after adjustment for
comorbiditiescomorbidities was madewas made Greater adherence to BPO reduced risk of both AFF and Greater adherence to BPO reduced risk of both AFF and
TFF.TFF.
*Conclusion *Conclusion –– Both FX should be considered as osteoporotic Both FX should be considered as osteoporotic fxfxas similar epidemiologyas similar epidemiology
Data from other registriesData from other registries
Risk for AFF was higher in patients exposed to Risk for AFF was higher in patients exposed to BPO BPO vsvs placebo but the risk for AFF was placebo but the risk for AFF was higher than placebo even before exposurehigher than placebo even before exposure -- Is Is underlying bone disease the cause?underlying bone disease the cause?
Duration of exposure was studied, overall Duration of exposure was studied, overall risk was found to be the same in patients risk was found to be the same in patients treated for 9 years versus those treated for 3 treated for 9 years versus those treated for 3 months, also 25% of fractures seen in BPO months, also 25% of fractures seen in BPO exposure of less than 3 yearsexposure of less than 3 years
Data from other registriesData from other registries Analysis of ageAnalysis of age--adjusted data from hospital adjusted data from hospital
admission rates, medical claims and incidence of all admission rates, medical claims and incidence of all types of fractures shows that types of fractures shows that for every 100 TFF for every 100 TFF prevented by BPO use, only 1 AFF fracture notedprevented by BPO use, only 1 AFF fracture noted
Increasing adherence rates with BPO medications Increasing adherence rates with BPO medications was associated with decreased AFF incidence, 3.75% was associated with decreased AFF incidence, 3.75% in MPR values more than 80% versus 5.1% in MPR in MPR values more than 80% versus 5.1% in MPR of less than 50%, supporting these were possibly a of less than 50%, supporting these were possibly a subset of TFFsubset of TFF
Data from other skeletal disordersData from other skeletal disorders
AFF seen in uncommon conditions like AFF seen in uncommon conditions like PagetPaget’’s disease of the bone, s disease of the bone, osteopetrosisosteopetrosisadult adult hypophosphatasiahypophosphatasia, X, X--linked linked hypophosphatemiahypophosphatemia
Marked abnormalities in bone structure are Marked abnormalities in bone structure are noted leading to fragility of bone and noted leading to fragility of bone and radiological abnormalities, radiological abnormalities, indicating other indicating other pathogeneticpathogenetic mechanisms apart from mechanisms apart from decreased bone turnoverdecreased bone turnover
Insights/EnigmasInsights/Enigmas AFF with distinctive features are rare events in AFF with distinctive features are rare events in
patients with PMOpatients with PMO Lot of publicity regarding BPO therapy and AFF but Lot of publicity regarding BPO therapy and AFF but
larger studies do not support the hypothesis that the larger studies do not support the hypothesis that the drugs caused the fracturedrugs caused the fracture
Increased cortical thickness associated with AFF but Increased cortical thickness associated with AFF but no data concerning the appearance of femurs prior to no data concerning the appearance of femurs prior to BPO exposureBPO exposure
Biochemical markers of bone turnover do not Biochemical markers of bone turnover do not provide useful predictive data provide useful predictive data
Identification of Identification of comorbiditiescomorbidities like rheumatoid like rheumatoid arthritis, COPD ,asthma, diabetes in 10% systemic arthritis, COPD ,asthma, diabetes in 10% systemic glucocorticoidglucocorticoid therapy in 25%, PPI use in about therapy in 25%, PPI use in about 33% of the patients33% of the patients
Insights/EnigmasInsights/Enigmas AFF higher in BPO users versus nonAFF higher in BPO users versus non--BPO users but BPO users but
also occurred in significant number of nonalso occurred in significant number of non--BPO BPO users and medical conditions other than osteoporosisusers and medical conditions other than osteoporosis
Overall benefits from BPO far exceeds the risk of Overall benefits from BPO far exceeds the risk of AFF, remember 100 :1AFF, remember 100 :1
*Association with BPO use and AFF established but *Association with BPO use and AFF established but Cause and effect relationship not establishedCause and effect relationship not established
* Are they a separate entity or are they a subset of * Are they a separate entity or are they a subset of typical osteoporotic fractures, not answeredtypical osteoporotic fractures, not answered
Report of Task Force Of the Report of Task Force Of the American Society for Bone and American Society for Bone and
Mineral ResearchMineral Research Established the definitionEstablished the definition Reviewed what is known and what is not known Reviewed what is known and what is not known
about AFF and a potential relationship with BPO about AFF and a potential relationship with BPO usageusage
Epidemiology of AFFEpidemiology of AFF Working on specific diagnostic and procedural Working on specific diagnostic and procedural
codes and establishment of international codes and establishment of international registeriesregisteries TreatmentsTreatments Research directionsResearch directions
Treatment of AFFTreatment of AFF
Should BPO therapy be stopped ?Should BPO therapy be stopped ? Most experts would probably answer yesMost experts would probably answer yes Should patients be treated with Should patients be treated with ForteoForteo? Some ? Some
data suggests might be a good idea, helps with data suggests might be a good idea, helps with wound healingwound healing
Future studies of bone biopsies closer to the Future studies of bone biopsies closer to the fracture site would aid in selection of surgical fracture site would aid in selection of surgical interventionintervention
Take home pointsTake home points
Evidence does not suggest changing your prescription habits Evidence does not suggest changing your prescription habits butbut
Do not deny BPO Do not deny BPO out of fearout of fear to patients who really need itto patients who really need it Do not prescribe BPO to patients who do not need it, use Do not prescribe BPO to patients who do not need it, use
calculation tools like FRAX to select appropriate patientscalculation tools like FRAX to select appropriate patients Assess Assess comorbiditiescomorbidities like diabetes, rheumatoid arthritis, like diabetes, rheumatoid arthritis,
steroid use. If significant, consider nonsteroid use. If significant, consider non--BPO pharmaceutical BPO pharmaceutical agentsagents
Educate patients about clinical symptoms of AFFEducate patients about clinical symptoms of AFF Drug holidays after 5Drug holidays after 5--6 years of BPO should be considered, as 6 years of BPO should be considered, as
no strong evidence for ongoing benefit, no strong evidence for ongoing benefit, reevalreeval in 2in 2--3 yrs3 yrs IndiviualizeIndiviualize treatmenttreatment
ReferencesReferences E. Shane, D. Burr and P.R. E. Shane, D. Burr and P.R. EbelingEbeling, , et al.et al. Atypical Atypical subtrochantericsubtrochanteric and and diaphysealdiaphyseal
femoral fractures: report of a task force of the American Societfemoral fractures: report of a task force of the American Society for bone and y for bone and mineral research. mineral research. J Bone Miner ResJ Bone Miner Res, , 2525 (2010), pp. 2267(2010), pp. 2267––22942294
Joint Bone Spine.Joint Bone Spine. 2011 May 16. [2011 May 16. [EpubEpub ahead of ahead of print]print]WhatWhat do we know about do we know about atypicalatypical femoral fracturesfemoral fractures? Insights and enigmas. ? Insights and enigmas. AudranAudran MM, , CortetCortet BB, Thomas, Thomas
Abrahamsen B, Abrahamsen B, EikenEiken P, P, EastellEastell R. R. SubtrochantericSubtrochanteric and and diaphysealdiaphyseal femur fractures femur fractures in patients treated with in patients treated with alendronatealendronate: a register based national cohort study. : a register based national cohort study. J Bone J Bone Miner ResMiner Res. 2009;24:1095. 2009;24:1095––11021102
SomfordSomford MP, MP, DraijerDraijer FW, FW, ThomassenThomassen BJ, BJ, ChavassieuxChavassieux PM, PM, BoivinBoivin G,PapapoulosG,PapapoulosSE. Bilateral fractures of the femur SE. Bilateral fractures of the femur diaphysisdiaphysis in a in a patientwithpatientwith rheumatoid arthritis rheumatoid arthritis on longon long--term treatment with term treatment with alendronatealendronate: clues to the mechanism of increased bone : clues to the mechanism of increased bone fragility. fragility. J Bone Miner. Res.J Bone Miner. Res. 2009;24:17362009;24:1736––17401740
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