Portal de Periódicos da CAPES

A. Michael Parfitt: Enlightened Scholar and Revered Mentor

2015; Oxford University Press; Volume: 30; Issue: 8 Linguagem: Inglês

10.1002/jbmr.2576

1523-4681

Stavros C. Manolagas, Juliet Compston, Sudhaker D. Rao, Ego Seeman,

Health and Medical Research Impacts

In my craft or sullen art Exercised in the still night When only the moon rages And the lovers lie abed With all their griefs in their arms, I labour by singing light Not for ambition or bread Or the strut and trade of charms On the ivory stages But for the common wages Of their most secret heart. Not for the proud man apart From the raging moon I write On these spindrift pages Nor for the towering dead With their nightingales and psalms But for the lovers, their arms Round the griefs of the ages, Who pay no praise or wages Nor heed my craft or art. ——Dylan Thomas, Deaths and Entrances, 1946 On May 18, 2015, the Bone and Mineral Community lost Alwyn Michael Parfitt, MD, one of its giants. Michael's career spanned over 50 years and three different continents and established him as mentor of the field and one of its most transformative figures. His contribution to bone research is unique in its breadth and depth. It is characterized by rigorous scholarship, passion for the subject, refusal to accept established dogma without critical reappraisal, and the ability to generate new concepts that often changed thinking and opened new avenues of exploration. Michael guided and influenced the entire field, brought honor and prestige to our discipline, and was exceptional in his contribution to the success of his associates and trainees. He was a true beacon for the field, universally respected and admired for his intellectual genius and huge contribution to our understanding of bone and its diseases, ranging from the rare to the most common. Many of his papers are classics that will stand the test of time and provide a lasting legacy—"monuments of unageing intellect" that should not be neglected by the younger generations (William Butler Yeats, Sailing to Byzantium, 1928). At the end of our In Memoriam, close friends and colleagues provide their own thoughts and memories of the life of this extraordinary thinker. Michael was born in Nottingham, England, to David Neil and Winifred (Childs) Parfitt. He graduated in preclinical sciences from the University of Cambridge and in clinical medicine from Kings College Hospital Medical School in the University of London. His lifelong fascination with calcium metabolism was kindled by the accidental finding of Albright and Reifenstein's classic monograph in the medical school library. He had no formal graduate subspecialty training, but learned what he needed about renal, intestinal, endocrine, and bone physiology along the way. From 1962 until 1971, he was senior lecturer in medicine at the University of Queensland, and from 1971 until 1995, he was the chief of bone and mineral research at Henry Ford Hospital in Detroit. In 1995, he joined the Division of Endocrinology and the Center for Osteoporosis and Metabolic Bone Diseases of the University of Arkansas for Medical Sciences, where he stayed as Professor until 2005 and Emeritus Professor until his passing. In his different posts, Michael worked closely with colleagues both as mentor and collaborator. In Detroit he formed fruitful collaborations with Sudhakar Rao, Michael Kleerekoper, Dorothy Nelson, and Shi-jing Qiu. His mentorship and active research collaborations were equally evident during his time at Little Rock, where he worked closely with Stavros Manolagas, Rob Weinstein, Bob Jilka, Charles O'Brien, Teresita Bellido, and others; and was able, with this group, to continue his research interests in bone cell apoptosis and osteocytes. Michael has also influenced, taught, and stimulated many leaders in the field of bone remodeling and structure including Fleming Melsen, Erik Eriksen, David Dempster, Bob Recker, Ego Seeman, Juliet Compston, Paul Lips, and Pierre Meunier. Through his active interest in others' work, his willingness to offer advice, and above all through his written works, he has provided mentorship for many. He wrote 325 full-length papers and 43 book chapters. He made two trans-Pacific sabbaticals in opposite directions: from Brisbane to Los Angeles in 1968 to study renal bone disease with Charles Kleeman and from Detroit to Brisbane in 1988 to study parathyroid cell kinetics with Martyn Lloyd. In recognition of his outstanding achievements, he received many honors. He delivered the Richard L. Cruess lecture at the Montreal Shriner's Hospital in 1991, the Boy Frame lecture at Henry Ford in 1999, and the Wells Bequest Lecture at the University of Queensland in 2000. In 1999 he became the Honorary President of the International Society of Bone Morphometry. He received the ASBMR Bartter Award in 1997, the Sun Valley Rib Award in 2002, and in 2010 the ASBMR William F. Neuman award—the most prestigious award of the society, which recognizes outstanding and major scientific contributions in the area of bone and mineral research and contributions to associates and trainees in teaching, research, and administration. Michael's early interests included the renal handling of calcium, plasma calcium homeostasis, and the diagnosis and treatment of hyperparathyroidism. His attention subsequently expanded to include normal and abnormal bone remodeling, the histomorphometric definition of osteomalacia, non-mass contributions to bone fragility, structural aspects of bone growth, the pathophysiology of primary and secondary hyperparathyroidism, bone cell apoptosis, and finally the role of osteocytes in health and disease. Michael made invaluable contributions to our understanding of parathyroid growth, both normal and abnormal. He insisted that when considering the function of any endocrine gland, cell number should receive as much attention as hormone secretion. Based on meticulous analysis of the published data and his own elegant experiments on parathyroid cell kinetics (done in collaboration with Martin Lloyd), he chronicled the growth pattern of parathyroid glands from birth to adulthood and the physiologic or pathologic conditions that influenced it. He asserted that understanding the mechanisms by which parathyroid cells change their replication was essential for a full understanding of the pathogenesis of disease and developing a rational treatment strategy. Lloyd's concept of two types of hyperparathyroid states laid the foundation for explaining the two distinct clinical manifestations of the disease. Michael was not fully satisfied with this concept because it did not explain the lack of disease progression in the absence of parathyroidectomy. Michael's revised proposal for neoplastic and set-point driven growth (with an asymptote in the latter, consistent with the Gompertizian model) of parathyroid tumors explained more completely the growth patterns in different hyperparathyroid states (primary, secondary, and tertiary, and even familial hypocalciuric hypercalcemia [FHH]). He further expanded on this proposal by introducing the concept of monoclonal, multiclonal, and polyclonal expansion, summing it all up brilliantly in a unified model of abnormal parathyroid growth. He steadfastly maintained that the genetic abnormalities in sporadic parathyroid adenomas could very well be the consequence rather the cause of parathyroid cell proliferation initiated by an yet to be determined set-point "mutation"! Michael was equally interested in the role of vitamin D in parathyroid adenoma growth and the development of osteitis fibrosa. In collaboration with the Detroit group, he demonstrated, for the first time, the relationship between vitamin D status and adenoma size. While working on this, he also demonstrated the contribution of loss of vitamin D and calcium sensing receptors (VDR and CaSR) in sporadic parathyroid adenomas. He strongly believed that both in primary and secondary hyperparathyroidism, cell proliferation is largely driven by increased secretory set point due to underexpression of CaSR. He insisted that further studies were necessary to find molecular mechanism(s) responsible for reduced VDR and CaSR expressions because no mutations were found in either genes. Later work in collaboration with Indian colleagues showed that the VDR loss was not due to hypermethylation. Nevertheless, he continued to challenge other investigators to explore the link between cell proliferation and hormone secretion, one of his many significant pursuits. Who else can better explain Michael's scientific journey than Michael himself? In the following paragraphs we have interspersed transcripts of his own words (how clear and precise they were), from the program of a Festschrift organized by the Little Rock group in his honor in 2004, during that year's ASBMR meeting in Seattle, WA. In Michael's words: "Martyn Lloyd, who was my colleague and my mentor in Brisbane, found that patients with primary hyperparathyroidism who presented with osteitis fibrosa (type I) had shorter histories and larger tumors, whereas patients who presented with stones (type II) had longer histories and smaller tumors, indicating that adenoma growth rate was a major factor in determining clinical manifestations. Hunter Heath at Mayo first documented the large increase in incidence that followed the widespread adoption of multichannel screening; such patients generally have even smaller and more slowly growing tumors. Dan Rao at first demonstrated that in such patients, the degree of hypercalcemia remained stable for prolonged periods, an observation confirmed and extended by John Bilezikian. The reason the adenoma stopped growing occurred to me when I was on sabbatical with Martyn Lloyd in Brisbane in 1998. If growth was driven by an increase in secretory setpoint, when the tumor was large enough to raise the patient's plasma calcium to the new setpoint, there would no longer be any stimulus for further growth. We thought this idea also applied to tertiary hyperparathyroidism in renal failure." One of Michael's major contributions has been in the field of bone remodeling and structure. He is one of very few people who both recognized and understood the seminal advances contained in Harold Frost's writing; without Michael much of the wisdom of Frost would have been lost to the world of bone research. Through a number of classical papers, Michael made Frost's writings accessible to a wider audience. He also developed the basic ideas set out by Frost to formulate novel concepts that have now become enshrined in bone physiology, including hemi-osteonal remodeling, targeted and non-targeted remodeling, coupling of formation to resorption, and the critical involvement of the vasculature in the process of bone remodeling. Until the 1970s the microarchitecture of bone and its implications for bone strength were largely ignored by bone researchers. The landmark paper published by Michael and his colleagues in the Journal of Clinical Investigation (JCI) in 1983 used a new approach (parallel plate model) to assess changes in trabecular bone microarchitecture and drew attention to trabecular thinning and trabecular perforation as structural mechanisms of bone loss. In this paper it was demonstrated that during age-related bone loss in women, entire trabecular elements are removed, a phenomenon that Michael attributed to greater resorption depth as a result of increased osteoclast activity. This paper stimulated a much needed reawakening of interest in bone architecture that has continued to the present time and has been fundamental to the rapidly growing body of bone biomechanical research. This is how Mike recounted the history of these seminal discoveries: "Around 1958, I remarked at an NIH conference that 'bone quality' had traveled in a few years from heresy to dogma without encountering much new evidence. Nevertheless, in 1978, I organized the first session at an international conference devoted to qualitative aspects of fracture risk. Bob Heaney, the keynote speaker, subsequently coined the term 'non-mass factors.' Fatigue microdamage accumulation is the first such factor, pioneered by Harold Frost; Mitch Schaffler [brought us] up to date on this topic and on the role of osteocytes. The next such factor is architecture; there are new methods of study in both patients and histologic material, but there has been little recent conceptual progress. The third such factor is unnecessarily high bone remodeling, discovered independently by Larry Riggs and myself and recently placed in evolutionary context by Bob Heaney. The fourth such factor is bone size, largely determined during growth, which in the adult can be changed only by periosteal apposition, as Ego Seeman has emphasized. The fifth such factor is osteocyte apoptosis [the subject of the work with the Little Rock group]. Non-mass factors together contribute more to bone fragility than does loss of bone mass, which undermines the continued use of WHO criteria for the so called 'diagnosis' of osteoporosis." The JCI paper published by Michael and his colleagues in 1983 became one of the most cited articles in the history of the journal. In 2013, Mike was asked to provide a "hindsight" perspective. This is how he summed it all up in his usual mellifluous style: "I devised a method of obtaining information on cancellous bone structure from iliac bone histomorphometry that led to the demonstration that architecture was an important component of bone strength and bone fragility, and contributed to the recognition of the importance of changes in osteoclast and osteocyte apoptosis in response to estrogen deficiency and replacement." In his work as Chairman of the ASBMR Bone Histomorphometry Nomenclature Committee, Michael performed a major service to the bone community. Previously, bone histomorphometry nomenclature had been complex and often counterintuitive, making it inaccessible to all but a few enthusiasts. The output of the Committee was published in the JBMR in 1987 and provided not only a clear and logical nomenclature for bone histomorphometry but also an explanation of the physiological basis and significance of the measured indices. This paper has become the standard reference for all researchers wishing to understand and use bone histomorphometry. Importantly, it has also made accessible to a wider community the growing number of studies addressing mechanisms of bone loss in osteoporosis and the safety and mechanism of action of bone active drugs. Michael developed the notion of bone envelopes. This concept is important because, as he has pointed out, the cellular machinery of bone modeling and remodeling is surface dependent. The addition of bone matrix to, and removal of bone matrix from, a skeletal region always takes place upon these envelopes or surfaces. Bone is that mineralized material that is "inside" the periosteum and "outside" the three components (intracortical, endocortical, and trabecular) of its inner "surface" or endosteal "envelope." When viewed in this way, the study of living bone is the study of its surface cellular activity. The net result of these surface activities determines the macrostructure and microstructure of bone. During growth the envelopes move apart as the total bone matrix volume increases. Site-specific and point-specific cellular activity increases bone size and alters bone shape point by point around the circumference of a cross section and from cross section to cross section along a bone, determining the thicknesses of cortices. Concurrent intracortical remodeling determines the number and size of the osteons, each with their Haversian canals, whereas apposition on trabeculae determines trabecular thickness and connectedness. This was discussed by Michael in a paper in Bone in 2000, one of the most comprehensive papers written on the structural basis of skeletal growth. With advancing age the cellular activity and negative bone balance of each remodeling event result in the net removal of a quantum of bone focally; trabeculae thin so the trabecular surfaces come closer together. Perforation of trabeculae results in complete loss of trabeculae with their surface so remodeling within the trabecular compartment decreases as there eventually is little trabecular surface upon which remodeling can be initiated. Intracortical remodeling initiated upon Haversian canals enlarges them focally, so the intracortical surface area increases. Adjacent canals come closer together, some coalesce, particularly those canals traversing cortex near the medullary canal, producing giant irregularly shaped pores which fragment and "trabecularize" the cortex. Michael was the only investigator to measure periosteal bone modeling and report slow deposition of bone during aging, albeit insufficient to offset the net intracortical and endocortical resorption that fragments and thins the cortices. Michael explored these issues in several wonderful papers comparing younger and older persons, African Americans and Caucasians, bringing together the cellular and structural basis of the earlier growth and later aging of the skeleton through the study of the cellular activity upon its outer and inner surfaces. In this work he quantified the extent of periosteal apposition, intracortical, endocortical, and trabecular remodeling (formation and resorption) on each of these envelopes to explain the morphological changes in bone structure throughout life. Michael's development of the concept of the transient remodeling space deficit is another area that is fundamental to the understanding of the effects of perturbation of remodeling after menopause, and in untreated and treated disease. The effects of disease and drug therapy cannot be understood without appreciation of tissue-level and cell-based remodeling—the distinct notion of resorption at the cellular and tissue levels is still not well appreciated. Michael defined the notion of the remodeling space transient as combined deficit produced by the excavated sites yet to refill with osteoid, excavated sites containing osteoid without mineral, remodeling sites containing osteoid that has undergone primary mineralization but not secondary mineralization, and finally remodeling sites that have completed matrix deposition and primary mineralization but are still at varying stages of secondary mineralization, the slowest component of the remodeling cycle. Indeed, secondary mineralization may continue for years and partly explains the changes in BMD that occur following drug therapy, not all of which are necessarily beneficial as we are now learning. Michael emphasized that secondary mineralization is part of the fully reversible remodeling transient that is distinct from the irreversible deficit in matrix and its mineral content that results from the negative BMU balance. Michael has written extensively on the notion of uncoupling and attempted to explain the fact that the negative BMU balance, which is the net result of many factors (still to be defined) that reduce the volume of bone formed in relation to the volume of bone resorbed is not uncoupling. This negative BMU balance is the necessary and sufficient morphological basis of bone loss but differs from uncoupling. The role of vitamin D insufficiency in age-related bone loss is now accepted and has changed clinical practice. Michael was the first person to recognize the critical distinction between prolonged severe vitamin D deficiency, which causes rickets or osteomalacia, and vitamin D insufficiency, which is accompanied by secondary hyperparathyroidism and increased cortical bone loss but in which mineralization of bone is essentially normal. This fundamental concept was developed through both biochemical and histological observations and was described in a groundbreaking paper in 1982. Michael was also responsible for the first detailed description of the dynamics of bone mineralization and from this proposed a new and now widely adopted histological definition of osteomalacia, based on the criteria of increased osteoid seam width and increased mineralization lag time. Michael's account of his contribution in this area of research: "There is no common theme except my own interests. When the lab at Ford embarked on a comprehensive study of osteomalacia in patients with intestinal malabsorption using double tetracycline labeling, we formulated strict criteria for defective mineralization that enabled recognition of two new disorders—high bone turnover due to secondary hyperparathyroidism and low bone turnover of unknown etiology. Juliet Compston has developed and we expanded this latter observation in a wide variety of contexts, including hepatobiliary and gastrointestinal disease. My interest in rickets and osteomalacia due to hypophosphatemia was initiated by Fuller Albright and consolidated by Reginald Nassim and Charles Dent. At that time, the focus was exclusively on primary defects in renal tubular reabsorption. The discovery of several nonparathyroid humoral factors that reduce phosphate reabsorption has been a fascinating story, started by Marc Drezner and others and developed further by Darryl Quarles. Charles Dent introduced me to idiopathic juvenile osteoporosis, which could easily be confused with osteogenesis imperfecta. When Francis Glorieux came to analyze his extensive normal pediatric histologic data, he invited me to collaborate in their interpretation. We developed several important new concepts of bone growth, which provided the framework for the reinterpretation of the osteopenic disorders of childhood and helped provide an explanation for the remarkable therapeutic efficacy of bisphosphonates that Francis discovered." Although death by necrosis was the fashion in the 19th and early 20th century, death by apoptosis is the rage in contemporary biology and Michael was the trend leader here. Michael's work with Rao in defining osteocytes in the superficial and deeper bone, the loss in deep bone but replenishment in bone near a surface (as it is accessible to being remodeled) signals an important area for research as this may be an independent cause of bone fragility and target for therapy. Moreover, modulation of the cell population by regulating longevity rather than production of cells is fundamental to understanding the efficient maintenance of a cell population. His influential thinking on bone cell apoptosis and the legacy of such thinking is also well reflected in the work of the Little Rock group and others during the last 15 years and in particular the notion of altered survival of osteoblasts and osteoclasts as a result of estrogen deficiency—a seminal contribution to understanding "killer" osteoclasts and the accelerated loss of bone after estrogen deficiency, resulting in a reduction in trabecular number, not thinning of trabeculae—a surprising observation that has been confirmed many times by other investigators. The understanding of bone fragility in glucocorticoid excess and the role of osteocyte death is yet another important and conceptually innovative contribution to the field. Indeed, with Michael's inspiration, his Little Rock colleagues have demonstrated that the reduction in bone strength following glucocorticoids precedes bone loss and can be abrogated by preventing osteocyte death. This opens doors to the prevention of bone fragility by targeting the osteocyte in this illness. This how Mike recounted it: "John Kerr, one of the pioneers of apoptosis, became Professor of Pathology at the University of Queensland Medical School in Brisbane while I was there. He convinced me of the reality of apoptosis, and I invoked its absence to explain the failure of post-renal transplant hyperparathyroidism to resolve. The first mention of apoptosis in the context of bone was the suggestion by Kardos of Otago that matrix vesicles were apoptotic bodies; his poster at the Gulf Shores meeting on mineralized tissues greatly appealed to me. When I concluded, from simple arithmetic applied to published data, that most osteoblasts that had assembled on the cement surface could not be accounted for as either lining cells or osteocytes, it was natural for me to attribute the deficit to osteoblast apoptosis, for which at that time there was no direct evidence. It has been most gratifying to me that my colleagues in Little Rock have devoted so much of their research effort to proving the existence and importance of bone cell apoptosis and pursuing its numerous ramifications. We recently drank a toast to John Kerr, who, at least for me, started it all." In Closing We have lost one of the finest scholars in the field. While we mourn his loss, he speaks in the memories to those of us fortunate to have known him. He will guide young investigators now entering the field, and do so during their evenings as they and the moon rage in silent reading. They will be struck by the thunderbolts of his written words: this is scholarship, this is discipline, this is reasoning, this is the pristine scientific method. Beware of the all too ready self-approval, it will obscure your vision, it will obstruct the courage of exploration at the heart of progress and leave silent your own voice seeking form. We will miss that lucid directness at the microphone holding the promise of an insightful repartee, his wit and wry humor, that restrained small upward curl of his lip as his knowing smile plays joyfully in exchanges with friends. He made the science so engaging, so relevant, and, so right. Michael was indeed a teacher of ageless lessons that (as Yeats put it in his Sailing to Byzantium) should not be neglected by the newer generations. Michael Parfitt began his journey to the stars in the warmth and comfort of his home at Hot Springs, Arkansas. He left peacefully bathed in the love of his life, his wife of 60 years, Elaine, also an MD from King's College in London, and the love of all of his family. In addition to Elaine, he is survived by his three children Caroline, Nigel, and Jeremy, five grandchildren, Jennifer, Samantha, Lewis, Brian, and Michael, and a great granddaughter, Kayden. This is what Michael's family wrote for his obituary in the local paper: "he was a scientist, a teacher, a mentor and never lost his sense of humanity. There were no short answers. His dry sense of humor, mischievous twinkle and wisdom will be deeply missed." To quote Richard Dawkins in his eulogy for Douglas Adams, "It has been our privilege to know a man whose capacity to make the best of a full life span was as great as was his charm and his humor and his sheer intelligence." Michael and I were married nearly 61 years. We trained at the same teaching hospital. He was a student of the University of Cambridge who had chosen to do his clinical training at Kings College Hospital in London. We were assigned to the same teaching unit but we met when I surprised him by recognizing a piece of classical music he was tapping out on a tabletop. Some weeks later he asked me whether I would like to go to a music concert at the new auditorium on the river Thames. And so began a life of discovery and exploration: be it music, medicine, books, or the world around us. Michael was a prodigious reader and had an amazing ability to understand and interpret what he was reading. "Why" was not a childish word but one that demanded serious thought and conversation. Our children learned quite early that the response to "why" was another question such as "What do you see?" Observation, discussion, and interpretation became a frequent, interesting, and fun occurrence. Family dinnertime was certainly conversational. Vacations planned by this consummate explorer are remembered by our adult children and me as adventures and lots of fun and sometimes a little scary, as when Michael's belief that every road on a map regardless of its state of repair had to be navigable. One time encountering a pothole that would swallow up the car provoked second thoughts and retreat where we discovered a sign obscured by overgrowth that read on close examination "Military Range. KEEP OUT!" These experiences balanced the long hours Michael worked at home, often retiring to his office immediately after dinner and sometimes occupying whole weekends or even weeks if attending a meeting overseas. The work he loved took us to Australia and our final home, America. It also allowed us to visit many wonderful places and we are blessed to have made friends all over the world. We will miss this husband, father, and granddad we love and cherish the memory of a certain twinkling smile that heralded some sort of mischief. The letters we have received from friends and colleagues have been both comforting and amazing. It has become obvious that we had not fully understood the depth and impact of Michael's work or how many people his writing and teaching had impacted. Thank you for telling us. It seems that he was able to accomplish much of what he wanted to do and for that we are grateful and proud. We as a family celebrate a life lived to the full. —Elaine Parfitt I first met Michael at the Sun Valley meeting in 1973. I realized at the time that Michael was the "brains" of the bone field. My subsequent encounters with Michael only cemented that impression more firmly. He was a major influence in my career choice of dynamic bone histomorphometry as the principal discipline for my study of bone physiology and pathology. I cannot count the number of times that I consulted Michael about various problems and their solutions regarding skeletal science. His help was indispensable. He extended Frost's idea regarding the bone "mechanostat." My favorite response from Michael came after I presented work at Sun Valley on a kindred with very high bone mass that had a G171V mutation in Lrp5. His quote was, "Recker, you have discovered the mechanostat." That was the most satisfying moment of my entire research career. Michael was an icon in the field of skeletal research. He was also a great friend. We will all miss him greatly. —Bob Recker It is hard to express my sense of loss—both personal and professional—