Patients with Legg-Calvé-Perthes disease were more likely to be obese according to the WHO criteria with a BMI ≥ 30 kg/m2 than were control subjects (1.3% [40 of 3183] versus 0.5% [144 of 31,817], adjusted RR, 2.8 [95% CI, 1.9-4.0]; p < 0.001). Likewise, hypothyroidism was more common among patients with Legg-Calvé-Perthes disease than among control subjects (1% [31 of 3183] versus 0.4% [121 of 31,817], adjusted RR, 2.6 [95% CI, 1.7-3.8]; p < 0.001). The mean delay between the diagnosis of Legg-Calvé-Perthes disease and a diagnosis of obesity was 10.4 years, and a mean of 8.5 years elapsed between the diagnosis of Legg-Calvé-Perthes disease and a diagnosis of hypothyroidism.
This study has some limitations. We must be aware that changes in diagnosing and coding practice from 1964 until 2011 have undoubtedly occurred. Although the Swedish Patient Register only reached 100% completeness of reporting diagnoses in 1987, the underreporting for inpatient data has currently been estimated to be < 1% [34, 35]. It seems unlikely that this would have introduced a serious selection bias, because patients with Legg-Calvé-Perthes disease and control subjects would probably be affected by failure to register any of the outcomes relevant to this study to a similar extent.
Furthermore, incomplete registration of conservatively treated Legg-Calvé-Perthes disease and other osteochondroses has a considerable influence on the number of registered patients with the investigated diagnoses. Legg-Calvé-Perthes disease and—even more so—many other osteochondroses may be managed on an outpatient basis, but until 2001, only diagnoses based on inpatient hospital episodes were registered in the Swedish Patient Register. As a result, an unknown number of patients with Legg-Calvé-Perthes disease or other osteochondroses who were treated on an outpatient basis before 2001 may have been missed. Stratified analyses performed on the time periods before and after 2001 and additional analyses stratified by the different ICD coding periods did not however result in notably different risk estimates (data not shown).
A drawback to this study is the lack of socioeconomic background variables, a confounder that generally is considered to be important in studies regarding Legg-Calvé-Perthes disease. Social deprivation has repeatedly been found to be associated with Legg-Calvé-Perthes disease [18, 40, 42, 49], but, conversely, the adjustment for education levels and family income in analyses on Swedish populations with Legg-Calvé-Perthes disease did not result in considerably changed risk estimates when compared with unadjusted analyses . Thus, there is reason to believe that adjustment for socioeconomic background would not have substantially altered our conclusions.
Another concern is detection bias, because patients with Legg-Calvé-Perthes disease have established repeated contacts with healthcare providers and might be more prone to be diagnosed with other diseases than Legg-Calvé-Perthes disease. This might especially apply to the osteochondroses that are primarily diagnosed by orthopaedic surgeons and that might have been more easily diagnosed in patients with Legg-Calvé-Perthes disease who were under the surveillance of an orthopaedic surgeon. In contrast, metabolic diseases are normally diagnosed by other specialists than orthopaedic surgeons, and metabolic conditions should thus have been detected similarly in patients with Legg-Calvé-Perthes disease and control subjects. Selection bias is also a source of error, because some patients with atypical manifestations may not have been coded as having Legg-Calvé-Perthes disease, but having related hip disorders, thereby selecting patients with more severe Legg-Calvé-Perthes disease to our study population. The same applies to our outcome measures, in which patients with more severe conditions may have been coded as having the specific disease, whereas less typical or subclinical manifestations may not have resulted in the diagnosis code of interest.
Our findings indicate that patients with Legg-Calvé-Perthes disease have a substantially increased prevalence of the secondary osteochondroses Blount’s, Osgood-Schlatter’s, Köhler-Freiberg’s, Panner’s, and Scheuermann’s disease; Sinding-Larsson-Johansson’s syndrome; and osteochondritis dissecans. Although the common occurrence of Legg-Calvé-Perthes disease and osteochondroses in locations other than the hip is rare, the association of Legg-Calvé-Perthes disease with subsequent osteochondroses indicates that a common pathophysiologic pathway may underlie the multilocular manifestation of osteochondroses. The scarcity of reports on this topic in the literature may be the result of the fact that the RR of having subsequent osteochondroses develop after Legg-Calvé-Perthes disease may be high, but the absolute number of individuals affected by both conditions is low, like in our cohort. Possibly, patients with multilocular osteochondroses such as those reported here have been categorized as having multiple epiphyseal dysplasia or spondyloepiphyseal dysplasia, but the clinical and radiographic findings in those dysplasias are usually characteristic and distinct from osteochondroses.
One could argue that Scheuermann’s disease of the spine does not belong to the group of classic osteochondroses, but rather should be classified as a degenerative disease with herniations of the nucleus pulposus in the vertebral bodies attributable to mechanical stress as the main pathologic landmark [15, 16, 27, 48]. We thus conducted a sensitivity analysis and excluded Scheuermann’s disease as an endpoint, only considering the other osteochondroses as relevant endpoints. The risk of having secondary osteochondroses develop was still elevated for patients with Legg-Calvé-Perthes disease when compared with control subjects, but the risk increase was considerably smaller than the estimates we attained in the main analyses including Scheuermann’s disease.
The mean age of patients at diagnosis of Legg-Calvé-Perthes disease was 7.4 years in our cohort, which is consistent with a previous report . In all but five patients, the age at diagnosis of other osteochondroses was consistently higher, indicating that Legg-Calvé-Perthes disease was the primary manifestation and that other osteochondroses were subsequent, secondary events. We cannot rule out that intrauterine exposure is involved in the pathogenesis of Legg-Calvé-Perthes disease, and it seems likely that genetically determined molecular and cellular disturbances cause osteochondroses. Perry et al.  found the caliber of arterial vessels was smaller in 149 children with Legg-Calvé-Perthes disease when compared with 146 children without the disease. Furthermore, derangement in the coagulation cascade such as Factor V Leiden mutations and decreased levels of proteins C and S have long been suspected of playing a major role in the pathophysiology of Legg-Calvé-Perthes disease [1, 3, 7, 24], and altered blood flow also could explain the association we observed. The association of specific genes with the occurrence of Legg-Calvé-Perthes disease has shown evidence for mutations in genes encoding for proteins that are part of the coagulation cascade such as the previously mentioned Factor V Leiden mutation in patients with Legg-Calvé-Perthes disease . Increased expression levels of proapoptotic factors such as Bax also have been described in a cohort of patients with Legg-Calvé-Perthes disease , and endothelial nitric oxide synthase polymorphisms are more frequent in patients with this disease than in control subjects . Although specific genes are implicated in the pathogenesis of Legg-Calvé-Perthes disease, heritability of the disease has been questioned. A recent Danish study of mono- and dizygotic twins provided strong evidence against a genetic etiology , although that study was relatively small and the findings need to be replicated. Taken together, although the proportion of additive genetic effects may not be very high in Legg-Calvé-Perthes disease, the available molecular evidence indicates that numerous genes involved in the coagulation cascade or in regulation of apoptosis and inflammation are associated with the development of Legg-Calvé-Perthes disease [2, 8, 9, 12, 25].
A potential systemic involvement seems plausible given the increased risk for having obesity and hypothyroidism develop in patients with Legg-Calvé-Perthes disease compared with control subjects. Perhaps because children with Legg-Calvé-Perthes disease are often underweight at the time of disease onset, the prevalence of obesity in patients with Legg-Calvé-Perthes disease has not been extensively investigated. A possible explanation for the association of obesity with Legg-Calvé-Perthes disease found in our study is that obesity in patients with this disease may have been related to physical inactivity that in turn was a consequence of hip pain. However, a retrospective report on 150 patients with Legg-Calvé-Perthes disease indicates that 48% of these patients are either overweight or obese , and free leptin levels are higher in patients than in matched control subjects , indicating that there actually is an association between both diseases on a molecular level. Findings on thyroid dysfunction in patients with Legg-Calvé-Perthes disease are conflicting. Although we found an association of Legg-Calvé-Perthes disease with hypothyroidism, a previous study describes elevated levels of free thyroxin in patients with Legg-Calvé-Perthes disease compared with control subjects . In contrast, another study found no differences in concentrations of thyroid-stimulating hormone and free thyroxin between patients with Legg-Calvé-Perthes disease and control subjects . The protein insulin growth factor-1 is reduced in patients with Legg-Calvé-Perthes disease, and this coincides with retarded skeletal maturation . Thus, general metabolic dysfunction in patients with Legg-Calvé-Perthes disease seems plausible, but causal relationships remain to be elucidated.
The co-occurrence of Legg-Calvé-Perthes disease and osteochondroses at other locations than the hip is rare, but our analysis strengthens the notion that Legg-Calvé-Perthes disease and osteochondroses of the juvenile and adolescent skeleton may be multiple manifestations of a systemic disease. For the orthopaedic surgeon and the pediatrician alike, it is important to be aware that patients with Legg-Calvé-Perthes disease can have additional osteochondroses, obesity, or hypothyroidism develop later. If patients report pain at other locations than the hip, radiographs should be considered to detect such secondary osteochondroses. Perhaps body weight and thyroid function should also be more closely monitored in these patients to detect and possibly prevent secondary metabolic disorders. However, before such general recommendations can be given, a stringent cost-benefit analysis would have to be performed, investigating numbers of patients needed to screen to detect secondary osteochondroses, obesity, or hypothyroidism. In conclusion, Legg-Calvé-Perthes disease seems not to be an isolated joint disease but a systemic condition, and further research on Legg-Calvé-Perthes disease may benefit from this novel approach.
We thank Olof Nilsson, Professor Emeritus, Section of Orthopaedics, Department of Surgical Sciences at Uppsala University, for his contribution to the ethics research committee application. We also thank Niclas Eriksson PhD, Uppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, Uppsala, Sweden, for the preparation of the initial database.
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