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Zebra Lines of Pamidronate Therapy in Children
M. Al Muderis, MD1; T. Azzopardi, FRCS(Ed)1; P. Cundy, FRACS1
1 Women's and Children's Hospital, 72 King William Road, North Adelaide SA 5006, Australia. E-mail address for M. Al Muderis: munj2@yahoo.com
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Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
Investigation performed at Women's and Children's Hospital, North Adelaide, Australia

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2007 Jul 01;89(7):1511-1516. doi: 10.2106/JBJS.F.00726
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Abstract

Background: Pamidronate therapy is increasingly used in children for the treatment of low bone mineral density and increased bone fragility resulting from a spectrum of conditions. The aim of the present study was to determine and describe the radiographic features associated with cyclical bisphosphonate therapy in the growing skeleton.

Methods: A retrospective review of the radiographs of thirty-five children who had been managed with cyclical pamidronate was carried out. The physeal growth rates were estimated by measuring the band intervals on radiographs and the corresponding time intervals between the administered doses of pamidronate.

Results: Metaphyseal bands, which we call zebra lines, were observed with band intervals that were dependent on the age of the patient, the rate of growth, and the dosing regimen. Epiphyseal and apophyseal bands were also observed in some patients. A distinction was made between Harris growth arrest lines and zebra lines. There was no evidence to suggest a deceleration in bone growth in children managed with pamidronate.

Conclusions: The term zebra lines is proposed as a descriptive term for the characteristic pattern of metaphyseal banding seen on the radiographs of children receiving cyclical bisphosphonate therapy.

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    References

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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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    Joseph A. Spadaro, PhD
    Posted on October 02, 2007
    Bisphosphonate Induced 'Zebra Lines'
    Department of Orthopedic Surgery, SUNY Upstate Medical University, Syracuse, NY

    To The Editor:

    Al Muderis et al.(1) nicely describe the transverse dense bands or lines following the administration of the bisphosphonate, pamidronate, to children with osteogenesis imperfecta and other conditions associated with low bone density in their article, "Zebra Lines of Pamidronate Therapy in Children"(1). We have observed similar bands during studies in growing male Sprague-Dawley rats following 6 weekly administrations of the bisphosphonate alendronate (0.3 mg/kg, SC) in normal animals or in conjunction with hind limb irradiation or systemic methotrexate(2,3). The bands could be seen throughout the growing portions of the skeleton, including the vertebrae, the ribs, the digits and the hind and forelimb bones (figure 1). They were associated with quantitative changes in several other aspects of the bone's geometry(2).

    Al Muderis et al.(1) note that because their patients had chronic conditions affecting the skeleton, they could not be sure whether the bisphosphonate itself affected growth. Our observations suggest that in rats during a 6-week treatment/observation period of rapid growth from post-weaning through late adolescence, there was a slight loss of length in the hind limb long bones (2-4%, p < 0.05). Although recovery of lost growth was not apparent in our animal experiments, it is uncertain whether it would be recovered in children by maturity and this issue likely needs further investigation.

    The banding in rat bone consisted of increases in trabecular density most likely due to the intermittent suppression of resorption during growth(4). Additional consequences of weekly alendronate were an apparent "expansion" in the cross-sectional area of the bone in treated animals (30-50% above controls) and an increase in cortical thickness measured with pQCT scans(2). If present in bisphosphonate-treated children these effects would combine to tend to give an important additional strength benefit to the skeleton.

    Finally, our findings also suggest that pulsed alendronate (capable of oral administration) may provide an accurate measure of intrinsic growth rates for pre-clinical studies as well as for monitoring the use of various chemical and physical interventions during growth in children.


    Figure 1. Micro-CT sagittal image of an 11 week old Sprague-Dawley rat after six weekly doses of alendronate.

    In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from N.I.H. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

    References:

    1. Muderis MA, Azzopardi T, Cundy P. Zebra lines of pamidronate therapy in children. J Bone Joint Surg Am. 2007;89:1511-1516.

    2. Spadaro JA, Damron TA, Horton JA et al. Density and structural changes in the bone of growing rats after weekly alendronate administration with and without a methotrexate challenge. J Orthop Res. 2006;24(5):936-44.

    3. Spadaro JA, Horton JA, Donohue M, Damron TA, Arrington S, Stringer M. Alendronate increases trabecular density but does not affect bone growth following radiotherapy in young rats. Trans. Orthop. Res. Soc. 2007;32:284.

    4. Azuma Y, Sato H., Oue Y, et al. Alendronate distributed on bone surfaces inhibits osteoclastic bone resorption in vitro and in experimental hypercalcemia models. Bone 1995;16(2):235-45.

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