One of Nature's Best Kept Secrets (1998)

Nearly 50 years ago, in a small industrial town in the western part of Siberia, something really exciting happened in the history of medicine. A physician named Gavril Ilizarov performed an osteotomy in a patient to correct a severe deformity of the lower limb. He knew that if he were to break the bone and then straighten the leg in one maneuver he would run the risk of stretching nerves and blood vessels and potentially do more harm than good. His strategy, therefore, was to use percutaneous wires to transfix the bone proximal and distal to the osteotomy site, connect the wires to an external circular frame, and then gradually distract the ends of the bone at a rate of about 1 mm per day. He assumed that this treatment would create a large gap at the osteotomy site which would require a subsequent bone graft procedure. When he attempted to perform the bone graft operation, however, he was stunned by the finding that the gap was completely filled with new bone! At that point in history the discovery of a method for regenerating bone in humans had been made. Ilizarov devoted his life to the research, development, and refinement of this minimally invasive procedure which would allow entire sections of the skeleton to be lost or resected and then filled in with abundant amounts of new bone. His clinical successes in the salvage of limbs which would otherwise have been amputated, and in the return of disabled patients to productive levels of activity, eventually spread by word of mouth throughout the communist block of countries. Unfortunately, news of this discovery did not travel beyond the Iron Curtain until 1981. At that time, an Italian explorer who had been injured in a mountain climbing accident in Siberia was transferred to Ilizarov's hospital for treatment. He then returned to Italy to report of his experience. Shortly thereafter, a group of Italian surgeons made a pilgrimage to visit Ilizarov to learn of this technique. Within a few years the method became adopted worldwide as the primary procedure for lengthening limbs, correcting deformities, and treating nonunions of bone secondary to trauma, infection, or tumor. One of the most profoundly interesting aspects of this biological phenomenon is that it seems to contradict some of the basic assumptions made about the formation of bone and the way by which mechanical forces affect osteogenesis. Most students of biology and biomechanics believe that compression, weight-bearing, and stress-generated potentials in bone lead to osteogenesis. On the contrary, distraction has never been thought to be a stimulus for osteogenesis and in fact, most orthopedic surgeons consider a fracture that is subjected to such forces to be at risk for becoming a nonunion. What no one understood is that if these forces could be applied to a healing bone in such a way that the rate and rhythm of distraction could be controlled, the human body has the capacity to make virtually unlimited amounts of new bone as long as the soft tissues in the limb can accommodate the lengthening. To appreciate the contributions of Ilizarov, it is necessary to recognize the historical events which preceded his achievements. Bone lengthening and the use of external fixation had both been reported earlier and, in fact, the first report of a successful lengthening of a limb was made by Codivilla in 1905.1 Yet it was Ilizarov who used his creative mind to take full advantage of this phenomenon and apply the new-found procedure to treat a spectrum of skeletal conditions. Among some of the most illustrative examples is the lengthening of amputation stumps to provide a weight-bearing foot (Fig. 1), the transport of bone to heal a segmental traumatic defect (Fig. 2), and the lengthening of limbs in patients with achondroplastic dwarfism (Fig. 3).2 Stump elongation procedure for a patient who underwent a tarsometatarsal amputation. (A) Clinical appearance of the amputation stump. (B) Patient's foot in circular frame apparatus during elongation of the talus and calcaneus. (C) Final roentgenographic appearance of the elongated midfoot. (Reprinted with permission from: Ilizarov GA 1990 Clinical application of the tension-stress effect for limb lengthening. Clin Orthop 250:8–26.) Treatment of a segmental defect of the tibia resulting from a traumatic injury to the leg. (Left) Radiograph before starting Ilizarov treatment showing an 8 cm bony defect. (Center) During treatment, after 3 months distraction. The bony defect is now small. (Right) After union, showing new bone at the corticotomy site (long arrows), and solid union at the level of the original defect (broad arrows). (Reprinted with permission from: Dagher F, Roukoz S 1991 Compound tibial fractures with bone loss treated by the Ilizarov technique. J Bone Joint Surg (Br) 73b:316–321.) Limb lengthening in achondroplasia. (A) Achondroplastic dwarf with tibia vara deformity of both lower limbs, prior to treatment. (B) The patient after completion of lower extremity lengthening and during bilateral simultaneous humeral elongation. In lower limb lengthening in achondroplasia, an extension osteotomy of the hip is used to reduce lumbar lordosis of the spine, thereby diminishing the likelihood of spinal problems for the patient. Note that the treatment accomplishes not only the lengthening of the limbs, but the correction of the angular deformities of the bone. (Reprinted with permission from Ilizarov GA 1990 Clinical application of the tension-stress effect for limb lengthening. Clin Orthop 250:8–26.) As one might have expected, orthopedic investigators from around the globe gravitated to this new field of study and began exploring ways of optimizing the method for clinical purposes. Different rates and rhythms of distraction were tried; one company in Alaska concocted a motor-drive apparatus for providing continuous distraction, and clinicians began reporting on their experiences. Unfortunately, the technique is associated with several problems and complications including pin tract infection, skin irritation, severe pain (presumably associated with the concomitant stretching of soft tissues) and other difficulties such as premature healing and joint dislocation. The upshot of all of this is that this may be an amazing biological phenomenon but there is much more we need to learn about it. In this issue of the Journal, Welch et al.3 make an important contribution to our knowledge of this process. By performing a careful histomorphometric analysis of bone formation and remodeling during distraction osteogenesis, they provide important quantitative data to characterize this phenomenon and lay the foundation for further investigations. In their study, unilateral tibial lengthenings of up to 30% of the original length of the bone were performed in goats. At a rate of 0.75 mm/day, and using three different rhythms of distraction, bone formation and remodeling activity were shown to be location-dependent within the distraction gap. The greatest indices of bone formation were found to be adjacent to the mineralization zones at the center of the distraction gap as was determined by calculations of mineral apposition rate, mineralized bone surfaces, osteoblast surfaces, and bone formation. Interestingly, no significant difference was found in the bone formation rates of the calluses in the animals which underwent distraction when compared with control animals in which an osteotomy was created but no distraction was induced. Thus, in distraction osteogenesis, bone forms just as rapidly as it does during fracture healing, but as long as a distraction force is applied, bone regeneration can be sustained almost indefinitely. Another important finding in this paper is that neither the rhythm of distraction nor the percent of the lengthening appears to influence any of the morphometric parameters. The enhanced bone formation and remodeling appears to result from increased recruitment and activation of bone forming and resorbing cells rather than from an increase in individual cellular activity. Because the ultimate goal of this technique is to develop lamellar bone to restore mechanical integrity to the limb, this is an extremely important observation. So where do we go from here? What do we need to do in order to exploit this new knowledge? I think that when an important discovery like this comes along, the scientific community has to do two things. First, it has to mobilize its technological resources in order to fully understand the new biology. Thanks to Welch et al., and several other investigators, this is now being done. But the other thing we need to do is to start to think “out of the box.” For example, once we know what transcription factors, signaling pathways, and genomic elements are affected by the mechanical forces, will it be possible to eliminate the need to mechanically distract the bone and instead induce these signals by some other means? If so, can we use the technology to restore bone mass in systemic conditions? Answers to questions such as these would have direct bearing on many of the clinical problems that now confront the bone community at large. Ilizarov died in 1992, less than a decade after his contributions to medicine had been embraced worldwide. Two recent studies have shown that the implementation of the method of Ilizarov in the treatment of osteomyelitis alone has contributed to a savings of approximately $30,000 per patient when compared with conventional methods of treatment.4 The challenge now is to extrapolate this knowledge in order to bring this technology to bear on a broader range of medical problems. Mother Nature is a wonderful scientific colleague, but she has been known to be stingy when it comes to sharing her best stuff. Ilizarov fell into her favor and thankfully taught us what he learned. Now it is our turn to pick up the ball and run with it.