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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