In this study a modified radiological index for non-bacterial osteitis (mRINBO) was used for standardized reporting and quantification of WBMRI findings in children with CNO. mRINBO was assessed initially and after treatment with pamidronate for one year. We implemented modifications of the RINBO-score  regarding the size of RALmax and exclusion of RAL in the metatarsal bones.
From baseline to year-one the mRINBO decreased from a median of 5 [IQR, 4-7] to a median of 4 [IQR, 3-5] (p=0.05) driven by a significant decrease of the number of RALs per patient and the size of RALmax whereas the median size of all RALs did not change from baseline to year-one. Signs of reduced radiological activity occurred especially in the pelvis, in the long tubular bones of the lower extremities and in the thoracic spine. Also, signs of extramedullary affection regressed.
When assessing the size of RALmax we observed, that the largest RAL at baseline was 65 mm and the median size of RALmax was 39 [IQR, 26-45] mm and at year-one, the largest RAL was 78 mm and the median size of RALmax was 28 [IQR, 20-40] mm. In the original RINBO study the largest RAL was considerable larger being 265 mm (mean 64±55 mm). The size of RAL depends on disease activity, but also on the size of the bone involved, implying that the age of the child can influence the size of RAL and RALmax. Therefore, a relative size measure of RAL might be advantageous, but was not obtained in the current study.
Assessment of the metatarsal bone lesions revealed that metatarsal lesions often were clinically silent. Radiological CNO findings in the feet have previously been reported in a WBMRI study of 53 children with CNO. This study also showed a mismatch between radiological and clinical findings in the metatarsal bones. Furthermore, metatarsal bone lesions are difficult to assess by coronal WBMRI and difficult to differentiate from non-specific hyperintensities in the feet which may be normal findings in children. Therefore, if lesions in the forefoot are considered of clinical significance, it is recommended to perform site specific MRI assessment or plain radiographs, which may disclose characteristic CNO changes in the feet, including osteolysis, osteosclerosis and new bone formation.[9, 41]
An advantage of the mRINBO score assessed is that it follows a systematic quantitative approach and results in a summary patient score. In this study, we assessed the longitudinal changes in radiological disease activity in children with CNO treated with pamidronate. However, mRINBO may also be used to assess radiological changes independently of the therapy used. In clinical practice WBMRI in CNO is often used for diagnosis and not as follow-up, but in clinical studies assessing treatment response a standardized radiological outcome measure is needed. Longitudinal assessment of changes in radiological disease activity in children with CNO has previously predominantly been descriptive, mainly reporting the number of bone lesions and changes in bone marrow oedema based on expert opinion.[3, 8, 46, 47, 29, 31, 32, 36, 42–45]. Changes in radiological disease activity following pamidronate therapy have been reported based on a WBMRI scoring system encompassing the number, relative size and signal intensity of active CNO lesions as well as soft tissue inflammation and structural lesions in the form of osseous hyperostosis and vertebral collapse, but the study was primarily performed to test reliability of the MR assessment and did not include global patient scores for disease severity. Furthermore, a consensus-driven method for semiquantitative grading of the various CNO lesions by WBMRI has been described, likewise including both active and structural changes and using the relative size of active bone lesion , but this system has to our knowledge not been tested in longitudinal studies probably because further studies are needed to determine the weighting of each variable.
The mRINBO has the advantage of following a systematic quantitative approach reporting the accumulated radiological disease activity in each individual with CNO. Also, the mRINBO quantification is relatively easy to obtain and takes the important features of CNO into account, considering anatomical locations in addition to lesion number and size. Some anatomical locations may be considered to imply an increased risk such as spinal lesions as they can be osteolytic and lead to vertebral collapse.[7, 8, 48] CNO lesions vary considerably in size; the largest lesions often occurring in the pelvis, and future studies may have to prove that the maximal size of RAL is an important feature of disease activity, measured as absolute or relative value.
Monitoring CNO activity is complicated by the fluctuating disease course with spontaneous development of new RALs, [3, 41] also during pamidronate treatment.[8, 36] Based on this study, it was not possible to determine if pamidronate prevented formation of new bone lesions.
The improvement regarding the number of spinal RALs was statistically significant, but it was not possible to show improvements in chronic vertebral changes during one year of pamidronate treatment. Previous studies have shown partial reconstitution of vertebral shape in CNO during long lasting pamidronate treatment up to 41 months.[8, 27] Also, it is well known that the radiological changes and clinical activity in CNO can resolve spontaneously and independently of treatment. In WBMRI studies, the number of radiological bone lesions have been shown to be lower in cohorts including a mixed population of clinically active and inactive patients [2, 21] compared to groups with only clinically active patients. [3, 5] Hence, spontaneous improvement of CNO might overestimate the response to pamidronate treatment in this study and controlled trials are warranted.
Further limitations of this study include the performance of WBMRI on two different MRI scanners and the protocol used did not always include a T1-weighted sequence. Systematically performed T1-weighted sequences might have contributed to a higher sensitivity and specificity in assessing bone lesions than STIR alone. Secondly, this study was limited by a small sample size. However, to our knowledge, this is the first study to systematically assess the individual radiological treatment response in children with CNO using a standardized quantification approach. Thirdly, the study population was selected based on inclusion and exclusion criteria regarding CNO severity, pamidronate treatment and uniform imaging regarding modality and timing. Six children who received TNF-α inhibitor treatment were excluded from the study. Exclusion of these patients might have influenced our results. Exclusion of children not fulfilling the imaging criteria might have led to bias as children not examined by WBMRI might have a milder clinical disease course. Finally, it was not possible retrospectively to assess the exact number of clinically active lesions, which may have influenced the lack of correlation between the clinical and radiological response.