On age-related mammalian bone loss: Insights of the Utah paradigm

SummaryAn elegant design stratagem would make its loads control the strength of an organ intended to carry loads without breaking. Healthy load-bearing mammalian bones do exactly that. Physiologists begin to understand how they do it, and this article reviews some of the biological “machinery” responsible for it. Why? Because that machinery’s features show what can cause age-related bone loss, how it occurs, how a long-overlooked mechanism in bone marrow would contribute to it, why loss of whole-bone strength seems more important than loss of bone ‘mass’, and why some absorptiometric indicators of whole-bone strength are unreliable. The machinery’s features also show why strong muscles normally make strong bones, why persistently weak muscles normally make weak bones, and why loss of muscle strength usually causes a disuse-pattern osteopaenia. Those things could question long-accepted ‘wisdom’, but four observations concern that; (1) the questions concern what facts mean far more than the accuracy of the facts, and the basic facts now seem pretty clear;(2) this article must leave resolution of such questions, and of the devils that can hide in the details, to other times, places and people;(3) the plate tectonics story showed that better facts and ideas can change accepted wisdom dramatically;(4) and poor interdisciplinary communication delayed and still delays diffusion of better facts and ideas to many skeletal science and clinical disciplines that needed and need them.

"OSTEOPOROSIS" IN 2000 AD: QUO VADIS?

Here, we suggest that new ideas and knowledge about "osteoporosis" reveal necessary new directions for future work. To explain, by 1999, five studies involving a total of 1827 healthy humans from two to over 80 years of age supported this proposal in the Utah paradigm of skeletal physiology: Momentary muscle strength strongly influences and may dominate control of the biologic mechanisms that determine the postnatal strength of load-bearing bones. That italicized proposal differed so much from former views that before 1999, few people thought it deserved testing in humans. The above five studies did finally test it, and they support it. If true, its implications would affect many things. In part, they include (A), genetic effects on bone strength and "mass", muscle and "osteoporosis"; (B) the pathogenesis, diagnosis, classification, prevention and management of "osteoporosis"; (C) the things osteoporosis-oriented basic, clinical and pharmaceutical research should study; (D) the absorptiometric methods and animal models used to study the disorder; (E) which research projects would receive preferred funding; (F) and the content of future texts, review articles, classroom lectures and many osteoporosis-oriented meetings. Many might find some of those implications dubious. While we will respect such doubts, this article describes some of those implications so others can exploit them and/or help to resolve any disagreements they may cause. Because they depend on the Utah paradigm of skeletal physiology, some of its pertinent features must be summarized.

The Utah paradigm of skeletal physiology: what is it?

SummaryAn elegant design stratagem for an organ intended to carry loads for life without fracturing, rupturing or wearing out would make those loads determine the organ's strength. It seems load-bearing mammalian bones, joints, fascia, ligaments and tendons do exactly that. Physiologists begin to understand how they do it, and that led to the Utah paradigm of skeletal physiology. Those adaptations occur in two major steps. The first step creates the genetically predetermined newborn skeleton with its anatomical relationships and biologic machinery. The second step adds to the first one all postnatal adaptations to mechanical and other challenges that would affect an organ's strength, size, architecture and composition. During postnatal growth, increasing loads make tissue-level biologic mechanisms correspondingly increase the strength of such organs. Mechanical strain-dependent signals help to control that process, which muscle strength, muscle anatomy and neuromuscular physiology strongly influence. Its problems seem to cause or help to cause numerous skeletal and some extraskeletal disorders. A Table in the article lists examples of them.This article summarizes salient features of the Utah paradigm, which includes both facts and some meanings inferred from them. Other times and people must resolve any questions about those meanings and about the devils that can lie in the details. Parenthetically, instead of the accuracy of the facts on which that paradigm stands, the above questions usually concern the different meanings people can infer from facts, and whether particular facts and ideas would be relevant to a particular issue.

NEW TARGETS FOR THE STUDIES OF BIOMECHANICAL, ENDOCRINOLOGIC, GENETIC AND PHARMACEUTICAL EFFECTS ON BONES: BONE'S "NEPHRON EQUIVALENTS", MUSCLE, NEUROMUSCULAR PHYSIOLOGY

As age, experience and common sense look at biomechanical, hormonal, genetic and other roles in bone physiology and its disorders, two questions can arise: (a) How did we fail? (b) How could we make it better? The acerbic Sam Johnson said that to teach new things, we should use examples of already known ones. If so, an analogy might help to clarify this article's message for people who work with bones and their disorders. Assume this: (a) Mythical physiologists were taught that renal physiology depends on "kidney cells" but were taught nothing about nephrons; (b) so they explained renal health and disorders in those terms. (c) For many decades, they "knew" that view was correct (as the ancients "knew" the world was flat). (d) But then others described nephrons and some errors their properties revealed in those views about renal physiology; (e) so controversies began. Today, an analogous situation confronts real biomechanicians and physiologists. (i) Most of them were taught that osteoblasts and osteoclasts (bone's "effector cells") explain bone physiology without "nephron-equivalent" input, so they explained bone disorders and mechanical effects in those terms. (ii) Yet nephron-equivalent mechanisms and functions, including biomechanical ones, in bones have the same operational relationship to their cells, health and disorders as nephrons and their functions do to renal cells, health and disorders. (iii) Adding that knowledge to former views led to the Utah paradigm of skeletal physiology. It also revealed errors in many former views about bone physiology; (iv) so real controversies have begun. Biomechanicians, physiologists, clinicians and pharmacologists from whom poor interdisciplinary communication hid that paradigm could think the view in (i) above remains valid, and keep analyzing data and designing studies within its constraints. Like Wegner's idea of plate tectonics in geology, the Utah paradigm came before its field was ready, so others fought it. But while the plate-tectonics war was won, it has just begun for the Utah paradigm. This article reviews how such things could apply to bone and some of their implications. Its conclusion offers succinct answers to the italicized questions above.