pathophysiology puenting

8/17/2019 pathophysiology puenting

1/11

CurrentConceptsReview

Pathophysiology and New Strategies for theTreatment of Legg-Calv ́e-Perthes Disease

Harry K.W. Kim, MD, MS, FRCSC

Investigation performed at Texas Scottish Rite Hospital for Children, Dallas, Texas

Legg-Calvé-Perthes disease is a juvenile form of idiopathic osteonecrosis of the femoral head that can lead to

permanent femoral head deformity and premature osteoarthritis.

According to two recent multicenter, prospective cohort studies, current nonoperative and operative treatments

have modest success rates of producing a good outcome with a spherical femoral head in older children with Legg-Calvé-Perthes disease.

Experimental studies have revealed that the immature femoral head is mechanically weakened following ischemic

necrosis.

Increased bone resorption and delayed new bone formation, in combination with continued mechanical loading of

the hip, contribute to the pathogenesis of the femoral head deformity.

Biological treatment strategies to improve the healing process by decreasing bone resorption and stimulating

bone formation appear promising in nonhuman preclinical studies.

Legg-Calv ́e-Perthes disease is a juvenile form of idiopathicosteonecrosis of the femoral head that affects children betweenthe ages of two and fourteen years. It is considered one of themost common forms of pediatric femoral head osteonecrosis,with the prevalence ranging from 5.1 to 16.9 per 100,000 invarious regions of the world1-4. Since the initial reports of thisunique condition approximately 100 years ago by Legg 5, Calv ́e6,and Perthes7, a number of studies have been published re-garding its etiology 8-15, epidemiology 1,3,4, natural history 16-20,radiographic classifications16,21-23, treatments24-29, and outcomes30-32.Despite the increase in knowledge, Legg-Calv ́e-Perthes dis-ease remains one of the most controversial conditions in

pediatric orthopaedics. Many aspects of the disease remainunknown or unclear, including the etiology and pathophys-iology of the disease and the best methods to treat the patientsin different age groups affected with the disease. The pur-

poses of this review are threefold: to provide an update on theoutcomes of current treatments according to the results of recent prospective studies, to provide an update on the path-ophysiology of Legg-Calv ́e-Perthes disease on the basis of theknowledge gained from recent experimental investigations, andto summarize the rationale, results, and concerns of new bio-logical therapeutic strategies that are being explored as possibletreatments for the disease.

Current Treatments and Outcomes

Current treatments for Legg-Calv ́e-Perthes disease are largely based on the principles of obtaining and maintaining good hip

range of motion, and obtaining and maintaining containmentof the femoral head in the acetabulum33,34. It is believed that, if these principles are followed, a soft femoral head will be moldedinto a spherical shape by the acetabular socket. Over the years,

Disclosure: The author did not receivepayments or services, either directly or indirectly (i.e., via his institution), froma third party in support of any aspect

of this work. Neither the author nor his institution has had any financial relationship, in the thirty-six months prior to submission of this work, with any

entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. The author has had a

relationship, or has engaged in another activity, that could be perceived to influence or have the potential to influence what is written in this work. The

complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

659

COPYRIGHT 2012 B Y T HE J OURNAL OF B ONE AND J OINT S URGERY, INCORPORATED

J Bone Joint Surg Am. 2012;94:659-69 d http://dx.doi.org/10.2106/JBJS.J.01834


2/11

various nonoperative28,35-39 and operative treatments24,27,29,40,41

were introduced on the basis of this concept. One of the crit-icisms of this concept has been the inability to accurately quantify femoral head containment and to establish a direct

relationship between the amount of containment of the fem-oral head and the ultimate outcome. According to hip mod-eling studies42,43, a clinical impression of containment based onradiographic assessment of the femoral head coverage may notaccurately represent the degree of containment of the femoralhead.

The effectiveness of current treatments based on theconcept of containment has been investigated in two multi-center prospective investigations (level-II prospective cohortstudies)30,44. In the study by Herring et al.30 (Table I), the successrate of achieving a spherical femoral head (Stulberg class-Ior II hips)20 after one of the five treatments (no treatment,physiotherapy, Scottish Rite orthosis, femoral osteotomy, or

Salter innominate osteotomy 29) ranged from 27% to 69% inthe 204 patients with the onset of the disease between the agesof six and eight years and from 25% to 62% in the 141 patientswith the onset of the disease between the ages of eight andtwelve years. The operative treatments, as a treatment group,produced better results than the nonoperative treatmentsfor the older age group; however, the effectiveness of thesetreatments in achieving a spherical femoral head was mod-est. In the study by Wiig et al.44 (Table II), the success rate of achieving a spherical femoral head after one of the threetreatments (physiotherapy, Scottish Rite orthosis, or femoralvarus osteotomy) ranged from 46% to 53% in the 168 pa-

tients with the onset of the disease before the age of six yearsand from 20% to 43% in the 146 patients with the onset of thedisease after the age of six years. While that study found that afemoral osteotomy was beneficial in the patients who weremore than six years old at the onset of the disease, the effec-tiveness of a femoral osteotomy in achieving a spherical femoralhead was also modest.

The results of these studies raise a question regarding why a femoral or Salter innominate osteotomy produces goodresults in some patients and not in the others. One theory isthat while these osteotomies do provide some load-relieving effects on the necrotic femoral head42,45, they do not directly orspecifically address the pathobiology of the disease and theimpaired healing observed in the older children with Legg-Calv ́e-Perthes disease. These results also clearly indicate a needto develop more effective treatments for the disease that pre-vent the femoral head deformity. It is generally agreed that abetter understanding of the pathophysiology of the femoral

head deformity in Legg-Calv ́e-Perthes disease is essential forthe development of more effective treatments.

Pathophysiology of Legg-Calvé-Perthes Disease

Various theories on the etiology of Legg-Calv ́e-Perthes diseasehave been proposed. These include trauma, an inflammatory process, vascular occlusion, thrombophilia, insulin-like growthfactor-1 pathway abnormality, maternal smoking, second-handsmoke exposure13,46-49, and, most recently, a subtle type-II col-lagen mutation12,14,50. Most of these theories remain unsub-stantiated. Thrombophilia as a cause of Legg-Calv ́e-Perthesdisease remains controversial, with some studies having shownan association between the disease and various coagulation factor

abnormalities8,51-55, while other studies have shown no association

TABLE I Stulberg Radiographic Outcome of Three Treatmentsin the Study by Herring et al.*

Radiographic OutcomeAccording to Stulberg

Class

I or II III, IV, or V

Age of 6 to 8 years at disease

onset (n = 204)

No treatment (n = 11) 27% (3) 73% (8)

Range of motion (n = 44) 48% (21) 52% (23)

Brace (n = 79) 62% (49) 38% (30)

Innominate osteotomy (n = 39) 69% (27) 31% (12)

Femoral osteotomy (n = 31) 68% (21) 32% (10)

Age of ‡8 to 12 years at disease

onset (n = 141)

No treatment (n = 8) 25% (2) 75% (6)

Range of motion (n = 33) 30% (10) 70% (23)Brace (n = 50) 36% (18) 64% (32)

Innominate osteotomy (n = 29) 41% (12) 59% (17)

Femoral osteotomy (n = 21) 62% (13) 38% (8)

*The data are from Herring JA, Kim HT, Browne R. Legg-Calvé-Perthes disease. Part II: Prospective multicenter study of the effectof treatment on outcome. J Bone Joint Surg Am. 2004;86:2121-34.

TABLE II Stulberg Radiographic Outcome of Three TreatmentsStudied by Wiig et al.*

Radiographic OutcomeAccording to Stulberg Class

I or II III, IV, or V

Age of


3/11

at all11,56-60. The prevailing opinion is that Legg-Calv ́e-Perthes dis-ease is a multifactorial disease with genetic and environmentalfactors playing a role. There is also the possibility that the disease iscaused by several etiological factors that share a common patho-logical and clinical presentation.

Regardless of the cause, a disruption of blood supply tothe femoral head, producing ischemic necrosis, appears to be akey pathogenic event, leading to the pathological and subse-quent structural changes to the growing femoral head. Diag-nostic imaging studies, such as selective angiography 61-63, bonescintigraphy 64, and gadolinium-enhanced magnetic resonanceimaging 65, provide evidence of absent blood flow to the affectedfemoral head. Although histological studies of the femoral headand biopsy specimens from the patients with Legg-Calv ́e-Perthesdisease are limited in number, they show changes consistent withischemic necrosis of the bone and the deep layer of the articularcartilage66,67. Animal studies also have shown that a disruption of the blood supply to the femoral head can produce radiographic

and histological changes resembling Legg-Calv ́e-Perthes disease68,69.The question of whether Legg-Calv ́e-Perthes disease is

due to a single episode of infarction or multiple episodes of infarction remains controversial. The evidence for the singleinfarction theory comes from studies of immature pigs inwhich one episode of ischemia induction surgery producedradiographic and histological changes resembling Legg-Calv ́e-Perthes disease. The evidence for the multiple infarction theory comes from studies on immature dogs in which a single epi-sode of infarction did not produce femoral head necrosis ordeformity, while consecutive interruptions of the blood supply produced changes resembling Legg-Calv ́e-Perthes disease insome femoral heads70,71. In a subsequent clinical study, 51% of

fifty-seven biopsy specimens from the femoral heads of patientswith the disease revealed dead woven bone superimposed ondead lamellar bone with the marrow space occupied by deadgranulation tissue, suggesting two episodes of infarction72.Catterall et al. also observed thickened trabeculae with many cement lines in the central area of two femoral heads with totalhead involvement (Group 4 in the Catterall classification)66.However, in the periphery of the specimens with less femoralhead involvement (Group 1 in the Catterall classification), theauthors observed osseous trabeculae showing only one episodeof infarction. One interpretation of these findings is thatmultiple episodes of infarction are necessary to produce Legg-Calv ́e-Perthes disease. This interpretation suggests that, if the

cause of the infarction episodes can be identified, and if in-tervention can be initiated early in the course of the diseaseprocess, then a full-blown disease may be prevented or theseverity of the disease can be reduced. Another interpretationof these findings is that the disease is due to one infarctionepisode, but subsequent mechanical overloading may injurethe vessels in the healing areas of the femoral head or produceintermittent compression of the blood vessels traversing thecartilage in the area of high loading, producing secondary episodes of infarction. This interpretation suggests that theprevention of mechanical overloading and a femoral head de-formity would be beneficial to the healing process.

Pathogenesis of Femoral Head Deformity

in Legg-Calvé-Perthes Disease

Development of the femoral head deformity is the most im-portant sequela of Legg-Calv ́e-Perthes disease since the extentof the deformity correlates with the long-term outcome18-20. A serial radiographic examination of patients with the diseasedemonstrates that the development of the deformity begins inthe initial stage of the disease (the stage of increased radio-density) and progresses during the resorptive stage (the stage of fragmentation). From the limited number of biopsy and nec-ropsy studies of Legg-Calv ́e-Perthes disease, various patho-logical changes from the proximal part of the femur thatinclude the articular cartilage, osseous epiphysis, physis, andmetaphysis have been reported66,67,73-76. The temporal sequenceof the pathological changes and the functional importance of the changes are difficult to appreciate from these few studiesas they only examined a limited number of specimens and invarious stages of the disease.

The lack of availability of clinical samples for research hasprompted an alternative approach, the use of experimentalmodels, to investigate the pathogenesis of the femoral headdeformity. In particular, a piglet model has allowed more sys-tematic and in-depth investigation. This model of ischemicnecrosis of the immature femoral head is created by applying aligature (resorbable suture) around the femoral neck to disruptthe blood flow to the femoral head. The femoral head becomesnecrotic and remains avascular in the first two weeks (theavascular stage). Revascularization and resorption of the ne-crotic head are initiated by three to four weeks after ischemiainduction (the vascular repair stage), and moderate to severefemoral head deformity is observed at eight weeks after is-

chemia induction68. The studies of this model have revealedthat the pathogenesis of the femoral head deformity following ischemic necrosis is complex, and multiple factors contributeto the development of the deformity 68,77-80 (Fig. 1). Mechanicaltesting of the normal and the infarcted femoral heads fromimmature pigs has revealed a significant and persistent decreasein the mechanical properties of the infarcted head from theearly avascular stage to the later vascular repair stage in thismodel80. Further studies have revealed that the mechanicalproperties of the articular cartilage and the bone from the in-farcted heads were decreased79. Proposed explanations for theearly compromise of the mechanical properties have includedthe necrosis of the deep layer of the articular cartilage as a result

of the ischemic injury, the inability of the necrotic bone torepair the microdamage incurred during normal loading of thehip, and the changes in the material properties of the calcifiedcartilage and the subchondral bone associated with the ische-mic damage. A recent study on the mineral content of the ne-crotic trabecular bone, with use of a technique called quantitativebackscatter electron imaging, showed a significant increase inthe calcium content of the calcified cartilage and the sub-chondral bone (p < 0.05), making the bone more homoge-neous in the calcium content and, likely, more brittle77. It ispostulated that since brittle bone is more prone to micro-damage and since there are no osteoclasts and osteoblasts in

661

T H E J O U R N A L O F B O N E & J O I N T S U R G E R Y d J B J S . O RGVO L U M E 9 4 - A d N U M B E R 7 d A P R I L 4 , 2 0 1 2

PA T H O P H Y S I O L O G Y A N D N E W S T R A T E G I E S F O R T H E

T R E A T M E N T O F L E G G - C A LV É- P E R T H E S D I S E A S E


4/11

the necrotic regions of bone to repair the microdamage in-

curred with the normal activities, this microdamage accu-mulates and results in a subchondral fracture or a compactionfracture with continued loading of the hip in the early stagesof Legg-Calv ́e-Perthes disease.

In the vascular repair stage of the piglet model, a path-ological repair process marked by a predominance of osteo-clastic resorption and delayed bone formation contributes tothe pathogenesis of the deformity 68 (Fig. 2). The uncoupling of bone resorption and formation, and the replacement of thenecrotic bone by a fibrovascular granulation tissue, impartfurther weakening to the femoral head. The repair process isclearly not ‘‘creeping substitution,’’ as defined by Phemister, inwhich dead bone is substituted by new bone in the infarcted

segment of adult femoral heads81. The uncoupling of boneresorption and formation observed in the piglet model is alsoobservable in the patients with Legg-Calv ́e-Perthes disease. Theresorptive stage or the stage of fragmentation in the diseasedemonstrates increased bone resorption seen as radiolucentareas on serial radiographs prior to the femoral head entering the stage of reossification several months or more after theappearance of the radiolucent areas. Femoral head specimensobtained from the patients at the stage of fragmentation indeedshow an increased presence of osteoclasts in the areas of repairand replacement of the bone with a fibrovascular tissue66,67. Thepathological repair process (imbalance of resorption and for-

mation) has been recognized by several investigators as a po-

tential therapeutic target to improve the remodeling of thenecrotic bone and to prevent the development of the deformity in the immature femoral head82-86.

In addition to these mechanisms, ischemic necrosis of the immature femoral head produces a growth arrest of thespherical growth plate surrounding the osseous epiphysis,which can potentially worsen the femoral head deformity (Fig.2). Histological studies of specimens from patients with Legg-Calv ́e-Perthes disease66,74,76 and the experimental models of ischemic necrosis78,87,88 have shown necrosis of the deep layerof the articular cartilage, where endochondral ossificationof the osseous epiphysis occurs. To obtain normal sphericalgrowth of the epiphysis, endochondral ossification of the osse-

ous epiphysis must be restored in a symmetric, circumferentialfashion as distorted, asymmetric growth may further contributeto the head deformity. At the present time, the mechanismsinvolved with the restoration of the epiphyseal growth arepoorly understood; however, vascular endothelial growthfactor appears to be involved in this process as it is increasedin the cartilage overlying the necrosis in the experimentalstudies89,90. It is also known to play an important role in angio-genesis and endochondral ossification91. A recent experimentalstudy has suggested that exogenous bone morphogeneticprotein (BMP)-2 administration may hasten the restorativeprocess92.

Fig. 1

A flowchart depicting the pathogenesis of the femoral head deformity in Legg-Calvé-Perthes disease. VEGF = vascular endothelial growth factor.

662





5/11

Role of Hip Loading on the Pathogenesis of Femoral

Head Deformity

Since the hip is a major load-bearing joint, the contribution of

mechanical loading to the pathogenesis of the deformity inLegg-Calv ́e-Perthes disease must be considered. Unfortunately,very little is known about the hip forces associated with variousactivities of daily living in children. In adults, however, the hipcontact pressures have been measured in a limited number of patients who had implantation of a strain gauge-instrumentedhip replacement with a telemetric capability to transmit hipcontact forces in real time93,94. These studies have shown thatsubstantial loading of the hip occurs with normal daily ac-tivities. For instance, walking at a normal rate can produce hipforces of approximately 2.5 times the body weight with eachstep, while running can produce hip contact pressure of ap-proximately five times the body weight with each stride. Along

with the magnitude of loading, the frequency of loading may be important as an active child can take >7500 steps per day on average95. While it is reasonable to postulate that loading of the necrotic head contributes to the worsening of the de-formity, the efficacy of restricting activities to prevent pro-gression of the deformity is not well studied and it remainscontroversial.

Antiresorptive Therapy To Inhibit Pathological

Resorption of the Necrotic Bone

Recognition of Legg-Calv ́e-Perthes disease as having an im-portant resorptive component contributing to the femoral

head deformity has led investigators to study the effects of inhibiting osteoclast-mediated bone resorption on preventing the deformity. The most direct evidence that osteoclastic re-

sorption plays an important role in the development of thedeformity comes from a large-animal study that used exoge-nous osteoprotegerin (OPG), a natural soluble decoy receptorof the receptor activator of nuclear factor (NF)-kß ligand(RANKL)83. It is well established that the interaction of thereceptor activator of NF-kß (RANK) and its ligand, RANKL, isessential for osteoclast formation, function, and activation96.The binding of OPG to RANKL prevents the RANK-RANKLinteraction and effectively inhibits osteoclast formation, ac-tivation, and survival. In a piglet model of ischemic necrosis,exogenous OPG therapy significantly decreased osteoclastnumber (p < 0.001), bone resorption (p < 0.001), and femoralhead deformity (p < 0.001), providing evidence that specific

targeting of osteoclastogenesis and osteoclastic function canpositively modulate the outcome in this model (Fig. 3)68.Recently, a RANKL inhibitor called denosumab, a mono-clonal antibody to RANKL, has become clinically availablefor the treatment of postmenopausal osteoporosis97. Its ef-fect on femoral head osteonecrosis, however, has not beeninvestigated.

More extensive studies have been performed with use of bisphosphonates, which are well-known inhibitors of osteo-clastic resorption82,84-86,98,99. The mechanism of action of theaminobisphosphonates (the newer bisphosphonates) is to in-hibit farnesyl pyrophosphatase, an enzyme in the HMG-CoA

Fig. 2

A drawingrepresenting a normal femoral head and an infarcted femoral head in an early stage of revascularization. Ischemic necrosis produces extensive

cell death in the deep layer of the articular cartilage. This is the growth cartilage responsible for the circumferential growth of the secondary center of

ossification. The ischemic damage produces a growth arrestof the secondary center, which may not be restored symmetrically during the healingprocess

andproducesgrowth disturbance of thesecondary center. Revascularization of theinfarcted femoralhead is associated witha predominanceof resorptive

activity, as shown in the drawing. (Reproduced, with permission, from: the Texas Scottish Rite Hospital for Children, Dallas, Texas.)

663





6/11

(3-hydroxy-3-methylglutaryl-coenyzyme A) reductase path-way, which interferes with prenylation of small GTPase pro-teins98. The uptake of these drugs by osteoclasts inhibits theirresorptive activity and accelerates apoptosis. Unlike RANKLinhibitors, bisphosphonates do not inhibit osteoclast forma-tion. Experimental studies in immature rat85,86 and pig modelsof ischemic necrosis84 have shown that systemically adminis-tered bisphosphonates can decrease bone resorption andfemoral head deformity. In those studies, multiple dosing regimens were used as only a small portion of each dose wasthought to access the necrotic femoral head. A study with use of 14C-labeled-ibandronate in immature pigs showed that the

local bioavailability and distribution of this bisphosphonate inthe necrotic head depended on the vascular status of the head99.In the early avascular stage of the piglet model, very little ra-dioactivity was detected in the necrotic head following an in-travenous dose of 14C-labeled ibandronate. A significantincrease in the radioactivity was observed when the dose wasadministered at a later stage when revascularization of thefemoral head had occurred (p < 0.05). These findings imply that oral or intravenous administration of a bisphosphonatehas very limited access to the necrotic bone in the early stages of the disease. Because of this limitation, a multiple-dosing regi-men is thought to be required to allow accumulation of the

drug in the necrotic region with each dose100. The repeateddosing over time is also thought to provide a greater oppor-tunity for the drug to access the necrotic bone since the vascularstatus of the necrotic head improves over time.

A concern for a wide distribution of bisphosphonate withits long half-life on the immature skeleton and the limitedaccessibility of the systemically administered bisphosphonateon the infarcted head have led to an experimental investigationon the retention, distribution, and effects of a local, intraos-seous administration of bisphosphonate for the treatment of femoral head osteonecrosis82,99. A single, local administrationwas shown to be effective and substantially decreased the total

amount of bisphosphonate required to decrease the deformity in immature pigs82. Only 5% of the systemic dose was requiredin the local administration study compared with the systemicadministration study. While antiresorptive drugs were found tobe effective in preserving the necrotic bone in these studies,their effect on bone remodeling and new bone formation hasbeen mixed. In rat models of osteonecrosis, new bone forma-tion has been shown to occur on the necrotic bone surface85,86.This has not been demonstrated in the piglet model. The os-teoblast surface was significantly lower in the OPG (88%; p <0.01) and the ibandronate treatment (93%; p < 0.05) groupscompared with their respective normal control groups83,84 (Fig.

Fig. 3

Fig.3-A Radiographs of the central region of immature femoral heads showinga progression of the femoral head deformity in the piglet model. w = weeks

following the induction of ischemic necrosis. Fig.3-B A microcomputed tomographic image of a central region of thefemoral head obtained at three weeks

after theinductionof ischemia, showinga circular area of bone resorption in thenecroticepiphysis. A radiodense, intravascularcontrast material (Microfil;

Flow Tech, Carver, Massachusetts) was infused into the distal aorta before imaging to detect revascularization in the necrotic epiphysis. The arrow is

pointing to a vesselwith multiple small branches withinthe area of resorption. Fig. 3-CA photomicrographof a peripheral areaof revascularization showing

the increased presence of multinucleated cells (osteoclasts) and resorption of the trabecular bone (hematoxylin and eosin staining, ·20). Fig. 3-D A

photomicrograph of a central area of revascularization showing fibrovascular tissue. The resorbed bone was not replaced by new bone (hematoxylin and

eosin staining, ·10). (Figs. 3-A and 3-C are reproduced from Kim HK, Su PH. Development of flattening and apparent fragmentation following ischemic

necrosis of the capital femoral epiphysis in a piglet model. J Bone Joint Surg Am. 2002;84:1329-34.)

664





7/11

4). At this point, it is unclear whether this is an issue of theduration of follow-up or an issue of the antiresorptive agentshaving an inhibitory effect on new bone formation due to acoupling of the two processes.

Currently, the use of bisphosphonate therapy to treatLegg-Calv ́e-Perthes disease is investigational. A randomizedclinical trial comparing intravenous administration of zole-dronic acid and standard care (weight-bearing restriction andcurrent treatments) for Legg-Calv ́e-Perthes disease (clinicaltrial registration ACTRN12610000407099) is under way inAustralia.

Bone Anabolic Therapy To Stimulate New

Bone Formation

The effects of BMP administration on bone formation in thecontext of femoral head osteonecrosis are being investigatedsince BMP-2 and BMP-7 are potent osteoinductive agentsshown to promote bone healing under difficult clinical cir-cumstances101-103. The use of BMP-2 to stimulate healing as anadjunct to core decompression or a strut graft has been in-vestigated in adult animal models of osteonecrosis104,105 andfemoral head defect106. The animal studies have described im-proved bone healing and increased new bone formation with

Fig. 4

Fig. 4-A Radiographs of infarcted femoral heads in the animals treated with subcutaneous saline solution or osteoprotegerin (OPG-Fc), which inhibits

osteoclast formation, function, and activation. The treatments were initiated two weeks after the induction of ischemic necrosis. The OPG group had a

significantlybetter preservationof thefemoral head, as indicatedby thebar graph representing themean epiphyseal quotient (ratioof femoral head height

to itsdiameter) andthe standarddeviation. *p< 0.001 comparedwith theothergroups. Fig.4-B Low-magnification(·0.5) photomicrographsof the femoral

heads from the control, saline solution, and OPG groups. The femoral heads from the saline solution group had areas of bone resorption (arrows) and

femoral head deformity. The femoral heads from the OPG group had significantly less bone resorption and better preservation of the femoral head shape

(McNeal tetrachromium staining). Fig. 4-C Higher-magnification (·10) photomicrographs of the femoral heads from the control, saline solution, and OPG

groups stained for osteoclasts (red stain) (tartrate-resistant acid phosphatase staining). The mean osteoclast number (and standard deviation) was

significantlylowerin theOPG group,as shown on thebar graph.*p < 0.0001compared with theothergroups.(Reproduced, withpermission,from:Kim HK,

Morgan-Bagley S, Kostenuik P. RANKL inhibition: a novel strategy to decrease femoral head deformity after ischemic osteonecrosis. J Bone Miner Res.

2006;21:1946-54. 2006 American Society for Bone and Mineral Research.)

665





8/11

the BMP treatment. BMP-2 has also been used clinically to treatfemoral head osteonecrosis in adults as an adjunct to coredecompression107. In a case series of seventeen hips (sixteen

Ficat Stage-II hips and one Ficat Stage-III hip), three hipsprogressed and required total hip replacement, while fourteenhips had good results at an average follow-up duration of fifty-three months107. Since the study was retrospective in naturewithout a control group, the true efficacy of BMP-2 treatmentcould not be determined.

The use of BMPs to treat femoral head osteonecrosis in apediatric population has not been reported, as far as we know.However, a combined treatment of bisphosphonate (ibandro-nate) and BMP-2 with use of a local intraosseous injectiontechnique has been reported in a large-animal study 92 (Fig. 5).The rationale for using bisphosphonate and BMP-2 together in

the study was that, along with osteoinductive properties,BMP-2 is known to transiently stimulate osteoclastogenesisand bone resorption108-111. In comparison with the group that

had local administration of ibandronate alone, the group thathad local administration of ibandronate and BMP-2 showed asignificantly greater percent of osteoblast surface on the tra-becular bone (p < 0.0001), greater bone volume (p < 0.0001),and remodeling of the necrotic femoral head92. Furthermore, inthree of the six femoral heads treated with ibandronate andBMP-2, a restoration of growth of the epiphysis was observed.Along with improved bone healing, the round shape of thefemoral heads was better preserved in the ibandronate andBMP-2 treatment group compared with the saline solutiongroup. In that study, however, heterotopic ossification wasobserved in the hip joint capsule of the animals treated with the

Fig. 5

Fig. 5-A Radiographs of the femoral head of animals treated with intraosseous saline solution, ibandronate (IB), or IB and bone morphogenetic protein

(BMP)-2. A single injection of the respective agent(s) was rendered one week following the induction of ischemic necrosis. Fig. 5-B Photomicrographs

showing osteoblasts (black arrows) on the surface of the trabecular bone in the IB1 BMP-2 group and the normal, control group (red arrows). The femoral

heads from the saline and the IB groups had a lack of osteoblasts on the trabecular surfaces. Bars = 100 mm. Fig. 5-C A bar graph showing the mean

percentage (and standard deviation) of trabecular bone surface on which osteoblasts were attached, with a significantly greater osteoblast surface, an

indicator of bone formation, in the IB1 BMP-2 group than in the saline solution and the IB groups. (Reproduced from: Vandermeer JS, Kamiya N, Aya-ay J,

Garces A, Browne R, Kim HKW. Local administration of ibandronate and bone morphogenetic protein-2 stimulates bone formation and decreases femoral

head deformity following ischemic osteonecrosis of the immature femoral head. J Bone Joint Surg Am. 2011;93:905-13.)

666





9/11

ibandronate and BMP-2. It is postulated that a leakage of BMP-2 into the joint on removal of the injection needle and injectionof BMP-2 shortly after the surgical trauma to create the femoralhead ischemia may have predisposed the soft tissues around thehip to heterotopic ossification. The use of BMPs to treat Legg-Calv ́e-Perthes disease is still experimental at this time, andfurther studies are warranted prior to the use of BMPs to treatchildren with femoral head osteonecrosis.

Clinical Studies on Bisphosphonate Therapy for Femoral

Head Osteonecrosis

To date, only a small number of studies have investigated theeffects of bisphosphonate therapy for the treatment of femoralhead osteonecrosis112-117. Most of those studies assessed short-term outcomes in adults with nontraumatic femoral headosteonecrosis. Four clinical studies on nontraumatic osteo-necrosis in adults have shown some beneficial effects of bis-phosphonate therapy on pain, function, and preservation of

the femoral head112-115. It is of note that, in the randomizedclinical trial reported by Lai et al., only two of twenty-nine hipsrequired total hip replacement following oral alendronatetherapy for six months compared with nineteen of twenty-fivehips in the nontreatment group at the minimum follow-upperiod of two years114. A study by Agarwala et al. showed thatoral bisphosphonate therapy produced the best results wheninitiated in the early stage of osteonecrosis (stage-1 disease). Atthe mean follow-up interval of four years, 56% (seventy-two)of 129 patients with stage-2 disease had a radiographic evidenceof collapse, whereas only 13% (twenty-seven) of 215 patientswith stage-1 disease had a collapse113. Limitations of that study were that the extent of the head involvement was not assessed

and that there were no controls.A prospective case series of adolescent patients who had

traumatic osteonecrosis because of unstable slipped capitalfemoral epiphysis, hip fracture, or dislocation showed thatthose who had a cold bone scan and who were treated withintermittent intravenous bisphosphonate therapy over an av-erage period of twenty months did reasonably well at theminimum follow-up of two years116. Nine of seventeen patientshad a spherical femoral head, and fourteen of seventeen pa-

tients were pain-free. That study, however, did not have acontrol group. A small study of seventeen patients with osteo-necrosis as a complication of chemotherapy for childhoodleukemia has also been reported117. In general, improvementsin the pain scores, analgesic requirement, and function wereobserved in the nine patients who received bisphosphonatetherapy; however, a radiographic benefit of the therapy couldnot be demonstrated. In a small number of patients with Legg-Calv ́e-Perthes disease, the systemic effects of intravenous bis-phosphonate have been reported recently 100; however, its ef-fect on the preservation of the femoral head has yet to bereported.

Overview

Multicenter prospective cohort studies (level-II evidence) haveshown that the benefits of treatment for older children affectedwith Legg-Calv ́e-Perthes disease are modest, even with opera-tive treatments. A better understanding of the pathogenesis of

the femoral head deformity is required to develop more ef-fective treatments. Experimental studies have revealed that animbalance of bone resorption and bone formation plays animportant role in the development of the deformity. Furtherstudies are needed to address the questions about why there isuncoupling of bone resorption and formation during theremodeling of the necrotic femoral head, what molecularmechanisms are involved, and how we can therapeutically target them more effectively. While recent experimental studieshave shown that antiresorptive and anabolic agents can effec-tively modulate the pathological repair process, further studiesare needed to address the clinical efficacy and safety of theseagents for the treatment of Legg-Calv ́e-Perthes disease. n

Harry K.W. Kim, MD, MS, FRCSCCenter for Excellence in Hip Disorders,Department of Orthopaedic Surgery,Texas Scottish Rite Hospital for Children,UT Southwestern Medical Center, 2222 Welborn Street,Dallas, TX 75218. E-mail address: [email protected]

References

1. Gray IM, Lowry RB, Renwick DH. Incidence and genetics of Legg-Perthes disease

(osteochondritis deformans) in British Columbia: evidence of polygenic determina-tion. J Med Genet. 1972;9:197-202.

2. Margetts BM, Perry CA, Taylor JF, Dangerfield PH. The incidence and distribution

of Legg-Calvé-Perthes’ disease in Liverpool, 1982-95. Arch Dis Child. 2001;84:

351-4.

3. Molloy MK, MacMahon B. Incidence of Legg-Perthes disease (osteochondritis

deformans). N Engl J Med. 1966;275:988-90.

4. Wiig O, Terjesen T, Svenningsen S, Lie SA. The epidemiology and aetiology of

Perthes’disease inNorway.A nationwide study of425 patients.J Bone JointSurgBr.

2006;88:1217-23.

5. Legg A. An obscure affection of the hip joint. Boston Med Surg J. 1910;162:

202-4.

6. Calvé J. [On a particular form of pseudo-coxalgia associated with a characteristic

deformity of the upper end of the femur]. Rev Chir. 1910;42:54-84. French.

7. Perthes G. [Concerning arthritis deformans juvenilis]. Deutsche Zeitschr Chir.

1910;107:111-59. German.

8. Balasa VV, Gruppo RA, Glueck CJ, Wang P, Roy DR, Wall EJ, Mehlman CT,

Crawford AH. Legg-Calve-Perthes disease and thrombophilia. J Bone Joint Surg Am.2004;86:2642-7.

9. Glueck CJ, Glueck HI, Greenfield D, Freiberg R, Kahn A, Hamer T, Stroop D, Tracy

T. Protein C and S deficiency, thrombophilia, and hypofibrinolysis: pathophysiologic

causes of Legg-Perthes disease. Pediatr Res. 1994;35:383-8.

10. Hall DJ. Genetic aspects of Perthes’ disease. A critical review. Clin Orthop Relat

Res. 1986;209:100-14.

11. Hresko MT, McDougall PA, Gorlin JB, Vamvakas EC, Kasser JR, Neufeld EJ.

Prospective reevaluation of the association between thrombotic diathesis and legg-

perthes disease. J Bone Joint Surg Am. 2002;84:1613-8.

12. Miyamoto Y, Matsuda T, Kitoh H, Haga N, Ohashi H, Nishimura G, Ikegawa S.

A recurrent mutation in type II collagen gene causes Legg-Calvé-Perthes disease in

a Japanese family. Hum Genet. 2007;121:625-9.

13. Neidel J, Zander D, Hackenbroch MH. Low plasma levels of insulin-like growth

factor I in Perthes’ disease. A controlled study of 59 consecutive children. Acta

Orthop Scand. 1992;63:393-8.

667





10/11

14. Su P,Li R,Liu S, Zhou Y,Wang X, Patil N,Mow CS, Mason JC,HuangD, Wang Y.Age at onset-dependent presentations of premature hip osteoarthritis, avascular necrosis of the femoral head, or Legg-Calvé-Perthes disease in a single family,consequent upon a p.Gly1170Ser mutation of COL2A1. Arthritis Rheum.

2008;58:1701-6.

15. Wynne-Davies R, Gormley J. The aetiology of Perthes’ disease. Genetic, epi-demiological and growth factors in 310 Edinburgh and Glasgow patients. J Bone

Joint Surg Br. 1978;60:6-14.

16. Catterall A. The natural history of Perthes’ disease. J Bone Joint Surg Br.1971;53:37-53.

17. Gower WE, Johnston RC. Legg-Perthes disease. Long-term follow-up of thirty-sixpatients. J Bone Joint Surg Am. 1971;53:759-68.

18. McAndrew MP, Weinstein SL. A long-term follow-up of Legg-Calvé-Perthes dis-ease. J Bone Joint Surg Am. 1984;66:860-9.

19. Mose K. Methods of measuring in Legg-Calv é-Perthes disease with specialregard to the prognosis. Clin Orthop Relat Res. 1980;150:103-9.

20. Stulberg SD, Cooperman DR, Wallensten R. The natural history of Legg-Calvé-Perthes disease. J Bone Joint Surg Am. 1981;63:1095-108.

21. Waldenstrom H. The definitive forms of coxa plana. Acta Radiol. 1922;1:384.

22. Herring JA, Neustadt JB, Williams JJ, Early JS, Browne RH. The lateral pillar classification of Legg-Calvé-Perthes disease. J Pediatr Orthop. 1992;12:143-50.

23. Salter RB, Thompson GH. Legg-Calvé-Perthes disease. The prognostic signifi-cance of the subchondral fracture and a two-group classification of the femoral headinvolvement. J Bone Joint Surg Am. 1984;66:479-89.

24. Axer A. Subtrochanteric osteotomy in the treatment of Perthes’ disease: apreliminary report. J Bone Joint Surg Br. 1965;47:489-99.

25. Brotherton BJ, McKibbin B. Perthes’ disease treated by prolonged recumbency and femoral head containment: a long-term appraisal. J Bone Joint Surg Br.1977;59:8-14.

26. Joseph B, Rao N, Mulpuri K, Varghese G, Nair S. How does a femoral varusosteotomy alter the natural evolution of Perthes’ disease? J Pediatr Orthop B.2005;14:10-5.

27. Kruse RW, Guille JT, Bowen JR. Shelf arthroplasty in patients who have Legg-Calvé-Perthes disease. A study of long-term results. J Bone Joint Surg Am.1991;73:1338-47.

28. Petrie JG, Bitenc I. The abduction weight-bearing treatment in Legg-Perthes’disease. J Bone Joint Surg Br. 1971;53:54-62.

29. Salter RB. The present status of surgical treatment for Legg-Perthes disease.J Bone Joint Surg Am. 1984;66:961-6.

30. Herring JA, Kim HT, Browne R. Legg-Calve-Perthes disease. Part II: prospectivemulticenter study of the effect of treatment on outcome. J Bone Joint Surg Am.2004;86:2121-34.

31. Rosenfeld SB, Herring JA, Chao JC. Legg-Calve-Perthes disease: a review of cases with onset before six years of age. J Bone Joint Surg Am. 2007;89:2712-22.

32. Wiig O. Perthes’ disease in Norway. A prospective study on 425 patients. ActaOrthop Suppl. 2009;80:1-44.

33. Eyre-Brook A. Osteochondritis deformans coxae juvenilis or Perthes’ disease:the results of treatment by traction in recumbency. Br J Surg. 1936;24:166.

34. Harrison MH, Menon MP. Legg-Calvé-Perthes disease. The value of roentgen-

ographic measurement in clinical practice with special reference to the broomstickplaster method. J Bone Joint Surg Am. 1966;48:1301-18.

35. Bobechko WP. The Toronto brace for Legg-Perthes disease. Clin Orthop RelatRes. 1974;102:115-7.

36. Curtis BH, Gunther SF, Gossling HR, Paul SW. Treatment for Legg-Perthes dis-ease with the Newington ambulation-abduction brace. J Bone Joint Surg Am.1974;56:1135-46.

37. Harrison MH, Turner MH, Nicholson FJ. Coxa plana. Results of a new form of splinting. J Bone Joint Surg Am. 1969;51:1057-69.

38. King EW, Fisher RL, Gage JR, Gossling HR. Ambulation-abduction treatment inLegg-Calvé-Perthes disease (LCPD). Clin Orthop Relat Res. 1980;150:43-8.

39. Purvis JM, Dimon JH 3rd, Meehan PL, Lovell WW. Preliminary experience withthe Scottish Rite Hospital abduction orthosis for Legg-Perthes disease. Clin OrthopRelat Res. 1980;150:49-53.

40. Vukasinovic Z, Spasovski D, Vucetic C, Cobeljic G, Zivkovic Z, Matanovic D.Triple pelvic osteotomy in the treatment of Legg-Calve-Perthes disease. Int Orthop.2009;33:1377-83.

41. Javid M, Wedge JH. Radiographic results of combined Salter innominate andfemoral osteotomy in Legg-Calvé-Perthes disease in older children. J Child Orthop.2009;3:229-34.

42. Rab GT. Containment of the hip: a theoretical comparison of osteotomies. ClinOrthop Relat Res. 1981;154:191-6.

43. Rab GT. Theoretical study of subluxation in early Legg-Calvé-Perthes disease.J Pediatr Orthop. 2005;25:728-33.

44. WiigO, TerjesenT, Svenningsen S. Prognostic factors and outcome of treatment

in Perthes’ disease: a prospective study of 368 patients with five-year follow-up.J Bone Joint Surg Br. 2008;90:1364-71.

45. Heikkinen E, Puranen J. Evaluation of femoral osteotomy in the treatment of Legg-Calvé-Perthes disease. Clin Orthop Relat Res. 1980;150:60-8.

46. Bahmanyar S, Montgomery SM, Weiss RJ, Ekbom A. Maternal smoking duringpregnancy, other prenatal and perinatal factors, and the risk of Legg-Calv é-Perthesdisease. Pediatrics. 2008;122:e459-64.

47. Gordon JE,SchoeneckerPL, Osland JD,Dobbs MB,SzymanskiDA, Luhmann SJ.Smoking and socio-economic status in the etiology and severity of Legg-Calv é-Perthes’ disease. J Pediatr Orthop B. 2004;13:367-70.

48. Matsumoto T, Enomoto H, Takahashi K, Motokawa S. Decreased levels of IGF binding protein-3 in serum from children with Perthes’ disease. Acta Orthop Scand.1998;69:125-8.

49. Neidel J, Schönau E, Zander D, Rütt J, Hackenbroch MH. Normal plasma levelsof IGF binding protein in Perthes’ disease. Follow-up of previous report. Acta OrthopScand. 1993;64:540-2.

50. Liu YF, Chen WM, Lin YF, Yang RC, Lin MW, Li LH, Chang YH, Jou YS, Lin PY, SuJS,Huang SF, Hsiao KJ,FannCS, HwangHW, Chen YT,TsaiSF.Type II collagen genevariants and inherited osteonecrosis of the femoral head. N Engl J Med. 2005;352:2294-301.

51. Arruda VR, Belangero WD, Ozelo MC, Oliveira GB, Pagnano RG, Volpon JB,Annichino-Bizzacchi JM. Inherited risk factors for thrombophilia among children withLegg-Calvé-Perthes disease. J Pediatr Orthop. 1999;19:84-7.

52. Eldridge J, Dilley A, Austin H, EL-Jamil M, Wolstein L, Doris J, Hooper WC,Meehan PL, Evatt B. The role of protein C, protein S, and resistance to activatedprotein C in Legg-Perthes disease. Pediatrics. 2001;107:1329-34.

53. Gruppo R, Glueck CJ, Wall E, Roy D, Wang P. Legg-Perthes disease in threesiblings, two heterozygous and one homozygous for the factor V Leiden mutation.J Pediatr. 1998;132:885-8.

54. Szepesi K, Pósán E, Hársfalvi J, Ajzner E, Szücs G, Gáspár L, Csernátony Z,Udvardy M. The most severe forms of Perthes’ disease associated with the homo-zygous Factor V Leiden mutation. J Bone Joint Surg Br. 2004;86:426-9.

55. Vosmaer A, Pereira RR, Koenderman JS, Rosendaal FR, Cannegieter SC. Co-agulation abnormalities in Legg-Calvé-Perthes disease. J Bone Joint Surg Am.2010;92:121-8.

56. Hayek S, Kenet G, Lubetsky A, Rosenberg N, Gitel S, Wientroub S. Doesthrombophilia play an aetiological role in Legg-Calvé-Perthes disease? J Bone JointSurg Br. 1999;81:686-90.

57. Kealey WD, Mayne EE, McDonald W, Murray P, Cosgrove AP. The role of coag-ulation abnormalities in the development of Perthes’ disease. J Bone Joint Surg Br.2000;82:744-6.

58. Kenet G, Ezra E, Wientroub S, Steinberg DM, Rosenberg N, Waldman D, HayekS. Perthes’ disease and the search for genetic associations: collagen mutations,Gaucher’s disease and thrombophilia. J Bone Joint Surg Br. 2008;90:1507-11.

59. López-Franco M, González-Mor ́an G, De Lucas JC Jr, Llamas P, de Velasco JF,Vivancos JC, Epeldegui-Torre T. Legg-perthes disease and heritable thrombophilia.J Pediatr Orthop. 2005;25:456-9.

60. Sirvent N, Fisher F, el Hayek T, Appert A, Giudicelli H, Griffet J. Absence of congenital prethrombotic disorders in children with Legg-Perthes disease. J Pediatr Orthop B. 2000;9:24-7.

61. Atsumi T, Yamano K, Muraki M, Yoshihara S, Kajihara T. The blood supply of thelateral epiphyseal arteries in Perthes’ disease. J Bone Joint Surg Br. 2000;82:392-8.

62. de Camargo FP, de Godoy RM Jr, Tovo R. Angiography in Perthes’ disease. ClinOrthop Relat Res. 1984;191:216-20.

63. Théron J. Angiography in Legg-Calvé-Perthes disease. Radiology. 1980;135:81-92.

64. Conway JJ. A scintigraphic classification of Legg-Calvé-Perthes disease. SeminNucl Med. 1993;23:274-95.

65. Lamer S, Dorgeret S, Khairouni A, Mazda K, Brillet PY, Bacheville E, Bloch J,Pennecxot GF,Hassan M, SebagGH. Femoral headvascularisation in Legg-Calvé-Perthesdisease: comparison of dynamic gadolinium-enhanced subtraction MRI with bonescintigraphy. Pediatr Radiol. 2002;32:580-5.

66. Catterall A, Pringle J, Byers PD, Fulford GE, Kemp HB, Dolman CL, Bell HM,McKibbin B, Rális Z, Jensen OM, Lauritzen J, Ponseti IV, Ogden J. A review of the

morphology of Perthes’ disease. J Bone Joint Surg Br. 1982;64:269-75.

67. Jonsater S. Coxa plana; a histo-pathologic and arthrografic study. Acta OrthopScand Suppl. 1953;12:5-98.

68. Kim HK, Su PH.Development of flatteningand apparent fragmentationfollowingischemic necrosis of the capital femoral epiphysis in a piglet model. J Bone JointSurg Am. 2002;84:1329-34.

69. Shapiro F, Connolly S, Zurakowski D, Menezes N, Olear E, Jimenez M, Flynn E,Jaramillo D. Femoral head deformation and repair following induction of ischemicnecrosis: a histologic and magnetic resonance imaging study in the piglet. J BoneJoint Surg Am. 2009;91:2903-14.

70. Sanchis M, Zahir A, Freeman MA. The experimental simulation of Perthes dis-ease by consecutive interruptions of the blood supply to the capital femoral epiph-ysis in the puppy. J Bone Joint Surg Am. 1973;55:335-42.

71. Zahir A, Freeman AR. Cartilage changes following a single episode of infarctionof the capital femoral epiphysis in the dog. J Bone Joint Surg Am. 1972;54:125-36.

668





11/11

72. Inoue A, Freeman MA, Vernon-Roberts B, Mizuno S. The pathogenesis of Perthes’ disease. J Bone Joint Surg Br. 1976;58:453-61.

73. Dolman CL, Bell HM. The pathology of Legg-Calvé-Perthes disease. A casereport. J Bone Joint Surg Am. 1973;55:184-8.

74. McKibbin B, Rális Z. Pathologicalchangesin a case of Perthes’ disease. J BoneJoint Surg Br. 1974;56:438-47.

75. Idiopathic osteonecrosis of the juvenile femoral head (Legg-Calve-Perthes dis-ease). In: Milgram JW. Radiologic and histologic pathologyof nontumorousdiseasesof bones and joints. Northbrook: Northbrook Pub Co; 1990. p 1093-113.

76. Ponseti IV. Legg-Perthes disease; observations on pathological changes in twocases. J Bone Joint Surg Am. 1956;38:739-50.

77. Hofstaetter JG, Roschger P, Klaushofer K, Kim HK. Increased matrix minerali-zation in the immature femoral head following ischemic osteonecrosis. Bone.2010;46:379-85.

78. Kim HK, Su PH, Qiu YS. Histopathologic changes in growth-plate cartilage fol-lowing ischemic necrosis of the capital femoral epiphysis. An experimental investi-gation in immature pigs. J Bone Joint Surg Am. 2001;83:688-97.

79. Koob TJ, Pringle D, Gedbaw E, Meredith J, Berrios R, Kim HK. Biomechanicalproperties of bone and cartilage in growing femoral head following ischemic osteo-necrosis. J Orthop Res. 2007;25:750-7.

80. Pringle D, Koob TJ, Kim HK. Indentation properties of growing femoral headfollowing ischemic necrosis. J Orthop Res. 2004;22:122-30.

81. Phemister DB. Treatment of the necrotic head of the femur in adults. J BoneJoint Surg Am. 1949;31:55-66.

82. Aya-ay J, Athavale S, Morgan-Bagley S, Bian H, Bauss F, Kim HK. Retention,distribution, and effects of intraosseously administered ibandronate in the infarctedfemoral head. J Bone Miner Res. 2007;22:93-100.

83. Kim HK, Morgan-Bagley S, Kostenuik P. RANKL inhibition: a novel strategy todecrease femoral head deformity after ischemic osteonecrosis. J Bone Miner Res.2006;21:1946-54.

84. Kim HK, Randall TS, Bian H, Jenkins J, Garces A, Bauss F. Ibandronate for prevention of femoral head deformity after ischemic necrosis of the capital femoralepiphysis in immature pigs. J Bone Joint Surg Am. 2005;87:550-7.

85. LittleDG, McDonald M, SharpeIT, Peat R,WilliamsP, McEvoyT. Zoledronic acidimproves femoral head sphericity in a rat model of perthes disease. J Orthop Res.2005;23:862-8.

86. Little DG, Peat RA, Mcevoy A, Williams PR, Smith EJ, Baldock PA. Zoledronicacid treatment results in retention of femoral head structure after traumatic osteo-necrosis in young Wistar rats. J Bone Miner Res. 2003;18:2016-22.

87. Carlson CS, Meuten DJ, Richardson DC. Ischemic necrosis of cartilage in spon-taneous and experimental lesions of osteochondrosis. J Orthop Res. 1991;9:317-29.

88. McKibbin B, Holdsworth FW. The nutrition of immature joint cartilage in the

lamb. J Bone Joint Surg Br. 1966;48:793-803.89. Kim HK, Bian H, Aya-ay J, Garces A, Morgan EF, Gilbert SR. Hypoxia andHIF-1alpha expression in the epiphyseal cartilage following ischemic injury to theimmature femoral head. Bone. 2009;45:280-8.

90. Kim HK, Bian H, Randall T, Garces A, Gerstenfeld LC, Einhorn TA. IncreasedVEGF expression in the epiphyseal cartilage after ischemic necrosis of the capitalfemoral epiphysis. J Bone Miner Res. 2004;19:2041-8.

91. Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N. VEGF coupleshypertrophic cartilage remodeling, ossification and angiogenesis during endochon-dral bone formation. Nat Med. 1999;5:623-8.

92. Vandermeer JS, Kamiya N, Aya-ay J, Garces A, Browne R, Kim HK. Local ad-ministration of ibandronate and bone morphogenetic protein-2 after ischemicosteonecrosis of the immature femoral head: a combined therapy that stimulatesbone formation and decreases femoral head deformity. J Bone Joint Surg Am.2011;18:905-13.

93. Bergmann G, Deuretzbacher G, Heller M, Graichen F, Rohlmann A, Strauss J,Duda GN. Hip contact forces and gait patterns from routine activities. J Biomech.2001;34:859-71.

94. Bergmann G, Graichen F, Rohlmann A. Hip joint loading during walking andrunning, measured in two patients. J Biomech. 1993;26:969-90.

95. Song KM, Bjornson KF, Cappello T, Coleman K. Use of the StepWatch activity monitor for characterization of normal activity levels of children. J Pediatr Orthop.2006;26:245-9.

96. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation.Nature. 2003;423:337-42.

97. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, DelmasP, Zoog HB,Austin M, Wang A,Kutilek S,Adami S, ZanchettaJ, Libanati C,SiddhantiS, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in post-menopausal women with osteoporosis. N Engl J Med. 2009;361:756-65.

98. Russell RG, XiaZ, Dunford JE,Oppermann U,Kwaasi A,Hulley PA, KavanaghKL,Triffitt JT,Lundy MW,Phipps RJ,BarnettBL, Coxon FP,Rogers MJ,Watts NB, EbetinoFH. Bisphosphonates: an update on mechanisms of action and how these relate to

clinical efficacy. Ann N Y Acad Sci. 2007;1117:209-57.

99. Kim HK, Sanders M, Athavale S, Bian H, Bauss F. Local bioavailability anddistribution of systemically (parenterally) administered ibandronate in the infarctedfemoral head. Bone. 2006;39:205-12.

100. Johannesen J,Briody J,McQuade M,Little DG,Cowell CT, Munns CF.Systemiceffects of zoledronic acid in children with traumatic femoral head avascular necrosisand Legg-Calve-Perthes disease. Bone. 2009;45:898-902.

101. Giannoudis PV, Einhorn TA. Bone morphogenetic proteins in musculoskeletalmedicine. Injury. 2009;40 Suppl 3:S1-3.

102. Mont MA, Ragland PS, Biggins B, Friedlaender G, Patel T, Cook S, Etienne G,Shimmin A,Kildey R,Rueger DC,EinhornTA.Use of bone morphogenetic proteins for musculoskeletal applications. An overview. J Bone Joint Surg Am. 2004;86 Suppl2:41-55.

103. Urist MR. Bone: formation by autoinduction. Science. 1965;150:893-9.

104. Simank HG, Manggold J, Sebald W, Ries R, Richter W, Ewerbeck V, Sergi C.Bone morphogenetic protein-2 and growth and differentiation factor-5 enhance thehealing of necrotic bone in a sheep model. Growth Factors. 2001;19:247-57.

105. Tang TT, Lu B, Yue B, Xie XH, Xie YZ, Dai KR, Lu JX, Lou JR. Treatment of osteonecrosis of the femoral head with hBMP-2-gene-modified tissue-engineered

bone in goats. J Bone Joint Surg Br. 2007;89:127-9.

106. Mont MA,JonesLC, Elias JJ,InoueN, Yoon TR, Chao EY, Hungerford DS.Strut-autografting with and without osteogenic protein-1: a preliminary study of a caninefemoral head defect model. J Bone Joint Surg Am. 2001;83:1013-22.

107. Lieberman JR, Conduah A, Urist MR. Treatment of osteonecrosis of the fem-oral head with core decompression and human bone morphogenetic protein. ClinOrthop Relat Res. 2004;429:139-45.

108. Itoh K, Udagawa N, Katagiri T, Iemura S, Ueno N, Yasuda H, Higashio K, QuinnJM, Gillespie MT, Martin TJ, Suda T, Takahashi N. Bone morphogenetic protein 2stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kappaB ligand. Endocrinology. 2001;142:3656-62.

109. Kamiya N, Ye L, Kobayashi T, Lucas DJ, Mochida Y, Yamauchi M, KronenbergHM, Feng JQ, Mishina Y. Disruption of BMP signaling in osteoblasts throughtype IA receptor (BMPRIA) increases bone mass. J Bone Miner Res. 2008;23:2007-17.

110. KanekoH, Arakawa T,Mano H,Kaneda T,Ogasawara A,NakagawaM, Toyama

Y, Yabe Y, Kumegawa M, Hakeda Y. Direct stimulation of osteoclastic bone re-sorption by bone morphogenetic protein (BMP)-2and expressionof BMPreceptors inmature osteoclasts. Bone. 2000;27:479-86.

111. Seeherman HJ, Li XJ, Bouxsein ML, Wozney JM. rhBMP-2 induces transientbone resorption followed by bone formation in a nonhuman primate core-defectmodel. J Bone Joint Surg Am. 2010;92:411-26.

112. Agarwala S, Jain D, Joshi VR, Sule A. Efficacy of alendronate, a bisphosphonate,in the treatment of AVN of the hip. A prospective open-label study. Rheumatology (Oxford). 2005;44:352-9.

113. Agarwala S, Shah S, Joshi VR. The use of alendronate in the treatment of avascularnecrosis of thefemoralhead:follow-up to eight years.J Bone JointSurgBr.2009;91:1013-8.

114. Lai KA, Shen WJ, Yang CY, Shao CJ, Hsu JT, Lin RM. The use of alendronate toprevent early collapse of the femoral head in patients with nontraumatic osteone-crosis. A randomized clinical study. J Bone Joint Surg Am. 2005;87:2155-9.

115. Nishii T, Sugano N, Miki H, Hashimoto J, Yoshikawa H. Does alendronateprevent collapse in osteonecrosis of the femoral head? Clin Orthop Relat Res.2006;443:273-9.

116. Ramachandran M, Ward K, Brown RR, Munns CF, Cowell CT, Little DG. Intra-venous bisphosphonate therapy for traumatic osteonecrosis of the femoral head inadolescents. J Bone Joint Surg Am. 2007;89:1727-34.

117. Kotecha RS, Powers N, Lee SJ, Murray KJ, Carter T, Cole C. Use of bis-phosphonates for the treatment of osteonecrosis as a complication of therapy for childhood acute lymphoblastic leukaemia (ALL). Pediatr Blood Cancer. 2010;54:934-40.

669




pathophysiology puenting

Documents

Transcript of pathophysiology puenting