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Ibandronate for Prevention of Femoral Head Deformity After Ischemic Necrosis of the Capital Femoral Epiphysis in Immature Pigs
Harry K.W. Kim, MD, MSC, FRCSC1; Timothy S. Randall, BS1; Haikuo Bian, MD1; Joe Jenkins, BS1; Amanda Garces1; Frieder Bauss, PhD2
1 Shriners Hospitals for Children, 12502 Pine Drive, Tampa, FL 33612. E-mail address for H.K.W. Kim: hkim@shrinenet.org
2 Roche Diagnostics, GmbH, Pharma Research, Bone Metabolism, Nonnenwald 2, Building 231, Room 321, D-82377 Penzberg, Germany
View Disclosures and Other Information
In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from Shriners Hospitals for Children and F. Hoffmann-La Roche, Ltd., Basel, Switzerland. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. A commercial entity (F. Hoffmann-La Roche) sponsored the study.
Investigation performed at the Center for Research in Skeletal Development and Pediatric Orthopaedics, Shriners Hospitals for Children, Tampa, Florida

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2005 Mar 01;87(3):550-557. doi: 10.2106/JBJS.D.02192
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Abstract

Background: Femoral head deformity is the most serious sequela of ischemic necrosis of the immature femoral head. The purpose of this study was to determine if a highly potent antiresorptive agent, ibandronate, can inhibit bone resorption during the repair of the infarcted femoral head and thus alter the repair process. We hypothesized that preservation of the trabecular framework by inhibiting osteoclastic bone resorption would minimize the development of deformity in a piglet model of ischemic necrosis. The effect of ibandronate on long-bone growth was also assessed.

Methods: Ischemic necrosis of the right femoral head was produced in twenty-four piglets by placing a ligature tightly around the femoral neck. The animals were divided into three groups according to whether they received saline solution, prophylactic treatment, or post-ischemia treatment. The contralateral, untreated femoral heads from the animals that had received saline solution served as the normal control group. At eight weeks, the femoral heads were assessed for deformity with radiography and for trabecular bone indices with histomorphometry. Also, the length of femur from the untreated side was measured on the radiographs and compared among the groups.

Results: Radiographic assessment showed that the epiphyseal quotient, determined by dividing the maximum height of the osseous epiphysis by the maximum diameter, was better preserved in the prophylactic (p < 0.001) and post-ischemia (p = 0.02) treatment groups than in the group treated with saline solution. Histomorphometric assessment also showed that the trabecular bone indices were better preserved in the prophylactic and the post-ischemia treatment groups than in the group treated with saline solution (p < 0.01). The mean femoral length on the untreated side of the animals treated with ibandronate was reduced compared with the length on the untreated side of the animals that had received saline solution (p = 0.01).

Conclusions: Ibandronate preserves the trabecular structure of the osseous epiphysis and prevents femoral head deformity during the early phase of repair of ischemic necrosis in the piglet model.

Clinical Relevance: Administration of an anti-osteolytic agent, ibandronate, during the fragmentation stage of Legg-Calvé-Perthes disease may prevent early flattening of the osseous epiphysis. Additional preclinical studies are needed to determine the optimum dose and delivery of the drug to prevent the deformity while minimizing its effect on long-bone growth. Studies are also needed to determine the long-term effects of ibandronate in terms of preventing deformity.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    David H. Gershuni
    Posted on May 10, 2005
    Drug Treatment for Prevention of Femoral Head Deformity after Necrosis of the Femoral Epiphysis
    University of California San Diego

    To the Editor:

    The study "Ibandronate for Prevention of Femoral Head Deformity after Ischemic Necrosis of the Capital Femoral Epiphysis in Immature Pigs" (2005; 87:550-7) by Kim et al, is based on their concept that it is the strength & shape of the bone of the ischemic capital femoral epiphysis which defines the future of the immature hip and that, in particular, these factors will determine the onset of premature osteoarthritis. This thesis and chronology is, I believe, only partially correct.

    The femoral capital epiphysis is an osteochondral structure and it is the cartilage embracing the bone that ultimately defines the overall shape of the femoral head at all ages. It is the joint cartilage shape & biomechanical characteristics that mainly determine the development of arthritic degeneration. That is, of course, not to claim that the characteristics of the underlying osseous structure have no significance at all.

    In Legg-Calve-Perthes disease (LCPD), which the authors specifically cite as an example of femoral capital ischemic necrosis, the femoral head cartilage becomes absolutely thickened & deformed, the superior region of the enlarged head being flattened parallel with the underlying osseous epiphysis very early in the disease process (1).The repair process in the osseous epiphysis may make the bone weaker and the deformity of the head greater but treatment aimed at strengthening the necrotic bony capital epiphysis, as described in the current work, cannot have "prevented femoral head deformity" because it is already deformed usually in the early stages of the disease process. The analysis of the experimental head deformity in this study was confined to examining the bony epiphysis and ignored the cartilaginous component of the head, thereby nullifying the possibility of reporting on the results of drug therapy on the complete osteochondral femoral head.

    Furthermore, the necrotic bone of the immature femoral capital epiphysis in LCPD inevitably reconstitutes its viability and structure. Based on this understanding, the consensus approach to treat LCPD has been to improve the mechanical environment of the osteochondral head in relation to the acetabulum by surgical or orthotic means and thereby decrease the inevitable, extremely early, articular deformity in children at risk for later osteoarthritis; there should not be any need for biphosphonate therapy to achieve this.

    When considering the clinical relevance of this study, enthusiastic clinicians should heed the authors' caveat that more animal studies will be necessary before subjecting any children with LCPD, or other causes of ischemic necrosis of the femoral capital epiphysis, to a potentially toxic drug which may well alter the children's bone growth.

    David H. Gershuni M.D., F.R.C.S. 61 Yigal Allon, Zichron Ya'akov 30900, Israel.

    gershuni@actcom.net.il

    Reference

    1. Gershuni DH, Axer A, Hendel D. Arthrographic findings in Legg- Calve-Perthes disease and transient synovitis of the hip. J. Bone Joint Surg Am. 1978;60:457-64.

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