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Short-term Osteoclastic Activity Induced by Locally High Concentrations of Recombinant Human Bone Morphogenetic Protein–2 in a Cancellous Bone Environment

Toth, Jeffrey M., PhD*; Boden, Scott D., MD; Burkus, J Kenneth, MD; Badura, Jeffrey M., MS§; Peckham, Steven M., PhD§; McKay, William F., ME§

doi: 10.1097/BRS.0b013e3181952695
Basic Science

Study Design. An experimental study investigating osteoclastic activity induced by rhBMP-2 in sheep.

Objective. To examine the effects of increasing local rhBMP-2 concentration on osteoclastic response and peri-implant bone resorption.

Summary of Background Data. Level I clinical studies have established the safe and effective volume and concentration of rhBMP-2 delivered on an absorbable collagen sponge. However, peri-implant bone resorption appearing as decreased mineral density has been observed radiographically in rare instances after implantation of rhBMP-2 on an absorbable collagen sponge (rhBMP-2/ACS).

Methods. Bilateral corticocancellous defects were created in the distal femora of 30 adult sheep. Combinations of rhBMP-2/ACS implant volume (V) (1V = normal fill or 2V = overfilled) and rhBMP-2 solution concentration (×) (1× = normal concentration or 3.5× = hyperconcentrated) resulted in local rhBMP-2 concentrations of 0×, 1×, 2×, 3.5×, and 7× the estimated effective concentration for this model. Faxitron radiography, quantitative CT, histology, and quantitative histomorphometry were conducted in a blinded fashion to analyze the effect of the treatments.

Results. At 1 week, the normal fill-normal concentration implants (1×) produced the least transient osteoclastic activity resulting in limited peri-implant resorption. Overfilled-hyperconcentrated implants (2×, 3.5×) demonstrated moderate resorption zones. Overfilled-hyperconcentrated implants (7×) demonstrated extensive osteoclastic activity and marked resorption. Results at 4 and 8 weeks revealed dense osteoid and bone in the voids with progressive bony healing. Control defects showed no osteoclastic activity with little to no bony healing.

Conclusion. Increasing the local rhBMP-2 concentration by overfilling the defect with rhBMP-2/ACS or hyperconcen-trating the rhBMP-2 solution on the absorbable collagen sponge led to a concentration-dependent osteoclastic resorption of peri-implant bone. The osteoclastic effect was transient, and progressive healing took place over the 8-week survival period.

Overfilling a bony defect with rhBMP-2/ACS or hyperconcentrating the rhBMP-2 solution on an absorbable collagen sponge led to concentration-dependent osteoclastic resorption of peri-implant bone in an ovine corticocancellous defect model. The osteoclastic effect was transient with progressive bony healing taking place over the 8-week survival period.

From the *Department of Orthopaedic Surgery, The Medical College of Wisconsin, Milwaukee, WI; †Department of Orthopaedic Surgery, The Emory Spine Center, Atlanta, GA; ‡The Hughston Clinic, Columbus, GA; and §Medtronic Spinal and Biologics Business, Memphis, TN.

Acknowledgment date: July 14 2008. Acceptance date: October 9, 2008.

The manuscript submitted does not contain information about medical device(s)/drug(s).

Corporate/Industry funds were received in support of this work. One or more of the author(s) has/have received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this manuscript: e.g. honoraria, gift, consultancies, royalties, stocks, stock options, decision making position.

This animal study was conducted in compliance with the Guide for the Care and Use of Laboratory Animals published by the National Research Council.

Address correspondence and reprint requests to Jeffrey M. Toth, PhD, Department of Orthopaedic Surgery, Medical College of Wisconsin, 9200 W. Wisconsin Ave, Box 26099, Milwaukee, WI 53226-0099; E-mail:

© 2009 Lippincott Williams & Wilkins, Inc.