Potential use of bisphosphonates in children with Legg–Calvé–Perthes disease with signs of osteoarthritis. Interim results from a single-center study

Abstract

BACKGROUND: Legg–Calvé–Perthes disease is a multifactorial disease with a non-inflammatory and avascular mechanism of necrotic lesions. In some cases, children may have more aggressive disease with signs of osteoarthritis. This variant of Legg–Calvé–Perthes disease is characterized by active inflammation of the bone tissue and arthritis, often leading to severe deformity of the femoral head and early coxarthrosis. The problem of treating osteoarthritis in children with Legg–Calvé–Perthe disease is not solved due to the low effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs). Osteoclast inhibition therapy with bisphosphonates in adults with idiopathic aseptic necrosis of the femoral head has been pathogenetically accepted. The use of bisphosphonates in children with Legg–Calvé–Perthe disease and osteoarthritis has not been evaluated.

AIM: The aim of the study was to evaluate the efficacy and safety of bisphosphonates in children with Legg–Calvé–Perthes disease who presented with signs of osteoarthritis.

MATERIALS AND METHODS: The study used data on the treatment of 14 children (mean age 7.5 ± 2.4 years, 71.4% girls) with Legg–Calvé–Perthe disease (at the impression fracture stage) and active hip osteoarthritis. All children had torpid arthritis refractory to NSAID therapy and present for at least 3 months. Treatment included ibandronic acid at 1.0 mg and 1.5 mg per infusion every 3 months in children younger than 7 years old and older than 7 years old, respectively. Five consecutive infusions were performed in the study. Treatment outcomes were assessed at 6, 12, and 18 months based on combined clinical, imaging, and laboratory changes. A modified SCORING OF HIP MRI FOR JIA score was used to assess osteoarthritis activity.

RESULTS: All children showed a decrease in hip pain after the first infusion of ibandronic acid. The inactive phase of osteoarthritis during bisphosphonate treatment was achieved in 78.5% (11) of children after three consecutive infusions and in 21.5% (3) of children after four infusions. Post-infusion reactions were reported in 85.7% (12) of children during the initial phase of bisphosphonate treatment and were transient. Serum erythrocyte sedimentation rate, C-reactive protein, interleukin-6, and tumor necrosis factor-alpha levels were within reference ranges in children with osteoarthritis. Only 28.5% (4) of patients were found to have 25(OH)Vitamin D deficiency at the time of osteoarthritis diagnosis.

CONCLUSIONS: The use of bisphosphonates in children with Legg–Calvé–Perthes disease and osteoarthritis can be considered an innovative pathogenetic treatment option. The data obtained suggest the potential for the use of bisphosphonates in children with Legg–Calvé–Perthes disease. Further follow-up of children in the study group is needed to assess long-term outcomes.

Keywords

aseptic necrosis of the femoral head / Legg–Calvé–Perthes disease / synovitis / osteoarthritis / bisphosphonates

References

[1] Pavone V, Chisari E, Vescio A, et al. Aetiology of Legg-Calvé-Perthes disease: a systematic review. World J Orthop. 2019;10(3):145–165. doi: 10.5312/wjo.v10.i3.145

[2] Pavone V., Chisari E., Vescio A., et al. Aetiology of Legg-Calvé-Perthes disease: a systematic review // World J Orthop. 2019. Vol. 10, N 3. P. 145–165. doi: 10.5312/wjo.v10.i3.145

[3] Kozhevnikov OV, Lysikov VA, Ivanov AV. Legg-Calve-Perthes disease: etiology, pathogenesis diagnosis and treatment. N.N. Priorov Journal of Traumatology and Orthopedics. 2017;24(1):77–87. EDN: YZJHUT doi: 10.17816/vto201724177-87

[4] Кожевников О.В., Лысиков В.А., Иванов А.В. Болезнь Легга–Кальве–Пертеса: этиология, патогенез, диагностика и лечение // Вестник травматологии и ортопедии им Н.Н. Приорова. 2017. Т. 24, № 1. С. 77–87. EDN: YZJHUT doi: 10.17816/vto201724177-87

[5] Mills S, Burroughs KE. Legg-Calve-Perthes Disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.

[6] Mills S., Burroughs K.E. Legg-Calve-Perthes disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2024.

[7] Martí-Carvajal AJ, Solà I, Agreda-Pérez LH. Treatment for avascular necrosis of bone in people with sickle cell disease. Cochrane Database Syst Rev. 2019;12(12). doi: 10.1002/14651858.CD004344.pub7

[8] Martí-Carvajal A.J., Solà I., Agreda-Pérez L.H. Treatment for avascular necrosis of bone in people with sickle cell disease // Cochrane Database Syst Rev. 2019. Vol. 12, N 12. doi: 10.1002/14651858.CD004344.pub7

[9] Kumar V, Ali S, Verma V, et al. Do bisphosphonates alter the clinico-radiological profile of children with Perthes disease? A systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2021;25(15):4875–4894. doi: 10.26355/eurrev_202108_26445

[10] Kumar V., Ali S., Verma V., et al. Do bisphosphonates alter the clinico-radiological profile of children with Perthes disease? A systematic review and meta-analysis // Eur Rev Med Pharmacol Sci. 2021. Vol. 25, N 15. P. 4875–4894. doi: 10.26355/eurrev_202108_26445

[11] Liu N, Zheng C, Wang Q, et al. Treatment of non-traumatic avascular necrosis of the femoral head (review). Exp Ther Med. 2022;23(5):321. doi: 10.3892/etm.2022.11250

[12] Liu N., Zheng C., Wang Q., et al. Treatment of non-traumatic avascular necrosis of the femoral head (review) // Exp Ther Med. 2022. Vol. 23, N 5. P. 321. doi: 10.3892/etm.2022.11250

[13] Leroux J, Abu Amara S, Lechevallier J. Legg-Calvé-Perthes disease. Orthop Traumatol Surg Res. 2018;104(1S):S107–S112. doi: 10.1016/j.otsr.2017.04.012

[14] Leroux J., Abu Amara S., Lechevallier J. Legg-Calvé-Perthes disease // Orthop Traumatol Surg Res. 2018. Vol. 104, N 1S. P. S107–S112. doi: 10.1016/j.otsr.2017.04.012

[15] Shabaldin NA, Golovkin, SI, Shabaldin AV. Clinical and immunological features of transient synovitis of the hip joint and disease Legg-Calve-Perthes in children of early and school age. Mother and Baby in Kuzbass. 2016;1(64):21–26. EDN: WZXSSX

[16] Шабалдин Н.А., Головкин С.И., Шабалдин А.В. Клинико-иммунологические особенности транзиторного синовита тазобедренного сустава и болезни Легга-Кальве-Пертеса у детей раннего и школьного возраста // Мать и дитя в Кузбассе. 2016. Т. 1, № 64. С. 21–26. EDN: WZXSSX

[17] Kim HK, Herring JA. Pathophysiology, classifications, and natural history of Perthes disease. Orthop Clin North Am. 2011;42(3):285–295. doi: 10.1016/j.ocl.2011.04.007

[18] Kim H.K., Herring J.A. Pathophysiology, classifications, and natural history of Perthes disease // Orthop Clin North Am. 2011. Vol. 42, N 3. P. 285–295. doi: 10.1016/j.ocl.2011.04.007

[19] Rampal V, Clément JL, Solla F. Legg-Calvé-Perthes disease: classifications and prognostic factors. Clin Cases Miner Bone Metab. 2017;14(1):74–82. doi: 10.11138/ccmbm/2017.14.1.074

[20] Rampal V., Clément J.L., Solla F. Legg-Calvé-Perthes disease: classifications and prognostic factors // Clin Cases Miner Bone Metab. 2017. Vol. 14, N 1. P. 74–82. doi: 10.11138/ccmbm/2017.14.1.074

[21] Nelitz M, Lippacher S, Krauspe R, et al. Perthes disease: current principles of diagnosis and treatment. Dtsch Arztebl Int. 2009;106(31–32):517–523. doi: 10.3238/arztebl.2009.0517

[22] Nelitz M., Lippacher S., Krauspe R., et al. Perthes disease: current principles of diagnosis and treatment // Dtsch Arztebl Int. 2009. Vol. 106, N 31–32. P. 517–523. doi: 10.3238/arztebl.2009.0517

[23] Divi SN, Bielski RJ. Legg-Calvé-Perthes Disease. Pediatr Ann. 2016;45(4):e144–e149. doi: 10.3928/00904481-20160310-03

[24] Divi S.N., Bielski R.J. Legg-Calvé-Perthes disease // Pediatr Ann. 2016. Vol. 45, N 4. P. 144–149. doi: 10.3928/00904481-20160310-03

[25] D Orth SA, Vijayvargiya M. A Paradigm shift in osteonecrosis treatment with bisphosphonates: a 20-year study. JB JS Open Access. 2021;6(4). doi: 10.2106/JBJS.OA.21.00042

[26] D Orth S.A., Vijayvargiya M. A paradigm shift in osteonecrosis treatment with bisphosphonates: a 20-year study // JB JS Open Access. 2021. Vol. 6, N 4. doi: 10.2106/JBJS.OA.21.00042

[27] Kozhevnikov AN, Barsukov DB, Gubaeva AR. Legg–Calvé–Perthes disease presenting with osteoarthritis: mechanisms of the development and prospects of conservative therapy using bisphosphonates. Pediatric Traumatology, Orthopaedics and Reconstructive Surgery. 2023;11(3):405–416. EDN: SRCYNI doi: 10.17816/PTORS456498

[28] Кожевников А.Н., Барсуков Д.Б., Губаева А.Р. Болезнь Легга–Кальве–Пертеса, протекающая с признаками остеоартрита: механизмы возникновения и перспективы консервативной терапии с применением бисфосфонатов // Ортопедия, травматология и восстановительная хирургия детского возраста. 2023. Т. 11, № 3. С. 405–416. EDN: SRCYNI doi: 10.17816/PTORS456498

[29] Guellec D, Prado G, Miceli-Richard C, et al. Hip pain associated with acetabular dysplasia in patients with suspected axial spondyloarthritis: DESIR cohort data. BMC Musculoskelet Disord. 2022;23(1):640. doi: 10.1186/s12891-022-05575-4

[30] Guellec D., Prado G., Miceli-Richard C., et al. Hip pain associated with acetabular dysplasia in patients with suspected axial spondyloarthritis: DESIR cohort data // BMC Musculoskelet Disord. 2022. Vol. 23, N 1. P. 640. doi: 10.1186/s12891-022-05575-4

[31] Tanturri de Horatio L, Shelmerdine SC, d’Angelo P, et al. A novel magnetic resonance imaging scoring system for active and chronic changes in children and adolescents with juvenile idiopathic arthritis of the hip. Pediatr Radiol. 2023;53(3):426–437. doi: 10.1007/s00247-022-05502-8

[32] Tanturri de Horatio L., Shelmerdine S.C., d’Angelo P., et al. A novel magnetic resonance imaging scoring system for active and chronic changes in children and adolescents with juvenile idiopathic arthritis of the hip // Pediatr Radiol. 2023. Vol. 53, N 3. P. 426–437. doi: 10.1007/s00247-022-05502-8

[33] Huang ZQ, Fu FY, Li WL, et al. Current treatment modalities for osteonecrosis of femoral head in Mainland China: a cross-sectional study. Orthop Surg. 2020;12(6):1776–1783. doi: 10.1111/os.12810

[34] Huang Z.Q., Fu F.Y., Li W.L., et al. Current treatment modalities for osteonecrosis of femoral head in Mainland China: a cross-sectional study // Orthop Surg. 2020. Vol. 12, N 6. P. 1776–1783. doi: 10.1111/os.12810

[35] Hospach T, Langendoerfer M, von Kalle T, et al. Spinal involvement in chronic recurrent multifocal osteomyelitis (CRMO) in childhood and effect of pamidronate. Eur J Pediatr. 2010;169(9):1105–1111. doi: 10.1007/s00431-010-1188-5

[36] Hospach T., Langendoerfer M., von Kalle T., et al. Spinal involvement in chronic recurrent multifocal osteomyelitis (CRMO) in childhood and effect of pamidronate // Eur J Pediatr. 2010. Vol. 169, N 9. P. 1105–1111. doi: 10.1007/s00431-010-1188-5

[37] Aruwajoye OO, Aswath PB, Kim HKW. Material properties of bone in the femoral head treated with ibandronate and BMP-2 following ischemic osteonecrosis. J Orthop Res. 2017;35(7):1453–1460. doi: 10.1002/jor.23402

[38] Aruwajoye O.O., Aswath P.B., Kim H.K.W. Material properties of bone in the femoral head treated with ibandronate and BMP-2 following ischemic osteonecrosis // J Orthop Res. 2017. Vol. 35, N 7. P. 1453–1460. doi: 10.1002/jor.23402

[39] Kraus R, Laxer RM. Characteristics, treatment options, and outcomes of chronic non-bacterial osteomyelitis in children. Curr Treat Options in Rheum. 2020;6:205–222. doi: 10.1007/s40674-020-00149-8

[40] Kraus R., Laxer R.M. Characteristics, treatment options, and outcomes of chronic non-bacterial osteomyelitis in children // Curr Treat Options in Rheum. 2020. Vol. 6. P. 205–222. doi: 10.1007/s40674-020-00149-8