Neurosurgical management of vertebral lesions in pediatric chronic recurrent multifocal osteomyelitis: patient series

Nicholas F. HugDepartment of Neurosurgery, Stanford University School of Medicine, Stanford, California

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David A. PurgerDepartment of Neurosurgery, Stanford University School of Medicine, Stanford, California

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Daphne LiDepartment of Neurosurgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
Pediatric Neurosurgery, Advocate Children’s Medical Group, Park Ridge, Illinois

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Lawrence RinskyDepartment of Orthopedic Surgery, Stanford University, Palo Alto, California; and

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David S. HongDivision of Neurosurgery, Lehigh Valley Health Network, Allentown, Pennsylvania

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BACKGROUND

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare pediatric autoinflammatory disorder involving 2 or more inflammatory bone lesions separated in time and space associated with pathological vertebral fractures. There are no current guidelines for the role of pediatric spine surgeons in the management of this condition. The authors demonstrate the importance of close and early involvement of neurosurgeons in caring for patients with CRMO with vertebral involvement.

OBSERVATIONS

Fifty-six pediatric patients with clinical and radiographic evidence of CRMO were identified and clinical, radiographic, laboratory, and histopathological data were reviewed. All were evaluated via Jansson and Bristol CRMO diagnostic criteria. Ten had radiographic evidence of vertebral involvement (17.9%). Nine of these had multifocal disease. Five patients had multiple vertebrae affected. Six patients were evaluated for possible surgical intervention and one required intervention due to vertebra plana leading to a progressive kyphotic deformity and significant spinal canal stenosis.

LESSONS

In conjunction with management by the primary pediatric rheumatology team using nonsteroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, immunotherapies, and bisphosphonates, given the risk of pathological fractures and potential resulting long-term neurological deficits, the authors recommend close monitoring and management by pediatric spine surgeons for any patient with CRMO with vertebral lesions.

ABBREVIATIONS

CT = computed tomography; CRMO = chronic recurrent multifocal osteomyelitis; DMARD = disease-modifying anti-rheumatic drug; EMR = electronic medical record; LPCH = Lucile Packard Children’s Hospital; MRI = magnetic resonance imaging; NSAID = nonsteroidal anti-inflammatory drug; STARR = Stanford Research Repository; STIR = short tau inversion recovery; TLICS = Thoracolumbar Injury Classification and Severity Score; TNF-α = tumor necrosis factor α; WB = whole-body

BACKGROUND

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare pediatric autoinflammatory disorder involving 2 or more inflammatory bone lesions separated in time and space associated with pathological vertebral fractures. There are no current guidelines for the role of pediatric spine surgeons in the management of this condition. The authors demonstrate the importance of close and early involvement of neurosurgeons in caring for patients with CRMO with vertebral involvement.

OBSERVATIONS

Fifty-six pediatric patients with clinical and radiographic evidence of CRMO were identified and clinical, radiographic, laboratory, and histopathological data were reviewed. All were evaluated via Jansson and Bristol CRMO diagnostic criteria. Ten had radiographic evidence of vertebral involvement (17.9%). Nine of these had multifocal disease. Five patients had multiple vertebrae affected. Six patients were evaluated for possible surgical intervention and one required intervention due to vertebra plana leading to a progressive kyphotic deformity and significant spinal canal stenosis.

LESSONS

In conjunction with management by the primary pediatric rheumatology team using nonsteroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, immunotherapies, and bisphosphonates, given the risk of pathological fractures and potential resulting long-term neurological deficits, the authors recommend close monitoring and management by pediatric spine surgeons for any patient with CRMO with vertebral lesions.

ABBREVIATIONS

CT = computed tomography; CRMO = chronic recurrent multifocal osteomyelitis; DMARD = disease-modifying anti-rheumatic drug; EMR = electronic medical record; LPCH = Lucile Packard Children’s Hospital; MRI = magnetic resonance imaging; NSAID = nonsteroidal anti-inflammatory drug; STARR = Stanford Research Repository; STIR = short tau inversion recovery; TLICS = Thoracolumbar Injury Classification and Severity Score; TNF-α = tumor necrosis factor α; WB = whole-body

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, autoinflammatory disease in adolescents characterized by multiple sterile, painful, bony lesions.1,2 First described by Giedion et al.1 in 1972, CRMO can be associated with skin, gastrointestinal involvement, and other rheumatological conditions. It most often affects females, with onset between 7 and 12 years of age.2–4 Patients often present with insidious bone pain, swelling, and tenderness.2,5 Symptoms can be short-lived and self-limited or persistent for years.2

Lesions most commonly occur in the long bones, pelvic bones, clavicles, and vertebral column.3,4,6–9 Approximately half of patients initially present with 1 lesion but have other asymptomatic lesions on further workup, most commonly in the spine.2,5,10–12

Studies show that up to 30% of patients with CRMO have vertebral involvement, commonly in the thoracic spine.2,5,10 Pathological fractures or vertebral deformity are reported in 30%–50% of these patients.2,5,10 Presentation of these lesions ranges from asymptomatic to kyphotic deformities, cord compression, and functional neurological deficits. The significant risk of pathological fractures and potential neurological injury makes early imaging with whole-body (WB) magnetic resonance imaging (MRI) including short tau inversion recovery (STIR) sequences crucial in suspected CRMO cases to detect any asymptomatic lesions.2,3,13 Because these lesions are often clinically silent, especially in the spine, serial MRI surveillance is important.14

Generally, spinal lesions are treated like other CRMO lesions: conservatively with rest and medication. Nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line medical therapy, although efficacy appears to wane over time, and most patients require second-line treatment—often with disease-modifying anti-rheumatic drugs (DMARDs), bisphosphonates, and/or biological therapies.2,3 Tumor necrosis factor α (TNF-α) inhibitors and bisphosphonates show the most promise, with reports demonstrating high remission rates.6,15–18 Notably, the bisphosphonate pamidronate has been demonstrated as effective for vertebral lesions.5,19–23 In more severe cases, surgery for decompression, fusion, or correction of deformity may be indicated.24,25 Long-term outcomes for CRMO lesions range from complete resolution to long-term deformity and pain; however, many studies were performed prior to the routine use of modern medical therapies.2 Use of novel medications with appropriate surgical intervention will likely result in improved overall outcomes.

Herein, we present a large case series describing patients with CRMO with vertebral involvement. We describe the clinical course of these patients, management, and outcomes, highlighting the importance of the role and decision making of neurosurgeons in monitoring and intervening in these cases.

Study Description

We conducted a retrospective review of the electronic medical records (EMRs) of pediatric neurosurgical patients evaluated at the Lucile Packard Children’s Hospital (LPCH) using the STAnford Research Repository (STARR). STARR is limited to data after 2014 due to the timing of EMR implementation at LPCH. The initial cohort consisted of patients with 1 or more of the following International Classification of Diseases, 10th Revision (ICD-10), codes listed in their EMR: M86.3 (chronic multifocal osteomyelitis) and all M86.3 subcodes (730.19, chronic multifocal osteomyelitis of multiple sites; 730.29, unspecified osteomyelitis involving multiple sites). Records were included if the patient had a clinical diagnosis of CRMO and at least 1 WB MRI during their disease course. Those with radiographic evidence of vertebral involvement were reviewed for relevant clinical data, including location and number of lesions, presenting symptoms, radiographic findings, laboratory and biopsy results, and medical and surgical management. Patients were evaluated via Jansson and Bristol criteria.10,12 Records were assessed from time of diagnosis to the most recent follow-up, prior to February 1, 2022. Average follow-up time was 39 months (range 1–135 months). Patients without vertebral involvement on radiography were excluded.

Results

We identified 56 patients with CRMO who were evaluated and treated at our institution. Ten (17.9%) had involvement of at least 1 vertebra (Table 1). Eight were female. The mean age of onset was 9 years (range 4–13 years). All patients initially presented with complaints of musculoskeletal pain; 3 patients had asymptomatic vertebral column lesion(s) (Table 2). With 1 exception, all patients had multifocal disease. Spinal involvement ranged from edema and sclerotic changes to compression deformities and fractures. All patients underwent WB MRI and 6 underwent skeletal scintigraphy. Biopsy specimens confirmed diagnosis in 8 patients, while the other 2 were diagnosed based on radiographic and clinical findings. All patients met Jansson criteria; 9 met Bristol criteria (Table 1). All were treated medically with NSAIDs and 9 received at least 1 additional class of medication. Seven trialed at least 1 TNF-α inhibitor (cases 2, 3, 4, 6, and 8–10 were treated with adalimumab; cases 3 and 8 were trialed on infliximab; case 3 also received etanercept) and 5 patients received a bisphosphonate (cases 4, 6, 8, and 10 were treated with pamidronate; cases 3 and 10 were also treated with zoledronic acid) (Table 2). Six patients were assessed for surgical management due to either pain or concerning radiographic findings such as vertebral collapse or compression deformities. Of these, only 1 patient (case 3) required an intervention. Below, we highlight 3 patients to illustrate variance in presentation, severity, and management of vertebral CRMO lesions.

TABLE 1.

Summary of diagnostic assessment for patients with CRMO

Case No.SymptomsRelevant HistoryNo. of Imaging-Positive LesionsLesion Location(s)BiopsyPathologyLab ResultsJansson CriteriaBristol Criteria
1TTPFHx autoimmune disease1 (MRI)L2*L2Fibrous changes, minimal inflammation, negative culturesCRP, ESR normal; ANA, RF negativeYesNo
2TTP, feverFHx rheumatoid arthritis8 (MRI, SS)T12–L1, B/L LE* & UE, clavicle, pelvis*NoneCRP, ESR elevated; ANA, RF negativeYesYes
3TTP, blister-like skin lesions, cervical LAD, headachesKawasaki disease (at 7 yrs old)4 (MRI, CT, SS)C4*, clavicle, pelvis, skullC4, at time of interventionPlasma cells, mixed lymphocytes, new bone formation, reactive vasculature, cultures not performedCRP, ESR elevated; NTxYesYes
4TTP, fever, chills, night sweats, rash, skin lesions4 (MRI, SS)T3, T4*, T7, T8, lt LE, lt UE, sternumPelvisAbnormally thickened bony trabeculae, negative culturesNo abnormal valuesYesYes
5Fever, arthralgia, B/L hypopigmentation, erythemaFHx autoimmune disease4 (MRI)S1*, B/L LE, pelvisNoneCRP, ESR elevated; ANA negativeYesYes
6TTP, swellingFHx hypothyroidism3 (MRI, SS)T3, T5, T7, T11*, clavicle, rt LEClavicleAcute & chronic osteomyelitis, negative culturesESR elevated; NTxYesYes
7TTP, swellingFHx psoriasis7 (MRI, CT)C1, B/L occipital bones, rt temporal bone, rt occipital condyle, rt mastoidRt occipital, temporal & mastoidNew bone formation osteoclastic activity, marrow / soft tissue fibrosis, chronic inflammation, negative cultures,CRP, ESR elevatedYesYes
8Pain, weight loss, gait abnormalities, hyperreflexiaFHx psoriasis, Hashimoto’s thyroiditis4 (MRI, CT)T5, T6, T7, T8T6Viable bone, organizing fibrin, inflammatory cells, negative culturesCRP, ESR elevated; NTxYesYes
9Worsening painFHx hypothyroidism4–5 (MRI)T3, T4, T5, T7, maybe lt fibulaT4Severe mixed inflammation, negative culturesCRP, ESR elevatedYesYes
10TTP, swelling, intermittent LE, lt UE numbness>15 (MRI, SS)T9, multiple B/L LE, multiple B/L UE, multiple pelvisLt fibulaHypercellular bone w/ marrow fibrosis, negative culturesESR elevatedYesYes

ANA = antinuclear antibody; B/L = bilateral; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; FHx = family history; LAD = lymphadenopathy; LE = lower extremity; NTx = urinary N terminal telopeptide; RF = rheumatoid factor; SS = skeletal survey; TTP = tenderness to palpation; UE = upper extremity; yo = years old; — = none.

Presenting lesion.

NTx has been described as a potential biomarker to monitor CRMO disease activity.19 It was only tested once in each of the patients described here and not trended over time.

TABLE 2.

Management of patient’s vertebral lesions

Case No.Age at Diagnosis (yr)SexImaging-Positive Vertebral Lesion Location(s)Vertebral Lesion PresentationInitial Spine Imaging & FindingsManagement
MedicalSurgical
112 ML2Pain radiating down LEs, difficulty walkingSclerotic changes, corner cortical deficit, absence of bone at vertebrae (MRI)NSAIDs, opiates, antibiotics; braceNone recommended due to symptomatic improvement & no concerns for spinal instability
27 FT12–L1PainL1 compression fracture (MRI, SS); Mild anterior compression deformity of 2 midthoracic vertebral bodies (SS)NSAIDs, adalimumab, sulfasalazine, opioids; Jewett-Taylor braceNone recommended due to symptomatic improvement & stable radiographic findings
313 FC4Pain, decreased cervical ROMC4 lytic lesion w/ surrounding sclerosis (CT, OSH); Abnormal C4 body w/ enhancement in cystic areas of lesion (MRI, OSH); no new vertebral lesions (SS, 3 yrs postdiagnosis)NSAIDs, steroid, adalimumab, etanercept, infliximab, sulfasalazine, gabapentin, zoledronic acid; cervical collarAnterior C4 corpectomy w/ anterior C3–5 fusion & bone bank graft for worsening pain, progression of lesion to vertebra plana w/ kyphotic deformity & significant spinal canal stenosis
410 FT3, T4, T7, T8Radicular pain, radiating weaknessT3 superior endplate compression; T4 collapse & wedge deformity, cord compression; T8 anterior superior endplate deformity, marrow edema (MRI); loss of height of T4 vertebral body (SS)NSAIDs, adalimumab, pamidronate; Minerva braceNone; Initial recommendation for thoracic fusion for stabilization & prevention of further kyphotic deformity, but reconsidered given improvement of pain w/ bracing & lack of neurological symptoms
59 FS1Radiographic evidence, no pain / neurological symptomsS1 marrow edema, cortical irregularity (MRI)NSAIDsNone recommended given significant improvement in symptoms w/ medical management
611 FT3, T5, T7, T11Pain, muscle spasmsT11 superior endplate compression fracture (MRI); compression deformities at T3, T5, T7 (MRI); increased uptake at T2, T3, T6, T7 (SS)NSAIDs, adalimumab, pamidronate; Milwaukee braceNone recommended given stable findings w/ no evidence of spinal instability
78 FC1Pain, limited ROMPatchy abnormal C1 lateral mass signal changes & erosions, C1 lamina enhancement, w/ surrounding soft tissue edema & inflammationNSAIDs, methotrexate, antibioticsConsidering occipito-cervical fusion pending further workup & medical management
813 MT5, T6, T7, T8Thoracic back pain, mild bowel/bladder incontinenceSevere T6 compression deformity, focal kyphosis; T5 endplate destruction; T5–6 anterior disc height loss, effacement of ventral CSF space, contact of ventral cord w/out cord compression / abnormal cord signal; T7, T8 compression deformities (MRI)NSAIDs, opiates, cyclobenzaprine, pamidronate, infliximab, adalimumab, TSLO braceDiscussed thoracic fusion, but holding off given improvement on medical therapy
911 FT3, T4, T5, T7Upper thoracic back pain, limited ROMT4 compression fracture, focal kyphosis at T4–5 w/ cord indentation, subtle cord signal abnormality; T3, T5 abnormal enhancement; T5 mild height loss; T7 superior endplate compression, no height lossNSAIDs, adalimumabNone recommended to date
106 FT9Radiographic evidence, pain over ribsT9 superior endplate edema w/out enhancementNSAIDs, zoledronic acid, pamidronate, adalimumabNone recommended to date

CSF = cerebrospinal fluid; F = female; M = male; OSH = outside hospital; ROM = range of motion, TSLO = thoracic lumbar sacral orthosis.

Case 3

A 12-year-old girl with a remote history of Kawasaki disease presented with weeks of progressive neck pain, decreased range of motion, and tender lymphadenopathy. Computed tomography (CT) and MRI of the cervical spine revealed a C4 lytic lesion consistent with CRMO (Fig. 1A and B). Skeletal scintigraphy at that time did not reveal other lesions. Two months later, her neck pain progressed and became intolerable. She was found to have interval progression of the lesion with vertebra plana and associated focal kyphotic deformity causing significant spinal canal stenosis. The patient underwent an urgent C4 corpectomy for resection of the lesion, with anterior C3–5 fusion and heterologous bone grafting (Fig. 1C). Pathology was notable for plasma cells, mixed lymphocytes, new bone formation, and reactive vasculature, consistent with CRMO. Development of additional bony lesions in the skull, clavicle, and pelvis with similar imaging findings supported the diagnosis.

FIG. 1.
FIG. 1.

Case 3. Neuroimaging demonstrating a focal lytic lesion in the C4 vertebral body with mild surrounding sclerosis and T2-enhancing cystic components. A: Preoperative sagittal and axial CT images. B: Preoperative sagittal and axial (at level of fracture) T2-weighted MRI sequence. C: Postoperative lateral and anteroposterior (AP) radiographs showing correction of kyphotic deformity.

Since her operation, she has had no neck pain and no evidence of recurrence, although she did continue to have pain and tenderness at other lesions. She has had no gastrointestinal symptoms but did have recurrent episodes of blister-like skin lesions. Medical management has consisted of a wide range of medications due to difficulty in controlling pain as well as use of a cervical collar following her operation; however, at her last visit, she was stable on infliximab and naproxen. In addition to vertebrectomy, she also underwent surgical resection of her frontoparietal skull lesion due to significant pain. At her most recent visit, 7 years after diagnosis, she described pain over a palpable, but radiographically occult, lesion at her right mandibular angle, but was otherwise stable without neck pain or focal neurological findings.

Case 4

A 10-year-old otherwise healthy girl presented with a several-week history of worsening thoracic back pain and radiculopathy with episodic fevers, chills, and night sweats. On workup, she was found to have T4 vertebral body collapse with mild spinal canal stenosis, cord compression, and focal kyphosis (27°) (Fig. 2). Further lesions were identified in her left acetabulum, sternum, and left first metacarpal. Biopsy of the left acetabular lesion was nonspecific but sterile and without evidence of Langerhans cell histiocytosis. Based on the clinical picture and these results, a presumptive diagnosis of CRMO was made. Recommendations were initially made for thoracic spinal decompression and fusion with resection of the T4 lesion, but given her lack of focal neurological symptoms and interim improvement in symptoms with conservative management (NSAIDs and Minerva bracing), no neurosurgical intervention was pursued.

FIG. 2.
FIG. 2.

Case 4. Neuroimaging demonstrating collapse of the T4 vertebral body with mild spinal canal and cord compression with focal kyphotic angulation (27°). A: Sagittal STIR and axial T2-weighted MRI sequences. B: Sagittal and axial CT images. C: Standing scoliosis AP and lateral radiographs.

After her initial diagnosis, she remained relatively asymptomatic, despite new evidence of contrast-enhancing vertebral lesions at the T3, T7, and T8 vertebral bodies on repeat spinal MRI. She received 1 course of pamidronate but was primarily maintained on NSAIDs and adalimumab. The patient also developed several annular, violaceous/erythematous, scaly plaques on her lower extremities. With no significant flares or progression of her vertebral lesions, no surgical intervention has been performed to date. At her most recent visit, 6 years after diagnosis, she was stable without any pain or focal neurological findings.

Case 6

An 11-year-old otherwise healthy girl presented with 3 weeks of right lower back pain following an accidental kick to the area while playing soccer. Her pain was severe, associated with muscle spasms, and minimally relieved with NSAIDs and physical therapy. The pain limited her ability to walk but was not associated with any neurological deficits or radicular symptoms. The midline structures of the spine were not tender to palpation. MRI of the spine revealed a T11 superior endplate compression fracture without retropulsion or cord compression (Fig. 3). At that time, a right clavicular mass that was sore but not associated with erythema or warmth was identified. Biopsy of the clavicular mass was notable for mixed inflammatory infiltrate, negative for CD1a and CD207 (Langerin), with no blasts or monoclonal lymphocytes. Aerobic, anaerobic, fungal, and acid-fast bacilli cultures were negative. Laboratory studies were only notable for an elevated erythrocyte sedimentation rate of 46 mm/hr. Based on these findings, she was diagnosed with CRMO and started on NSAID therapy.

FIG. 3.
FIG. 3.

Case 6. Neuroimaging demonstrating T11 superior endplate compression fracture with mild vertebral body height loss and edema, with edema in the anterior inferior aspect of T12. No retropulsion or cord compression was observed. A: Sagittal STIR MRI sequence of the cervical and thoracic spine. B: Sagittal STIR MRI sequence of the thoracic and lumbar spine. C: Skeletal scintigraphy. D: Standing scoliosis lateral radiograph.

Approximately 1 year after initial presentation, she developed new-onset back pain without associated trauma and was found to have new compression deformities of T5 and T7 as well as vertebra plana of T3. She underwent a course of pamidronate, resulting in symptomatic and radiographic resolution of the vertebral lesions. Several months later, her pain recurred and a new compression fracture was found at T5 with worsening of the T3 lesion and increased focal kyphotic deformity. She was started on adalimumab and placed in a Milwaukee brace, which led to resolution of her pain. She was weaned off adalimumab and, at her last visit, 8 years after her diagnosis, she was symptomatically and radiographically stable.

Discussion

Although relatively rare, CRMO is an important clinical entity for pediatric neurosurgeons to be aware of. There are no diagnostic or treatment guidelines for CRMO involving the spine. Most of the guidance available is derived from observational and cohort studies, the majority of which focus on medical management.2,3,13,26 The literature regarding the role of spine surgeons is limited to case reports.24,25 Given the potential for severe complications in patients with CRMO with vertebral lesions, we propose early involvement of spine surgeons in their care. Evaluation and monitoring by a surgical team allows for early intervention and prevention of long-term morbidity. Here we provide an overview of the diagnostic approach to and management of vertebral CRMO lesions based on the literature and our institutional experience with these patients, emphasizing the surgeon’s role.

Observations

CRMO is considered a diagnosis of exclusion as there is not a specific objective finding that is diagnostic and because the presentation varies widely. Two sets of diagnostic criteria, the Bristol and Jansson criteria, emphasize taking the entire clinical picture into account and heavily weight the clinical and radiographic findings.10,12

Evaluation should be considered in adolescents with insidious bone pain, swelling, and tenderness, especially in patients with personal or familial history of rheumatic disease. Patients should be assessed for signs of skin or gastrointestinal inflammation.2,3 Vertebral lesions, especially when associated with pathological fractures, commonly present with pain and tenderness; however, they may be asymptomatic. Three patients in this series (cases 5, 6, and 10) had initially asymptomatic vertebral lesions, while the rest presented due to back pain. The patient in case 6 had both asymptomatic and painful vertebral lesions over the course of their disease, highlighting the variability in presentation.

MRI or radionuclide bone scans are considered the most important imaging studies; radiography and CT are less consistent in identifying and characterizing lesions.9,29 They appear as osteolytic lesions or cortical erosion of the vertebral body corner at any vertebral level, although most often in the thoracic spine.9,27,28 Similar to other bony CRMO lesions, vertebral lesions show an early lytic phase followed by chronic sclerosis, representing a transformation from an active to inactive lesion.27,28 Active lesions can show high STIR signal and contrast enhancement on MRI or increased uptake on radionuclide bone scans.1,2,8 If CRMO is suspected based on the lesion(s) identified on radiography, WB MRI should be obtained to detect silent lesions and provide a baseline for comparison with future radiography to assess disease course and response to therapies.2,3,13

If the diagnosis remains uncertain, histopathological analysis via biopsy can be useful.2 The differential diagnosis will often include several neoplasms and malignancies. Lesions are histologically similar to bacterial osteomyelitis, but sterile, which helps distinguish them from subacute osteomyelitis.4,28 Early lesions may show neutrophilic marrow infiltration, while chronic lesions demonstrate fibrosis, lymphocytic infiltrates, and reactive bone formation.28 As these are nonspecific findings, biopsy is not required if the clinical picture and radiographic findings are consistent with CRMO.2,3,12,13 In fact, biopsy is not an absolute requirement for diagnosis by either the Bristol or Jansson criteria.10,12

Initial treatment for all patients with CRMO is almost always conservative, with medical therapy primarily overseen by a pediatric rheumatology team with NSAIDs as first-line agents. Given that NSAIDs often do not provide long-term relief, most patients receive second-line therapies.3 These include DMARDs (methotrexate, sulfasalazine), TNF-α inhibitors (adalimumab, etanercept, infliximab), and bisphosphonates (pamidronate, zoledronic acid).2,3 Retrospective series and case reports evaluating these second-line therapies show that TNF-α inhibitors and bisphosphonates have consistently the highest rates of complete or partial remission.6,7,15,16,29 A recent consortium of CRMO experts estimated, based on Bayesian analysis of published studies on CRMO treatment outcomes, that a patient with newly diagnosed CRMO would have a greater than 80% chance of symptomatic improvement when treated with either pamidronate or adalimumab.30 The prevailing theory regarding the underlying pathophysiology of CRMO is an imbalance between pro- and anti-inflammatory cytokines.2 TNF-α inhibitors directly correct this imbalance by blocking the actions of TNF-α, a key proinflammatory cytokine.2,30 The reason for improvement on bisphosphonates is less clear; however, inhibition of pathologically activated osteoclasts may reduce lesion expansion.2,30 Pamidronate specifically has been shown to relieve pain, improve function, and lead to resolution of and/or reduction in active lesions, with improvement in vertebral modeling and height.2,5,19–23

Zhao et al.31 developed 3 standardized medical treatment plans for patients refractory to NSAIDs and/or with active vertebral lesions: (1) nonbiological DMARDs (methotrexate or sulfasalazine), (2) TNF-α inhibitors ± methotrexate, and (3) bisphosphonates. Their suggested therapeutic strategy is a 1- to 3-month trial of 1 treatment plan before switching or adding another treatment. At our institution, rheumatologists use TNF-α inhibitors and bisphosphonates for spine patients with CRMO.

Of these patients, 30%–50% may develop pathological fractures, which can lead to neurological deficits, deformity, and spinal instability, and may require surgical intervention.5,10 Further, they are at high risk of development of occult lesions. Serial imaging to evaluate for changes in existing lesions or development of new lesions is crucial. Although presenting in the setting of a unique disease process, established guidelines regarding fracture and deformity management dictate intervention, with adjustments as appropriate for this pediatric population. A detailed discussion of fracture/deformity grading and management algorithms is beyond the scope of this series; however, a few general points can be noted. The 2- and 3-column models for the cervical and thoracolumbar spine, respectively, assess fracture severity and spinal cord injury risk. The Thoracolumbar Injury Classification and Severity Score (TLICS), or modified TLICS, may be used and evaluates radiography, neurological status, and presence of posterior ligament complex injury.32,33 Alternatively, the AOSpine Trauma Classification assesses trauma at any vertebral level.34,35 Regardless of system, classification guides nonsurgical or surgical intervention. Common indications for intervention include neurological deficits, severe and progressive deformities, or unremitting pain. Nonoperative management includes bedrest, analgesics, and/or bracing. Operative management is often decompression and fusion, although plans are individualized and account for a patient’s medical and surgical concerns. In pediatric patients, continued skeletal growth must be considered and favors nonoperative management. Orthotics or bracing may obviate or delay surgical intervention for stable or borderline fractures. Braces alleviate pain and provide external support while lesions resolve. Six patients in our series used orthotic braces or collars for the initial management of compression fractures; only 1 patient (case 3) required surgical intervention after conservative management.

In our cohort, 1 patient (case 8) developed gait abnormalities, hyperreflexia, and incontinence over the course of their disease, which responded to medical therapy. No other patients had neurological deficits, although all were followed closely. Surgical management was discussed in 6 patients due to pathological vertebral body fractures causing kyphotic deformities or evidence of radiographic progression, with only case 3 requiring surgical intervention. Overall, in concordance with the literature, these patients were primarily managed with conservative measures. However, surgical intervention was considered on a patient-by-patient basis.

Potential side effects of medical treatments should be considered when discussing spinal fusion. NSAIDs inhibit osteogenic activity: human studies show that high doses of NSAIDs post- fusion increase nonunion rates, although short courses of normal or low doses do not.36–38 Bisphosphonate use in animal studies variably shows decreased fusion. Alendronate increased radiographically defined fusion rate without any change in clinical outcome in 1 trial.39–41 Zoledronic acid may have either no effect or slightly increase the fusion rate.42,43 Importantly, these studies assessed adults with osteoporosis and may not be directly applicable to a pediatric population. Further studies investigating these and other biological therapies in the context of pediatric spinal fusion would inform postoperative CRMO medical treatment.

Lessons

Although initial treatment for CRMO involves conservative, multimodal management, spine surgeons serve an important role in the early care of patients with vertebral lesions. Surgical intervention may become necessary to prevent or address neurological deficits, pain, deformity, or instability. Management in these cases follows established guidelines for fractures and deformities, with consideration given to age, potential for disease progression and occult lesions, and the effects of concurrent medical management. The surgical team should follow both operative and nonoperative patients long term and work closely with the pediatric rheumatology team to identify sudden clinical or radiographic changes that may indicate new lesions or development of pathological fractures. Encouraging early diagnosis, medical treatment, and external bracing can be a successful means to avoid more invasive fusion procedures.

Acknowledgments

This research used data or services provided by STARR, a clinical data warehouse containing live Epic data from Stanford Health Care, the Stanford Children’s Hospital, the University Healthcare Alliance, and Packard Children’s Health Alliance clinics and other auxiliary data from hospital applications such as radiology picture archiving and communication system (PACS). The STARR platform is developed and operated by Stanford Medicine Research IT team and is made possible by the Stanford School of Medicine Research Office.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Purger, Rinsky, Hong. Acquisition of data: Hug, Purger, Rinsky. Analysis and interpretation of data: Hug, Purger, Li. Drafting of the article: Hug, Purger. Critically revising the article: Hug, Purger, Li, Hong. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Hug. Statistical analysis: Hug, Purger. Study supervision: Hong.

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    • Export Citation
  • 8

    Girschick HJ, Zimmer C, Klaus G, Darge K, Dick A, Morbach H. Chronic recurrent multifocal osteomyelitis: what is it and how should it be treated? Nat Clin Pract Rheumatol. 2007;3(12):733738.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Greenwood S, Leone A, Cassar-Pullicino VN. SAPHO and recurrent multifocal osteomyelitis. Radiol Clin North Am. 2017;55(5):10351053.

  • 10

    Jansson A, Renner ED, Ramser J, et al. Classification of non- bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford). 2007;46(1):154160.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Jurik AG. Chronic recurrent multifocal osteomyelitis. Semin Musculoskelet Radiol. 2004;8(3):243253.

  • 12

    Roderick MR, Shah R, Rogers V, Finn A, Ramanan AV. Chronic recurrent multifocal osteomyelitis (CRMO)—advancing the diagnosis. Pediatr Rheumatol Online J. 2016;14(1):47.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Zhao Y, Dedeoglu F, Ferguson PJ, et al. Physicians’ perspectives on the diagnosis and treatment of chronic nonbacterial osteomyelitis. Int J Rheumatol. 2017;2017:7694942.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Voit AM, Arnoldi AP, Douis H, et al. Whole-body magnetic resonance imaging in chronic recurrent multifocal osteomyelitis: clinical longterm assessment may underestimate activity. J Rheumatol. 2015;42(8):14551462.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Concha S, Hernández-Ojeda A, Contreras O, Mendez C, Talesnik E, Borzutzky A. Chronic nonbacterial osteomyelitis in children: a multicenter case series. Rheumatol Int. 2020;40(1):115120.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Kostik MM, Kopchak OL, Chikova IA, Isupova EA, Mushkin AY. Comparison of different treatment approaches of pediatric chronic non-bacterial osteomyelitis. Rheumatol Int. 2019;39(1):8996.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Schnabel A, Range U, Hahn G, Berner R, Hedrich CM. Treatment response and longterm outcomes in children with chronic nonbacterial osteomyelitis. J Rheumatol. 2017;44(7):10581065.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Girschick H, Finetti M, Orlando F, et al. The multifaceted presentation of chronic recurrent multifocal osteomyelitis: a series of 486 cases from the Eurofever International Registry. Rheumatology (Oxford). 2018;57(7):12031211.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Miettunen PMH, Wei X, Kaura D, Reslan WA, Aguirre AN, Kellner JD. Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J. 2009;7(1):2.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Gleeson H, Wiltshire E, Briody J, et al. Childhood chronic recurrent multifocal osteomyelitis: pamidronate therapy decreases pain and improves vertebral shape. J Rheumatol. 2008;35(4):707712.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Simm PJ, Allen RC, Zacharin MR. Bisphosphonate treatment in chronic recurrent multifocal osteomyelitis. J Pediatr. 2008;152(4):571575.

  • 22

    Compeyrot-Lacassagne S, Rosenberg AM, Babyn P, Laxer RM. Pamidronate treatment of chronic noninfectious inflammatory lesions of the mandible in children. J Rheumatol. 2007;34(7):15851589.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Kerrison C, Davidson JE, Cleary AG, Beresford MW. Pamidronate in the treatment of childhood SAPHO syndrome. Rheumatology (Oxford). 2004;43(10):12461251.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Baulot E, Bouillien D, Giroux EA, Grammont PM. Chronic recurrent multifocal osteomyelitis causing spinal cord compression. Eur Spine J. 1998;7(4):340343.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Carr AJ, Cole WG, Roberton DM, Chow CW. Chronic multifocal osteomyelitis. J Bone Joint Surg Br. 1993;75(4):582591.

  • 26

    Schultz C, Holterhus PM, Seidel A, et al. Chronic recurrent multifocal osteomyelitis in children. Pediatr Infect Dis J. 1999;18(11):10081013.

  • 27

    Mortensson W, Edeburn G, Fries M, Nilsson R. Chronic recurrent multifocal osteomyelitis in children. A roentgenologic and scintigraphic investigation. Acta Radiol. 1988;29(5):565570.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Anderson SE, Heini P, Sauvain MJ, et al. Imaging of chronic recurrent multifocal osteomyelitis of childhood first presenting with isolated primary spinal involvement. Skeletal Radiol. 2003;32(6):328336.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Bustamante J, Murias S, Enriquez E, Alcobendas R, Remesal A, De Inocencio J. Biological therapy in refractory chronic nonbacterial osteomyelitis: a case series of 19 patients. Joint Bone Spine. 2021;88(2):105120.

    • Search Google Scholar
    • Export Citation
  • 30

    Ramanan AV, Hampson LV, Lythgoe H, et al. Defining consensus opinion to develop randomised controlled trials in rare diseases using Bayesian design: an example of a proposed trial of adalimumab versus pamidronate for children with CNO/CRMO. PLoS One. 2019;14(6):e0215739.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Zhao Y, Wu EY, Oliver MS, et al. Consensus treatment plans for chronic nonbacterial osteomyelitis refractory to nonsteroidal antiinflammatory drugs and/or with active spinal lesions. Arthritis Care Res (Hoboken). 2018;70(8):12281237.

    • Search Google Scholar
    • Export Citation
  • 32

    Patel AA, Dailey A, Brodke DS, et al. Thoracolumbar spine trauma classification: the Thoracolumbar Injury Classification and Severity Score system and case examples. J Neurosurg Spine. 2009;10(3):201206.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Park HJ, Lee SY, Park NH, et al. Modified Thoracolumbar Injury Classification and Severity Score (TLICS) and its clinical usefulness. Acta Radiol. 2016;57(1):7481.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Kepler CK, Vaccaro AR, Koerner JD, et al. Reliability analysis of the AOSpine thoracolumbar spine injury classification system by a worldwide group of naïve spinal surgeons. Eur Spine J. 2016;25(4):10821086.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Divi SN, Schroeder GD, Oner FC, et al. AOSpine-Spine Trauma Classification System: the value of modifiers: a narrative review with commentary on evolving descriptive principles. Global Spine J. 2019;9(1)(suppl):77S88S.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Glassman SD, Rose SM, Dimar JR, Puno RM, Campbell MJ, Johnson JR. The effect of postoperative nonsteroidal anti-inflammatory drug administration on spinal fusion. Spine (Phila Pa 1976). 1998;23(7):834838.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Li Q, Zhang Z, Cai Z. High-dose ketorolac affects adult spinal fusion: a meta-analysis of the effect of perioperative nonsteroidal anti-inflammatory drugs on spinal fusion. Spine (Phila Pa 1976). 2011;36(7):E461E468.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Sivaganesan A, Chotai S, White-Dzuro G, McGirt MJ, Devin CJ. The effect of NSAIDs on spinal fusion: a cross-disciplinary review of biochemical, animal, and human studies. Eur Spine J. 2017; 26(11):27192728.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Hirsch BP, Unnanuntana A, Cunningham ME, Lane JM. The effect of therapies for osteoporosis on spine fusion: a systematic review. Spine J. 2013;13(2):190199.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Huang RC, Khan SN, Sandhu HS, et al. Alendronate inhibits spine fusion in a rat model. Spine (Phila Pa 1976). 2005;30(22):25162522.

  • 41

    Nagahama K, Kanayama M, Togawa D, Hashimoto T, Minami A. Does alendronate disturb the healing process of posterior lumbar interbody fusion? A prospective randomized trial. J Neurosurg Spine. 2011;14(4):500507.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Park YS, Kim HS, Baek SW, Kong DY, Ryu JA. The effect of zoledronic acid on the volume of the fusion-mass in lumbar spinal fusion. Clin Orthop Surg. 2013;5(4):292297.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Ding Q, Chen J, Fan J, Li Q, Yin G, Yu L. Effect of zoledronic acid on lumbar spinal fusion in osteoporotic patients. Eur Spine J. 2017;26(11):29692977.

    • PubMed
    • Search Google Scholar
    • Export Citation
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    FIG. 1.

    Case 3. Neuroimaging demonstrating a focal lytic lesion in the C4 vertebral body with mild surrounding sclerosis and T2-enhancing cystic components. A: Preoperative sagittal and axial CT images. B: Preoperative sagittal and axial (at level of fracture) T2-weighted MRI sequence. C: Postoperative lateral and anteroposterior (AP) radiographs showing correction of kyphotic deformity.

  • View in gallery
    FIG. 2.

    Case 4. Neuroimaging demonstrating collapse of the T4 vertebral body with mild spinal canal and cord compression with focal kyphotic angulation (27°). A: Sagittal STIR and axial T2-weighted MRI sequences. B: Sagittal and axial CT images. C: Standing scoliosis AP and lateral radiographs.

  • View in gallery
    FIG. 3.

    Case 6. Neuroimaging demonstrating T11 superior endplate compression fracture with mild vertebral body height loss and edema, with edema in the anterior inferior aspect of T12. No retropulsion or cord compression was observed. A: Sagittal STIR MRI sequence of the cervical and thoracic spine. B: Sagittal STIR MRI sequence of the thoracic and lumbar spine. C: Skeletal scintigraphy. D: Standing scoliosis lateral radiograph.

  • 1

    Giedion A, Holthusen W, Masel LF, Vischer D. [Subacute and chronic “symmetrical” osteomyelitis]. Ann Radiol (Paris). 1972;15(3):329342.

  • 2

    Roderick MR, Sen ES, Ramanan AV. Chronic recurrent multifocal osteomyelitis in children and adults: current understanding and areas for development. Rheumatology (Oxford). 2018;57(1):4148.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Hofmann SR, Kapplusch F, Girschick HJ, et al. Chronic recurrent multifocal osteomyelitis (CRMO): presentation, pathogenesis, and treatment. Curr Osteoporos Rep. 2017;15(6):542554.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Gamble JG, Rinsky LA. Chronic recurrent multifocal osteomyelitis: a distinct clinical entity. J Pediatr Orthop. 1986;6(5):579584.

  • 5

    Hospach T, Langendoerfer M, von Kalle T, Maier J, Dannecker GE. Spinal involvement in chronic recurrent multifocal osteomyelitis (CRMO) in childhood and effect of pamidronate. Eur J Pediatr. 2010;169(9):11051111.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Borzutzky A, Stern S, Reiff A, et al. Pediatric chronic nonbacterial osteomyelitis. Pediatrics. 2012;130(5):e1190e1197.

  • 7

    Schnabel A, Range U, Hahn G, Siepmann T, Berner R, Hedrich CM. Unexpectedly high incidences of chronic non-bacterial as compared to bacterial osteomyelitis in children. Rheumatol Int. 2016;36(12):17371745.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Girschick HJ, Zimmer C, Klaus G, Darge K, Dick A, Morbach H. Chronic recurrent multifocal osteomyelitis: what is it and how should it be treated? Nat Clin Pract Rheumatol. 2007;3(12):733738.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Greenwood S, Leone A, Cassar-Pullicino VN. SAPHO and recurrent multifocal osteomyelitis. Radiol Clin North Am. 2017;55(5):10351053.

  • 10

    Jansson A, Renner ED, Ramser J, et al. Classification of non- bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford). 2007;46(1):154160.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Jurik AG. Chronic recurrent multifocal osteomyelitis. Semin Musculoskelet Radiol. 2004;8(3):243253.

  • 12

    Roderick MR, Shah R, Rogers V, Finn A, Ramanan AV. Chronic recurrent multifocal osteomyelitis (CRMO)—advancing the diagnosis. Pediatr Rheumatol Online J. 2016;14(1):47.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Zhao Y, Dedeoglu F, Ferguson PJ, et al. Physicians’ perspectives on the diagnosis and treatment of chronic nonbacterial osteomyelitis. Int J Rheumatol. 2017;2017:7694942.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Voit AM, Arnoldi AP, Douis H, et al. Whole-body magnetic resonance imaging in chronic recurrent multifocal osteomyelitis: clinical longterm assessment may underestimate activity. J Rheumatol. 2015;42(8):14551462.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Concha S, Hernández-Ojeda A, Contreras O, Mendez C, Talesnik E, Borzutzky A. Chronic nonbacterial osteomyelitis in children: a multicenter case series. Rheumatol Int. 2020;40(1):115120.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Kostik MM, Kopchak OL, Chikova IA, Isupova EA, Mushkin AY. Comparison of different treatment approaches of pediatric chronic non-bacterial osteomyelitis. Rheumatol Int. 2019;39(1):8996.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Schnabel A, Range U, Hahn G, Berner R, Hedrich CM. Treatment response and longterm outcomes in children with chronic nonbacterial osteomyelitis. J Rheumatol. 2017;44(7):10581065.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Girschick H, Finetti M, Orlando F, et al. The multifaceted presentation of chronic recurrent multifocal osteomyelitis: a series of 486 cases from the Eurofever International Registry. Rheumatology (Oxford). 2018;57(7):12031211.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Miettunen PMH, Wei X, Kaura D, Reslan WA, Aguirre AN, Kellner JD. Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J. 2009;7(1):2.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Gleeson H, Wiltshire E, Briody J, et al. Childhood chronic recurrent multifocal osteomyelitis: pamidronate therapy decreases pain and improves vertebral shape. J Rheumatol. 2008;35(4):707712.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Simm PJ, Allen RC, Zacharin MR. Bisphosphonate treatment in chronic recurrent multifocal osteomyelitis. J Pediatr. 2008;152(4):571575.

  • 22

    Compeyrot-Lacassagne S, Rosenberg AM, Babyn P, Laxer RM. Pamidronate treatment of chronic noninfectious inflammatory lesions of the mandible in children. J Rheumatol. 2007;34(7):15851589.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Kerrison C, Davidson JE, Cleary AG, Beresford MW. Pamidronate in the treatment of childhood SAPHO syndrome. Rheumatology (Oxford). 2004;43(10):12461251.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Baulot E, Bouillien D, Giroux EA, Grammont PM. Chronic recurrent multifocal osteomyelitis causing spinal cord compression. Eur Spine J. 1998;7(4):340343.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Carr AJ, Cole WG, Roberton DM, Chow CW. Chronic multifocal osteomyelitis. J Bone Joint Surg Br. 1993;75(4):582591.

  • 26

    Schultz C, Holterhus PM, Seidel A, et al. Chronic recurrent multifocal osteomyelitis in children. Pediatr Infect Dis J. 1999;18(11):10081013.

  • 27

    Mortensson W, Edeburn G, Fries M, Nilsson R. Chronic recurrent multifocal osteomyelitis in children. A roentgenologic and scintigraphic investigation. Acta Radiol. 1988;29(5):565570.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Anderson SE, Heini P, Sauvain MJ, et al. Imaging of chronic recurrent multifocal osteomyelitis of childhood first presenting with isolated primary spinal involvement. Skeletal Radiol. 2003;32(6):328336.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Bustamante J, Murias S, Enriquez E, Alcobendas R, Remesal A, De Inocencio J. Biological therapy in refractory chronic nonbacterial osteomyelitis: a case series of 19 patients. Joint Bone Spine. 2021;88(2):105120.

    • Search Google Scholar
    • Export Citation
  • 30

    Ramanan AV, Hampson LV, Lythgoe H, et al. Defining consensus opinion to develop randomised controlled trials in rare diseases using Bayesian design: an example of a proposed trial of adalimumab versus pamidronate for children with CNO/CRMO. PLoS One. 2019;14(6):e0215739.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Zhao Y, Wu EY, Oliver MS, et al. Consensus treatment plans for chronic nonbacterial osteomyelitis refractory to nonsteroidal antiinflammatory drugs and/or with active spinal lesions. Arthritis Care Res (Hoboken). 2018;70(8):12281237.

    • Search Google Scholar
    • Export Citation
  • 32

    Patel AA, Dailey A, Brodke DS, et al. Thoracolumbar spine trauma classification: the Thoracolumbar Injury Classification and Severity Score system and case examples. J Neurosurg Spine. 2009;10(3):201206.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Park HJ, Lee SY, Park NH, et al. Modified Thoracolumbar Injury Classification and Severity Score (TLICS) and its clinical usefulness. Acta Radiol. 2016;57(1):7481.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Kepler CK, Vaccaro AR, Koerner JD, et al. Reliability analysis of the AOSpine thoracolumbar spine injury classification system by a worldwide group of naïve spinal surgeons. Eur Spine J. 2016;25(4):10821086.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Divi SN, Schroeder GD, Oner FC, et al. AOSpine-Spine Trauma Classification System: the value of modifiers: a narrative review with commentary on evolving descriptive principles. Global Spine J. 2019;9(1)(suppl):77S88S.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Glassman SD, Rose SM, Dimar JR, Puno RM, Campbell MJ, Johnson JR. The effect of postoperative nonsteroidal anti-inflammatory drug administration on spinal fusion. Spine (Phila Pa 1976). 1998;23(7):834838.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Li Q, Zhang Z, Cai Z. High-dose ketorolac affects adult spinal fusion: a meta-analysis of the effect of perioperative nonsteroidal anti-inflammatory drugs on spinal fusion. Spine (Phila Pa 1976). 2011;36(7):E461E468.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Sivaganesan A, Chotai S, White-Dzuro G, McGirt MJ, Devin CJ. The effect of NSAIDs on spinal fusion: a cross-disciplinary review of biochemical, animal, and human studies. Eur Spine J. 2017; 26(11):27192728.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Hirsch BP, Unnanuntana A, Cunningham ME, Lane JM. The effect of therapies for osteoporosis on spine fusion: a systematic review. Spine J. 2013;13(2):190199.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Huang RC, Khan SN, Sandhu HS, et al. Alendronate inhibits spine fusion in a rat model. Spine (Phila Pa 1976). 2005;30(22):25162522.

  • 41

    Nagahama K, Kanayama M, Togawa D, Hashimoto T, Minami A. Does alendronate disturb the healing process of posterior lumbar interbody fusion? A prospective randomized trial. J Neurosurg Spine. 2011;14(4):500507.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Park YS, Kim HS, Baek SW, Kong DY, Ryu JA. The effect of zoledronic acid on the volume of the fusion-mass in lumbar spinal fusion. Clin Orthop Surg. 2013;5(4):292297.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Ding Q, Chen J, Fan J, Li Q, Yin G, Yu L. Effect of zoledronic acid on lumbar spinal fusion in osteoporotic patients. Eur Spine J. 2017;26(11):29692977.

    • PubMed
    • Search Google Scholar
    • Export Citation

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