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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="StatPearls [Internet]" /><meta name="citation_title" content="Osteonecrosis Imaging" /><meta name="citation_publisher" content="StatPearls Publishing" /><meta name="citation_date" content="2024/05/25" /><meta name="citation_author" content="Oana M. Stroie" /><meta name="citation_author" content="Van H. Vu" /><meta name="citation_pmid" content="38861639" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK604199/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Osteonecrosis Imaging" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="StatPearls Publishing" /><meta name="DC.Contributor" content="Oana M. Stroie" /><meta name="DC.Contributor" content="Van H. Vu" /><meta name="DC.Date" content="2024/05/25" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK604199/" /><meta name="description" content="Osteonecrosis is ischemia of bone due to inadequate vascular supply. This condition results in bone tissue death and loss of structural integrity. If left untreated, it can lead to bone collapse. This condition is also known as avascular necrosis or aseptic necrosis when it involves the epiphysis and as bone infarct when it involves metadiaphyseal regions of bone." /><meta name="og:title" content="Osteonecrosis Imaging" /><meta name="og:type" content="book" /><meta name="og:description" content="Osteonecrosis is ischemia of bone due to inadequate vascular supply. This condition results in bone tissue death and loss of structural integrity. If left untreated, it can lead to bone collapse. This condition is also known as avascular necrosis or aseptic necrosis when it involves the epiphysis and as bone infarct when it involves metadiaphyseal regions of bone." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK604199/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-statpearls-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/statpearls/article-155093/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK604199/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><meta name="book-collection" content="NONE" />
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/statpearls/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-statpearls-lrg.png" alt="Cover of StatPearls" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>StatPearls [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK604199_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK604199_dtls__"><div>Treasure Island (FL): <a href="https://www.statpearls.com/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">StatPearls Publishing</a>; 2025 Jan-.</div></div><div class="half_rhythm"></div><div class="bk_noprnt"><form method="get" action="/books/n/statpearls/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK604199_"><span class="title" itemprop="name">Osteonecrosis Imaging</span></h1><p class="contrib-group"><span itemprop="author">Oana M. Stroie</span>; <span itemprop="author">Van H. Vu</span>.</p><a data-jig="ncbitoggler" href="#__NBK604199_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK604199_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Oana M. Stroie</span><sup>1</sup>; <span itemprop="author">Van H. Vu</span><sup>2</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> Walter Reed Military Medical Center</div><div class="affiliation"><sup>2</sup> Louisiana State University Health Sciences Center, Shreveport, LA</div></div><p class="small">Last Update: <span itemprop="dateModified">May 25, 2024</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="article-155093.s1"><h2 id="_article-155093_s1_">Continuing Education Activity</h2><p>Osteonecrosis refers to the ischemic death of elements of a bone caused by compromised vascular integrity, such as loss of blood supply to a region of bone. This condition is a common pathology with diverse etiologies and can affect nearly any bone in the body. The most common etiologies are chronic corticosteroid use, alcoholism, trauma, and idiopathic factors.</p><p>Timely and accurate identification of osteonecrosis changes through imaging is crucial to prevent irreversible joint damage. Magnetic resonance imaging is the most sensitive imaging modality as it can demonstrate early osseous changes that may be present before plain radiographic changes are visible. Integrated models incorporating clinical and imaging findings have been developed to aid healthcare professionals in understanding, diagnosing, and stratifying the risk of potential subchondral collapse and the benefits of prompt and appropriate treatment to improve patient outcomes in this important, potentially debilitating, yet prevalent condition. </p><p>This activity enhances clinicians' understanding and proficiency in diagnosing and managing osteonecrosis through advanced imaging techniques. In addition, this activity comprehensively covers various imaging modalities available, including x-rays, computed tomography scans, magnetic resonance imaging, and nuclear medicine studies, highlighting their specific applications and sensitivities at various disease stages. By providing this knowledge, healthcare professionals are equipped to ensure timely diagnosis, mitigate complications, and optimize patient outcomes.</p><p>
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<b>Objectives:</b>
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||
<ul><li class="half_rhythm"><div>Assess the typical imaging modalities used for diagnosing osteonecrosis and determine their appropriate usage, depending on the patient's clinical presentation and the availability of diagnostic imaging resources.</div></li><li class="half_rhythm"><div>Identify the various imaging presentations of osteonecrosis in different osseous areas of the body.</div></li><li class="half_rhythm"><div>Differentiate the potential complications of osteonecrosis and the methods for assessing them.</div></li><li class="half_rhythm"><div>Collaborate with an interprofessional team to ensure comprehensive imaging assessments for patients with osteonecrosis.</div></li></ul>
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</p></div><div id="article-155093.s2"><h2 id="_article-155093_s2_">Introduction</h2><p>Osteonecrosis is ischemia of bone due to inadequate vascular supply. This condition results in bone tissue death and loss of structural integrity. If left untreated, it can lead to bone collapse. This condition is also known as avascular necrosis or aseptic necrosis when it involves the epiphysis and as bone infarct when it involves metadiaphyseal regions of bone.</p><p>Osteonecrosis is common and typically asymptomatic in its early stages. This condition affects various bones in the body, including hips, knees, shoulders, ankles, and small bones of hands and feet. Some of the most common causes of osteonecrosis include chronic corticosteroid use, alcohol use disorder, trauma, and idiopathic causes. Other common predispositions include systemic diseases such as sickle cell anemia and collagen vascular disease.<a class="bk_pop" href="#article-155093.r1">[1]</a><a class="bk_pop" href="#article-155093.r2">[2]</a> </p><p>Osteonecrosis may be asymptomatic in its early stage. This condition can also present with limited movement, inability to bear weight, significant pain, and swelling of the affected joint. Recognizing various presentations of osteonecrosis is crucial. In addition, understanding when and what further necessitates evaluation is important.</p><p>When osteonecrosis involves the small bones of hands and feet or epiphysis of long bones, it is essential to assess the risk of secondary complications such as subchondral collapse. Imaging modalities used to evaluate osteonecrosis include plain radiographs, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine studies. However, knowing which modality is most sensitive at a certain point in the patient's clinical presentation and when it is necessary is crucial. Early diagnosis and treatment of osteonecrosis affecting epiphyseal locations remains the key to joint preservation.</p></div><div id="article-155093.s3"><h2 id="_article-155093_s3_">Anatomy</h2><p>The bone is a complex organ composed of cortical and trabecular bone structures. Osteonecrosis involves the trabecular and subcortical bone. The pathophysiology of osteonecrosis is characterized by cell death due to lack of blood supply, followed by a complex process of bone resorption and formation in an attempt to heal. The healing process includes walling off the dead bone by forming a fibrotic rim at the margin between the living and dead bone. At this interface, granulation tissue develops with osteoblasts encapsulating the dead trabeculae and osteoclasts that partially reabsorb the dead bone. In the subchondral trabeculae, the bone resorption rate exceeds the bone formation rate, leading to a net removal of bone and loss of structural integrity.<a class="bk_pop" href="#article-155093.r3">[3]</a> This area is then predisposed to increased compressive forces and subsequent subchondral collapse. </p><p>These histological changes can be observed on radiographs as serpentine areas of sclerosis and lucency. The lucent areas represent bone resorption, whereas the sclerotic areas represent mixed areas of living and dead bone trabeculae.<a class="bk_pop" href="#article-155093.r1">[1]</a><a class="bk_pop" href="#article-155093.r3">[3]</a> These changes are most prominently observed in the diaphysis and metaphysis of long bones. Osteonecrosis affecting the diaphysis and metaphysis is less clinically important because dead bone in long bones is not subject to the same compressive forces, and it is considered just as strong as living bone without the ability to remodel.<a class="bk_pop" href="#article-155093.r1">[1]</a> In these locations, it often goes underdiagnosed as it is typically asymptomatic and often incidentally found. </p><p>Osteonecrosis affecting small bones commonly has a history of antecedent trauma. This condition affects many bones of the hands and feet, the most commonly involved being the scaphoid bone, lunate, and talus. On plain film, it often appears as an increased area of sclerosis requiring MRI for further evaluation. </p><p>Most osteonecrosis sites are associated with a specific eponym (see <b>Table 1.</b> Common Osteonecrosis Eponyms).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figarticle155093table0"><a href="/books/NBK604199/table/article-155093.table0/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobarticle155093table0"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="article-155093.table0"><a href="/books/NBK604199/table/article-155093.table0/?report=objectonly" target="object" rid-ob="figobarticle155093table0">Table</a></h4><p class="float-caption no_bottom_margin">Table 1. Common Osteonecrosis Eponyms. </p></div></div><p>The etiologies of osteonecrosis are diverse. Trauma is a frequent cause of symptomatic osteonecrosis of the femoral head, scaphoid, and talus due to disruption of the end arterial supply. The most common nontraumatic causes of osteonecrosis include chronic corticosteroid use, excessive alcohol consumption, and idiopathic factors. Sickle cell disease is an important consideration of nontraumatic causes due to the precipitation of hemoglobin S in low-oxygen environments, leading to vasocclusion and bone ischemia.<a class="bk_pop" href="#article-155093.r2">[2]</a> Drug therapy with bisphosphonates has a well-known association with osteonecrosis of the jaw due to inhibition of bone turnover.<a class="bk_pop" href="#article-155093.r4">[4]</a> In the renal transplant population, there is also a high prevalence of this condition due to chronic high-dose steroid use and chronic immunosuppression. Nontraumatic causes are often bilateral and have multiple affected sites. A detailed clinical history, including the patient's predisposing risk factors, is crucial when interpreting diagnostic imaging studies, particularly for plain radiographs, to improve sensitivity in detecting subtle areas of osteonecrosis, particularly in the epiphysis. </p><p>Some of the more common causes of osteonecrosis include the following:</p><ul><li class="half_rhythm"><div>Trauma</div></li><li class="half_rhythm"><div>Chronic high-dose corticosteroid use </div></li><li class="half_rhythm"><div>Alcohol use disorder</div></li><li class="half_rhythm"><div>Sickle cell disease or hemoglobinopathies</div></li><li class="half_rhythm"><div>Systemic lupus erythematosus</div></li><li class="half_rhythm"><div>Antiphospholipid antibody syndrome</div></li><li class="half_rhythm"><div>Gaucher disease </div></li><li class="half_rhythm"><div>Metabolic diseases such as hyperlipidemia</div></li><li class="half_rhythm"><div>Renal transplantation</div></li><li class="half_rhythm"><div>HIV</div></li><li class="half_rhythm"><div>Prior radiation therapy</div></li><li class="half_rhythm"><div>Chemotherapy</div></li><li class="half_rhythm"><div>Decompression sickness </div></li><li class="half_rhythm"><div>Bisphosphonate use</div></li></ul></div><div id="article-155093.s4"><h2 id="_article-155093_s4_">Plain Films</h2><p>Plain films or radiographs are good initial imaging exams to begin the evaluation. Although not as sensitive for detecting early changes in osteonecrosis, plain radiographs are readily accessible, inexpensive, and can exclude other underlying causes of bone pain. Radiographs have imaging characteristics that may limit the need for additional imaging evaluations.<a class="bk_pop" href="#article-155093.r1">[1]</a></p><p>Early findings may show minor osteopenia compared to the contralateral bone. In small bones, osteonecrosis appears as areas of increased sclerosis compared to adjacent bones. In long bones, early to chronic characteristic imaging findings show patchy areas of lucency with a serpentine rim of sclerosis. The serpentine sclerotic rim is most conspicuous in meta-diaphyseal zones (see <b>Image.</b> Metaphyseal Osteonecrosis).</p><p>Early findings may show slight osteopenia in comparison to the opposite bone. In small bones, osteonecrosis will appear as areas with increased hardness compared to nearby bones. In long bones, characteristic imaging findings from early to chronic stages include scattered areas of hollowness surrounded by a winding rim of hardness. This winding hard rim is most noticeable in the areas between the metaphysis and diaphysis</p><p>Plain radiographs also show late findings and complications involving the epiphysis, such as articular collapse. Articular collapse occurs when there is epiphyseal osteonecrosis with areas extending to the junction of the articular surface and subchondral bone (see <b>Image.</b> Articular Collapse). When stress is maximally exerted at these sites, the underlying necrotic subchondral bone collapses, creating a linear crescentic subchondral lucency known as the crescent sign (see <b>Image.</b> Crescent Sign).<a class="bk_pop" href="#article-155093.r5">[5]</a> Eventually, the bone cortex collapses and fragments, leading to secondary progressive degenerative changes.</p></div><div id="article-155093.s5"><h2 id="_article-155093_s5_">Computed Tomography</h2><p>CT is useful in the advanced stages of osteonecrosis and for surgical planning once the diagnosis of osteonecrosis is established. This technique is valuable in evaluating bony details to delineate the location and extent of articular collapse, particularly when there is epiphyseal involvement. CT scans typically share similar imaging characteristics as observed in plain radiographs, showing a serpentine sclerotic rim around the area of osteonecrosis and detecting subchondral fractures with the crescent sign (see <b>Image.</b> Crescent Sign on CT scan).</p><p>There is limited use of CT for early detection, and it should not be used as first-line imaging when clinically suspecting osteonecrosis.<a class="bk_pop" href="#article-155093.r6">[6]</a> Consideration should be given to the risk of radiation exposure, particularly in younger patients. However, preoperative CT before total hip arthroplasty has shown improved sensitivity for femoral head collapse, ultimately upstaging femoral head osteonecrosis in 20% of patients, according to the Association Research Circulation Osseous (ARCO) classification.<a class="bk_pop" href="#article-155093.r7">[7]</a> Thus, the advantages and disadvantages of CT imaging before surgery should be considered with the patient individually. </p></div><div id="article-155093.s6"><h2 id="_article-155093_s6_">Magnetic Resonance</h2><p>MRI is the gold standard for imaging and characterizing osteonecrosis, with a high sensitivity and specificity of nearly 100%. MRI should be performed when there is clinical suspicion for osteonecrosis as the next line imaging study, after plain radiographs, if needed for further characterization. MRI allows for the evaluation of volume and associated inflammatory changes.<a class="bk_pop" href="#article-155093.r6">[6]</a> Imaging findings on MRI can manifest as early as 1 week from vascular injury.<a class="bk_pop" href="#article-155093.r1">[1]</a> The classic MRI pattern is a rim of low signal intensity on all pulse sequences followed by a second inner rim of high signal intensity observed on fluid-sensitive sequences, known as the double-line sign (see <b>Image. </b>MRI of Double-Line Sign with Subchondral Collapse).<a class="bk_pop" href="#article-155093.r5">[5]</a> The rim of low signal intensity observed on all sequences represents the outside rim of sclerosis, and the inner rim of the high signal represents the reactive interface or zone of creeping substitution.<a class="bk_pop" href="#article-155093.r1">[1]</a></p><p>In small bones, a double-line sign may not be as apparent. Characteristic findings of osteonecrosis in small bones generally demonstrate low signal intensity on T1 sequences (compared to skeletal muscle) with variable T2 signal. Fluid-sensitive sequences show early increased signal in acute osteonecrosis and decreased signal in advanced stages of the disease. Other secondary signs may be observed, such as changes in morphology and malignment of, and relative to, the adjacent bones and the development of secondary osteoarthritis.<a class="bk_pop" href="#article-155093.r1">[1]</a></p><p>Contrast is generally not necessary in evaluating osteonecrosis. Occasionally, contrast-enhanced MRI and dynamic contrast-enhanced studies may be used to distinguish between transient bone marrow edema syndrome and subchondral insufficiency fracture. Contrast-enhanced exams may demonstrate areas of reduced enhancement in osteonecrosis, thus confirming areas of devascularization.<a class="bk_pop" href="#article-155093.r8">[8]</a><a class="bk_pop" href="#article-155093.r9">[9]</a></p><p>MRI is useful for assessing the volume and presence of bone marrow edema and joint effusions, which in turn help predict the risk of subchondral collapse. However, MRI has limitations in evaluating the extent of articular collapse required for surgical planning. In contrast, CT is better suited for assessing osseous details and visualizing fractures that extend to the cortex.<a class="bk_pop" href="#article-155093.r10">[10]</a> CT and MRI can be complementary to each other.</p></div><div id="article-155093.s7"><h2 id="_article-155093_s7_">Nuclear Medicine</h2><p>When MRI is inconclusive or when there are contraindications to MRI, bone scans are often used as an alternative route to image early changes of osteonecrosis and determine the risk of impeding bone collapse.<a class="bk_pop" href="#article-155093.r11">[11]</a> The most common bone scan is technetium-99m methylene diphosphonate (99mTc-MDP). This scan is often performed as a single delayed phase or in 3 phases—flow, blood pool, and delayed phase. MDP is a phosphate analog taken up by osteoblasts through chemisorption, binding to crystalline hydroxyapatite in the osseous matrix.</p><p>Osteonecrosis is a progressive condition, and its appearance in bone scans often depends on the stage of the disease. Osteonecrosis can be visualized on bone scans as soon as 7 to 10 days from an event, typically appearing as normal or as a general area of photopenia on delayed images due to a lack of radioisotope uptake in avascular bone.<a class="bk_pop" href="#article-155093.r5">[5]</a> Increased radiotracer activity is observed after 1 to 3 weeks due to increased osteoblastic activity at the reactive interface around the necrotic component as the tissue attempts to heal. On imaging, this gives the classic donut sign or ring sign with a hot area of increased activity around a central cold photopenic defect. Overall sensitivity in diagnosing osteonecrosis of the femoral head ranges from 78% to 91%, depending on the healing phase. However, it remains relatively nonspecific as many bone pathologies may present similarly. MDP bone scans are limited by spatial resolution; however, combining them with single-photon emission computed tomography/CT has improved accuracy at 3-dimensional localization.<a class="bk_pop" href="#article-155093.r11">[11]</a></p><p>Positron emission tomography (PET) imaging using F18 glucose is a diagnostic imaging technique used to detect metabolic abnormalities. Although it is not ideal for examining the bone in isolation, it can detect areas of increased bone metabolism. Thus, it is useful for identifying osteoblastic activity and bone turnover. Studies on femoral head osteonecrosis have shown that F18 PET/CT has improved sensitivity and accuracy compared to MRI.<a class="bk_pop" href="#article-155093.r12">[12]</a> Evidence suggests that the metabolic information obtained may predict the risk of impeding femoral head collapse before changes become apparent on plain film.<a class="bk_pop" href="#article-155093.r13">[13]</a> Metabolic activity is quantified through maximum standardized uptake value (SUVmax) and increases with stage progression. Kubota et al concluded that SUVmax >6.45 leads to femoral head collapse within 12 months. When combined with plain radiographs or MRI for type classification, PET imaging has shown increased specificity for predicting femoral head collapse.<a class="bk_pop" href="#article-155093.r13">[13]</a> Thus, PET can be used as an adjunct in early clinical management for joint preservation but should not be used as first-line screening due to its excessive cost and radiation exposure.</p></div><div id="article-155093.s8"><h2 id="_article-155093_s8_">Clinical Significance</h2><p>Patients with osteonecrosis in epiphyseal locations in the femoral head and small bones, such as the lunate, are at an increased risk of subchondral collapse. Early diagnosis and treatment are crucial for joint preservation. The goal of imaging should be to identify osteonecrosis before it undergoes irreversible change. The care of patients with osteonecrosis necessitates a collaborative approach among healthcare professionals to ensure patient-centered care and improved overall outcomes. Radiograph and MRI classification systems have been developed in conjunction with clinical findings to help accurately describe the progression of osteonecrosis for further risk stratification. Below is a summary of commonly used classification systems in clinical practice for femoral head and lunate osteonecrosis. </p><p>Osteonecrosis affecting long bone metaphysis and diaphysis is often clinically occult and may go underdiagnosed. A rare complication of osteonecrosis that clinicians should be made aware of when new clinical findings arise is described. </p><p>
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<b>Staging of Femoral Head Osteonecrosis </b>
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</p><p>The most common site for osteonecrosis is the femoral head, with an increased prevalence observed among younger adults aged 20 to 40, accounting for 10% of annual total hip arthroplasties in the United States.<a class="bk_pop" href="#article-155093.r14">[14]</a> There are a few staging systems developed for adult femoral head osteonecrosis, the 3 main ones being—Ficat and Arlet (see <b>Table 2.</b> Ficat and Arlet Staging of Osteonecrosis of the Hip), Steinberg (see <b>Table 3.</b> Steinberg Staging System of Osteonecrosis of the Hip), and the Association Research Circulation Osseous (ARCO) classification (see <b>Table 4.</b> ARCO 2019 Revised Staging System). These systems are designed to stage osteonecrosis from clinically occult disease to positive imaging findings to subchondral collapse and the late findings of secondary osteoarthritis. These classifications are clinically significant for epiphyseal osteonecrosis as they predict the likelihood of articular collapse. Successful treatment depends on accurate staging. There is no consensus on the best classification system, as all have demonstrated interobserver and intraobserver reliability.<a class="bk_pop" href="#article-155093.r15">[15]</a></p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figarticle155093table1"><a href="/books/NBK604199/table/article-155093.table1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobarticle155093table1"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="article-155093.table1"><a href="/books/NBK604199/table/article-155093.table1/?report=objectonly" target="object" rid-ob="figobarticle155093table1">Table</a></h4><p class="float-caption no_bottom_margin">Table 2. Ficat and Arlet Staging of Osteonecrosis of the Hip. </p></div></div><p>Reference for the table.<a class="bk_pop" href="#article-155093.r16">[16]</a></p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figarticle155093table2"><a href="/books/NBK604199/table/article-155093.table2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobarticle155093table2"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="article-155093.table2"><a href="/books/NBK604199/table/article-155093.table2/?report=objectonly" target="object" rid-ob="figobarticle155093table2">Table</a></h4><p class="float-caption no_bottom_margin">Table 3. Steinberg Staging System of Osteonecrosis of the Hip (the University of Philadephia System). </p></div></div><p>* Stages 1 through 6 are further categorized into 3 subsets—mild (<15% articular surface), moderate (15% to 30%), and severe (>30%).<a class="bk_pop" href="#article-155093.r17">[17]</a><a class="bk_pop" href="#article-155093.r18">[18]</a></p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figarticle155093table3"><a href="/books/NBK604199/table/article-155093.table3/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobarticle155093table3"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="article-155093.table3"><a href="/books/NBK604199/table/article-155093.table3/?report=objectonly" target="object" rid-ob="figobarticle155093table3">Table</a></h4><p class="float-caption no_bottom_margin">Table 4. ARCO 2019 Revised Staging System. </p></div></div><p>References for the table.<a class="bk_pop" href="#article-155093.r19">[19]</a><a class="bk_pop" href="#article-155093.r20">[20]</a></p><p>When osteonecrosis occurs in the epiphyses of the femoral head and other long bones, the report should include specific items to communicate prognostic findings to the clinician as follows:</p><ul><li class="half_rhythm"><div>Location of osteonecrosis</div></li><li class="half_rhythm"><div>Estimated volume of the femoral head and the percentage of weight-bearing surface </div></li><li class="half_rhythm"><div>Presence of coexisting degenerative changes</div></li><li class="half_rhythm"><div>Presence of joint effusion </div></li><li class="half_rhythm"><div>Presence of unstable osteochondral fragments or subchondral fracture <a class="bk_pop" href="#article-155093.r5">[5]</a></div></li></ul><p>The extent of the femoral head involved in osteonecrosis is a crucial factor in predicting femoral head collapse and is best evaluated using an MRI in the sagittal plane.<a class="bk_pop" href="#article-155093.r21">[21]</a> Osteonecrosis affecting >50% of the femoral head is much more likely to progress to articular collapse. Osteonecrosis affecting <30% of the femoral head is unlikely to lead to articular collapse. Additional factors associated with an increased risk of femoral head collapse include an increased thickness of the relative zone, joint effusion, surrounding edema, older age, and increased body mass index.<a class="bk_pop" href="#article-155093.r22">[22]</a> </p><p>
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<b>Kienbock Disease </b>
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</p><p>Osteonecrosis affecting the lunate is referred to as Kienbock disease or lunatomalacia. Although its etiology is often unknown, most patients have an antecedent history of trauma that disrupts the blood supply and ligaments surrounding the lunate.<a class="bk_pop" href="#article-155093.r23">[23]</a> Due to its variable blood supply, the lunate bone is at an increased risk of osteonecrosis. Radiographs are the initial imaging modality used to diagnose Kienbock disease, which often demonstrates an area of increased sclerosis or flattening with negative ulnar variance (see <b>Image.</b> Plain Film of Kienbock Disease). On MRI, the condition is diagnosed with near certainty when there is a diffuse T1 dark signal in the lunate, particularly in the setting of ulnar variance and normal appearing surrounding bones with variable T2 signal (see <b>Image.</b> MRI findings of Kienbock Disease). </p><p>Delayed diagnosis can lead to lunate collapse and subsequent alternation of the surrounding capital architecture. Once recognized, surgery is often required to prevent wrist degenerative changes.</p><p>A reproducible osseous classification system called the Lichtman classification combines radiologic and clinical findings to help surgeons make the appropriate treatment decision preoperatively to prevent resulting carpal pathology (see <b>Table 5.</b> Lichtman Classification).<a class="bk_pop" href="#article-155093.r24">[24]</a> When radiographic findings are inconclusive, MRI can aid in identifying radiographically occult disease. </p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figarticle155093table4"><a href="/books/NBK604199/table/article-155093.table4/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobarticle155093table4"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="article-155093.table4"><a href="/books/NBK604199/table/article-155093.table4/?report=objectonly" target="object" rid-ob="figobarticle155093table4">Table</a></h4><p class="float-caption no_bottom_margin">Table 5. Lichtman Osseous Classification. </p></div></div><p> References for the table.<a class="bk_pop" href="#article-155093.r24">[24]</a><a class="bk_pop" href="#article-155093.r25">[25]</a></p><p>
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<b>Malignant Transformation </b>
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</p><p>Another important but rare complication of osteonecrosis is the malignant degeneration of extensive bone infarcts into secondary osteosarcoma, also known as bone infarct-associated sarcoma. This entity is extremely rare, however well documented, and important to recognize and consider in patients with osteonecrosis affecting metadiaphyseal locations of long bones.</p><p>This condition is believed to arise from the reactive interface at the periphery of a lesion where excessive proliferative activity occurs.<a class="bk_pop" href="#article-155093.r26">[26]</a> Ostenecrosis-associated sarcoma occurs in the fifth to sixth decade of life and typically has a poor prognosis.<a class="bk_pop" href="#article-155093.r27">[27]</a> </p><p>Radiographs demonstrate previous characteristics of osteonecrosis with new focally aggressive osteolytic lesions extending through the cortex and involving the reactive interface of cancellous bone (see <b>Image.</b> Osteolytic Lesion). MRI shows a new mass-like replacement of the bone marrow in the area of osteonecrosis with associated cortical destruction and new soft tissue components (see <b>Image.</b> MRI of Malignant Transformation). Lesions are hypermetabolic on PET/CT and markedly hot on bone scintigraphy.<a class="bk_pop" href="#article-155093.r28">[28]</a> New bone pain in patients with known osteonecrosis affecting the metaphysis of long bones should be vigilantly monitored. </p></div><div id="article-155093.s9"><h2 id="_article-155093_s9_">Review Questions</h2><ul><li class="half_rhythm"><div>
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</div></li></ul></div><div class="floats-group" id="article-155093.s10"><div class="iconblock whole_rhythm clearfix ten_col fig" id="figarticle155093imagef1" co-legend-rid="figlgndarticle155093imagef1"><a href="/books/NBK604199/figure/article-155093.image.f1/?report=objectonly" target="object" title="Figure" class="img_link icnblk_img figpopup" rid-figpopup="figarticle155093imagef1" rid-ob="figobarticle155093imagef1"><img class="small-thumb" src="/books/NBK604199/bin/knee__osteonecrosis.gif" src-large="/books/NBK604199/bin/knee__osteonecrosis.jpg" alt="Metaphyseal Osteonecrosis" /></a><div class="icnblk_cntnt" id="figlgndarticle155093imagef1"><h4 id="article-155093.image.f1"><a href="/books/NBK604199/figure/article-155093.image.f1/?report=objectonly" target="object" rid-ob="figobarticle155093imagef1">Figure</a></h4><p class="float-caption no_bottom_margin">Metaphyseal Osteonecrosis. AP radiograph shows a serpentine rim of sclerosis affecting the distal femur and proximal tibial metaphysis. AP, antero-posterior.  Contributed by O Stroie, MD </p></div></div></div><div class="floats-group" id="article-155093.s11"><div class="iconblock whole_rhythm clearfix ten_col fig" id="figarticle155093imagef2" co-legend-rid="figlgndarticle155093imagef2"><a href="/books/NBK604199/figure/article-155093.image.f2/?report=objectonly" target="object" title="Figure" class="img_link icnblk_img figpopup" rid-figpopup="figarticle155093imagef2" rid-ob="figobarticle155093imagef2"><img class="small-thumb" src="/books/NBK604199/bin/Screenshot__2024-03-17__at__6.32.07xAM.gif" src-large="/books/NBK604199/bin/Screenshot__2024-03-17__at__6.32.07xAM.jpg" alt="Crescent Sign" /></a><div class="icnblk_cntnt" id="figlgndarticle155093imagef2"><h4 id="article-155093.image.f2"><a href="/books/NBK604199/figure/article-155093.image.f2/?report=objectonly" target="object" rid-ob="figobarticle155093imagef2">Figure</a></h4><p class="float-caption no_bottom_margin">Crescent Sign. The frog-leg radiograph of the left femur displays a subtle subchondral lucency (arrow), also known as a crescent sign. No secondary arthrosis was demonstrated. Contributed by O Stroie, MD </p></div></div></div><div class="floats-group" id="article-155093.s12"><div class="iconblock whole_rhythm clearfix ten_col fig" id="figarticle155093imagef3" co-legend-rid="figlgndarticle155093imagef3"><a href="/books/NBK604199/figure/article-155093.image.f3/?report=objectonly" target="object" title="Figure" class="img_link icnblk_img figpopup" rid-figpopup="figarticle155093imagef3" rid-ob="figobarticle155093imagef3"><img class="small-thumb" src="/books/NBK604199/bin/articular__collapse.gif" src-large="/books/NBK604199/bin/articular__collapse.jpg" alt="Articular Collapse" /></a><div class="icnblk_cntnt" id="figlgndarticle155093imagef3"><h4 id="article-155093.image.f3"><a href="/books/NBK604199/figure/article-155093.image.f3/?report=objectonly" target="object" rid-ob="figobarticle155093imagef3">Figure</a></h4><p class="float-caption no_bottom_margin">Articular Collapse. AP radiograph of the hip shows irregularity and flattening of the femoral head, with underlying subchondral sclerosis, findings suggestive of articular collapse. AP, antero-posterior. Contributed by O Stroie, MD </p></div></div></div><div class="floats-group" id="article-155093.s13"><div class="iconblock whole_rhythm clearfix ten_col fig" id="figarticle155093imagef4" co-legend-rid="figlgndarticle155093imagef4"><a href="/books/NBK604199/figure/article-155093.image.f4/?report=objectonly" target="object" title="Figure" class="img_link icnblk_img figpopup" rid-figpopup="figarticle155093imagef4" rid-ob="figobarticle155093imagef4"><img class="small-thumb" src="/books/NBK604199/bin/humeral__epiphyseal__osteonecrosis__with__subchodnral__collapse.gif" src-large="/books/NBK604199/bin/humeral__epiphyseal__osteonecrosis__with__subchodnral__collapse.jpg" alt="Crescent Sign on CT scan" /></a><div class="icnblk_cntnt" id="figlgndarticle155093imagef4"><h4 id="article-155093.image.f4"><a href="/books/NBK604199/figure/article-155093.image.f4/?report=objectonly" target="object" rid-ob="figobarticle155093imagef4">Figure</a></h4><p class="float-caption no_bottom_margin">Crescent Sign on CT scan. Coronal CT shows humeral epiphyseal osteonecrosis with subchondral collapse and secondary osteoarthritis. Contributed by O Stroie, MD </p></div></div></div><div class="floats-group" id="article-155093.s14"><div class="iconblock whole_rhythm clearfix ten_col fig" id="figarticle155093imagef5" co-legend-rid="figlgndarticle155093imagef5"><a href="/books/NBK604199/figure/article-155093.image.f5/?report=objectonly" target="object" title="Figure" class="img_link icnblk_img figpopup" rid-figpopup="figarticle155093imagef5" rid-ob="figobarticle155093imagef5"><img class="small-thumb" src="/books/NBK604199/bin/osteonecrosis__of__the__humeral__head.gif" src-large="/books/NBK604199/bin/osteonecrosis__of__the__humeral__head.jpg" alt="MRI findings of Double-Line Sign with Subchondral Collapse" /></a><div class="icnblk_cntnt" id="figlgndarticle155093imagef5"><h4 id="article-155093.image.f5"><a href="/books/NBK604199/figure/article-155093.image.f5/?report=objectonly" target="object" rid-ob="figobarticle155093imagef5">Figure</a></h4><p class="float-caption no_bottom_margin">MRI findings of Double-Line Sign with Subchondral Collapse. Osteonecrosis affecting the superior humeral head with findings of subchondral collapse on MRI. Sag T1 (A) and coronal T1 (C) demonstrate a dark rim of sclerosis. Sag PD FS (B) and Cor PD FS <a href="/books/NBK604199/figure/article-155093.image.f5/?report=objectonly" target="object" rid-ob="figobarticle155093imagef5">(more...)</a></p></div></div></div><div class="floats-group" id="article-155093.s15"><div class="iconblock whole_rhythm clearfix ten_col fig" id="figarticle155093imagef6" co-legend-rid="figlgndarticle155093imagef6"><a href="/books/NBK604199/figure/article-155093.image.f6/?report=objectonly" target="object" title="Figure" class="img_link icnblk_img figpopup" rid-figpopup="figarticle155093imagef6" rid-ob="figobarticle155093imagef6"><img class="small-thumb" src="/books/NBK604199/bin/lunatomalacia.gif" src-large="/books/NBK604199/bin/lunatomalacia.jpg" alt="Plain Film of Kienbock Disease" /></a><div class="icnblk_cntnt" id="figlgndarticle155093imagef6"><h4 id="article-155093.image.f6"><a href="/books/NBK604199/figure/article-155093.image.f6/?report=objectonly" target="object" rid-ob="figobarticle155093imagef6">Figure</a></h4><p class="float-caption no_bottom_margin">Plain Film of Kienbock Disease. AP radiograph of the wrist shows flattening and sclerosis of the lunate, consistent with osteonecrosis of the lunate. AP, antero-posterior. Contributed by O Stroie, MD </p></div></div></div><div class="floats-group" id="article-155093.s16"><div class="iconblock whole_rhythm clearfix ten_col fig" id="figarticle155093imagef7" co-legend-rid="figlgndarticle155093imagef7"><a href="/books/NBK604199/figure/article-155093.image.f7/?report=objectonly" target="object" title="Figure" class="img_link icnblk_img figpopup" rid-figpopup="figarticle155093imagef7" rid-ob="figobarticle155093imagef7"><img class="small-thumb" src="/books/NBK604199/bin/lunatomalacia__MR.gif" src-large="/books/NBK604199/bin/lunatomalacia__MR.jpg" alt="MRI findings of Kienbock Disease" /></a><div class="icnblk_cntnt" id="figlgndarticle155093imagef7"><h4 id="article-155093.image.f7"><a href="/books/NBK604199/figure/article-155093.image.f7/?report=objectonly" target="object" rid-ob="figobarticle155093imagef7">Figure</a></h4><p class="float-caption no_bottom_margin">MRI findings of Kienbock Disease. MRI Cor T1 and Cor PD FS of the wrist shows a dark T1 signal in the lunate with diffuse marrow replacement. No evidence of collapse exists. There is a widening of the scapholunate space and volar tilting of the lunate. <a href="/books/NBK604199/figure/article-155093.image.f7/?report=objectonly" target="object" rid-ob="figobarticle155093imagef7">(more...)</a></p></div></div></div><div class="floats-group" id="article-155093.s17"><div class="iconblock whole_rhythm clearfix ten_col fig" id="figarticle155093imagef8" co-legend-rid="figlgndarticle155093imagef8"><a href="/books/NBK604199/figure/article-155093.image.f8/?report=objectonly" target="object" title="Figure" class="img_link icnblk_img figpopup" rid-figpopup="figarticle155093imagef8" rid-ob="figobarticle155093imagef8"><img class="small-thumb" src="/books/NBK604199/bin/sarcoma.gif" src-large="/books/NBK604199/bin/sarcoma.jpg" alt="Osteolytic Lesion" /></a><div class="icnblk_cntnt" id="figlgndarticle155093imagef8"><h4 id="article-155093.image.f8"><a href="/books/NBK604199/figure/article-155093.image.f8/?report=objectonly" target="object" rid-ob="figobarticle155093imagef8">Figure</a></h4><p class="float-caption no_bottom_margin">Osteolytic Lesion. AP radiograph displays a destructive lytic lesion in the proximal tibia within the area of metadiaphyseal osteonecrosis. These findings raise suspicion for malignant transformation of osteonecrosis. AP, antero-posterior. Contributed <a href="/books/NBK604199/figure/article-155093.image.f8/?report=objectonly" target="object" rid-ob="figobarticle155093imagef8">(more...)</a></p></div></div></div><div class="floats-group" id="article-155093.s18"><div class="iconblock whole_rhythm clearfix ten_col fig" id="figarticle155093imagef9" co-legend-rid="figlgndarticle155093imagef9"><a href="/books/NBK604199/figure/article-155093.image.f9/?report=objectonly" target="object" title="Figure" class="img_link icnblk_img figpopup" rid-figpopup="figarticle155093imagef9" rid-ob="figobarticle155093imagef9"><img class="small-thumb" src="/books/NBK604199/bin/T2__FS__and__T1__post__con.gif" src-large="/books/NBK604199/bin/T2__FS__and__T1__post__con.jpg" alt="MRI of Malignant Transformation" /></a><div class="icnblk_cntnt" id="figlgndarticle155093imagef9"><h4 id="article-155093.image.f9"><a href="/books/NBK604199/figure/article-155093.image.f9/?report=objectonly" target="object" rid-ob="figobarticle155093imagef9">Figure</a></h4><p class="float-caption no_bottom_margin">MRI of Malignant Transformation. Coronal T2 FS and T1 post-contrast images reveal multifocal areas of osteonecrosis with malignant sarcomatous transformation of the proximal tibial metadiaphysis. The images show diffuse enhancement of an eccentric medullary <a href="/books/NBK604199/figure/article-155093.image.f9/?report=objectonly" target="object" rid-ob="figobarticle155093imagef9">(more...)</a></p></div></div></div><div id="article-155093.s19"><h2 id="_article-155093_s19_">References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="article-155093.r1">Murphey MD, Foreman KL, Klassen-Fischer MK, Fox MG, Chung EM, Kransdorf MJ. 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The 2019 Revised Version of Association Research Circulation Osseous Staging System of Osteonecrosis of the Femoral Head. <span><span class="ref-journal">J Arthroplasty. </span>2020 Apr;<span class="ref-vol">35</span>(4):933-940.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31866252" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31866252</span></a>]</div></dd><dt>21.</dt><dd><div class="bk_ref" id="article-155093.r21">Ha AS, Wells L, Jaramillo D. Importance of sagittal MR imaging in nontraumatic femoral head osteonecrosis in children. <span><span class="ref-journal">Pediatr Radiol. </span>2008 Nov;<span class="ref-vol">38</span>(11):1195-200.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18712375" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18712375</span></a>]</div></dd><dt>22.</dt><dd><div class="bk_ref" id="article-155093.r22">Nam KW, Kim YL, Yoo JJ, Koo KH, Yoon KS, Kim HJ. Fate of untreated asymptomatic osteonecrosis of the femoral head. <span><span class="ref-journal">J Bone Joint Surg Am. </span>2008 Mar;<span class="ref-vol">90</span>(3):477-84.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18310696" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18310696</span></a>]</div></dd><dt>23.</dt><dd><div class="bk_ref" id="article-155093.r23">Kennedy C, Abrams R. In Brief: The Lichtman Classification for Kienböck Disease. <span><span class="ref-journal">Clin Orthop Relat Res. </span>2019 Jun;<span class="ref-vol">477</span>(6):1516-1520.</span> [<a href="/pmc/articles/PMC6554122/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6554122</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30507834" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30507834</span></a>]</div></dd><dt>24.</dt><dd><div class="bk_ref" id="article-155093.r24">Lichtman DM, Lesley NE, Simmons SP. The classification and treatment of Kienbock's disease: the state of the art and a look at the future. <span><span class="ref-journal">J Hand Surg Eur Vol. </span>2010 Sep;<span class="ref-vol">35</span>(7):549-54.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20621943" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20621943</span></a>]</div></dd><dt>25.</dt><dd><div class="bk_ref" id="article-155093.r25">Lichtman DM, Pientka WF, MacLean S, Bain G. Precision Medicine for Kienböck Disease in the 21st Century. <span><span class="ref-journal">J Hand Surg Am. </span>2022 Jul;<span class="ref-vol">47</span>(7):677-684.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/35809999" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35809999</span></a>]</div></dd><dt>26.</dt><dd><div class="bk_ref" id="article-155093.r26">Laranga R, Focaccia M, Evangelista A, Lucarelli E, Donati DM, Spazzoli B. Bone Infarct-Associated Osteosarcoma: Epidemiologic and Survival Trends. <span><span class="ref-journal">Oncol Res Treat. </span>2022;<span class="ref-vol">45</span>(6):326-335.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/35034028" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35034028</span></a>]</div></dd><dt>27.</dt><dd><div class="bk_ref" id="article-155093.r27">Domson GF, Shahlaee A, Reith JD, Bush CH, Gibbs CP. Infarct-associated bone sarcomas. <span><span class="ref-journal">Clin Orthop Relat Res. </span>2009 Jul;<span class="ref-vol">467</span>(7):1820-5.</span> [<a href="/pmc/articles/PMC2690751/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2690751</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19229663" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19229663</span></a>]</div></dd><dt>28.</dt><dd><div class="bk_ref" id="article-155093.r28">Konarski W, Poboży T, Hordowicz M, Śliwczyński A, Kotela I, Krakowiak J, Kotela A. Bone Infarcts and Tumorigenesis-Is There a Connection? A Mini-Mapping Review. <span><span class="ref-journal">Int J Environ Res Public Health. </span>2022 Jul 29;<span class="ref-vol">19</span>(15)</span> [<a href="/pmc/articles/PMC9367991/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9367991</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35954639" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35954639</span></a>]</div></dd></dl></div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_top_margin">
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<b>Disclosure: </b>Oana Stroie declares no relevant financial relationships with ineligible companies.</p></div></dd><dt></dt><dd><div><p class="no_top_margin">
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<b>Disclosure: </b>Van Vu declares no relevant financial relationships with ineligible companies.</p></div></dd></dl></div></div></div>
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