Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO)

Abstract

Background: Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory, non-infectious osteopathy that affects predominantly patients </= 18 years of age. There is no uniformly effective treatment. Our objective is to describe clinical, magnetic resonance imaging (MRI), and bone resorption response to intravenous pamidronate in pediatric CRMO.

Methods: We report our prospectively documented experience with all CRMO patients treated with pamidronate between 2003 and 2008 at a tertiary pediatric centre. Pamidronate was administered as intravenous cycles. The dose of pamidronate varied among subjects but was given as monthly to every 3 monthly cycles depending on the distance the patient lived from the infusion center. Maximum cumulative dose was </= 11.5 mg/kg/year. Pamidronate treatment was continued until resolution of MRI documented bone inflammation. Visual analog scale for pain (VAS) and bone resorption marker urine N-telopeptide/urine creatinine (uNTX/uCr) were measured at baseline, preceding each subsequent pamidronate treatment, at final follow-up, and/or at time of MRI confirmed CRMO flare. MRI of the affected site(s) was obtained at baseline, preceding every 2nd treatment, and with suspected CRMO recurrence.

Results: Nine patients (5 F: 4 M) were treated, with a median (range) age at treatment of 12.9 (4.5-16.3) years, and median (range) duration of symptoms of 18 (6-36) months. VAS decreased from 10/10 to 0-3/10 by the end of first 3-day treatment for all patients. The mean (range) time to complete MRI resolution of bone inflammation was 6.0 (2-12) months. The mean (confidence interval (CI)) baseline uNTX/uCr was 738.83 (CI 464.25, 1013.42)nmol/mmol/creatinine and the mean (CI) decrease from baseline to pamidronate discontinuation was 522.17 (CI 299.77, 744.56)nmol/mmol/creatinine. Median (range) of follow-up was 31.4 (24-54) months. Four patients had MRI confirmed CRMO recurrence, which responded to one pamidronate re-treatment. The mean (range) uNTX/uCr change as a monthly rate from the time of pamidronate discontinuation to flare was 9.41 (1.38-19.85)nmol/mmol/creatinine compared to -29.88 (-96.83-2.01)nmol/mmol/creatinine for patients who did not flare by the time of final follow-up.

Conclusion: Pamidronate resulted in resolution of pain and MRI documented inflammation in all patients. No patient flared while his/her uNTX/uCr remained suppressed. We propose that pamidronate is an effective second-line therapy in persistent CRMO.

Figure 1

Imaging data of sacral involvement by CRMO in patient 2, a 16-year-old boy. (A) Pre-treatment imaging: Coronal STIR MRI images reveal increased T2 signal in the ilium adjacent to the right sacroilial joint (SIJ), consistent with inflammation. (B) Imaging 2 months after initiation of pamidronate: Abnormal signal on coronal STIR has resolved. (C) Imaging at clinical relapse: Coronal STIR MRI image reveals increased T2 signal in the ilium adjacent to the left SIJ, consistent with inflammation. The previously affected right ilium demonstrates no abnormal signal. (D): Imaging 2 months post 1 day pamidronate retreatment: Previously demonstrated abnormal signal on coronal STIR is no longer seen.

Figure 2

Imaging data of CRMO involving both distal femurs in patient 2, an 11-year-old girl. (A-E) Pre-treatment imaging: (A) Pre-treatment technetium⁹⁹nuclear bone scan demonstrates abnormal uptake in both distal femurs with more prominent changes on the left (arrow). (B-C) Anterior-posterior radiographs of both distal femurs demonstrate ill-defined areas of sclerosis (arrows) mixed with small focal lucent areas. Periosteal reaction is noted on the left side. (D) Coronal STIR MRI images obtained 4 months after the bone scan reveal increased signal in the right femur. The left femur reveals post-operational changes on the site of previous bone biopsy (arrow). (E) Post-gadolinium fat-saturated T1 weighted image shows marked enhancement of the right distal femoral lesion, with post-operational changes in the left femur. (F-G) Imaging 10 months after initiation of pamidronate: Complete resolution of the right femoral lesion is demonstrated on STIR image (F) and post-gadolinium fat-saturated T1 weighted image (G). (H) Imaging at clinical relapse: Coronal STIR MRI images reveal increased T2 signal in the right aspect of the sacrum, consistent with inflammation. (I): Imaging 2 months post 1 day pamidronate retreatment: Previously demonstrated abnormal signal on coronal STIR has resolved (arrow).

Figure 3

Imaging data of spinal and sacral CRMO lesions in a 10-year old girl. (A-C). Pre-treatment sagital (A and B) and axial (C) MRI. (A) STIR sequence and (B and C) post-gadolinium T1-weighted sequence reveal abnormal signal in vertebral bodies of T10, T11, and S1 (arrows), as well as in sacral ala (arrow). (D-F). Post-treatment (5 months after initiation of pamidronate) MRI using the same technique as (A-C): Complete resolution of the previously seen abnormal signal.

Figure 4

Imaging data of CRMO lesion involving left clavicle in a 7-year old girl (A). Pre-treatment imaging. Plain radiograph of the left clavicle demonstrates periosteal new bone formation (arrow). (B-C). Pre-treatment MRI: (B) Axial (fat-saturated, T2-weighted) and (C) post gadolinium MRI: Hyper-intense T2 signal with post-contrast enhancement is seen within the clavicle (arrow) with marked soft tissue inflammation (arrow). (D-E). Post-treatment MRI (5 months after initiation of treatment with pamidronate) with the same technique as B and C, respectively. The intra-osseous abnormal signal has significantly improved, and marked soft tissue abnormality has almost completely resolved. (F-G). Post-treatment MRI (8 months after initiation of treatment with pamidronate) with the same technique as B and C, respectively, reveals complete resolution of the intra-osseous abnormal signal.

Figure 5

Urinary N-telopeptide/urinary creatinine ratio (uNTX/uCr) in girls (upper panel) and in boys (lower panel). Data is shown for each individual patient prior to the first intravenous pamidronate treatment (IVP); just after the first IVP; at the time of pamidronate discontinuation; and either at the time of last follow-up for patients who did not flare or at the time of CRMO flare. Continuous lines represent the 75^th (top), 50^th (middle), and 25^th (bottom) percentile, respectively, of the reference range for healthy subjects [24].