Osteochondritis Dissecans of the Knee: Etiology and Pathogenetic Mechanisms. A Systematic Review

Abstract

Objective

The purpose of this manuscript is to analyze the evidence regarding etiopathogenesis of knee osteochondritis dissecans (OCD) lesions through a systematic review, so to summate the current understanding of the origin and progression of this pathologic articular processes.

Design

A systematic review of the literature was performed on the PubMed and Cochrane databases on October 2017 by 2 independent authors and included all levels of evidence. This included all English language literature, pertaining specifically to etiopathology of knee OCD with exclusions for review articles and expert opinion. Of 965 identified records, 154 full-text articles were assessed for eligibility and 86 studies met the inclusion criteria.

Results

According to these studies, the etiology of OCD can be of a biological or mechanical origin: 40 articles proposed a biological hypothesis, including genetic causes (27), ossification center deficit (12), and endocrine disorders (9); conversely, 52 articles supported a mechanical hypothesis, including injury/overuse (18), tibial spine impingement (5), discoid meniscus (16), and biomechanical alterations (20) as the cause of the onset of OCD. The pathogenic processes were investigated by 36 of these articles, with a focus on subchondral bone fracture and ischemia as the ultimate events leading to OCD.

Conclusions

Biological and mechanical factors are found to result in subchondral bone remodeling alterations, acting independently or more likely synergically in the progression of knee OCD. The former includes genetic causes, deficit of ossification centers and endocrine disorders; the latter, tibial spine impingement, discoid meniscus, and biomechanical alterations, together with injuries and overuse. The resultant subchondral bone ischemia and/or fracturing appears to determine the onset and progression of OCD.

Level of Evidence

Systematic review of level II-IV studies, level IV.

Introduction

Osteochondritis dissecans (OCD) is a pathology known for centuries,¹ even before König² coined the term in 1888, which is currently in use. It defines a pathologic process involving the osteochondral unit, resulting in delamination and sequestration of subchondral bone with or without articular cartilage involvement and instability.³ Orthopedic surgeons, family doctors, and sports medicine specialists should be aware of this condition, since OCD is not a rare source of knee pain and dysfunction, mostly affecting young patients between 10 and 20 years of age,³ with a prevalence of 15 to 29 per 100,000 population and an incidence reported to be increasing.^4,5 Its impact on those affected varies significantly, with skeletal age at time of symptoms onset being the most important prognostic factor, in terms of selecting intervention algorithm and predicting outcome success. Thus, the disease is essentially divided into two categories according to the time of clinical recognition as either juvenile OCD or adult OCD. The former affects skeletally immature patients and has a generally better prognosis⁶ the latter is typical of young adult patients (defined by closed physis) and typically presents a poorer prognosis.⁷ Theories on the etiopathogenesis are postulated to explain both the occurrence, progression and thus the prognosis of OCD. Historically, traumatic events were deemed to be the cause of the loose bodies, but over the centuries this theory was dispelled by others, such as “quiet necrosis” by Sir James Paget or the inflammatory theory of König.¹ Although the shortcomings of these hypotheses were highlighted by subsequent advancements in research, the exact nature of OCD remains elusive.

The purpose of this study is to assess the available evidence on the etiopathogenesis of knee OCD lesions through a systematic review, to better understand the origin and progression of the pathologic processes and possibly identifying areas for future curative therapeutic intervention.

Methods

A systematic review of the literature was performed. The search was conducted on the PubMed and Cochrane databases on October 2, 2017 using the following parameters: ((osteochondritis dissecans) AND (knee)). The guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) were used.⁸ The screening process and analysis were conducted separately by two independent observers. In the first step, the articles were screened by title and abstract. Inclusion criteria for relevant articles used during the initial screening were reports of all levels of evidence, English language, no time limitation, specific to etiopathology of knee OCD. Exclusion criteria were reviews and expert opinions, or manuscripts with focus on joints other than the knee. In the second step, the full texts of selected articles were evaluated for exclusion according to same criteria. Reference lists from the selected papers and from the excluded reviews were reviewed for potential further potentially inclusive reports. Relevant data (type of study, number of patients, demographic of study population, lesion site, proposed theory for etiology and pathogenesis, and remarks) were then extracted. The etiologic theories about OCD proposed in the selected articles were the divided into biological and mechanical, based on the prevalent hypothesis endorsed in each study. A unique data set, composed of consensus of the 2 observers (LA and AC), was established and then analyze for the purposes of the present manuscript.

Results

The PubMed and Cochrane search after duplicates removal identified 965 potential abstracts for inclusion, which were screened, as shown in Figure 1 , for a total of 154 full-text articles assessed for eligibility. Sixty-eight full-text articles were further excluded, thus leaving a total of 86 studies to meet the inclusion criteria and use for the literature analysis. These included studies from 1953 to 2017 and ranged from cohort studies up to 133 patients to laboratory studies up to 64 specimens. Of interest an increasing number of studies, almost half of the included articles, have been published in the past 7 years (42/86) ( Fig. 2 ).

Figure 1.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) flowchart of the systematic literature review.

Figure 2.

Etiopathogenesis studies published over time.

The levels of evidence of the included studies included: 39 case reports, 31 case series, 11 laboratory studies and 5 comparative studies. Among the included studies, 40 articles proposed a biological hypothesis,^9-47 including genetic causes (n = 27), ossification center deficit (n = 12), and endocrine disorders (n = 9). Conversely, 52 articles supported a mechanical hypothesis,^{12,13,17,29,34,35,47-92} including injury/overuse (n = 18), tibial spine impingement (n = 5), discoid meniscus (n = 16), and biomechanical alterations (n = 20) as the cause of OCD onset.

Among biologic theories, genetic factors are the most investigated, with 27 studies on 548 patients. Theories vary from an autosomal dominant pattern of inheritance in older studies,^39,40 to the association with genetic determined diseases^12,27 and to gene mutations causing protein alteration leading to OCD in more recent articles.^20,21,44 Other biological hypothesis concerned a deficit in the ossification center; one of the first theories was described in 1955³⁴ and was analyzed in 12 studies on 153 patients, or lastly endocrinological factors (including vitamin D deficit,^10,42,43 glucocorticoid alterations,¹⁴ human growth hormone (hGH) deficiency,¹⁸ or association with endocrinologic and sexual abnormalities),³⁶ stressed in 9 studies reporting data of 180 patients.

Among mechanical theories, the traumatic theory was the first one described in the early 1950s.³⁵ This hypothesis, however, has evolved from that of a single event macrotrauma to one proposing repetitive microtraumatic. None the less, it remains one of the most accepted of the proposed etiologies with 18 articles on 297 patients. The other mechanical theories have gained interest more recently. Biomechanical alterations represent one of the most described theory, reported in 20 studies on 527 patients. This category includes lower limb deviation,^59,91 ligament or meniscus instability,^50,53 knee anatomical features,^56,88 shearing stress on patella,^71,80 or knee activity–related position.⁸⁷ Discoid meniscus was first described in 1984 as factor associated with OCD lesions, and subsequently gained increasing credit, being described in 16 studies on 260 patients. The majority of those described the association between lateral discoid meniscus and lateral femoral condyle (LFC) OCD, but the presence of medial discoid meniscus has also been associated with OCD of the medial femoral condyle (MFC).⁵¹ Discoid meniscus plays its role in the etiopathogenesis of OCD both if normal or torn, and also related meniscal surgical procedures may influence the history of OCD lesions.⁸⁹ Finally, tibial spine impingement represents a most recent theory, first described in the late nineties, and it was supported by 5 studies on 97 patients. However, this may explain only the “classic” OCD lesion (secondary to juxtaposition), on the notch side (lateral aspect) of the MFC.

Interestingly, analyzing the number of articles published over the decades by etiology ( Fig. 3 ), a shift is seen in the past 20 years from biologic toward mechanical hypothesis. In fact, 55% of the articles published in the past century supported a biologic theory, while 61% of the studies published from 2000 to 2017 supported the mechanical hypothesis. Overall, based on the number of studies supporting their importance, the strongest factors are genetic causes (27), biomechanical alterations (20), injury/overuse (18), and discoid meniscus (16). Fewer studies supported the importance of ossification center deficit (12), endocrine disorders (9), and tibial spine impingement (5). Nevertheless, also these factors are likely to significantly contribute to the onset of OCD in some patients, with the importance of each factor and the interplay among concomitant factors leading to OCD being related to the specific case.

Figure 3.

Trend of etiological hypothesis over time.

The cascade of events leading to OCD was specifically described in 36 articles, with subchondral bone fracture (28 articles) or subchondral bone ischemia (8 articles) as the most common final pathogenetic mechanisms ( Fig. 4 ). While subchondral bone is almost universally recognized as the primarily affected tissue, one article suggested that OCD is a cartilaginous disease with the subchondral bone secondarily damaged.¹⁹

Figure 4.

Trend of pathogenetic theories over time.

More detailed aspects of the selected studies, including type of study, number of patients, age, lesion site, proposed theory for etiology and pathogenesis, and results, are reported in Table 1 .

Table 1.

Detailed Description of the 86 Studies Selected in the Systematic Review.

Author Year	Type of Study	No. of Patients Mean Age Lesion Site	Etiological Theory	Biologic	Mechanic	Pathogenesis	Note
Kumahashi 201792	Case report: bilateral OCD	1 13 y lateral trochlea	Repetitive microtrauma		✓	/	OCD of lateral femoral trochlea developed bilaterally without coexisting patellofemoral abnormalities
Gonzalez-Herranz 201791	Retrospective study: mechanical axis and OCD	48 13.7 y MFC, LFC	Biomechanical alterations		✓	/	Lower limb mechanical axis deviations are more strictly associated than anatomical axis deviations with OCD lesions
Takigami 201790	Case series: discoid lateral meniscus and OCD	133 12 y LCF	Discoid meniscus		✓	/	Male sex, young age and type C discoid lateral meniscus (Ahn) were found to be predictive factors for OCD of LFC
Ishikawa 201689	Case report: OCD and lateral discoid meniscus	1 19 y LFC	Discoid meniscus (meniscectomy)		✓	/	A stable JOCD LFC lesion associated with lateral discoid meniscus developed into an unstable status after its meniscectomy (altered environment of mechanical force transmission)
Ishikawa 201688	Case-control study: PCL anatomy and MFC OCD	39 15 y MFC, LFC	Biomechanical alterations		✓	/91	PCL in patients with MCF OCD attached more distally at the lateral aspect of the MFC compared with LFC OCD, ACL and meniscal injuries
Gornitzky 201646	Retrospective study: familial OCD	103 13 y knee	Genetic	✓		/	14% of patients with OCD have a family history of the condition (higher than previously reported prevalence in general population)
McElroy 201687	Retrospective study: OCD in baseball	78 12 y knee	Biomechanical alterations		✓	/	Catchers developed OCD at a younger age and in a more posterior location MFC and LFC than noncatchers, maybe because of repetitive and persistent hyperflexion
Ellermann 201645	Case series: MRI findings	13 14.9 y knee	Ossification centers defect	✓		Epiphyseal cartilage ischemia	OCD may have an epiphyseal cartilage origin with subsequent osseous repair stages with osseous bridging, which can heal or detach
Yellin 201544	Comparative study: genes in OCD vs. control	209 / knee	Genetic	✓		/	The genome analysis revealed 35 single-nucleotide polymorphism at several loci having a possible association with OCD
Persiani 201586	Case report: OCD and osteogenesis imperfecta	1 14 y LFC	Trauma		✓	/	OCD developed after a trauma in a patient with weak bone structure due to osteogenesis imperfecta
Tòth 201585	Laboratory study: MRI findings in human cadaver	5 13.6 mo distal femur	Biomechanical alterations		✓	Vascular failure and ischemia	Vascular architecture in human, with vessel primarily arising from perichondrium and disappearing with ages in OCD predilection sites, may cause vascular failure, due to biomechanical alteration or structural weakness
Cavaignac 201584	Comparative study: OCD vs control	37 (vs 42) 14.3 y MFC	Tibial spine impingement		✓	/	Patients with OCD have a more prominent tibial spine that patients without OCD
Gorter 20159	Case report: familial OCD	3 13.3 y MFC	Genetic	✓		/	Bilateral MFC OCD in a mother, her daughter and her MZ twin sister suggests a genetic role
Krause 201543	Laboratory study: histological analysis and vitamin D	64 12 y knee	Endocrinologic (vitamin D)	✓		Subchondral insufficiency fracture	Vitamin D deficiency leads to lack of mineralization making the bone segment more prone to mechanical stress and may result in subchondral insufficiency fractures. No sign of ischemia
Chow 201549	Case-control study: MFC OCD risk factors	35 12 y MFC	Tibial spine impingement		✓	Subchondral bone fracture	OCD knees have smaller notch width than controls, leading to tibial spine impingement and OCD
Bruns 201410	Case series: vitamin D deficit	23 31.3 y knee, talus, elbow	Endocrinologic (vitamin D)	✓		/	18/23 patients presented vitamin D3 deficit, which causes bone metabolism alterations
Deroussen 201450	Case report: cruciates agenesis and OCD of LTP	1 12 y LTP	Biomechanical alterations		✓	Subchondral bone fracture	Anteroposterior instability caused by agenesis of ACL and PCL may lead to LM lesions and OCD
Mine 201451	Case report: discoid medial meniscus and OCD	1 13 y MFC	Discoid meniscus		✓	/	Torn discoid medial meniscus may cause OCD through a stress redistribution
Wechter 201452	Case series: proximal tibial morphology	72 15.4 y MFC, LFC	Biomechanical alterations		✓	/	Medial and posterior tibial slope lead to focally increased mechanical forces on condyles
Camathias 201453	Cohort study: meniscal stabilization treating OCD	28 / MFC, LFC	Biomechanical alterations		✓	Subchondral bone stress	Meniscal instability (i.e., a hypermobile anterior horn) may impinge between articular surfaces leading to OCD
Sebaaly 201483	Case report: discoid lateral meniscus and OCD	1 14 y LFC	Discoid meniscus		✓	/	OCD associated with Wrisberg variant of discoid meniscus, which is characterized by poor stabilization with subluxation of the anterior horn in the intercondylar notch
Maruyama 201454	Case report: discoid lateral meniscus and OCD	1 14 y LFC, trochlea	Discoid meniscus		✓	Subchondral bone fracture	Discoid lateral meniscus and repeated trauma in sport activity might cause OCD
Richie 201311	Case report: MZ twin brothers	2 15 and 16 y lateral trochlea	Genetic	✓		Subchondral bone fracture	Similar locations and timing are suggestive of a genetic component
Park 201312	Case report: Wilson disease	1 17 y MFC, LFC	Genetic (Wilson disease)/trauma	✓	✓	/	Subchondral cysts, osteoporosis, copper deposition in joints/clumsy patients often sustaining trauma
Gans 201313	Case report: MZ twin brothers	4 16 y LFC, MFC	Genetic/discoid meniscus/trauma	✓	✓	Subchondral bone alteration	OCD associated with discoid meniscus, dominant limb, and genetic factors
Kroger 201314	Case series: juvenile idiopathic arthritis and OCD	13 6.5 y knee, ankle	Endocrinologic (glucocorticoid)/inflammation	✓		Subchondral bone fracture	Glucocorticoid injection and persistent synovitis affect osteochondral metabolism
Jeong 201315	Case report: bilateral OCD in brothers	2 32 and 28 y bilateral bicondylar	Ossification centers defect/genetic	✓		/	Probable not-identified genetic factors affected structural integrity and pathophysiology
Kilcoyne 201382	Case report: discoid lateral meniscus and OCD	1 21 y LFC	Discoid meniscus		✓	Subchondral bone stress	OCD developed in a skeletally mature patient with intact discoid meniscus after minor trauma
Shea 201355	Case series: acute bone contusion and OCD	2 11 and 15 y MFC, LFC	Single trauma		✓	Acute subchondral bone contusion	Single traumatic events may also play a role in the development of OCD
Grimm 201357	Case report: multiple OCD lesions in single knee	1 15 y LFC, MFC, trochlea	Biomechanical alterations		✓	/	OCD of MFC developed after using a varus unloader brace (repetitive stress on medial compartment)
Onoda 201216	Case report: MZ twin brothers	2 18 and 20 y MFC, LFC	Genetic	✓		Subchondral bone alteration	Genetic factors are considered to affect the integrity of the subchondral bone
Kamei 201256	Case series: lateral meniscus alterations and OCD	58 17.7 y LFC	Biomechanical alterations		✓	/	The shape of the LFC (prominence ratio of LFC) may be associated with the development of OCD
Laor 201217	Comparative study: JOCD vs. normal ossification variants	30 vs. 30 11.2 y MFC, LFC	Ossification centers defect/ repetitive trauma	✓	✓	/	JOCD results from an insult (repetitive trauma) affecting endochondral ossification
Jans 201258	Comparative study: JOCD vs. normal ossification variants	116 11.5 y knee	Repetitive microtrauma		✓	Subchondral bone ischemia	Ossification variants do not correlate with OCD. Repetitive microtrauma may compromise the physis blood supply (typical MRI sign)
Hussain 201118	Case report: hGH deficiency and multiple OCD	1 16 y MFC, LFC, elbow	Endocrinologic/ossification centers defect	✓		Subchondral bone fracture	Changes in hGH (deficit or supplementation) levels may lead to atypical ossification nuclei and OCD
Skagen 201119	Case series: histologic findings	4 23.3 y MFC, LFC	Genetic/ossification centers defect	✓		Cartilaginous disease	OCD may be an endoplasmic reticulum storage disease, which disturbs endochondral ossification
Stattin 201020	Case series: familial OCD	15 / knee, hip, elbow	Genetic (ACAN gene)	✓		/	The altered protein is involved in the organization of cartilage matrix
Jackson 201021	Case series: OCD associated with collagen deseases	19 / /	Genetic (collagen IX gene)	✓		/	Collagen mutation causes endoplasmic reticulum stress with increased chondrocyte apoptosis
Jacobi 201059	Case series: OCD and mechanical axis of the limb	93 22 y MFC, LFC	Biomechanical alterations		✓	/	Varus axis is associated with MFC OCD and valgus with LFC OCD (higher compartment loading)
Yonetani 201060	Case series: histologic findings	8 13 y MFC	Trauma		✓	Subchondral bone fracture	The initial damage may occur at the border between hyaline articular cartilage and subchondral bone
Mackie 201022	Case report: MZ twin brothers	2 17 and 19 y MFC	Genetic	✓		Subchondral bone lesion	The presence of identical lesions in MZ twins suggests the possibility of a genetic predisposition
Lippi 201062	Historical article: examination of skeletal remains	1 16.5 y patella	Trauma		✓	/	Repetitive microtrauma or macrotrauma during sport activity (kickball) may have caused OCD
Uozumi 200961	Laboratory study: histologic findings	11 16 y MFC	Repetitive microtrauma		✓	Subchondral bone fracture or necrosis	The initial subchondral change is fracture or necrosis depending on the etiology of OCD
Beyzadeoglu 200863	Case report: hypoplastic medial meniscus and OCD	1 10 y MFC	Biomechanical alterations/impingement		✓	/	Big tibial spine (impingement) and abnormal menisci (repetitive microtrauma) may cause OCD
Hashimoto 200864	Case report: discoid lateral meniscus and OCD	1 12 y LFC	Biomechanical alterations/discoid meniscus		✓	/	Discoid lateral meniscus, valgus axis after meniscectomy and sport cause repetitive trauma on LFC
Stattin 200823	Case report: familial OCD	15 / knee, hip, elbow	Genetic	✓		/	OCD with an autosomal dominant inheritance. Hypothesis of candidate genes (cartilage and bone proteins)
Hanna 200824	Case report: bicondylar OCD and histologic findings	2 15 y MFC, LFC	Ossification centers defect	✓		/	Defect in ossification centers of distal femur causes OCD. Trauma separates ossification nucleus
Deie 200665	Case series: discoid lateral meniscus and OCD	28 13.3 y LFC	Discoid meniscus		✓	/	Correlation between intact discoid lateral menisci and LFC OCD (increased mechanical stress)
Quan 200542	Case report: OCD and rickets	1 12 MFC	Endocrinologic (vitamin D)	✓		/	Since the osteoid matrix is abnormal and weakened, rachitic joints are prone to trauma
Cetik 200525	Case report: bilateral LFC OCD	1 20 y LFC	Ossification centers defect	✓		/	Defect in the ossification center of the distal LFC may play a role in the etiology of OCD
Gebarski 200526	Case series: stage-I OCD vs normal ossification variants	23 13 y knee	Ossification centers defect	✓		Subchondral bone defect	Central condylar lesion with edema and characteristic puzzle aspect favors OCD diagnosis
Stanitski 200466	Case report: discoid lateral meniscus and OCD	2 6 y LFC	Discoid meniscus		✓	Subchondral bone fracture	LFC OCD is related to increased stress caused by the discoid lateral meniscus or its meniscectomy
Bramer 200467	Retrospective study: increased tibial exotorsion and OCD	23 13 y MFC	biomechanical alterations/impingement		✓	/	Increased tibial exotorsion may cause OCD because enhances the tibial spine impingement on MFC
Hughes 200368	Case series: pathologic progression of OCD	19 11.3 y knee	Trauma		✓	Subchondral bone stress fracture	Intact cartilage becomes vulnerable to trauma if it loses support of the damaged subchondral bone
Kilic 200227	Case report: hyper IgE syndrome	1 13 y LFC	Genetic (hyper IgE syndrome)	✓		Subchondral bone fracture	Osteopenia caused by hyper IgE syndrome is a favorable etiologic factor of OCD
Atay 200270	Case report: menisci anomalies and OCD	1 16 y MFC	Biomechanical alterations/discoid meniscus		✓	/	MFC OCD is associated with a ring-shape lateral meniscus with cystic formation
Mizuta 200169	Case series: discoid lateral meniscus and OCD	6 9 y LFC	Discoid meniscus/trauma		✓	/	Meniscectomy of discoid LM and repeated sporting impaction on the immature structures may cause OCD
Bruns 199971	Case series: patellar OCD	15 / patella	Biomechanical alterations		✓	Subchondral bone damage	Repetitive motions of a plain patellar surface result in subchondral damage, initiating the OCD process
Mitsuoka 199972	Case series: discoid lateral meniscus and OCD	13 18.4 y LFC, MFC	Discoid meniscus		✓	/	Discoid meniscus produces repetitive stress on weaker growing structures leading to OCD
Raber 199874	Case series: discoid lateral meniscus and OCD	14 9 y LFC	Biomechanical alterations/discoid meniscus		✓	/	Weak correlation between total meniscectomy of discoid lateral meniscus and OCD; it may be due to the increased focal stress concentration after total meniscectomy
Mitsuoka 199873	Case report: OCD and tibial spine impingement	1 13 y MFC	Tibial spine impingement		✓	/	Anterior tibial spine impinging on the MFC because of the narrow intercondylar notch may cause OCD
Koch 199775	Laboratory study: histologic findings	30 30 y MFC	Biomechanical alterations		✓	Subchondral bone lesion	Biomechanical alterations cause the first change in subchondral bone and the progression to OCD
Livesley 199247	Case report: patellar OCD	3 16, 15, 12 y patella	Biomechanical alterations/genetic	✓	✓	/	Recurrent patella subluxation in this family may be the biomechanical alteration causing OCD
Aichroth 199176	Case series: discoid lateral meniscus and OCD	52 10.5 y LFC	Discoid meniscus		✓	/	Among 52 patients with lateral discoid meniscus, 7 presented OCD and 4 ossification defects
Fonseca 199028	Case report: familial OCD	3 16, 11, 9.7 y MFC	Genetic	✓		Subchondral bone ischemia	The higher incidence of OA suggests for familial OCD a separate pathogenesis from nonfamilial OCD
Desai 198777	Case series: patellar OCD	11 16 y patella	Biomechanical alterations		✓	Subchondral bone alteration	OCD might be caused by the repetitive shear stress on patella during knee flexion
Kozlowski 198593	Case reports: familial OCD	2 12, 44 y knee, elbow, metacarpal	Genetic	✓		/	Familial OCD may be a hereditary dysplasia of articular cartilage characterized by abnormal chondrocyte metabolism
Phillips 198541	Case report: familial multiple OCD	3 20, 25, 45 y knee, elbow	Genetic	✓		/	Association of OCD involving multiple joints with short stature
Irani 198478	Case report: discoid lateral meniscus and OCD	1 15 y LFC	Discoid meniscus		✓	Subchondral bone fracture	First case of association between injured discoid lateral meniscus and OCD of the LFC
Barrie 198429	Laboratory study: histologic findings of loose bodies	/ / /	Ossification centers defect/trauma	✓	✓	Subchondral bone fracture	Ossification defect causes subchondral bone separation. Trauma detach cartilage, including tidemark
Andrew 198140	Case report: familial OCD and dwarfism	12 / knee, elbow	Genetic (associated with dwarfism)	✓		/	OCD may be associate with dwarfism, and its pedigree is consistent with an autosomal dominant pattern of inheritance
Mubarak 198130	Case series: role of constitutional factors	73 13.4 y MFC, LFC, patella	genetic/endocrinologic/ossification centers defect	✓		/	Genetics, endocrine dysfunction, epiphyseal abnormalities seem the most important for OCD onset
Mubarak 197839	Case series: familial OCD	20 / MFC, LFC, patella	Genetic (associated with dwarfism)	✓		/	The autosomal dominant pattern of OCD and association with mild dwarfism were observed during a study of 4 generation of one family, with 20 of 31 members affected
Milgram 197879	Laboratory study: histologic findings	50 / knee	Trauma		✓	Osteochondral fracture	Major or minor (e.g., sudden pivoting) trauma might cause OCD through an osteochondral fracture
Edwards 197780	Case series: patellar OCD	5 15.4 y patella	Biomechanical alterations		✓	Fracture	Repetitive shearing stress on patella associated with recurrent subluxation could cause OCD
Petrie 197794	Case series: relatives of patients with OCD	34 / knee, ankle, elbow	Multifactorial			/	Only 1 of 86 relatives of 34 patients presents the disease: common form of OCD is not familial
Linden 197748	Laboratory study: histologic findings	14 20 y MFC	Trauma		✓	Subchondral bone fracture	Single/repetitive trauma cause sub-chondral bone fracture; poor blood supply blocks reparative process
Chiroff 197581	Laboratory study: histologic findings	6 22.6 y MFC	Single trauma		✓	Osteochondral fracture	OCD represents the effect of a trauma and the subsequent reparative process
Hanley 196738	Case report: familial OCD	2 16 and 14 y knee, elbow	genetic/endocrinologic	✓		/	Description of OCD in 2 brothers with associated multiple abnormalities (endocrinal problems, pectum excavatum, short little fingers, altered facies)
Campbell 196631	Laboratory study: histologic findings	/ / /	Ischemic/metabolic	✓		Subchondral bone ischemia	A vascular or localized metabolic disturbance in the distal end of the long bone during a period of rapid growth causes subchondral bone necrosis
Stougaard 196437	Case report: familial OCD	10 / knee, elbow	Genetic	✓		/	In this family 10 of 31 members affected by OCD. Association with short stature
White 195736	Case report: familial OCD	3 28, 21, 21 y knee, elbow	Genetic/endocrinologic	✓		/	Association with endocrinologic and sexual abnormalities
Tobin 195732	Case report: OCD associated with tibia vara	4 / MFC	Genetic/ossification centers defect	✓		/	OCD in 4 members of the same family affected by adolescent type of tibia vara supports a genetic theory
Pick 195533	Case report: familial OCD	4 17.5 y knee, elbow	Genetic	✓		/	Occurrence of bilateral knee or elbow OCD in various member of a family supports a genetic theory
Ribbing 195534	Case series and laboratory study: histologic findings	/ / /	Ossification centers defect/trauma	✓	✓	Subchondral bone ischemia	Mild trauma alters blood supply of partially detached bone nucleus, which is a locus minoris resistentiae
Green 195335	Laboratory study: histologic findings	27 9.5 y knee, elbow, ankle	Trauma/genetic	✓	✓	Subchondral bone aseptic necrosis	In a genetic predisposition context, trauma cause OCD directly or by subchondral blood supply alteration

hGH = human growth hormone; JOCD = juvenile osteochondritis dissecans; LFC = lateral femoral condyle; LM = lateral meniscus; MFC = medial femoral condyle; MRI = magnetic resonance imaging; MZ = monozygotic; OA = osteoarthritis; OCD = osteochondritis dissecans.

Discussion

This systematic review presented the entire spectrum of evidence on the etiopathology of OCD in the knee. The main study finding is that, based on the results provided by the selected articles, OCD can be caused by biological and/or mechanical factors. Furthermore, most of the studies identified subchondral bone fracture and ischemia as the ultimate cause in the pathogenetic processes leading to knee OCD.

It has to be pointed out that the level of evidence for the literature on OCD etiopathogenesis is generally low, with several case reports and studies reporting a relatively low number of patients. More over these studies are very heterogeneous for what concerns methods and results, thus making impossible to perform a quantitative evaluation of the overall data reported. Nevertheless, the theories documented in the current literature were reported, summarized and critically analyzed to best fit the spectrum of hypotheses into a etiopathogenic categorical framework ( Fig. 5 ).

Figure 5.

Framework of the etiopathogenetic theories documented in the current literature.

Biological Etiological Factors

Genetic Hypothesis

Several authors^{9,11-13,15,16,19-23,27,28,30,32,33,35-41,44,46,47,93} found a familial occurrence of OCD and some also identified specific gene alterations which can directly or indirectly cause the disease. Stattin et al.²⁰ identified a possible candidate gene, the ACAN gene, which encodes a protein involved in the organization of the aggrecan network, whose alteration leads to the disruption of extracellular matrix interactions causing a familial OCD with an autosomal dominant inheritance. Extra-cellular matrix alterations were also investigated by Jackson et al.,²¹ who found that patients with type IX collagen gene mutations presented OCD lesions combined with multiple epiphyseal dysplasia and a form of mild myopathy. They postulated that the expression of mutant type IX collagen may elicit a stress response involving endoplasmic reticulum and mitochondrial function. Skagen et al.¹⁹ speculated a role for altered chondrocyte extracellular matrix synthesis that may cause similarly effect endoplasmic reticulum storage. This effect then disturbs the endochondral ossification leading to OCD.

Alterations of bone remodeling and bone quality were found to be associated with OCD in 2 case reports about patients affected by systemic disease. Kilic et al.²⁷ described a patient with hyper IgE syndrome who developed a knee OCD lesion, proposing osteopenia related to the immunologic condition may represent an etiological factor. Park et al.¹² described development of OCD in a patient affected by Wilson disease, suggesting a correlation between the osteochondral lesion and osteoporosis, osteomalacia, and copper deposition in joints typical of this genetically determined condition.

Several reports describe patients affected by OCD within families and among several generations, stressing the importance of a genetic susceptibility and considering the frequent involvement of both in monozygotic twins.^{11,13,15,19,22,30,35,47} Nevertheless, Petrie et al.⁹⁴ examined first- and second-degree relatives of 34 patients with OCD and found only 1 affected by OCD, concluding that the most common form of this disorder is not familial.

Ossification Deficit Hypothesis

Defects in the ossification centers of the distal femur are thought to predispose to OCD lesions.^{15,17,19,24-26,29,30,32,34,45} Ribbing³⁴ was the first (1955) to describe an accessory bone nucleus detachment in childhood, that may partly fuse during adolescence into the adjacent cancellous bone, remaining partially separated from the latter by islands of persisting cartilage. The incomplete connection between the vascular system of the bone nucleus causes a locus minoris resistentiae, which enables mild injury or strain to produce a slight dislocation with deleterious effects and the separation of the osteochondral unit. Pathologically this seemed consistent with analysis of loose bodies later performed by Barrie.²⁹ Conversely, Laor et al.¹⁷ suggested how an exogenous chronic mechanical insult can affect endochondral ossification of the physis resulting in juvenile OCD.

The detection of pathologic ossification can be challenged by the presence of physiologic variants. In fact, in skeletally immature patients, early stages of OCD might be confused with normal ossification variants, which might account for the “better prognosis” of JOCD with respect to AOCD.²⁶ Jans et al.⁵⁸ confirmed the independent occurrence of normal variants and OCD in a comparative study on large cohorts of patients: 12% out of 116 patients affected by OCD presented normal ossification variants, the same percentage reported in the analysis of the healthy population. A correct differential diagnosis is thus fundamental to prevent unnecessary treatment: location in the inferocentral posterior femoral condyles with intact overlying cartilage, accessory ossification centers, spiculations, residual cartilaginous model, and lack of bone marrow edema are features of normal variants and not typical of OCD.

Endocrine Hypothesis

Hormonal alterations might affect bone metabolism by inducing a process of bone remodeling and subsequent onset of osteochondral lesions. A link between various endocrine abnormalities and OCD was first suggested in 1981 by Mubarak and Carrol,³⁰ who observed a common occurrence of endocrine dysfunction in their patients, but the endocrine theory was further explored only recently.^10,14,18,30 In 2013, Kröger et al.¹⁴ documented 13 cases of OCD in children with juvenile idiopathic arthritis, and suggested either an alteration of the articular surface due to the persistent synovitis, or the possible detrimental effects of glucocorticosteroid injections on cartilage metabolism. Hussain et al.¹⁸ focused instead on changes in hGH levels (it is still not clear whether it is the deficit itself or the hormone supplementation) which may lead to atypical ossification nuclei and subsequent OCD lesions. Finally, in 2014, Bruns et al.¹⁰ shed light on another contributing factor in the progression of the pathology, with 21 out of 23 patients affected by OCD presenting low vitamin D₃ levels.

Mechanical Etiological Factors

Injury and Overuse

Historically, the most advocated theory is the traumatic one, even though a singular macrotrauma was not found to be common, but rather a curiosity.^{12,13,29,31,35,48,55,58,60-62,68,69,79,81,86,92} Shea et al.⁵⁵ reported the case of a patient who developed OCD after an acute traumatic event and proposed a correlation between femoral condyle bone contusion and disease development as an explanation for the OCD finding. What seems more likely is repetitive microtrauma or chronic loading might play a role in the OCD etiopathogenetic process. These events can act by themselves^{48,55,58,60-62,68,79,81} or in combination with other predisposing factors, (e.g. biological or the other mechanical factors).

Tibial Spine Impingement Hypothesis

In 1933, Fairbank was the first to suggest the role of tibial spine impingement against the lateral aspect of the medial condyle as an etiological factor for OCD: abnormal shear forces, caused by the impingement, are generated during internal rotation of the tibia with loading in flexion.⁹⁵ Bramer et al.⁶⁷extended this hypothesis noting increased external tibial torsion might play a role, compensating for the externally rotated position of the foot. Although this theory fails to account for OCD lesions at other sites, it has been subsequently advocated by several authors, thus suggesting that impingement is a valid explanation for OCD in specific joint locations.^{49,63,67,73,84}

Discoid Meniscus Hypothesis

A link between the discoid meniscus variant and femoral condyle OCD is well described.^{13,51,54,64-66,69,72,74,76,78,82} The alterations of joint mechanics produced by the presence of a discoid meniscus may cause an increase in peak loading forces to the subchondral bone lesion predisposing onset of fragment formation.⁶⁶ This hypothesis is supported by the fact that the lateral location is uncommon for OCD except in patients with discoid lateral meniscus.⁶⁵ Furthermore, Deie et al.⁶⁵ even linked the type of lateral discoid meniscus, complete or incomplete, to OCD at specific sites of the lateral femoral condyle.

Although it is likely that the abnormal menisci may cause OCD due to the effect of repetitive abnormal stress on weaker osteochondral growing structures,⁶³ it is still unclear whether the link derives more from the presence of an intact discoid meniscus,^65,82 a torn discoid meniscus,^51,78 or if it is secondary to the alterations provoked by the meniscectomy of the discoid meniscus.^64,66,69,74

More controversial is the role of skeletal maturity on the effects of discoid meniscus presence. While Mitsuoka et al.⁷² underlined the consequences of the abnormal stress produced by a discoid meniscus on the weaker osteochondral structures in the growing period, Kilcoyne et al.⁸² stated that the link between discoid meniscus and OCD extended also beyond the skeletally immature phase.

Biomechanical Alteration Hypothesis

Abnormal biomechanics may have chronic effects on the articular load distribution with a marked impact on the joint homeostasis, which may also contribute to onset of OCD.^{47,50,52,53,56,57,59,63,64,67,70,71,74,75,77,80}

Many conditions can account for this, such as meniscectomy, joint instability, genu recurvatum, and condylar flattening, that increase contact forces at the joint and explain chronic repetitive microtrauma.^5,96 Camathias et al.⁵³ suggested that meniscal instability, specifically a hypermobile anterior horn, might be a decisive factor in the origin of OCD. The meniscus in this condition may work like a “doorstop,” so that the peripheral edge of the loose meniscus impinges repeatedly between the tibial plateau and femoral condyle as the knee moves from flexion to extension, in the end damaging the corresponding femoral osteochondral unit.⁵³

Other examples of OCD associated with biomechanical alterations include: a greater tibial slope,⁵²a more prominent lateral femoral condyle,⁵⁶ or the agenesis of both cruciate ligaments causing anteroposterior instability.⁵⁰ Similarly, varus or valgus deviations of the knee lead to increased mechanical loading of the respective knee compartments.^57,59,75 Besides femoral condyles, the patellar surface may also suffer from abnormalities, thus causing a biomechanical disequilibrium: an atypical patellar surface⁷¹ as well as a recurrent patellar subluxation can cause a repetitive shear stress during knee flexion.^47,77,80 All these conditions might result in a chronic mechanical insult of the osteochondral unit and subsequent development of OCD.

Pathogenetic Mechanisms

Many of the selected articles refer to a pathogenetic progression of OCD through either ischemia^28,31,35,58 or subchondral fracture.^{11,14,18,22,26,27,29,48-50,54,60,61,66,68,71,75,78-81} Whether there is interplay of these 2 conditions or how they are interdependent remains unclear. Uozumi et al.⁶¹ following a histologic analysis hypothesized that the pathologic progression depends on the cause of OCD. Thus, resulting subchondral bone changes reflect the pathologic “primum movens.” In the case of ischemic etiology, the initial change in the subchondral area is necrosis followed by subchondral fracture. In support of a primarily vascular cause, Campbell and Ranawat³¹ point to the simultaneous occurrence of OCD and Osgood-Schlatter disease in childhood and early adolescence. Thereby suggesting a regional vascular insufficiency based metabolic disturbance of the long bone during rapid growth periods, as a common etiology.³¹ If the underlaying cause is a repetitive microtrauma, it is possible to find a subchondral fracture with subsequent bone necrosis due to the lack of the blood supply from the basal side.⁶¹

In any case, regardless of the initiating events, there is agreement on the primary involvement of the subchondral bone in the development of OCD.^{11,14,16,18,22,26-29,31,34,35,48-50,53-55,58,60,61,66,68,71,75,77-82} In fact, besides an isolated position suggesting that OCD is a cartilaginous disease with the subchondral bone secondarily damaged,¹⁹ all other authors referred to the ischemia or fracture of the subchondral bone as etiological “primum movens” acting primarily on the subchondral bone.

Ischemia

Green and Banks³⁵ emphasized the role of ischemic subchondral bone back in 1953. Their histological examination confirmed the basic process in OCD is an aseptic necrosis involving the subchondral bone and subsequent changes are secondary. They speculated that in the earlier phases of the pathologic progression the cartilage remains healthy, because of the nutrition received from the synovial fluid. As dead bone is absorbed, the cartilage gradually loses its mechanical and structural support, becoming more susceptible to trauma and exogenous factors. A few years later, Ribbing³⁴ introduced the hypothesis of ossification nuclei defects, stressing how the bone nucleus partially connected to the cancellous bone represents a locus minoris resistentiae, which enables low-intensity trauma to produce harmful effects on the blood supply of the bone nucleus.

Campbell and Ranawat³¹ subsequently classified OCD as idiopathic aseptic necrotic lesions of the growing epiphysis. Their histological examinations showed a large area beneath the detached fragment which had the characteristic findings of a bone infarct. This, together with the intact overlying articular cartilage, confirmed the necrosis of the underlying bone as a primary event for the formation of the loose body.

The idea of subchondral bone ischemia was recently emphasized by Jans et al.,⁵⁸ who supported the involvement of arterial end branches for the developmental OCD sequence beginning with the separation of the subchondral bone. However, they also advocated repetitive microtrauma as the cause of the compromised blood supply in rapidly growing patients, with interplay of vascular and traumatic factors leading to the onset of OCD.

Fractures

The impingement etiology supports a traumatic mechanism of onset leading to the subchondral bone fracture. Shea et al.⁵⁵ even reported a case ascribed to a single macrotrauma, whereas others observed repetitive microtrauma that provoked a subchondral bone stress fracture which leading to OCD in otherwise normal knee joints.^49,54,68 The occurrence of OCD at the patella also supports the traumatic origin. The plain patellar surface or the recurrent subluxation of the sesamoid bone during knee flexion causes repetitive microtrauma.^71,77,80 Moreover, besides the biomechanical predisposition, the site of the lesion is more suggestive of a traumatic source rather than an ischemic one. In fact, whereas the type of patellar vascularization might entail proximal damage in case of a vascular mechanism, the most common OCD location is in the lower and middle thirds of the articular surface, which are the patellofemoral contact areas subjected to the maximal forces during knee flexion.⁷⁷

Constitutional factors may weaken the subchondral bone and favor the fracture mechanism. Among these, osteopenia caused by hyper IgE syndrome²⁷ or endocrine abnormalities alter metabolism, structure and function of the subchondral bone.¹⁸ Changes in hGH levels may lead to atypical ossification nuclei and decreased ability of the growth plate to absorb energy, and vitamin D deficit¹⁰ has also been indicted as predisposing factor in leaving the subchondral bone susceptible to damage and separation and eventually the development of OCD lesions.

Conclusions

According to this summation of the historic literature, the etiology of OCD can be attributed to either biological or mechanical factors. The former includes genetic causes, deficit of ossification centers and endocrine disorders; the latter, tibial spine impingement, discoid meniscus, and biomechanical alterations, together with injuries and overuse. Interplay of the hypothesized factors that affect the osteochondral unit may support a connection of the different theories in a common etiopathologic framework. These hypotheses, however, are based on generally low levels of evidence. Moreover, these studies are heterogeneous and confound performing a quantitative evaluation of the overall data reported. Despite this, we have presented and organized an account of the historical and current thinking on OCD of the knee in the English literature to better understand and compare the evidence to date. Confirmation and exploration of this framework by further study may allow further clarification of risk factors and mechanisms to be better identified. This in turn may enable customized treatment, and the development of more effective etiology-based therapies for OCD.