Tribute to Harold M. Frost, honorary president of ISMNI, who received the William F. Neuman Award from the American Society of Bone and Mineral
Research October 2001

Burr, David B.

Forwood, Mark R

Jee, Webster S

Recker, Robert R

Talmage, Roy V

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Harold M. Frost T J Musculoskel Neuron Interact 2001; 2(2):117-119 William F. Neuman Awardee 2001

117oday, the Journal pays tribute to Harold M. Frost, our honorary president of ISMNI, whoreceived the William F. Neuman Award from the American Society of Bone and MineralResearch this October 2001. The Award is well deserved because Harold has been the mostinfluential theoretician in skeletal biology. You will realize after reading the nominating letter andthe excerpts from seconding letters, that in Harold we encounter one whose impact will liveforever. In addition we are fortunate to be publishing two more articles of Harold's that emphasizehis advances in basic science of skeletal biology that improve clinical treatment.The nominating letter of Robert Recker, M.D.April 12, 2001ChairpersonAwards Nominating CommitteeThe American Society for Bone and Mineral Research1200 19th Street, NW,  Suite 300, Washington, DC 20036-2412Dear Sir/Madam, I am writing this letter to nominate Harold M. Frost, M.D. for the William F. Neuman Award of the ASBMR.Harold Frost has been a friend and colleague for 24 years. Dr. Frost has made seminal contributions to bone research thathave resulted in massive paradigm shifts in the field.Dr. Frost first characterized in vivo bone remodeling through fluorochrome labeling. His work began with examination of crosssections of ribs from humans who had been given tetracycline for treatment of infections in their past. He described boneresorption and formation as occurring in physically and temporarily discreet units of cellular activity. Using light and fluorescencemicroscopy he described the sequence of activation, resorption, and formation, first in Haversian bone and later in trabecular bone.With light microscopy alone he reported in Nature in 1965 that 96.7% of the bone formation process in adult spongy bone occursonly after resorptive processes occurred beforehand on the same bone surface. He also suggested that bone formation occurringon surfaces that were not scalloped from prior resorption were due to bone formation after a pause at a previous formation site.He is and has been an iconoclast. At the time of his characterization of remodeling and, for many years after theirpublication, bone investigators tended to regard bone cells as individual “atoms” that worked independently of one another.His major contribution in this area was noting that bone cells are organized to work together, in concert, in a stereotyped timesequence. He was the first to suggest that osteoclast and osteoblast activities are coupled, pointing out that if the function ofone of these cells is perturbed, the other is virtually always perturbed as well.He invented the idea of the basic multicellular unit of bone, the “BMU”. By this he refers to the unit of cells and their activitythat accomplish bone remodeling, starting with activation on a surface followed by resorption of bone on that surface followed finallyby formation by osteoblasts on that same surface. These ideas have become a part of the basic canon of modern skeletal science.In our world of modern, “high-tech”, expensive, elaborate, team-based research, it is fascinating that Dr. Frost performed themajority of his laboratory work in a crude sink arrangement where he sawed cross sections of intact ribs and ground them underflowing water to sections less than 100 microns thick. The costliest and most technical instrument he used was a microscope witha fluorescence attachment. He recognized that demineralizing bone specimens for purposes of histologic examination resultedin loss of the most interesting information about bone biology. Thus, he was responsible for the turn toward studying non-demineralized bone specimens among scientists studying bone biology from the standpoint of morphology.An important facet of Dr. Frost’s brilliance is that he has generated most of his ideas and paradigms from observationsmade in living humans and in human biological specimens. He has developed great powers of observation during a long clinicalHarold M. Frost TJ Musculoskel Neuron Interact 2001; 2(2):117-119William F. Neuman Awardee 2001Harold M. Frost, M.D.Honorary President of ISMNI118career of encountering patients with various skeletal diseases, injuries and handicaps. He observed, for example, that whenone lower limb is paralyzed in a child, the bones tend to elongate at nearly the same pace in that limb as in the unparalyzedlimb but the accumulation of bone mass is markedly reduced. Nevertheless, the general shape of the bone of the paralyzedlimb remains intact. He was the first to recognize the significance of this fact, and to this day there have been few that graspit or report on it. Frost formulated the concept of load driven modeling beginning with these observations. Since then he hasdeveloped and refined ideas about skeletal adaptation to loading and has introduced the concept of a mechanostat, a sensingmechanism that detects mechanical loads, their intensity and direction, and directs bone cellular machinery to respond tothem. This paradigm has resulted in a flurry of research activity. Over the course of time, it has gradually become part of theconventional wisdom in the field. Subsequent expansion of  these ideas has led to new paradigms regarding biomechanicalfactors involved in osteoarthritis, particularly of the knee, as well as factors involved in fracture healing.Dr. Frost is a prolific writer who has showered his colleagues with manuscripts, letters and papers containing the gems ofhis thought and observation. They are treasured. Many of us venture to feedback on the ideas presented in them, and thus hehas fostered a protracted, prolific and fascinating discourse on bone science over the years in these correspondences with hiscolleagues.In a March 1996 volume of the Journal of NIH Research I quote the following which characterizes Dr. Frost rather well.“Harold Frost fits almost perfectly a Hollywood image of a brilliant but controversial scientist. The iconoclastic tinkererworking alone in his cluttered basement laboratory, uses a technique of his own invention to make unprecedented observationsof how human bones maintain their structure. He proposes a revolutionary theory that bone remodeling is a dynamic butspecific interaction of bone resorption with bone formation–the latter almost never going on without the former. But therenegade scientist’s ideas contradict those of the academic establishment and he suffers professional rejection for them. Heloses government funding for his work and later resigns his position of chairman of a department of a major metropolitanhospital. Thirty years later our scientist, successful but relatively isolated in a small desert town, recounts his story. The yearshave proven him right and modern scientists who study bones respect him. His once ridiculed ideas have become a modernparadigm of bone resorption and formation.”I believe it is altogether fitting that the ASBMR recognize this renegade scientist who has had such a major impact on thefield. I heartily support his nomination for the William F. Neuman Award of the ASBMR for 2001.Sincerely,Robert R. Recker, M.A.C.P., F.A.C.EProfessor of MedicineSection of Endocrinology and MetabolismExcerpts from seconding letters“He is the one and only genuine theoretician in the field of skeletal tissue biology and medicine. The late Dr. Marshall Urist,past editor of Clinical Orthopaedics and discoverer of BMP, calls him 'Orthopaedic surgery's idea man or theorist'. Dr.William Peck at Washington University in St. Louis called him a genius.”“Harold Frost will go down in time as one of the most important names in the field of bone health and disease. Accordingto Science Citation Index he is one of the most cited investigators in skeletal research.”“Harold Frost's view of bone biology was once controversial but is now well accepted. Many of the acronyms Frostconstructed to describe bone cellular processes are now part of the bone lexicon and are commonplace in bone biology.”“I cannot think of any other scientist that has had more influence than Harold Frost's worldview. In the words of the late ThomasKuhn, Frost changed the paradigm of bone biology. The most fundamental change came with his explanation for the intermediaryorganization of bone. To this day, bone is the only connective tissue for which structural remodeling can be quantitated and it is nocoincidence that there is currently a revolution in drug development for treatment of metabolic bone diseases and osteoporosis.”Webster S.S. Jee, Ph.D.Professor of Anatomy and NeurobiologyResearch Professor of RadiobiologyOrganizer of Sun Valley Hard Tissue Workshops119“Besides specific accomplishments, he has exemplified the fine qualities of a teacher by acting as a mentor to many youngscientists who have yet to reach their full potential. In this way, the full impact of Dr. Frost's accomplishments has not yetbeen felt.”“Over the past 35 years, Dr. Frost has transformed our basic and clinical understanding of biological processes in the skeletonthrough the publication of more than 400 articles, 16 books, and contributions to more than 20 symposia. No other individualhas so completely transformed the face of a scientific discipline as has Harold Frost in skeletal biology and orthopeadic science.It is not an overstatement to say that he has been the most influential theoretician in skeletal biology in this century.”“Dr. Frost is responsible for most widely accepted concepts about how the skeleton adapts to metabolic, hormonal andmechanical influences. These concepts transcend any single discipline, extending to the entire field of skeletal health anddisease. Collectively, these ideas led to the formation of the quantum concept of bone turnover, and the development ofdynamic histomorphometry, which is the standard used today both for experimental measurements of bone change over timeand for all quantitative clinical assessment of bone diseases from iliac crest biopsies.”“He has had a profound effect on thinking in the biomechanics community as regards to the adaptation of bone to mechanicalstimuli. He was the first to describe flexural strain as the major mechanical determinant of bone architecture (1964).”“. . . . .The concept of a mechanical feedback system that affects modeling and remodeling differentially began with Frostin the 1960's. These ideas culminated in the theory of the mechanostat in the mid 1980's. The idea of a mechanostat is nowused routinely by bioengineers. It has become an established concept in the biomechanical and bone adaptive lexicon.”“More recently, Dr. Frost has proposed another concept that is fundamentally biomechanical: that bone mass is directly tiedto lean muscle mass, and muscle force.     . . . . . the idea has sparked controversy.     . . . .Whether the idea ultimately turnsout to be correct or incorrect is immaterial; the fact that it has initiated an active dialogue about the role that muscle forceplays in the adaptation of bone is important. This is the basis of scientific inquiry.”“It is impossible to overestimate his influence and contributions in the field of skeletal biology. He has molded the thoughtsof a generation, in areas as widely divergent as orthopaedics, endocrinology, rheumatology, clinical medicine, anatomy,physiology, orthodontics. In the past 15 years he has had a particularly profound effect on the biomechanics community.”David B. Burr, Ph.D.Professor and Chairman of Anatomy & Cell BiologyProfessor of Orthopeadic Surgery“The conceptual framework elucidated in his research and seminal works have transformed our understanding of skeletalbiology, and formed the basis of clinical practice across a range of disciplines.”“Dr. Frost is undoubtedly one of the monumental figures in the field of bone and mineral research. His contribution to thebasic and clinical science performed by members with the Society is impossible to estimate.”Mark R. Forwood, Ph.D.Associate ProfessorDepartment of Anatomical SciencesUniversity of Queensland“He worked for almost twenty years with little or no recognition from his peers. Finally, when recognition came and hisconcepts were studied, his descriptions of bone growth, renewal and health were accepted. His work affected the researchemphasis of the entire field of bone. As the result of his work, a completely new subdiscipline of bone function has developed.Every area of the health and wellbeing of human bone was influenced by his studies.”“He is long overdue for honor and recognition for his contributions to our knowledge of bone and to the problems of healthand disease in all areas related to human bone.”Roy V. Talmage, Ph.D.Professor of Orthopaedics, RetiredUniversity of NC, School of Medicine, North CarolinaWilliam F. Neuman Awardee 1984

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Harold M. Frost T J Musculoskel Neuron Interact 2001; 2(2):117-119 William F. Neuman Awardee 2001

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