Fracture healing in osteoporotic fractures: Is it really different

$Page 1: Fracture healing in osteoporotic fractures: Is it really different$
1 Abstracts in German, French, Italian, Spanish, Japanese,and Russian are printed at the end of this supplement.

Basic concepts relevant to the design anddevelopment of the Point Contact Fixator (PC-Fix)

Stephan M. Perren andJoy S. Buchanan

AO/ASIF Research Institute, Clavadelerstrasse, 7270 Davos, SwitzerlandAO/ASIF Research Institute, Clavadelerstrasse, 7270 Davos, Switzerland

KEyWORDS:One silly fountain;Progressive dwarves;Umpteen mats;Five silly trailers;

Summary1 bla bla bla bla One aardvark marries the pawnbroker, even though fivebourgeois cats tickled umpteen Macintoshes, but two obese elephants drunkenlytowed umpteen almost irascible sheep. Two bureaux easily telephoned Paul, eventhough the wart hogs gossips, but one elephant tastes partly putrid wart hogs,because umpteen purple botulisms kisses Mark, although the subways bought oneextremely angst-ridden lampstand, even though five obese televisions perusedsubways, then five progressive mats auctioned off the bureau, although two trail-ers grew up, but irascible Jabberwockies untangles five speedy fountains, yet onecat ran away, then the trailer very cleverly kisses two irascible bureaux.

Fracture healing in osteoporotic fractures:Is it really different?A basic science perspective

Peter Giannoudis1, Christopher Tzioupis1, Talal Almalki2,Richard Buckley2

1 Academic Department of Trauma & Orthopaedic Surgery, School of Medicine, University of Leeds,Leeds, UK

2 Division of Orthopaedic Trauma, University of Calgary, Canada

KEyWORDS:Fracture healing,acceleration,osteoporosis,mesenchymalstem cells,growth factors

Summary1 Osteoporosis is a major health problem characterized by compro-mised bone strength that predisposes patients to an increased risk of fracture.Osteoporotic patients differ from normal subjects in bone mineral composition,bone mineral content, and crystallinity. Poor bone quality in patients with oste-oporosis presents the surgeon with difficult treatment decisions. Much effort hasbeen expended on improving therapies that are expected to preserve bone massand thus decrease fracture risk.Manipulation of both the local fracture environment in terms of application ofgrowth factors, scaffolds and mesenchymal cells, and systemic administrationof agents promoting bone formation and bone strength has been considered as atreatment option from which promising results have recently been reported. Sur-prisingly, less importance has been given to investigating fracture healing in oste-oporosis. Fracture healing is a complex process of bone regeneration, involvinga well-orchestrated series of biological events that follow a definable temporaland spatial sequence that may be affected by both biological factors, such as ageand osteoporosis, and mechanical factors such as stability of the osteosynthe-sis. Current studies mainly focus on preventing osteoporotic fractures. In recentyears, the literature has provided evidence of altered fracture healing in oste-oporotic bone, which may have important implications in evaluating the effectsof new osteoporosis treatments on fracture healing. However, the mechanics ofthis influence of osteoporosis on fracture healing have not yet been clarified andclinical evidence is still lacking.

Introduction

Osteoporosis is a devastating disease that affectsmore than ten million people in the United States,with annual costs in excess of $13.5 billion [75], andis characterized by low bone mass and microarchi-

tectural deterioration of bone structure, resultingin bone fragility and an increase in susceptibility tofracture [61].Worldwide, 100−200 million people are at risk

of an osteoporotic fracture each year. Statisticspredict that by the year 2012, 25% of the Europeanpopulation will be over the age of 65 and by theyear 2020, 52 million will be over 65-years-old inthe USA [21]. Based on changing demographics and

1 Abstracts in German, French, Spanish, Japanese, andRussian are printed at the end of this supplement.

Injury, Int. J. Care Injured (2007) 38S1, S90—S99

www.elsevier.com/locate/injury

0020–1383/$ — see front matter # 2007 Published by Elsevier Ltd.doi:10.1016/j.injury.2007.02.014

Fracture healing of osteoporotic fractures: Is it really different?—A basic science perspective S91

the increase in life expectancy, there will be an89% increase in the male osteoporotic populationby 2025, resulting in 800000 hip fractures per year;in women, numbers affected will rise by 69% withup to 1.8 million hip fractures [28]. Multinationalsurveys of osteoporotic fracture management [68]clearly indicate that many orthopedic surgeons stillneglect to identify, assess, and treat patients withfragility fractures.

Osteoporosis both increases the number of atrau-matic fractures and contributes to the severity oftraumatic fractures. The management of these frac-tures is difficult due to the poor bone stock involved,and there may be problems with inadequate fixationstrength (purchase) of implants used to stabilize thefracture until union occurs. In particular, fixation offractures affecting the metaphyseal region of longbones is associated with an increased rate of com-plications. Various reports suggest nonunion rates of2−10%, rates ofmalalignment after surgery of 4−40%,metal work failure rates of 1−10%, and reoperationrates of 3−23% [69, 72].

Research in osteoporosis has focused so far on theepidemiology, pathophysiology, diagnosis, and moni-toring of the disease, as well as on its metabolic andcellular basis and the effects of novel therapeuticconcepts. Significant progress has been made in eachof these areas. Only recently has attention beengiven to the diagnosis and treatment of osteoporosisin patients who have suffered a fracture. Traumasurgeons are coming to understand that treatmentof patients with osteoporotic fractures need to ad-dress the underlying osteoporosis in order to reducethe incidence of further fractures [66].

Appropriate treatment of skeletal injuries second-ary to osteoporosis requires an understanding of theeffect of osteoporosis on the material and structuralproperties of bone, the mechanisms of fracture, andthe mode of fracture healing. Sufficient stabilizationof fractures in the weight-bearing extremities is theprimary goal of treatment. However, those fracturespresent unique challenges, because stabilization isfrequently complicated by fixation failure [71].

The ability of a bone fracture to heal and remodeldepends on the ensuing microvascular and biome-chanical conditions, therefore. The musculoskel-etal system and the mechanical environment play akey role in repairing, maintaining, and remodelingthe material property and structural strength [15,51, 81].

Fracture healing is a complex process during whicha cascade of gene expression drives the iterative for-mation and resorption of various tissues, eventuallyleading to bone formation that bridges the brokenbone ends. The rate and efficacy of fracture repairdepends on a variety of factors, including those

related to the patient (eg, age); factors resultingfrom trauma (severity of trauma, fracture geometryand location) and factors operating during healing(nutritional status, hormonal milieu).

The decline in the capacity for fracture repair hasbeen shown to be age related [67]. Disturbance ofthe development of strength within fracture callusesin the elderly has been shown in experimental ratmodels [22], but little is known about the causes ofosteoporosis and its effect on the fracture repairprocess in humans [44].

The relationship between fracture healing andosteoporosis is complex. The underlying etiology(which may include aging, hypogonadism, rheuma-tism, thyroid and parathyroid disorders, malignancy,and mastocytosis) and the therapies commonly usedfor osteoporosis (estrogens, vitamin D, and bisphos-phonates) may all potentially affect fracture heal-ing. Due to these complexities, animal osteoporoticmodels, such as the rat, rabbit, or dog, may be moreappropriate to study the effects of osteoporosis andto test drugs on the fracture repair process [60].

Clinical experience is inconsistent regardingwhether bone healing is delayed in the presence ofosteoporosis. Too few studies are available on thedifferences of bone healing in normal and osteopo-rotic individuals to suggest a reduced capacity forbone remodeling and bone healing in osteoporosis[11, 13, 50].

The purpose of this paper is to present the currentevidence regarding the influence of osteoporosis onfracture healing.

Properties and characteristics ofosteoporotic bone

Bone mass and the mechanical performance ofthe skeleton are affected by a variety of local andsystemic factors. Systemic control results from anumber of calcium-regulating hormones such asparathyroid hormone, calcitonin, and vitamin D aswell as growth hormone and sex hormones. Localcontrol is exerted primarily by mechanical demandsthat result from gravity and the stressing of boneby muscular contraction. Many studies have shownthat bone, as a tissue, adapts to these mechanicaldemands by producing a structure optimized formass and geometry [22].

Mechanical properties of bone can be describedat different levels from the macroscopic to theultramicroscopic levels, and under different me-chanical basic assumptions, such as heterogeneousor homogeneous and isotropic or anisotropic as-sumptions [36].

S92 P Giannoudis et al

Bone mass diminishes with increasing age as aresult of changes in circulating levels of hormones,particularly decreased estrogen levels after meno-pause, but possibly also because of the decreasedanabolic effects of mechanical loading as a result ofdeclining levels of physical activity [57, 76].

The cellular and biochemical deficiencies relatedto osteoporosis lead to structural bone alterationsin bone structure which profoudly affect traumaticfractures and their repair. Loss of cortical bone oc-curs through a decrease in bone thickness and an in-crease in porosity, which compromises its strength.This thinner layer of cortex neighboring plentifulcancellous bone is weaker and predisposes to low-energy fractures. Loss of trabecular bone resultsin thinning, perforation, and reduced connectivityamong the trabecular plates. The abundance ofcancellous bone also adversely affects the fixationof osteoporotic fractures [17].

Hagiwara et al analyzed the distribution of bonedensity and trabecular orientation in the osteoporot-ic human vertebral body [28]. The results illustrateda considerably higher vertical trabecular orientationin the anterior 1/3 regions of the osteoporotic verte-bral body. This finding is consistent with the higherincidence of the vertebral fracture associated withosteoporosis in the anterior part of the vertebralbody (a wedge-shaped fracture) [30].

While the overall diameter of the long bones mayremain the same, the ratio of cancellous to corticalbone is increased [11]. Fracture resistance is deter-mined by the strength of the bone, which in turndepends on its geometric properties (size, shape,and connectivity), the activities of the cells in thetissue, and the material properties of the tissue [18,41]. Osteoporotic bone is characterized not only bya reduced amount of bone, but also by modificationsin the composition and structure of the affected os-seous tissues [2, 54].

Raman microscopic imaging has been used re-cently to analyze the mineral properties of osteo-porotic tissues [12]. In general, the mineral content(degree of mineralization) of osteoporotic tissues isdecreased, the HA crystal size and perfection is in-creased, the carbonate content is increased, and theacid phosphate content is decreased [8, 9], whichsubsequently affects bone microarchitecture. Thereisadecrease in cross-linkingοf subchondral boneanda thinning of trabeculae from resorption, resultingin fewer, thinner connections. Subtle reduction inthe bone mass in the transverse direction increasesthe intensity of the trabecular orientation in theloading axis. This structural change may effectivelyresist loading when the direction of the loadingcoincides with that of the trabecular orientation.However, such structural change narrows the toler-

able loading directions, which in turn may increasethe fracture risk [9].

Bone density appears to be the major factor linkedto the biomechanical functioning of osteoporoticbone. Bone cells from osteoporotic donors werefound to differ in their response to cyclic strain,measured as enhanced cell proliferation and therelease of transforming growth factor (TGF-b) andnitric oxide (NO) [37, 56]. These results indicatethat bone cells from osteoporotic patients may beimpaired in their long-term response to mechanicalstress [68].

The decreased thickness and increased porosity ofthe cortical bone, as well as the rarefaction of thetrabecular network, are partially compensated forby a higher bone diameter—as long as the bone is in-tact. However, these factors also dramatically affectthe fixation strength (primary stability) of implantsused for fracture fixation [46], the postoperativecomplications, and the recovery times [33].

Studies have shown that density is directly relatedto the strength of bone. The loss of density is seenglobally, and affects both cortical and cancellousbone, with the cancellous bone being affected to amuch greater degree, which places the elderly at anincreased risk of fractures [2, 33, 54].

Fracture healing in osteoporotic bone:what evidence do we have?

Although a plethora of information exists document-ing the influence of ovariectomy οn bone mass andmetabolism [34, 48, 65], very little basic scienceor clinical research has been conducted that docu-ments the effects of established osteoporosis onthe healing of these fractures [55, 77]. This lackis surprising considering the clinical importance ofosteoporotic fractures and the wealth of informa-tion regarding osteoporotic animal models. Table 1summarizes the most recent findings regarding theeffect of osteoporosis on bone healing.

Fracture healing is a complex physiological pro-cess that involves the coordinated participation ofhematopoietic and immune cells within the bonemarrow in conjunction with vascular and skeletalcell precursors, including mesenchymal stem cells(MSCs), that are recruited from the surroundingtissues and the circulation. Multiple factors regu-late this cascade of molecular events by affectingdifferent points in the osteoblast and chondroblastlineage through various processes such as migra-tion, proliferation, chemotaxis, differentiation,inhibition, and extracellular protein synthesis. Anunderstanding of the fracture healing cellular and


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Tabl

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oste

opor

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actu

rehe

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g.


molecular pathways is not only critical for the futureadvancement of fracture treatment, but may alsobe informative for our further understanding of themechanisms of skeletal growth and repair as well asthe mechanisms of aging [28, 43, 49].

Many scholars have investigated the hypothesisthat osteoporosis can impair fracture healing. Lind-holm et al prepared a bone fracture model usingrats fed with a low calcium diet, and reported thatbone mineral density in the repaired tibial bone wasas low as in the nonfractured bones [47]. Langelandexamined the tensile strength of fractured tibialbone in female rats five or two weeks after produc-ing fractures, and found out that neither strengthnor collagen content differed significantly betweenovariectomized rats and normal controls [40]. How-ever, age-related effects in fracture healing weredemonstrated by Bak and Andreassen, who foundconsiderable delay in regaining strength of fracturedlimbs in older rats [3].

Li and Nishimura showed that osteopenic bonemay express an altered phenotypic expression ofcells associated with bone formation and noted adifferent composition of calcified tissue within thefracture callus of osteoporotic animals [42].

Nordsletten et al produced tibial fractures in ratswith and without sciatic neurectomy and immobilizedthe lower extremities with casts [58]. They examinedthe fracture healing 25 days later, and found thatcallus formation was accelerated and bone mineraldensity was high in the neurectomy legs, but tensilestrength did not differ significantly between the legswith sciatic neurectomy and those without.

Recently, Hill et al reported on three-month-oldrats that underwent ovariectomy and fracture sixweeks later that were tested to failure in torsionat one, two, three and four weeks after fracture[31]. A statistically significant reduction in torsionalstrength 30 days after fracture was observed thatwas not present at earlier points. The researchersconcluded that ovariectomy in rats impaired frac-ture healing and this model of osteopenia could beuseful for studying treatments if end points of morethan 30 days are used.

Kubo et al examined the effects of estrogendeficiency and a low-calcium diet on 30-week-oldWistar female rat models that were estrogen de-ficient for twelve weeks prior to fracturing [39].Tensile mechanical testing, dual energy x-ray ab-sorptiometry, and light histology were performed.These authors reported that estrogen deficiencyand low-calcium conditions did not markedly affectthe early healing process, but largely affected thebones in the later period of healing. Newly gener-ated bone formed at twelve weeks after the frac-ture showed histological osteoporotic changes and

a lower mineral density in the estrogen-deficientgroup compared to controls [39].

Investigating the impact of age and ovariectomyon the healing of femoral fractures in a osteopo-rotic rat model (ovariectomy and low calcium diet),Meyer Jr et al concluded that age and ovariectomysignificantly impair the process of fracture healingin female rats as judged by measurements of rigid-ity and breaking load in three-point bending and byaccretion of mineral into the fracture callus [53].

Namkung et al have demonstrated for the firsttime, the influence of bone loss on the early phaseof fracture healing in a rat osteoporotic modelinduced by ovx and LCD [55]. A significant reduc-tion in fracture callus size, BMD, and mechanicalstrength was seen in osteoporotic rats three weekspost fracture, which is indicative of early failure ofthe repair process.

Lill et al performed in vivo bending stiffnessmeasurements and found a delay of two weeks intheir osteoporotic sheep model (ovariectomy, lowcalcium diet, and steroids), but no difference in finalstrength when compared to healthy sheep [45]. Theyconcluded that ovariectomy significantly impairs theprocess of fracture healing in adult animals as alsojudged by measurements of rigidity and breakingload in 3-point bending and by accretion of mineralinto the callus.

Walsh et al reported on the histological and bio-mechanical properties of femora fractures followinga six-week estrogen-deficient state in three-month-old female CD Ι COB rats with a normal diet usinga standard closed fracture mode [77]. Tensile and4four-point bending mechanical testing resu1ts re-vealed a significant impairment in fracture healingin the estrogen-deficient state. Histology revealedthat the estrogen-deficient fractures lag behind inhealing.

Wang et al aimed to evaluate the influence ofosteoporosis on the middle and late periods offracture healing in rat osteoporotic models [78].He found a lower callus bone mineral density andcallus failure stress in the osteoporosis group, inwhich endochondral bone formation was delayedand in which the new bone trabeculae were ar-ranged loosely and irregularly, demonstrating anhistomorphological impairment of healing. Similarresults were obtained by Qiao et al who concludedthat fracture healing in the presence of osteopo-rosis results in poor bone quality [59].

Another source of information on osteopenic bonecomes from the paraplegic literature, where clinicalfindings on fracture healing are controversial. Rapidhealing with rare nonunion has been reported inosteopenic bone of paraplegics, as well as malunionand nonunion of simple long-bone fractures [26].


When performing a study using an estrogen-de-ficient model, there are a number οf factors to beconsidered that have been shown to significantly in-fluence the level οf osteopenia [74]. Furthermore,explanations for the diversity in biomechanicalfindings are complicated by the marked differencesin the animal models in terms of age, length οf es-trogen deficiency, fracture site, and biomechanicaltesting conditions.

This area of research warrants further study andstandardization of models and endpoints used toevaluate the effects of estrogen deficiency, as well asthe methods of noninvasive and invasive therapy.

Discussion

Fracture healing is the most remarkable of all repairprocesses in the body since it results in the actualreconstitution of the injured tissue. The relation be-tween metabolic bone disease and fracture healingdepends on the role of the skeleton as a metabolicresource.

Even though delayed fracture healing is not obvi-ous in patients, the decreased healing capacity inosteoporosis is reflected in a dramatically increasedfailure rate of implant fixation [16].

Various theories have been proposed to attemptto delineate the underlying mechanisms of impairedfracture healing in osteoporotic fractures.

Extracellular matrix metabolism plays a centralrole in the development of skeletal tissues and inmost orthopaedic diseases and trauma such as frac-ture healing [25].

Specific genes must be expressed to make or repairappropriate extracellular matrix. These genes areregulated by a balance of positive and negative fac-tors in order to exhibit a strictly restricted expres-sion. Runx2 is a vital transcription factor for skeletalmineralization that is expressed in osteoblasts at ahigh level as well as in hypertrophic chondrocytesand in mesenchymal cells in the periosteum/peri-chondrium. It stimulates osteoblast differentiationof mesenchymal stem cells, promotes chondrocytehypertrophy, and contributes to endothelial cellmigration and vascular invasion of developing bones[79]. Homozygous Runx2-mutant mice exhibit com-plete arrest of osteoblast differentiation, whichresults in severe developmental defects of osteo-genesis [38].

With the loss of ovarian estrogen, menopausalwomen lose trabecular bone at several sites in theskeleton, including the spine [62]. Woven bone playsa key role in fracture healing. Most of the immedi-ate hard callus is initially formed with woven bone,

which stabilizes the healing bone while remodelingoccurs to restore the cortical bone of the diaphysis.If this woven bone is also estrogen sensitive, as isthe trabecular bone in the metaphysis, then it isnot unreasonable to expect ovariectomy to delayfracture healing because of impairment in boneformation. However, direct experimental evidencefor this expectation is limited [53].

The inferior mechanical properties of osteopo-rotic bone may reflect alterations in the momentof inertia or cross-sectional area, or bonding inter-actions between the mineral and organic constitu-ents of the bone matrix. The alterations in healingobserved may reflect compositional differences interms of osteoinductive molecules present in thebone matrix compounded by delayed osseous differ-entiation. This proposal is supported by findings thatthe osteoinductive capacity of demineralized bonematrix may decrease with age and in ovariectomised(ovx) rats due to an alteration in the composition ofthe matrix [13, 73, 77].

It has also been shown that estrogen modulatesthe mechano-sensitivity of bone cells. In the pres-ence of estrogen, the expression of prostaglandinas a response to mechanical strain was significantlyenhanced, which indicates that fractures in post-menopausal women may react differently to themechanical signal that occurs during fracture repair,compared to fractures in premenopausal women ormen [34].

While bone resorption can increase, formation de-creases, possibly because osteoblasts decrease withage [64]. Osteoblasts originate from MSCs [6, 80] thatreside in bone marrow together with hematopoieticstem cells. These two stem cell types cooperatethrough direct cell-to-cell interactions and releaseof cytokines and growth factors [4, 23].

Sinceosteoblastnumbersmightrelatetoprogenitornumbers, D’ippolito et al [20] hypothesized that thenumber of MSCs (with osteogenic potential) residingin the bone marrow of human thoracic/lumbar verte-brae—a skeletal site of high turnover in bone—couldbe associated with age-related osteoporosis [19].They concluded that the bone-marrow microenviron-ment changes with age, resulting in cell-to-cell andcell-to-matrix interactions that may be unfavorablefor MSC proliferation or that may favor MSC matura-tion toward a different lineage (eg, adipogenic).Total marrow fat increases with age, and there isan inverse relationship between marrow adipocytesand osteoblasts with aging [6, 10]. Bergman et al [7]also concluded that defects in the number and pro-liferative potential of MSCs may underlie age-relateddefects in osteoblast number and function.

Rodriguez et al showed that MSCs derived fromboth control and osteoporotic postmenopausal


women share some functional dynamic responsesbut differ importantly in others [63]. Some of thedifferences observed, like the differential mitogenicresponse to IGF-1 and the diminished ability of MSCsderived from osteoporotic donors to differentiateinto the osteogenic lineage, suggest that these cellshave a diminished ability to produce mature boneforming cells.

Furthermore, osteoporotic cells present a lowerproliferation rate and exhibit a differential responseto IGF-1.Thus, clinical and in vitro observationsdocument an inverse relationship between adipo-cytes and osteoblasts.

In osteoporotic patients, increased bone marrowadipose tissue correlates with decreased trabecularbone volume [27]. Early histomorphometric observa-tions suggested that a change in bone cell dynam-ics, causing osteoporosis, is the consequence ofthe adipose replacement of the marrow functionalcell population [52]. These findings suggest that amechanism that could account for the decrease inbone volume, and hence mechanical strength, mayresult from opposing effects on differentiation ofthe two cell lines. The commitment to the adipocytedifferentiation pathway occurs at the expense ofosteoblast numbers and osteogenic function [27].This commitment may contribute to osteoporoticbone involution but may also negatively effect boneformation during fracture healing [1].

Conclusion

The highly complex process of fracture repair is stillnot fully understood; however, research in recentyears has identified various associations betweenfactors that affect the repair process and healingoutcome. Clinical experience is inconsistent regard-ing a possible delay of bone healing in osteoporosisand clinical studies that confirm delayed healing inelderly people are scarce.

Patient-based research regularly suffers fromlimitations including that no control group can beattained, that it is difficult to create homogeneousstudy groups, and that there are ethical limitations.As a result, experimental studies on the effect ofosteoporosis on fracture healing have been carriedout on ovariectomized rats. These studies haveshown that ovariectomy significantly reduces bonemass and that the mechanical strength of the boneafter completion of healing appears to be reduced.Furthermore, fracture healing appears to be delayedwith respect to callus mineralization and biome-chanical properties.

However, animal models have disadvantages such

as differences in bone metabolism compared withhumans, lack of prominent decrease of bone massafter ovariectomy, and animal protection aspects.Moreover, they permit the study of interventionsand new treatment procedures that might not beappropriate in patients.

The mechanical and biological factors that areinvolved in the healing process of bone are certainlyaffected by age and osteoporosis.Alterations in bonemetabolism, like osteoporosis, seem to delay callusmaturation and consequently decelerate fracturehealing. Nevertheless, it still remains an unsolvedquestion as to whether fracture healing is impairedby osteoporosis.

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Correspondence Address

P. Giannoudis MD, EEC (ortho)ProfessorAcademic Department of Trauma & Orthopaedics,Clarendon Wing, Floor ALeeds General InfirmaryGreat George StreetLeeds, LS1 3EX, United KingdomTel: 0044-113-3922750email: [email protected]

This paper has been written entirely by the authors, andhas received no external funding. The authors have nosignificant financial interest or other relationship.

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