Four questions for Dr. Joseph M. Lane, Professor of orthopaedic surgery at Cornell, and the recent recipient of the Nicolas Andry Lifetime Achievement Award

Linked Orthopaedia chapter: https://www.orthopaedia.com/osteoporosis/

Dr. Joseph M. Lane, Professor of orthopaedic surgery at Cornell, was the recent recipient of the Nicolas Andry Lifetime Achievement Award for his basic science and clinical research related to bone matrix disorders. [Related information can be found in the Orthopaedia chapter on osteoporsis.]

Orthopaedia: Congratulations on winning the Nicolas Andry Lifetime Achievement Award for your work studying bone matrix biology. This award recognizes the knowledge you have added to our understanding. In a way, though, the award also recognizes subtractions too: the revisions we had to make to prior misconceptions. Can you share an example of something you learned in your career that was contrary to what you were taught as a student? Or to put it bluntly, what did your professors at Harvard Medical School get completely wrong?

Joseph M Lane: Scientific fact is just a stop on the highway. Most “truths” are modified with time and further investigation. But if I had name the first truth that I was taught in medical school that I had to unlearn it was this: that a child would not survive without the nutrition acquired through a functioning gastrointestinal tract. I was taught to question that “fact” by Dr. Stanley Dudrick, my senior resident in the surgery department at the Hospital of the University of Pennsylvania. Stanley was always leaving our surgical cases at the earliest time, leaving me to finish the procedure, so that he could oversee his beagles. These dogs had their GI tracts removed, and were raised from birth to adulthood solely on intravenous solution Stanley had devised, now known as total parenteral nutrition (TPN). My small contribution to this discovery was to permit Stanley to have uninterrupted research time. This experience taught me that breakthrough scientific discovery requires time and effort, a lesson I never forgot throughout my career. While it is easier for non-MD scientists to dedicate full time effort to research, clinician investigators have the special opportunity to bridge the gap between bench discoveries and patient care in translational research.

Orthopaedia: Along those lines, if you had to guess, what is something that we “know” today that is likely to be disproven, or at least, significantly readjusted?

Joseph M Lane: Today, we know that bone possesses an intrinsic capacity for regeneration–but only in limited quantities. That dictum might not be completely disproven, but the definition of what qualifies as a “limited quantity” will get larger and larger. That is, preliminary studies in our laboratory and several other colleagues strongly suggest that we should be able to fully regain lost bone and reestablish a biomechanically stable skeleton within one or two decades –something that was clearly false years ago, and still not true today. Large defects created by trauma and tumor resection are the last frontier. The Ilizarov limb lengthening is one example of major bone regeneration that has entered the oncologic arena

Orthopaedia: Can you give an example of how basic science research on bone matrix biology will lead to the development of new therapies for osteoporosis?

Joseph M Lane: Medical students are taught that bone remodeling is a process of osteoclasts breaking down the organic tissue in bones, followed by osteoblasts synthesizing new bone matrix. That is certainly a reasonable introductory description, but bone remodeling is of course a complex process, with key stimulators and inhibitors. For example, basic scientists discovered that naturally occurring human mutations in the Wnt signaling pathway led to changes in bone metabolism. Loss-of-function mutations in a Wnt receptor caused a syndrome characterized by low bone mass and increased incidence of fragility fractures, whereas gain-of-function mutations in this receptor were associated with a high bone mass phenotype. Scientists further discovered that sclerostin is a key inhibitor of the WnT pathway. As such, by creating a monoclonal antibody to inactivate the sclerostin, scientists were able to enhance functioning of the WnT pathway and produce more bone. This drug, romosozumab, is now the most powerful tool to stimulate new bone formation and reverse osteoporosis.

Orthopaedia: Bone matrix biology research is important not only for so-called metabolic bone disorders such as osteoporosis, but for treating healthy-but-injured bone as well. How might basic science research on bone matrix biology improve fracture care?

Joseph M Lane: Fracture healing reproduces the growth plate now at the fracture site. The callus recreates all the steps of embryonic bone development and uses this pathway to repair the fracture. Many individuals through aging, sickness or hormone imbalance lack all the critical elements needed for fracture healing. The anabolic osteoporotic bone drugs are strong stimulators of bone formation and can be channeled to stimulate fracture repair. Basic science has tailored these agents to reproduce bone for osteoporosis. Traumatologists have successfully repurposed them toward repairing deficient fracture healing as well. Still, because the drugs do not maintain alignment, surgical fixation must also be part of the treatment, except rare cases, such as stable impacted fractures. Also, these drugs do not fully address fractures that involve the cartilage at joint surface. Cartilage repair has proven to be a tough problem for scientists. Bone naturally remodels, as noted above, so scientists only had to harness this process. On the other hand cartilage does not remodel normally, and therefore it remains a more challenging clinical and scientific problem.