The observed fit of bone mass to a healthy animal's typical mechanical usage indicates some mechanism or mechanisms monitor that usage and control the three longitudinal growth, bone modeling, and BMU-based remodeling activities that directly determine bone mass. That mechanism could be named a mechanostat. Accumulated evidence suggests it includes the bone itself, plus mechanisms that transform its mechanical usage into appropriate signals, plus other mechanisms that detect those signals and then direct the above three biologic activities. In vivo studies have shown that bone strains in or above the 1500-3000 microstrain range cause bone modelling to increase cortical bone mass, while strains below the 100-300 microstrain range release BMU-based remodeling which then removes existing cortical-endosteal and trabecular bone. That arrangement provides a dual system in which bone modeling would adapt bone mass to gross overloading, while BMU-based remodeling would adapt bone mass to gross underloading, and the above strain ranges would be the approximate "setpoints" of those responses. The anatomical distribution of those mechanical usage effects are well known. If circulating agents or disease changed the effective setpoints of those responses their bone mass effects should copy the anatomical distribution of the mechanical usage effects. That seems to be the case for many agents and diseases, and several examples are discussed, including postmenopausal osteoporosis, fluoride effects, bone loss in orbit, and osteogenesis imperfecta. The mechanostat proposal is a seminal idea which fits diverse evidence but it requires critique and experimental study.

The still-evolving mechanostat hypothesis for bones inserts tissue-level realities into the former knowledge gap between bone's organ-level and cell-level realities. It concerns loadbearing bones in postnatal free-living bony vertebrates, physiologic bone loading, and how bones adapt their strength to the mechanical loads on them. Voluntary mechanical usage determines most of the postnatal strength of healthy bones in ways that minimize nontraumatic fractures and create a bone-strength safety factor. The mechanostat hypothesis predicts 32 things that occur, including the gross anatomical bone abnormalities in osteogenesis imperfecta; it distinguishes postnatal situations from baseline conditions at birth; it distinguishes bones that carry typical voluntary loads from bones that have other chief functions; and it distinguishes traumatic from nontraumatic fractures. It provides functional definitions of mechanical bone competence, bone quality, osteopenias, and osteoporoses. It includes permissive hormonal and other effects on bones, a marrow mediator mechanism, some limitations of clinical densitometry, a cause of bone "mass" plateaus during treatment, an "adaptational lag" in some children, and some vibration effects on bones. The mechanostat hypothesis may have analogs in nonosseous skeletal organs as well. Anat Rec Part A 275A: 1081-1101, 2003.

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From the nature of a bone's endload and its local surface strains, the theory computes a modeling operator, Gamma (gamma), that predicts whether mechanical factors will cause lamellar bone modeling drifts, and where and of what kind. A given mechanical bone strain history then provides a separate modeling rate function, M, to specify the rate of such modeling drifts as fractions of the largest possible ones. Multiplying the two functions, e.g., gamma.M, then predicts mechanically controlled bone modeling responses for cortical and trabecular bone, both quantitatively and qualitatively. The theory correctly predicts each of the 6 known "principal adaptations" of lamellar bone, which provide a critical test of any such theory for this organ. The theory accounts for biologic, biomechanical, and clinical-pathologic knowledge not available in Wolff's time nor accounted for by most biomechanicians since. Existing proven methods can provide all numerical data needed to satisfy the theory's mathematical equations and already suggest provisional values for most of them. Its originator views the theory as the kernel of more and better theories to come rather than a finished work, a kernel that suggests a new and in some respects novel logical framework for analysing the problems, and a kernel that invites critique, refinement, and/or exploitation by others.

Basic multicellular unit (BMU)-based remodeling of lamellar bone causes bone turnover, net gains and losses of bone on some bone surfaces or "envelopes," and a remodeling space comprising bone temporarily absent due to evolving resorption spaces and incomplete refilling of them by new bone. Those features depend a) on how many new BMU arise annually, b) on how much bone each BMU has resorbed and c) formed upon its completion, and d) on how long the typical BMU takes to become completed. Because a, b, and c have limiting or maximal values in life that direct and/or indirect effects of mechanical usage of the skeleton can change, the theory presented here derives mechanical usage functions that express what fractions of those maxima a given mechanical usage history allows to happen. The theory predicts some changes in bone formation, resorption, balance, turnover, and remodeling space that depend on how remodeling responds to the vigor of a subject's mechanical usage. The theory can predict specific effects of specific mechanical challenges that experiments can test, and it fits abundant published evidence. As the kernel of a new approach to the problem it awaits critique and refinement by others. It plus the 3-way rule can redefine Wolff's law conceptually and also in mathematical and quantifiable form.

Efforts to understand our anatomy and physiology can involve four often overlapping phases. We study what occurs, then how, then ask why, and then seek clinical applications. In that regard, in 1960 views, bone's effector cells (osteoblasts and osteoclasts) worked chiefly to maintain homeostasis under the control of nonmechanical agents, and that physiology had little to do with anatomy, biomechanics, tissue-level things, muscle, and other clinical applications. But it seems later-discovered tissue-level mechanisms and functions (including biomechanical ones, plus muscle) are the true key players in bone physiology, and homeostasis ranks below the mechanical functions. Adding that information to earlier views led to the Utah paradigm of skeletal physiology that combines varied anatomical, clinical, pathological, and basic science evidence and ideas. While it explains in a general way how strong muscles make strong bones and chronically weak muscles make weak ones, and while many anatomists know about the physiology that fact depends on, poor interdisciplinary communication left people in many other specialties unaware of it and its applications. Those applications concern 1.) healing of fractures, osteotomies, and arthrodeses; 2.) criteria that distinguish mechanically competent from incompetent bones; 3.) design criteria that should let load-bearing implants endure; 4.) how to increase bone strength during growth, and how to maintain it afterwards on earth and in microgravity situations in space; 5.) how and why healthy women only lose bone next to marrow during menopause; 6.) why normal bone functions can cause osteopenias; 7.) why whole-bone strength and bone health are different matters; 8.) why falls can cause metaphyseal and diaphyseal fractures of the radius in children, but mainly metaphyseal fractures of that bone in aged adults; 9.) which methods could best evaluate whole-bone strength, "osteopenias" and "osteoporoses"; 10.) and why most "osteoporoses" should not have bone-genetic causes and some could have extraosseous genetic causes. Clinical specialties that currently require this information include orthopaedics, endocrinology, radiology, rheumatology, pediatrics, neurology, nutrition, dentistry, and physical, space and sports medicine. Basic science specialties include absorptiometry, anatomy, anthropology, biochemistry, biomechanics, biophysics, genetics, histology, pathology, pharmacology, and cell and molecular biology. This article reviews our present general understanding of this new bone physiology and some of its clinical applications and implications. It must leave to other times, places, and people the resolution of questions about that new physiology, and to understand the many devils that should lie in its details. (Thompson D'Arcy, 1917). Anat Rec 262: 2001.

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