Commentary by Thomas A. Einhorn, MD*,
Boston University Medical Center, Boston, MA
"No Need To Believe In Magic"
The use of electrical fields in the treatment of medical conditions dates back to the beginnings of the first millennium when the physician Scribonius Largus suggested that a patient "stand on a wet beach near an electric fish" as a way of treating headaches and gout1. Over the centuries, various forms of electrical stimulation have been used to treat epilepsy, diarrhea, hemorrhage, surgical wounds, baldness, and cancer1, 2. Nor is the concept of utilizing electricity to heal ununited fractures or nonunions new. In 1841, Hartshorne reported on a patient with a nonunion of the tibia who, in 1812, was treated with "shocks of electric fluid passed daily between the ends of the bones" for six weeks3. More than a century later, Yasuda demonstrated new bone formation in the vicinity of a cathode in a rabbit femur4, and similar reports from Bassett and Becker5, Shamos et al.6, and Friedenberg and Brighton7 followed. By the early 1980s, electrical stimulation was firmly established as a treatment modality for the management of nonunions3. However, despite an abundance of undeniably valid data, from both basic and multicenter clinical trials, demonstrating the effects of electrical stimulation on skeletal biology and healing, a certain amount of skepticism remains among biologists and clinicians because we really do not understand how this works.
In the current issue of The Journal, Brighton et al. report the results of an in vitro study demonstrating that treatment of cultured osteoblasts with any of three clinically used forms of electrical stimulation (capacitive coupling, inductive coupling, or combined electromagnetic fields) leads to an increase in both cytosolic calcium ions and cytoskeletal calmodulin. Although there have been previous attempts to elucidate the cellular mechanisms and biochemical pathways activated by electrical and electromagnetic fields, this is the first report that identifies a final common pathway, by suggesting that an osteoblast responds to these different stimuli with an identical net change in its intracellular biochemical milieu. That a variety of stimuli are found to induce a cascade of signaling events that result in a unified effect makes this finding more attractive than those reported previously because this is consistent with the overarching principle of biological conservation, the underpinning of development and evolution.
The various types of electrical stimulation evoke initial responses in the osteoblast at different sites. With capacitive coupling, the initial event is calcium ion translocation through voltage-gated calcium channels at or within the cell membrane. With inductive coupling and combined electromagnetic fields, the initial event is the release of calcium from intracellular stores. However, independent of which signal transduction mechanism is activated, the resultant effect on the cell is the same—an increase in cytosolic calcium and in activated calmodulin. As the concentration of cytosolic calcium is a key factor in many intracellular regulatory events, any mechanism which increases its concentration will likely lead to an enhancement in the activity of that cell. Moreover, if an accompanying mechanism is induced to control the flux in intracellular calcium, further regulation of cellular activity will result. Calmodulin, as a calcium-binding protein may serve as a buffer to fine tune the availability of intracellular calcium. The net result of all of this would be an upregulation of the second messenger system and hence, an enhancement of osteoblast function.
With this new insight, it will now be possible for investigators to understand how this increased intracellular calcium affects the behavior of the osteoblast. Indeed, the mystery of how electrical stimulation heals nonunions is not yet solved. Nevertheless, this report represents an important piece of the puzzle and advances our understanding of these phenomena in a very meaningful way.
*The author did not receive grants or outside funding in support of research for or preparation of this manuscript. He did not receive 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, educational institution, or other charitable or nonprofit organization with which the author is affiliated or associated.
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2. Overmier JA, Senior JE. Books and manuscripts of the Bakken. Metuchen, NJ: Scarecrow Press; 1992. p 1-16.
3. Brighton CT. Current Concepts Review: The treatment of non-unions with electricity. J Bone Joint Surg Am. 1981;63:847-51.
4. Yasuda I. [Fundamental aspects of fracture treatment]. J Kyoto Med Soc. 1953;4:395-406. Japanese.
5. Bassett CAL, Becker RO. Generation of electric potentials by bone in response to mechanical stress. Science. 1962;137:1063-4.
6. Shamos MH, Lavine LS, Shamos MI. Piezoelectric effect in bone. Nature. 1963;197:81.
7. Friedenberg ZB, Brighton CT. Bioelectric potentials in bone. J Bone Joint Surg Am. 1966;48:915-23.