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From Wolff's law to the Utah paradigmInsights about bone physiology and its clinical applications.

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THE ANATOMICAL RECORD 262:398 – 419 (2001)
Invited Review
From Wolff’s Law to the Utah
Paradigm: Insights About Bone
Physiology and Its Clinical
Department of Orthopaedic Surgery, Southern Colorado Clinic, Pueblo, Colorado 81004
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:
398 – 419, 2001. © 2001 Wiley-Liss, Inc.
Key words: bone; biomechanics; endoprostheses; osteoporosis; healing; Wolff’s
law; homeostasis; muscle; microgravity
*Correspondence to: Dr. Harold M. Frost, Department of Orthopaedic Surgery, Southern Colorado Clinic, Pueblo, CO 81004.
Received 3 August 2000; Accepted 16 November 2000
Published online 28 February 2001
“. . .between muscle and bone there can be no change
in the one but it is correlated with changes in the
other. . .” (Thompson, 1917)
We try to understand the anatomy and physiology of our
body’s organ systems to achieve better management of
their clinical problems. In that vein, for over 100 years
anatomists and orthopaedic surgeons looked to Wolff’s
Law (Wolff, 1892). One translation of it from German to
English reads thus (Rasche and Burke, 1962): “Every
change in the form and function of bone or of their function
alone is followed by certain definite changes in their internal architecture, and equally definite alteration in their
external conformation, in accordance with mathematical
laws.” Hindsight reveals some limitations of that Law. For
example, in 1892 it had no clinical applications; it said
mechanical influences can affect bone architecture, but
not how; and it could not predict particular effects of
specific mechanical challenges.
Later evidence began to resolve such limitations and led
to the still-evolving Utah paradigm of skeletal physiology
that sprang from a soil of multidisciplinary evidence and
ideas (Burr and Martin, 1992; Frost, 1992, 2000a; Jee and
Frost, 1992; Schönau, 1996; Takahashi, 1995, 1999). It
adds tissue-level and anatomical features and roles to
former views that emphasized cell-level features and
roles. The new paradigm has growing applications to
joints, ligaments, tendons, and fascia (Frost, 1995), but
this article concerns its applications to bone as material
and to bones as organs. Table 1 lists some of the things the
paradigm can explain. Three of its propositions concern
the purpose of load-bearing bones and how that is
Proposition 1: Healthy, postnatal load-bearing bones
are designed to have only enough strength to keep chronically subnormal, normal or supranormal voluntary loads
(not injuries) from causing spontaneous fractures (Frost,
1997a). Achieving that “mechanical competence” should
be the ultimate test of a bone’s health and the main goal of
its biologic mechanisms. In that view, bone “health” and
“strength” differ. The former would depend on the relationship between a bone’s strength and the size of the
peak loads it usually carries. Thus mouse and horse femurs that satisfied Proposition 1 in the animals they came
from would be equally healthy, even though their
strengths differ more than 1,000 times. Likewise for the
ribs and femurs in a single human being.
Proposition 2 (in three parts): 1.) To achieve mechanical competence bone’s tissue-level biologic mechanisms
need nonmechanical factors and effector cells (osteoblasts
and osteoclasts), just as cars need motors, fuel and wheels
in order to move. 2.) In a negative feedback arrangement
bone loads and strains guide those biologic mechanisms in
time and anatomical space**, just as steering, brakes, and
accelerators guide cars. 3.) Most nonmechanical factors
can help or modulate that guidance but cannot replace
it**. In proof, such factors cannot normalize bones, joints
or tendons in paralyzed limbs. Equally, motors and fuel do
not tell cars where to go or when.
To explain, the newborn skeleton already has its basic
architecture and relationships, and the biologic mechanisms, responses, and signaling mechanisms that can
adapt it to postnatal influences (Cruess, 1982; Enlow,
1963; Hanes and Mohidden, 1965; Weinmann and Sicher,
1955). The signaling mechanisms could include osteocytes, bone lining cells, and other cells in the marrow, and
TABLE 1. Clinical phenomena the Utah paradigm
can explain plausibly*
Why strong muscles usually associate with strong bones.
Why too stiff and too compliant internal fixations can each
impair the healing of fractures, bone grafts, and
What makes fracture callus reshape itself.
Why some screws or external fixation pins in bone loosen or
pull out.
Why the bone supporting some endoprosthetic designs
Why most aging adults lose bone strength and “mass.”
Why chronic muscle weakness associates with an
Why chronic debilitating illness usually associates with an
Why whole-bone strength and stiffness usually correlate
What makes healthy bones stronger than needed for their
usual voluntary mechanical usage.
What makes net bone losses usually come from bone next to
Why obese people have more bone strength than equally
active slender people.
Why some patients with “osteoporosis” develop spontaneous
fractures but others do not.
What causes stress fractures, “spontaneous fractures,” and
Why most men have more bone strength than most women.
The chief cause of increased bone fragility in osteogenesis
Why “vigorous” exercise can help to keep but not increase
bone strength in adults.
How to distinguish mechanically competent bones from
incompetent ones.
Why osteoclasts are not essential for effective homeostasis.
Why remodeling could not cure an osteopenia but modeling
The direct cause of most so-called “osteoporosis fractures.”
*While plausible need not mean correct too, as the number of
things a paradigm can explain increases, so do its credibility
and usefulness.
could depend on streaming and piezoelectric potentials,
some chemical phenomena, and fluid shear over cell membranes (Marotti et al., 1996; Martin, 2000). Chiefly gene
expression patterns in utero would predetermine those
baseline conditions (mechanical effects in the last trimester of pregnancy are ignored here; Carter and Wong,
1990). At any time after birth, the skeletal organs in
neonatally paralyzed and normal limbs show typical differences in their strength, architecture, and other features. Those differences should reveal the kinds and magnitudes of the adaptations to postnatal mechanical loads
in the normal limbs. Structures in the totally paralyzed
limbs should reveal the baseline conditions, presumably
affected by postnatal nonmechanical agents including
genes (Jaffurs and Evans, 1998), but not by normal postnatal loads (Frost, 1995).
Implication: Bones, fascia, ligaments, and tendons
should not completely disappear in total permanent disuse. Indeed, in the lower limbs of patients with congenital
complete paralysis due to myelomeningocele, some bone
and other structural tissues always remain (Frost, 1986).
The following sections demonstrate how those postnatal
bone differences develop and some clinical applications of
that physiology. A Glossary at the end defines some of the
Fig. 1. Bone modeling by drifts. A: An infant’s long bone with its
original size and shape in solid line. To keep its shape as it grows in
length and diameter, drifts move its surfaces in tissue space as the
dashed lines suggest. Formation drifts make and control new osteoblasts to build some surfaces up. Resorption drifts make and control
new osteoclasts to remove bone from other surfaces. B: A different drift
pattern can correct the fracture malunion in a child shown in solid line.
The cross-section view (right) shows the endocortical as well as the
periosteal drifts that do that. C: How the drifts in B would move the
whole segment to the right. Changing the anatomy in that way reduces
the bone’s bending moments. Drifts are created when and where they
are needed, and include capillaries, precursor and “supporting” cells,
and some wandering cells. They are multicellular entities in the same
sense as renal nephrons Reproduced from Frost (1997d) with permission
of the publisher.
terms used in the text. Note: Throughout the text, a double
asterisk (**) after a statement will mean: “While some
might consider that statement controversial and I will
respect such views, I am sure the statement is valid.”
Why not on “1” too? When compared to the big differences
in strength of our ribs and femurs, bone’s materials properties change relatively little with aging, sex, species,
bones, and most diseases, osteomalacia excepted (Martin
et al., 1998). Like bone “mass,” normally whole-bone
strength increases during growth; it plateaus in young
adults and declines afterwards (Ferretti, 1999; Garn,
1970; Schiessl et al., 1998). This article emphasizes wholebone strength, since nature seems to rank its importance
above bone “mass.”
Four Physical Features Combine to Determine
Whole-Bone Strength
(Currey, 1984; Martin et al, 1998)
1.) That strength depends on bone’s stiffness, ultimate
strength, resilience, true density, etc. (the materials property factor). 2.) It depends on the kinds of bone— woven,
plexiform and lamellar, compacta, and spongiosa— and
their amounts in a cross-section (the “mass” factor). That
amount usually increases during growth, plateaus in
young adults, and then declines, so by 80 years of age less
than 60% of the young-adult bone “mass” (and strength)
can remain (Buckwalter et al., 1993; Marcus et al., 1996;
Smith and Gilligan, 1989). 3.) Its size, shape, and the
distribution of its bony tissue in space affect a bone’s
strength (the architectural factor). Thus, doubling outside
bone diameter while keeping the same amount of bone in
the cross-section so the cortex becomes thinner, increases
bending strength about eight times. 4.) Fatigue damage or
microdamage also affects a bone’s strength (the microdamage factor) (Burr et al., 1997; Forwood and Parker,
1989; Martin 1995, 2000).
Longitudinal bone growth and the baseline conditions
excepted, normally a bone’s anatomy depends on “2” and
“3,” and whole-bone strength depends chiefly on “2,3,4.”
Two Biologic Determinants of Whole-Bone
Strength: Bone Modeling and Remodeling
In former views, independently working osteoblasts
controlled gains of bone, and independently working osteoclasts controlled bone losses (Aegerter and Kirkpatrick,
1975; Albright and Reifenstein, 1948; McLean and Urist,
1961; Snapper, 1957). But, except longitudinal bone
growth, tissue-level modeling and remodeling mechanisms chiefly control those gains and losses and help to
control a bone’s gross anatomy. Both mechanisms need
osteoblasts and osteoclasts as well as precursor, stem, and
other cells to do their work (Jee, 1989; Martin et al., 1998;
Parfitt et al., 1996; Schönau, 1996).
Modeling by resorption and formation drifts (Fig. 1) can
move bone surfaces in tissue space to determine the crosssectional size and shape and longitudinal shape of bones
and trabeculae (Jee, 1989). That seems to be nature’s
preferred way to increase a bone’s strength. Modeling
would seldom if ever reduce a bone’s strength.
Fig. 2. Bone remodeling BMUs. A–C: An activation event on a bone
surface at A causes a packet of bone resorption at B, and then replacement of the resorbed bone by osteoblasts at C on the right. The BMU
makes and controls the new osteoclasts and osteoblasts that do this.
D–F: This emphasizes the amounts of bone resorbed (E) and formed
(F) by completed BMUs. G–I: In these “BMU graphs” (after Frost),
G shows a small excess of formation over resorption. H: Equalized
resorption and formation as on haversian surfaces and in “conservation-
mode” remodeling. I: Net deficit of formation, as in “disuse-mode”
remodeling of endocortical and trabecular bone. Bottom: These “stair
graphs” (after P.J. Meunier) show the effects of a series of BMUs of the
kind immediately above on the local bone “bank.” BMUs are created
when and where they are needed, and include a capillary, precursor and
“supporting” cells, and some wandering cells. They are multicellular
entities in the same sense as renal nephrons Reproduced from Frost
(1997d) with permission of the publisher.
Remodeling by BMUs (Basic Multicellular Units, Fig. 2)
turns bone over in small packets in which osteoclasts
resorb some bone and then osteoblasts fill the resulting
hole or excavation with new bone (Jee, 1989). This remodeling can work in at least two modes. In a “conservationmode,” completed BMUs resorb and make nearly equal
amounts of bone so no significant bone gain or loss ensues;
but in a “disuse-mode,” BMUs make less bone than they
resorb, but only for bone next to or close to marrow (trabecular and endocortical bone) in both children and adults
(Frost, 1998b)**. This disuse-mode remodeling should
cause all adult-acquired osteopenias on earth and in astronauts in orbit (Frost, unpublished data1)**. It should
help to explain why, in healthy human subjects, bone
“mass” can decrease over 40% between 25 and 75 years of
age (Marcus et al., 1996), and over 90% of that bone loss
comes from bone next to marrow. During that age span,
intracortical porosity increases from ⬃ 3.5% to ⬃ 7%
(Frost, 1969). BMUs seldom, if ever, increase bone
strength and “mass.” Here one should distinguish perma-
nent bone losses caused by disuse-mode remodeling, from
temporary losses from the increased remodeling space
(Heaney, 1994) that always accompanies increased remodeling-dependent bone turnover (Jaworski, 1984).
Frost unpublished data: Personal observations during 50
years of experience in orthopaedic surgery, education, research
and pathology, strongly supported by unpublished findings of
Mechanical Control of Bone Modeling and
(Burr, 1998; Burr et al., 1995; Forwood and
Turner, 1995; Frost, 1990a,b; Jee and Frost, 1992;
Martin et al., 1998; Martin, 2000; Umemura et al.,
Mechanical loads on bones deform or strain them, and
larger loads cause bigger strains. Where strains exceed a
modeling threshold range, modeling slowly increases bone
strength to reduce later strains towards that range; otherwise mechanically controlled modeling turns off. Those
responses make bones strong enough to keep “typical peak
strains” (see Glossary) from exceeding that threshold**.
Since the threshold lies below bone’s ultimate strength,
those responses make healthy bones stronger than needed
for their peak voluntary loads. In young adult mammals,
that “strength-safety factor” (see Glossary) ⬇ 6 when expressed in stress terms. When strains stay below a lower
remodeling threshold range, disuse-mode remodeling permanently removes bone, but only next to or close to mar-
TABLE 2. Examples of nonmechanical factors that
could influence bone adaptations to mechanical
usage and strains (so they could influence bone
strength and “mass” too)
Dietary calcium
Paracrine effects
Amino acids
Gene expression
Other minerals
Autocrine effects
Ethnic origin
Some diseases
D metabolites
Cell-cell interactions
The genome
Medications and Other Artificial Agents
row**. That causes a “disuse-pattern osteopenia” characterized by less spongiosa, an enlarged marrow cavity, and
a thinned cortex, but not a decreased outside bone diameter. When strains exceed that threshold, conservationmode remodeling begins to reduce or stop those bone
losses. That prevents an osteopenia or progression of an
existing one.
In such ways, strain indirectly but strongly influences
the postnatal strength and architecture of load-bearing
Those threshold ranges make the largest strains control
modeling and remodeling effects on whole-bone strength,
and make lesser strains have little effect on it (Lanyon,
1996; Martin et al., 1998; Rubin and McLeod, 1994; Torrance et al., 1994). The thresholds also provide natural
criteria that help to distinguish “normal” from too little or
too much bone strength**. Their existence and values
would reside as genetically determined internal standards
in some skeletal cells (we do not yet know which cells).
During mechanical usage, strain-dependent signals from
bone would be compared to those standards, and if that
reveals an error a corresponding “error signal” would arise
that made modeling or remodeling correct the error. How
aging affects these thresholds is uncertain but under
study (Raab-Culen et al., 1996). The signaling mechanisms, pathways, and cells that help to control those
things now form separate fields of study in skeletal science
(El Haj, 1990; Fukada and Yasuda, 1957; Marotti et al.,
1996; Martin, 1995, 2000; Martin et al., 1998; Skerry,
adults, and then declines (Burr, 1997; Faulkner et al.,
1990; Larsson et al., 1979).
That should help to explain why strong muscles usually
do make strong bones, and chronically weak muscles usually do make weak bones** (Doyle et al., 1970; Frost and
Schönau, 2000; Jee, 1999, 2000; Jee and Li, 1990; Jee et
al., 1991; Jee and Frost, 1992; Li et al., 1990; Li and Jee,
1991; Snow-Harter et al., 1990; Yao et al., 2000). For
example, most women have weaker muscles than most
men, so they should have less bone strength (and “mass”)
too. They do, even if gender has additional effects. As Burr
(1997) and Schönau et al. (1998) noted, neuromuscular
influences on bone strength were long misunderstood and
minimized, but they are becoming another field of study in
skeletal science. That realization led Dr. GP Lyritis in
Greece to form the new International Society for Musculoskeletal and Neuronal Interactions.
Variations in how different individuals use different
parts of their bony skeletons mechanically can cause variable differences in the strength and tissue dynamics of
different bones (Podenphant and Engel, 1987). That helps
to explain why some bones need not predict the strength of
some other bones very well. Such problems puzzled many
osteoporosis authorities who, because of the lingering
views mentioned in the Summary (Cohn et al., 1984),
sought exclusively nonmechanical explanations.
Nonmechanical Control of Bone Modeling and
(Frost and Schönau, 2000; Kannus et al., 1996;
Pauwels, 1986; Rittweger et al., 1999; Schiessl et
al., 1998; Schiessl and Willnecker, 1999; Schönau
et al., 1998)
In former views, factors like those in Table 2 dominated
control of the postnatal strength of load-bearing bones
(Bilezikian et al., 1996; Canalis, 1993; Duncan and
Turner, 1995; Favus, 1999; Huffer, 1988; Parfitt, 1993,
1995; Parfitt et al., 1996). However the omissions of such
views make them suspect.
In fact, most such factors can help or modulate but
cannot replace the mechanical control of postnatal bone
modeling and remodeling**. As examples, by direct actions on bone cells things like hormones, calcium, vitamin
D, and genes might determine 3% to as much as 10% of a
bone’s postnatal strength, but mechanical usage effects on
modeling and remodeling determine over 40% of it**. In
proof, years after a paraplegia bones in lower but not
upper extremities can lose over 40% of their original bone
“mass” (Kiratli, 1996). Similar events occur after total
lower extremity paralysis from anterior poliomyelitis
(Frost, unpublished results), while lower limb bones of
patients paralyzed by a myelomeningocele show even
larger deficits (Frost, unpublished observations).
Figure 3 indicates some combined effects of modeling,
remodeling, and their strain thresholds on a bone’s
Muscles work against such bad lever arms that it takes
well over 2 kg of muscle force on bones to move each
kilogram of body weight around on earth (Crowninshield
et al., 1978; English and Kilvington, 1979; Lu et al., 1997;
Martin et al., 1998). Ergo, the largest voluntary bone loads
and bone strains come from muscles, not body weight as
formerly thought (Koch, 1917). Since those strains help to
control modeling and remodeling effects on bone strength,
momentary muscle strength (see the Glossary) indirectly
but strongly affects the strength of load-bearing bones. Or:
muscle forces 3 bones 3 strains 3 control of modeling
and remodeling. Like bone strength, usually muscle
strength also increases during growth, plateaus in young
Jee WSS: Hard Tissue Workshops organized annually since
1965 by Professor Jee provide a uniquely seminal and multidisciplinary forum for presenting and discussing new methods, evidence and ideas about human skeletal disease. These workshops
are attended by hundreds of international authorities and fellows
in many disciplines, sponsored by the University of Utah and
supported by private and federal funds. They have had a more
profound effect on how people think about and study skeletal
disease than any other meetings in this century. The Utah paradigm had its genesis at these Workshops; hence its name.
Role of Momentary Muscle Strength in WholeBone Strength
Fig. 3. Combined modeling and remodeling effects on bone strength
and “mass.” The horizontal line at the bottom suggests typical peak
bone strains from zero on the left, to the fracture strain on the right (Fx),
plus the locations of the remodeling, modeling, and microdamage
thresholds (MESr, MESm, MESp, respectively). The horizontal axis represents no net gains or losses of bone strength. The lower dotted line
curve suggests how remodeling would remove bone where strains stay
below the MESr range, but otherwise would tend to keep existing bone
and its strength. The upper dashed line curve suggests how modeling
drifts would begin to increase bone strength where strains enter or
exceed the MESm range. The dashed outlines suggest the combined
modeling and remodeling effects on a bone’s strength. D.H. Carter
originally suggested such a curve (Carter, 1984). At and beyond the
MESp range, woven bone formation usually replaces lamellar bone
formation. Fx ⫽ the fracture strain range centered near 25,000 microstrain. At the top, DW ⫽ disuse window; AW ⫽ adapted window as in
normally adapted young adults; MOW ⫽ mild overload window as in
healthy-growing mammals; POW ⫽ pathologic overload window (Frost,
1992a). In the nearly flat region between the MESr and MESm, bone
strength and “mass” change little as typical strains change. Reproduced
from Frost (1997d) with permission of the publisher.
Putative Marrow Mediator Mechanism
Microdamage (MDx)
A still-enigmatic mechanism in marrow should help
to control modeling and remodeling of bone next to or
close to it, but not of intracortical (haversian) and subperiosteal bone (Chow et al., 1993; Erben, 1996; Frost,
1998b)**. This could explain why endocortical bone
losses expand the cross-section area of the marrow cavity in human ribs by more than 50% between 20 and 75
years of age. During normal and supranormal mechanical usage, as well as under the influence of estrogen
(Fig. 4), this mediator mechanism would make conservation-mode remodeling keep existing bone and thus
prevent an osteopenia or progression of an existing one.
In acute disuse, or in acute loss of estrogen (Wronski et
al., 1993) or androgen (Christiansen et al., 1981; Erben
et al., 2000, Yao et al., 2000), or during treatment with
adrenalcortical steroid analogs like Prednisone, this
mechanism would help to make disuse-mode remodeling
cause a disuse-pattern osteopenia**. That should explain the usual loss of bone next to marrow in women
going through menopause. Figure 4 shows how those
responses to estrogen and muscle can affect bone “mass”
and, by implication, whole-bone strength.
(Burr and Stafford, 1990; Burr et al., 1997; Kimmel, 1993; Mori and Burr, 1993; Pattin et al., 1996)
Repeated strains cause microscopic fatigue damage
(MDx) that weakens bones. Normally remodeling BMUs
replace the damaged bone with new bone, and strains
below an operational MDx threshold range cause so
little MDx that remodeling can repair it. When larger
strains cause too much to repair, the resulting accumulated MDx causes or helps to cause all “spontaneous”
and stress fractures (so “spontaneous” fractures are not
really spontaneous) (Devas, 1975; Frost, 1989a; Markey, 1987), as well as pseudofractures in osteomalacia
and pathologic fractures**. Such accumulations can
also allow pull-outs or loosening of pedicle and other
screws, or make a bone weak enough to let a minor
incident (low energy trauma; Freeman et al., 1974;
Greenspan et al., 1994) fracture it.
Apparently this threshold lies above bone’s modeling
threshold but below its ultimate strength. That arrangement would minimize MDx, and it has been argued that bone design does minimize fatigue failures
(Alexander, 1984; Frost, 2000b). Controversial when
first described (Frost, 1960), MDx in bone now forms
Fig. 4. A bone-muscle mass comparison. H. Schiessl constructed
this graph from an Argentine study of 345 healthy boys and 443 healthy
girls between 2 and 20 years of age (Zanchetta et al., 1995). It plots the
grams of total body bone mineral content (TBMC, an indicator of wholebone strength) on the vertical axis that correspond to the grams of lean
body mass (LBM, an indicator of muscle strength) on the horizontal axis,
as determined by a Norland DEXA machine. Crosses: girls. Open circles:
boys. Each data point stands for an age one year older than the data
point on its left, and it shows the means for all subjects in that one-year
age group. Around 11 years of age TBMC began increasing faster than
before in girls. By ⬇ 15 years of age, their TBMC and LBM both
plateaued. Since both indices were still increasing in 20-year-old males,
they ended up with more muscle and bone than the 20-year-old girls.
This evidence supports the roles of muscle and estrogen discussed in
the main text. It has been suggested that the extra bone stored during a
woman’s fertile years could serve needs of lactation more than to
increase whole-bone strength. Reproduced from Schiessl et al. (1998)
with permission of the publisher.
another field of study in skeletal science (Fazzalari et
al., 1998; Martin, 1995, 2000; Schaffler et al., 1995;
Verborgt et al., 2000).
transections or in the lower extremities of patients with
diabetic neuropathy (Frost, 1986). Interestingly, motor
denervation alone, as in post-polio states, does not impair
development of an RAP (Frost, unpublished observations).
A, RAP usually responds to local need (Hernandez et al.,
1995). It causes three of the classical signs of inflammation: Edema, erythema, and increased warmth. Pathological RAPs known as algodystrophies or migratory osteoporoses also occur (Duncan et al., 1973; Langloh et al.,
1973; Mailis et al., 1992; Schiano et al., 1976). They usually respond well to prostaglandin inhibitors but poorly to
physical therapy (Frost, unpublished data)**.
Regional Acceleratory Phenomenon (RAP)
(Frost, 1983, 1986, 1995; Kelly, 1990; Kozin, 1993;
Martin, 1987; Martin et al., 1998; Shih and Norrdin, 1985)
This ubiquitous phenomenon is a necessary factor in the
normal healing of all hard and soft tissues. Injuries and
other noxious stimuli usually increase all ongoing biologic
activities in the affected body region. The increases include local perfusion, cell metabolism and turnover, and
any ongoing growth (Ring and Ward, 1958), modeling,
remodeling, healing, maintenance, and inflammatory activities. In combination, those things comprise the RAP**.
A RAP can last from a week when caused by a small
pimple to over 2 years when caused by a complex largebone fracture or a spinal fusion. Presumably it causes the
long bone overgrowth that occurs after some fractures in
children (Blount, 1955; Cozen, 1990; Frost, 1997b). Failure to develop a RAP can retard healing of all tissues.
Inadequate regional blood supply can cause that, but so
can sensory denervation after major peripheral nerve
Mechanostat Hypothesis
For over 75 million years (Romer, 1966) it seems all
load-bearing bones satisfied Propositions 1 and 2 in all
healthy amphibians, birds, mammals, and reptiles of any
size, age, and sex**. Whatever orchestrates such a universal effect was called the mechanostat (Frost, 1987b; Jee,
2000; Martin et al., 1998). As currently viewed it would
combine some of the above-mentioned features to form a
negative feedback system that makes modeling, remodeling, and their thresholds increase bone strength where
necessary, or remove bone when it is not needed mechan-
ically (Frost, 1996)**. The marrow mediator, estrogen,
growth hormone, androgens, drugs, and other factors
might modulate how the mechanostat affects whole-bone
strength, in part by modulating the above thresholds or
internal standards (Burr and Martin, 1992; Slemenda et
al., 1994). A car can provide a useful analogy. Its steering,
brakes, accelerator, and ignition switch would be like the
features mentioned above; its wheels would be like effector cells. and its fuel and engine would be like the nonmechanical things in Table 2. Its driver would be like voluntary mechanical usage.
Implications. Just as studying only its wheels could
not explain why a car drove to Berlin instead of Paris,
studying only bone’s effector cells could seldom explain the
cause of an osteopenia, osteoporosis, impaired bone healing or other bone disorder**. Aided by the modeling and
remodeling thresholds, this mechanostat could tell exactly
where and when a bone or trabecula needs more strength
or has too much, and then make modeling or remodeling
correct the local error. No hormone, other humoral agent
or gene can do such things (Ferretti, personal communication, 1999). The strain range between the modeling and
remodeling thresholds in Figure 3 would provide a natural
definition of “normal” whole-bone strength relative to the
size of a bone’s peak voluntary loads. The strength and
architecture of some weakly-loaded cranial bones may
depend more on their baseline conditions than on the
mechanostat. They include the turbinates, nasal bones,
ethmoids, wing of the sphenoid, frontal and parietal
bones, and inner ear ossicles.
Muscle strength and anatomy combined with neuromuscular physiology determine the size and orientation of
the voluntary muscle forces on bones. Because of that and
the physiology summarized above, voluntary neuromuscular activities strongly influence and could even dominate control of the major fraction of the postnatal strength
of our load-bearing bones**. That should help to make
bones satisfy Proposition 1. The physiology supporting
those sentences could represent a kind of “quantum jump”
in our understanding of Wolff’s Law when it is compared
to earlier views, including some of my own (Brand and
Claes, 1989; Chamay and Tschantz, 1972; Evans, 1957;
Frost, 1964; Jansson, 1920; Muller, 1926; Roesler, 1987;
Roux, 1895; Treharne, 1981; Vico et al., 1987; Welten et
al., 1994; Whedon, 1984; Woo et al., 1981; Wunder et al.,
The above summary concerns some of the “what, how,
and why” of our 300⫹-year effort to understand bone
anatomy and physiology. That makes this question pertinent: Does that understanding have clinical applications?
Yes, it does.
Two Meanings of “Vigorous” Exercise and Their
Effects on Whole-Bone Strength
(Frost, 1998a, 1999b)
These meanings could have special importance in space,
sports, and physical medicine, and in rehabilitation, geriatrics, biomechanics, and pharmacology.
To explain, muscle power and neuromuscular coordination help to achieve excellence in many sports, but at
present it seems whole-bone strength adapts chiefly to
peak momentary muscle forces. Thus, low-force muscle
contractions repeated to exhaustion, as in marathon or
treadmill running, or in long distance walking, swimming,
and bicycling, can increase muscle endurance but not momentary muscle strength or whole-bone strength (Micklesfield et al., 1995). However, maximal-force muscle contractions, as in weight lifting or sports like soccer (Wittich
et al., 1998) that involve violent accelerations of the
body— “supranormal” has that meaning here— can increase momentary muscle strength and put much larger
loads on bones than low-force exercises like those above.
Note that muscle strength can increase faster than wholebone strength (Heinonen et al., 1995).
Implications.Weight lifters and soccer players should
have greater bone strength than devotees of low-force
exercises and they do (Frost, 1990a; Karlsson et al., 1993;
Marcus et al., 1996; Riggs and Melton, 1995; Smith and
Gilligan, 1989; Taafe et al., 1995). Because the remodeling
threshold lies well below the modeling threshold (Fig. 3),
low-force exercises could still cause large enough strains
to make or help to make conservation-mode remodeling
keep the existing bone strength. It seems they do (Frost,
1999b, 2000a; Smith et al., 1989)**.
Physical Exercise and Whole-Bone Strength in
Children, Adults, and Young Athletes
(Frost, 1999b; Nilsson et al., 1978; Sumner and
Andriacchi, 1996)
These matters could have special importance in pediatrics, in space, sports, and physical medicine, and in anthropology, pharmacology, geriatrics, and biomechanics.
Besides aging effects on those matters (Stanulis-Praeger,
1989), biomechanical effects would occur too.
Increasing body weight and muscle strength keep increasing the size of the loads on a child’s bones, so the
sluggish modeling could lag behind in making bones
strong enough to keep strains from exceeding the modeling threshold (Frost and Jee, 1994). That was called the
adaptational lag (Frost, 1997c). When body weight and
muscle strength plateau in young adults, modeling could
“catch up,” reduce strains below that threshold and turn
off. Declining muscle strength in most aging adults should
put bones adapted to young-adult muscle strength into
gradual partial disuse. That could downshift bone strains
to the remodeling threshold and cause slow losses of bone
next to marrow.
Implications. More vigorous exercise should more
readily increase bone strength in children and young athletes than in aged subjects. That is true (Tsuji et al., 1996).
Also, in aged subjects such exercise could cause large
enough strains to limit further bone losses but not large
enough strains to make modeling increase bone strength.
That does happen (Marcus et al., 1996; Smith and Gilligan, 1989; Smith et al., 1989). That emphasizes the value
of regular exercise to increase bone strength during
growth, and hopefully help to maintain it in order to
minimize fractures in aging adults (Schönau et al., 1998).
The above “adaptational lag” should increase fractures
during our adolescent growth spurt but let them decrease
in young adults. Both of these things occur (Frost, 1997c;
Rockwood and Green, 1991; Wiley and McIntyre, 1980). In
microgravity conditions in orbit, exercising against maximal resistance might minimize bone losses more effec-
tively than treadmill running or riding a stationary bicycle (Rittweger et al., 1999), although this idea has not been
tested yet.
Fracture Patterns of the Radius
This “natural experiment” offers insight into fracture
patterns in general. It could hold special interest for pediatricians, gerontologists, orthopaedic surgeons, osteoporosis experts, biomechanicians, and physiologists.
In children, radius fractures from falls can affect both
the diaphysis (shaft) and the metaphyseal region, but in
aged adults falls usually only fracture the metaphyseal
region (the wrist) (Rockwood and Green, 1991, 1997).
While nonmechanical explanations were suggested for
that difference (Deng et al., 2000), the above physiology
offers a plausible biomechanical explanation too (granted:
“plausible” does not automatically mean “correct”).
Consider that in children the radius would adapt its
strength to increasing loads from growing voluntary muscle forces. Its diaphysis would adapt to combined uniaxial
compression, bending, and torsional loads from muscles**,
but the very low friction of the radiocarpal joint would
make the metaphyseal region of the radius carry and
adapt mainly to uniaxial compression muscle loads**. In
young adults both parts of the radius would have adapted
to such loads.
Falls on the outstretched hand can put momentarily
large combined bending, torsional, and compression loads
on the whole radius. In aged adults, its diaphysis would
have adapted to such loads, but its metaphysis would have
adapted mainly to compression loads. As a result, the
bending forces from such falls would more likely fracture
the metaphysis than the diaphysis. Hence the common
Colle’s fracture in aging adults.
Implication. Similar things could help to explain why
falls in aging adults seldom fracture the femoral, humeral
or tibial diaphyses**. Instead, they usually fracture the
metaphyseal regions of those bones (which include the hip
[femoral neck, greater and lesser trochanters, and intertrochanteric region], surgical neck of the humerus, and
malleolar regions of the ankle) (Ferretti et al., 1995).
Whole-Bone Strength in Obesity
This matter would have special importance for internists, endocrinologists, metabolic bone disease, nutrition
authorities, and anthropologists (Nishizawa et al., 1991).
To explain, body weight provides a resistance muscles
must overcome to let us work and play on earth (Ferretti
et al., 1998a; Martin et al., 1998). Ergo, to pursue similar
physical activities obese people would need stronger muscles than less heavy slender people. The stronger muscles
would put larger loads on bones, to which the above physiology should respond by increasing bone strength**, even
if nonmechanical factors help to do it. That seems to be the
case (Riggs and Melton, 1995; Nishizawa et al., 1991). Presumably for such reasons most bed-ridden or otherwise
chronically very inactive obese people lose bone, even when
their obesity increases (Frost, unpublished observations).
Table 4 lists conversion factors for English and metric
units of measure, and some stress-strain conversions for
healthy lamellar bone.
Some Clinical Features That Depend on Bone
Modeling (Frost, 1995; Jee, 1989; Schönau, 1996)
These matters could have special importance for physiologists, anatomists, anthropologists, pediatricians, geneticists, internists, dentists, pathologists, histologists,
pharmacologists, cell and molecular biologists, and histomorphometrists.
Some modeling functions. Modeling formation
drifts create our initial supplies of cortical bone (Jee,
1989). Modeling can slowly increase bone strength by increasing bone “mass” and reshaping a bone as in Figure
1B. Aided by the modeling threshold it sets the upper limit
on a bone’s strength relative to the size of the loads the
bone carries. Over time periods of months or, in large
bones, even years, it reshapes and strengthens an initial
fracture callus or a healing bone graft to provide enough
strength to endure voluntary activities (where “enough
strength” means keeping strains from exceeding the modeling threshold, and satisfying Proposition 1). In such
ways, modeling helps to provide the greatest strength
with the least amount of material (Currey, 1984), and it
affects whole bones and individual trabeculae. It might
strengthen the bone supporting load-bearing implants, if
the bone is alive and if its strains exceed its modeling
threshold but stay below its microdamage threshold
(Frost, 1992b)**. Normal modeling makes bones strong
enough to minimize microdamage, fatigue failures, and
the true osteoporoses described in Classifying “Osteopenias” and “Osteoporoses.”
Some modeling disorders. These can make bones
fail to satisfy Proposition 1. That failure helps to increase
bone fragility in osteogenesis imperfecta** (Damjanov and
Linder, 1996; Frost, 1987a; Seeforf, 1949; Sillence et al.,
1979). Curiously, so far no research studied how an abnormal Type I collagen could cause the modeling and
remodeling disorders that chiefly reduce bone strength,
increase bone fragility and let spontaneous fractures occur
in this disease (Frost, 1987a; Jaffe, 1972)**. An analogous
modeling malfunction should help to cause the true osteoporoses described in Classifying “Osteopenias” and “Osteoporoses”** in which the affected bones do not satisfy
Proposition 1 (Frost, 1997a; Marcus et al., 1996). Decreases or failures of modeling to make healing fractures,
bone grafts, osteotomies, and arthrodeses strong enough
to carry voluntary loads can cause late but uncommon
failures of that healing (Frost, 1998c). A clinical clue to
such a late failure: Initially the bone heals well enough to
let function resume, but later the healed region develops a
stress fracture or begins to angulate (Frost, unpublished
observations). Excessive periosteal formation drifts in
Paget’s disease and congenital lues cause many of the
bone deformities associated with those disorders (Jaffe,
1972; Luck 1950). Inability to form woven bone is lethal
for mammals (Dickman, 1997), but not for elasmobranchs
like sharks and skates, which only have cartilage in their
skeletons. Most laminar periosteal reactions called “periostitis” by radiologists represent new formation drifts of
woven bone, in reaction to some local pathology such as a
stress fracture, an inflammatory process or a neoplasm in
the bone. Sometimes humoral agents can cause them, as
in pulmonary hypertrophic osteoarthropathy and scurvy
(Damjanov and Linder, 1996; Jaffe, 1972; Luck 1950), and
in the formation drifts incited by systemically administered prostaglandin E-2 (High, 1988; Tang et al., 1997).
Some Clinical Features That Depend on Bone
These matters could also have special importance for
physiologists, anatomists, anthropologists, pediatricians,
internists, geneticists, dentists, pathologists, histologists,
pharmacologists, cell and molecular biologists, and histomorphometrists.
Some remodeling functions. Remodeling replaces
primary spongiosa beneath growth plates with the secondary spongiosa made of lamellar bone (Frost and Jee, 1994;
Jee, 1989). It helps to replace mineralized cartilage in
osteochondromas with a normal secondary spongiosa
(Jaffe, 1958). Aided by the remodeling threshold, remodeling sets the lower limit on whole-bone strength, and
thereby helps to determine the width of a bone’s adapted
window (AW) in Figure 3. It replaces fracture callus with
lamellar bone. It repairs limited amounts of microdamage
(Mori and Burr, 1993). In its disuse mode, it removes
mechanically unneeded bone next to marrow (Frost,
1998b). Presumably that explains the nearly total lack of
spongiosa in postnatal diaphyseal marrow cavities, and
the loss of spongiosa and expansion of the marrow cavity
diameter in all adult-acquired osteopenias**. Disusemode remodeling of bone next to marrow causes a woman’s normal postmenopausal bone loss**. Where woven
bone carries postnatal loads, remodeling usually replaces
it with lesser amounts of lamellar bone. Remodeling has a
minor role in homeostasis (see Homeostasis and Bone).
Acute disuse increases BMU creations and bone turnover
by remodeling, while increased mechanical usage tends to
depress those creations and turnover**. Still, it seems
increased microdamage during suddenly increased mechanical usage can override the latter effect and independently increase BMU creations and bone turnover (Frost,
1992a; Martin, 2000; Martin et al., 1998).
Some remodeling disorders. These can fail to replace fracture callus with lamellar bone to cause some
healing problems of fractures, autografts, allografts, xenografts, osteotomies, and arthrodeses (Frost, 1998c)**.
That same failure impairs bone healing in osteopetrosis
(Bollerslev, 1989; De Palma et al., 1994). Failure to replace primary spongiosa with secondary spongiosa causes
one kind of osteopetrosis (Jaffe, 1972). Combined with
modeling malfunctions, disuse-mode remodeling would
help to cause all true osteoporoses including osteogenesis
imperfecta**, and it (not osteoclasts alone) seems to cause
all adult-acquired osteopenias on earth and in orbit**.
Disuse-mode remodeling helps to cause loss of femoral
calcar bone after some total hip replacement arthroplasties (Frost, 1992b; Pritchett, 1995), and it (not osteoclasts
alone) causes the bone loss associated with treatment with
adrenalcortical steroid analogs like Prednisone**. It helps
to cause subchondral cysts in osteoarthritis, and may help
to cause some lytic bone lesions associated with things like
sarcoid, multiple myeloma, some kinds of bony metastases, unicameral bone cysts, and giant cell tumors of bone
(Jaffe, 1958, 1972). Antiremodeling agents like estrogen
and the bisphosphonates depress disuse-mode remodeling
(not just osteoclasts) and help to retard local and generalized bone losses (Fleisch, 1995; Frost, 1997a). Impaired
microdamage repair by BMUs causes or helps to cause
osteochondritis dissecans, aseptic necroses of bone, and
spontaneous fractures of irradiated bone (Frost, 1986), as
well as stress fractures in athletes and military trainees,
pathologic fractures, pseudofractures in osteomalacia, and
spontaneous fractures in true osteoporoses (Frost,
1989a)**. That impaired repair also helps to explain the
loosening of some internal fixation implants and some
load-bearing endoprostheses (Frost, 1992b).
Addenda. Modeling and remodeling may have other as
yet unrecognized functions and disorders. A special bone
resorption mechanism that remained unstudied after its
original report may also participate in some bone disorders (Jaworski et al., 1972). While woven bone can form de
novo, meaning where no bone of any kind existed before,
lamellar bone only forms on preexisting bone of any kind
(Frost, 1986).
Classifying “Osteopenias” and “Osteoporoses”
This could have special importance in metabolic bone
disease, absorptiometry, radiology, internal medicine, endocrinology, geriatrics, genetics, anthropology, nutrition,
pathology, space medicine, pharmacology, and histomorphometry.
In the 1990s, participants in WSS Jee’s seminal Hard
Tissue Workshops (Jee, unpublished data2) suggested the
physiology summarized in Summary of the New Physiology above could cause four kinds of “osteoporosis” that
could have similar bone “mass” deficits, and thus similar Z
scores (Frost, 1997a). They do occur and some of their
clinical features were known for over 40 years (Riggs and
Melton, 1995; Snapper, 1957; Urist, 1960). Those participants suggested the following names.
In physiologic osteopenias, chronic muscle weakness
and physical inactivity would make normal modeling and
remodeling cause a corresponding disuse-pattern osteopenia in which voluntary activities and loads on bones do not
cause spontaneous fractures. Here bones would satisfy
Proposition 1, and only injuries like falls cause fractures,
usually of extremity bones like the hip and wrist (Lauritzen, 1996). As Runge et al. (2000) and Overstall et al.
(1997) noted, impairments of muscle strength, coordination, balance, and vision help to increase falls and fractures in aging adults. These osteopenias can affect children, women, men, most aged adults, and most persons
with chronic muscle weakness and/or debilitating illnesses (Table 3)**.Presumably the loss of bone in women
going through menopause also causes such an osteopenia
(Christiansen et al., 1981), since over two-thirds of such
women never develop spontaneous fractures. In former
times and in older people, these osteopenias were often
called “senile osteoporoses.”
In true osteoporoses, still-enigmatic modeling and remodeling malfunctions cause a disuse-pattern osteopenia
in which voluntary activities and muscle forces do cause
spontaneous fractures. Here the affected bones do not
satisfy Proposition 1. Much less common than physiologic
osteopenias, these osteoporoses include in part osteogenesis imperfecta, hyperphosphatasia, and idiopathic juvenile osteoporosis, in which the spontaneous fractures can
affect both the spine and extremity bones (Dimar et al.,
1995; Marcus et al., 1996). A more widely discussed kind
affects women more than men and seldom affects children
(Riggs and Melton, 1995). Its spontaneous fractures affect
thoracic and lumbar vertebrae but, curiously, rarely affect
the pelvis and extremity bones (the still-debated issue of
TABLE 3. Some conditions that cause chronic disuse and muscle weakness in humans
(and related osteopenias)*
Renal failure
Metastatic cancer
Muscular dystrophy
Organic brain syndrome
Lou Gehrig disease
Cystic fibrosis
Drug addiction
Hepatic failure
Multiple sclerosis
Huntington’s chorea
Still’s disease
Nursing home residence
Pulmonary fibrosis
Cardiac failure
Alzheimer’s disease
Juvenile RA
*In causing an osteopenia, the relative importance of the mechanical disuse and muscle weakness,
and of the biochemical-endocrinologic abnormalities accompanying some of these entries, is still
uncertain. So far, few studies tried to quantify the muscle and mechanical usage effects. The Utah
paradigm suggests the mechanical effects would dominate most biochemical-endocrinologic ones.
RA: rheumatoid arthritis.
how to classify spontaneous vertebral “fractures” is not
discussed here; Eastell et al., 1991; Marcus et al., 1996).
Presumably, it also involves excessive microdamage accumulations (Heaney, 1993; Vernon-Roberts and Pirie,
1997). Here too the osteopenia facilitates extremity-bone
fractures from falls. In former times these were often
called “symptomatic osteoporoses.”
In combined states features of those two affections seem
to combine in various ways**.
In transient osteopenias, a regional disuse-pattern osteopenia occurs after a fracture, burn, or other severe
injury. Two or more years after the injury heals and physical activities resume, the affected bones regain the
strength needed to endure voluntary activities for the rest
of life**. In proof, late refractures of such fractures are
rare (Frost, unpublished data). It seems the associated
mechanical disuse and an accompanying regional acceleratory phenomenon cause this “naturally reversible osteopenia”** as Z.F.G. Jaworski dubbed it (Jaworski,
1984). Since spontaneous fractures do not occur in it, it
should constitute a physiologic bone response to an injury
(Garland et al., 1994). In former times these were sometimes called “posttraumatic osteodystrophies.”
Implications. X-ray absorptiometry cannot distinguish those four conditions from each other, nor can it
alone evaluate bone health**. Defining “osteoporosis” by
BMD-derived Z scores (Kanis, 1994; Marcus et al., 1996)
could need revision or supplementation, since that could
suggest that “osteoporoses” and “osteopenias” are only
different severities of the same thing, like the hemoglobin
in mild and severe pernicious anemias**. Yet as defined
above, they differ biologically, pathologically, and pathogenetically. We need new standards for the muscle
strength– bone strength relationship** (Ferretti et al.,
1998b; Schiessl et al., 1998; Schönau et al., 1998), and will
need to learn more about muscle itself (Dickinson et al.,
2000; Worton, 1995). Muscle weakness plus impairments
of balance (Schroll et al., 1999), neuromuscular coordination, and vision cause most of the falls that, in turn, cause
most extremity bone fractures (so-called “osteoporotic
fractures”) in aging and aged humans. The literature
shows growing recognition of that fact (Lauritzen, 1996;
Nguyen and Eisman, 2000; Runge et al., 2000; Tinetti et
al., 1994), so future “risk of fracture” studies might try to
account for it. Increased exercise and/or increased muscle
strength [perhaps due to exercise, androgens (Bhasin et
al., 1996) or growth hormone (Ogle et al., 1994; Ullman
and Oldfors, 1989)] should help physiologic osteopenias,
but they could make true osteoporoses worse (Frost, unpublished data). If so, it would be imperative to distinguish
between those disorders before prescribing or advising
such things. Agents that could turn modeling on, could
normalize and cure an osteopenia**, while agents that
could turn disuse-mode remodeling off could prevent one
or progression of an existing one**. Yet we need better
agents to do such things than the currently available
bisphosphonates, parathyroid hormone, prostaglandins,
and estrogens (Harris et al., 1996; Ma et al., 1994; Takahashi et al., 1991; Wronski et al., 1989). Searches for
intrinsic bone disorders, including genetic disorders in
bone cells, that could cause physiologic and transient osteopenias should be futile, since the chief cause of the
former would be muscle weakness (which of course could
depend on genetic factors), and of the latter, trauma. In
my experience, physiologic osteopenias outnumbered true
osteoporoses by more than five to one. In the past, did we
exaggerate the need for abundant dietary calcium to minimize or prevent osteopenias, osteoporoses and fractures
(Bronner, 1994; Gallagher, 1990; Nordin and Heaney,
1990; Recker and Heaney, 1985)? The bone loss in microgravity situations should exemplify a disuse-pattern osteopenia caused by greatly reduced muscle loads on bones.
At least in my view, the nonmechanical explanations proposed are erroneous. Searches for genetic errors in bone
that might explain “osteoporosis” as diagnosed by Z scores
(Kanis, 1994) should be futile in the cases of physiologic
osteopenias (since their cause would usually lie in muscle)
and transient osteopenias (which should represent normal
responses to trauma). Seeking other bone effector-cell disorders that would cause physiologic osteopenias should be
futile too, and so should seeking the cause of spontaneous
fractures only in the spine by studying unaffected bones
like the ilium and tibia. Physiologic osteopenias should
only affect hollow bones with marrow cavities, which
seems to be true (Frost, unpublished data).
Noninvasive Absorptiometric Evaluation of
Whole-Bone Strength
This matter could have special importance in metabolic
bone disease, in absorptiometry by X-ray, magnetic reso-
nance imaging, and/or ultrasound, in radiology, and in
“osteoporosis”-related research.
To explain, material in classifying “Osteopenias” and
“Osteoporoses” indicates the need to evaluate whole-bone
strength noninvasively in patients. Yet no current absorptiometric method can reliably evaluate a bone’s materials
properties or its microdamage burden. As for the other two
factors in whole-bone strength (see Four Physcial Features Combine to Determine Whole-Bone Strength,
above), bone mineral “density” (BMD) and content (BMC)
measured by dual energy X-ray absorptiometry (DEXA)
became popular ways to evaluate the “mass” factor, but
they cannot distinguish between woven, plexiform, and
lamellar bone (Jiang et al., 1999; Kanis, 1994). Also,
“mass” factors alone do not indicate whole-bone strength
reliably (Banu et al., 1999)**, and neither do current ultrasound methods** (Ferretti et al., 1998b; Nielsen, 2000;
van der Perre and Lowet, 1996).
However, Bone Strength Indices (BSIs) obtained by peripheral quantitative computed tomography (pQCT) that
account for both the “mass” and architectural factors can
provide much better estimates of a bone’s true strength
(Banu et al., 1999; Ferretti, 1997, 1999; Ferretti et al.,
1998a,b; Jiang et al., 1999; Schiessl and Willnecker, 1999;
Wilhelm et al., 1999), so they should see increasing use in
the future. Please note that the major issue in life seems
to be bone health, which in my view would constitute the
relationship between a bone’s strength and the size of the
voluntary loads it carries and would normally adapt to.
Implications. Evaluating bone health would require
comparing a bone’s strength to the usual loads on it, and
then comparing that relationship to suitable norms. Because the largest voluntary loads come from muscles, that
would require comparing bone strength to muscle
Ferretti et al. (1989), Schiessl and Willnecker (1999),
and Schönau et al. (1998) have begun to obtain such “bone
strength-muscle strength” norms. No current method of
bone absorptiometry can by itself evaluate a bone’s health
as Proposition 1 defines it. Nor can any such method
distinguish the four conditions described in Classfying
“Osteopenias” and “Osteoporoses” from each other, nor
can the T and Z scores currently used in such work (Kanis,
1994). Such distinctions would require adding to bone
strength data, further information obtained from X-rays,
clinical facts, and muscle strength data.
Design and Use of Load-Bearing Implants
This matter would have special importance for orthopaedic surgeons, dental and maxillofacial surgeons, biomedical engineers, biomechanicians, and implant manufacturers. The following paragraphs concern only one of
the problems such implants have (Bauer and Hirokawa,
1995; Doyle, 1993; Hamilton and Gorczyca, 1995; Jasty et
al., 1994).
To explain, the above physiology suggests the design of
load-bearing endoprostheses should 1.) keep typical peak
strains in the supporting bone below its microdamage
threshold, but 2.) let them exceed its remodeling threshold
(Frost, 1992b)**. Strains in the mild overload window
(Frost, 1992a) in Figure 3 might help modeling to
strengthen the supporting bone, and should keep disusemode remodeling from removing it. These criteria should
apply to load-bearing artificial joints, partial bone replace-
ment endoprostheses, dental implants, and some spinal
While a bone microdamage threshold was suggested in
1983 (Burr et al., 1983) and verified later (Carter, 1984;
Pattin et al., 1996), even in 2000 AD no marketed loadbearing skeletal implant intentionally tried to satisfy
those two criteria. Yet it seems Branemark’s dental implant system does it unintentionally, which should prove
it can be done (Branemark, 1988).
As for other kinds of implants, including ones used for
internal and external fixation, very osteopenic bones with
thin cortices and reduced amounts of spongiosa would
need more and/or larger screws, pins, and other devices to
provide larger load-bearing bone-implant interfaces
(Okuyama et al., 1995). Combined with suitable postoperative management, that could help to keep the unit loads
on those interfaces below bone’s microdamage threshold,
which in stress terms seems to lie in the region of ⬇ 60
megapascals. Otherwise, accumulating fatigue damage in
the bone supporting the implants could and often does
loosen them before satisfactory healing occurred.
Implications for Bone Healing in Fractures,
Bone Grafts, Osteotomies, and Arthrodeses
These implications could have special importance for
orthopaedic surgeons, pathologists, and pharmacologists,
for cell and molecular biologists who study hard tissue
healing, and for the designers of internal and external
fixation devices. Of course, this healing poses other clinical and basic science problems, too.
To explain, in earlier views bone healing comprised a
single indivisible process, and its supposed key players,
osteoblasts, were aided by things like angiogenesis, apoptosis, chondroblasts, and stem cells (Aho et al., 1994;
Burchardt, 1983; Brand and Rubin, 1987; Habal and
Reddi, 1992; Hall, 1991; Luck, 1950; Rahn, 1982; Rhinelander and Wilson, 1982; Sherman and Phemister, 1947).
However, its omissions make that view suspect. The
true key players in that healing include four tissue-level
phases, the callus, remodeling, and modeling phases, accompanied by a regional acceleratory phenomenon
(RAP)** (Frost, 1998c; Woodard, 1991). Each phase can
malfunction independently of the others**, so many different kinds of healing problems could and do occur that
do not stem from known treatment errors. While former
anatomists, histologists, and pathologists described the
light-microscopic tell-tales of those things quite well (Gegenbaur, 1867; Lewis, 1906; Putschar, 1960; Weinmann
and Sicher, 1955), their functional significance in this
matter remained unknown until the Utah paradigm
Initially a soft fracture callus forms with new vessels,
supporting and precursor cells, osteoblasts making woven
bone, and often chondroblasts making hyaline cartilage. It
fills the gaps and surrounds, embeds, and welds to the
fragments of the fracture or graft, and it lacks a general
“grain” (Weinmann and Sicher, 1955). After the callus
mineralizes remodeling BMUs begin to replace it and/or
any graft material with packets of new lamellar bone, the
“grain” of which usually parallels the largest local compression and tension strains. Presumably guided by those
strains and partly overlapping “2,” modeling begins to
modify the shape and size of the callus to make it strong
enough to satisfy Proposition 1. Those three phases last
longer in adults, large bones, and diaphyses than in children, small bones, and metaphyses. A fracture, arthrode-
sis, osteotomy, or grafting operation normally incites a
RAP (Garland et al., 1994) that lasts throughout the healing process and accelerates the “1,2,3” phases**. Otherwise, a delayed union or a “biologic failure” of healing can
ensue (Frost, 1989b). Besides impaired regional blood supply, sensory denervation as in some diabetics increases
the likelihood of an inadequate RAP, which nevertheless
seldom happens in children (Frost, 1986). The possibility
that cigarette smoking might impair a RAP, and thus bone
healing too, seems to deserve study (Cook et al., 1997).
The osteoclast defect that causes osteopetrosis impairs
replacement of fracture callus with lamellar bone (“B”
above) (de Palma et al., 1994), which should help to explain impaired bone healing in that disease**.
In my experience, most impairments of bone healing not
due to treatment errors stemmed from disorders in the “1”
and “4” phases, the “4” disorder being the most common.
Role of Strain. Mounting evidence indicates that
small strains help to guide the remodeling and modeling
phases of bone healing (Blenman et al., 1989; Carter et al.,
1988; Claes et al., 1994; Frost, 1989b; Hanafusa et al.,
1995; Kenwright and Goodship, 19889; Mosely and
Lanyon, 1988; Wolff et al., 1981). Lacking any strains,
disuse-mode remodeling tends to remove the callus, modeling stays off, and healing can retard or fail** (see “disuse” in the Glossary). All orthopaedists know that excessive strains (gross motion) can prevent healing. The
“permissible” strains might lie in the 100 –2,000 microstrain region. For comparison, bone’s fracture strain is a
range centered near ⬇ 25,000 microstrain (Currey, 1984;
Reilly and Burstein, 1991). The 100 –2,000 microstrain
span includes the adapted and mild overload windows in
Figure 3 (Frost, 1992a). In compliant (i.e., not yet rigid
and strong) healing fractures, bone grafts, or arthrodeses
including spinal fusions, very small loads could cause
harmfully large strains.
Cell and Molecular Biology on Which “1– 4”
Should Depend. Bone healing should also depend on
the growing numbers of known humoral and molecularbiologic influences on bone cells. The humoral influences
include in part hormones, vitamins, minerals, and drugs
(Bak et al., 1991). The molecular-biologic influences include in part cytokines, growth factors, other ligands,
angiogenesis, apoptosis, stem cell hierarchies, “supporting
cell” functions, cell proliferation and differentiation, and
gene expression mechanisms and patterns (Barnes et al.,
1999; Caplan and Dennis, 1998; Goldring and Goldring,
1996; Gowen, 1992; Manolagas and Jilka, 1995; Ridley,
2000; Urist, 1995). One might add electrical treatment to
that list (Lavine and Grodzinski, 1987). So far, a lack of
appropriate studies leaves us uncertain about how such
things would affect the true key players in this healing,
the tissue-level “1– 4” phases.
According to the Utah paradigm, very similar observations would apply to the healing of fascia, ligaments, tendons, and articular cartilage (Frost, 1995).
Homeostasis and Bone
This matter would have special importance for physiologists, internists, endocrinologists, and specialists in nutrition.
In early views, the responses of osteoclasts and BMUs to
parathyroid hormone, calcitonin, and other humoral
agents were viewed as essential for calcium homeostasis
(Albright and Reifenstein, 1948; Barzel, 1970; Favus,
1999; Rasmussen and Bordier, 1974; Snapper, 1957).
Some people even viewed that as their chief function.
Yet bone can handle most homeostatic challenges without BMUs or osteoclasts (Frost, 1986)**. In proof, problems with homeostasis, tetany, and acid-base physiology
seldom occur in osteopetrosis, where osteoclasts function
poorly or not at all (Bollerslev, 1989; Key and Ries, 1996).
Also, in dogs large doses of a bisphosphonate suppressed
osteoclastic and osteoblastic activities for 9 months without causing hyper- or hypocalcemia, tetany, or disturbed
acid-base physiology (Flora et al., 1981). Since those doses
did cause spontaneous fractures that did not heal until the
treatment stopped, it became necessary to ensure such
agents do not do similar things in humans (Fleisch, 1995).
Parenthetically, while preclinical studies of some bisphosphonates claimed they did not increase microdamage in
bone, a later study could suggest otherwise (Mashiba et
al., 2000).
At least three other mechanisms that do not involve
osteoclasts help in the homeostatic function of bone and
handle most homeostatic challenges very well (Frost,
1986; Norimatsu et al., 1979)**. One of them could involve
an osteocyte-based mechanism originally proposed by Arnold et al. (1971) and later supported by studies by, among
others, Borgens (1984), Tate et al. (1998), and Rubinacci et
al. (2000). However, in prolonged calcium deprivation or
malabsorption, disuse-mode remodeling probably can help
to maintain homeostasis.
Role of Nutrition
In former views, adequate nutrition dominated the development of healthy and strong bones (Bronner, 1994;
Heaney, 1990; McLean and Urist, 1961; Kuhlencordt and
Bartelheimer, 1981; Tylavsky and Anderson, 1988;
Vaughn et al., 1975). While serious malnutrition certainly
can affect bone strength adversely, and muscle strength
too (Shires et al., 1980), in the Utah paradigm most things
like protein, calcium, vitamins, and calories would act
mainly like the fuel and engine in a car. Without them a
car cannot move, but they do not drive it. Instead, the car’s
driver does that. For the bone “car,” the “driver” seems to
be mechanical usage, muscle strength, and the related
bone strains instead of nutritional factors**. In proof, no
nutritional supplements can make sedentary people develop the strong bones of weight lifters, nor can they
normalize whole-bone strength in paralyzed limbs (Frost,
unpublished data). Furthermore, supplemental dietary
calcium seems to have little effect on bone “mass” in normal children (Lee et al., 1996).
Three Caveats
Besides dynamic longitudinal bone strains, other things
could help to control modeling and remodeling. They include shear, strain gradients (Frost, 1993; Gross et al.,
1979; Judex et al., 1997), and strain rates, frequencies and
repetitions, and other things too (Evans, 1957; Lanyon,
1996; Martin et al., 1998; Mosely and Lanyon, 1988;
O’Connor et al., 1982; Rubin and McLeod, 1995). Until
those things are resolved, longitudinal strains can provide
reliable indicators of the loads on bones. Ergo, where this
text mentions strain as a control of a biologic activity, “or
equivalent stimulus” is always understood.
Bone physiology combines anatomical and biomechanical concerns with subjects like endocrinology, biochemis-
try, cell biology, and homeostasis. The resulting amalgam
has important mechanical functions, but poor interdisciplinary communication left people in many fields unaware
of that amalgam and its applications (Brown and Haglund, 1995; Parfitt, 1997). As one result, they tried to
explain bone’s anatomy, physiology, and clinical disorders
with generally accepted earlier views about independently
working effector cells. In retrospect, they may have tried
to explain too much with too little.
As another result, when those early views met the
newer ones in this text, controversies began that only time
and help from many people can resolve. But controversies
fuel progress in all science, so why not air, instead of
discourage, any about issues raised by the newer physiology?
On the Cartilage-Bone Relationship
On What Cellular, Molecular-Biologic, Genetic,
and Pharmacologic Roots Does the Above
Physiology Depend?
Past, Present, Future
It must depend on such roots, but the post-1950 rush to
study bone’s effector cells pretty much overlooked that.
For recent reviews about those cells see Caplan and Dennis (1996), Goldring and Goldring (1996), Duncan and
Turner (1995), Mundy (1996), Parfitt and colleagues
(1993, 1995, 1996), Raisz (1988), Rodan (1997), and
Turner et al. (1994).
Yet growth hormone and somatomedins (Inzucchi and
Robbins, 1994; Kalu et al., 2000), androgens (Bhasin et al.,
1996), cortisone analogs, vitamin D, calcium, and genes all
affect muscle strength and could indirectly affect bone
strength in that way (Dickinson et al., 2000). These and
other factors might also potentiate the mechanostat’s responsiveness to mechanical and other influences to affect
whole-bone strength in that way too (Frost and Schönau,
2000); recent studies support that idea (Gasser, 1999;
Halioua and Anderson, 1989; Jee, 1999; Tang et al., 1997;
Yao et al., 2000). Some factors might even affect the impaired balance and neuromuscular coordination that help
to cause the falls that, in turn, cause most extremity bone
fractures in aged adults (Guralnik et al., 1995; Runge,
1997; Steinhagen-Thiessen and Borchelt, 1996). While few
if any efforts to find genetic causes for so-called “osteoporosis fractures” studied the associated problems with balance, neuromuscular coordination, muscle strength and
vision, simple, effective ways to study such things in outpatient settings do exist (Runge et al., 2000).
Consequently future studies must find how such roots
support the above physiology. That may depend heavily on
live-animal research, because as Parfitt (1995) and Gasser
(1999) also note, bone’s tissue-level mechanisms do not
function normally in vitro (Frost, 1986). W.S.S. Jee’s laboratory at the University of Utah pioneered ways to do
such in vivo work (Jee, 1995).
Role for Controlled Vibration?
High loading rates of frequent loads with small amplitudes (including but not limited to ultrasound) may have
useful effects in treating “osteoporoses,” some hard and
soft tissue healing problems, and other matters (Abendroth et al., 1998; Flieger et al., 1998; Heckman et al.,
1994; Wood, 1987). Among others, H. Schiessl in Germany
and H. Sievanen (Sievanen et al., 1996) in Finland study
the effects of such vibration on human bones, joints, muscles, and neuromuscular physiology (personal communications, 1998).
Question: Are things like congenital hip dysplasia
(Stanisaljevic, 1964), genu varum, scoliosis, club foot,
metatarsus varus, achondroplastic dwarfism, Madelung’s
deformity, Marfan’s syndrome (Joseph et al., 1992), and
hallux rigidus examples of bone disorders? They are not.
Instead they stem from modeling disorders of the cartilage
in joints and growth plates (Frost, 1995, 1999a; Frost and
Jee, 1994). Usually cartilage conducts and bone plays first
violin in the skeletal “orchestra” (Frost, unpublished observations), and far more often than not the statistical
abnormalities in bone architecture in such conditions represent effective adaptations to loading changes caused by
the cartilage problems (Frost, 1995). In proof, spontaneous
fractures of such bones are rare (Frost, unpublished data).
As a young man, my “bibles” for bone physiology included books by Jaffe (1958, 1972), McLean and Urist
(1961), and Weinmann and Sicher (1955), and a chapter
by Putschar (1960). Comparing their content to the above
material suggests how much progress occurred in understanding bone, bones, and Wolff’s Law. History suggests
more progress will come (Maddox, 1999; Mayr, 1961,
2000), and many devils will show up in the details too. But
the above physiology’s parent, the Utah paradigm, keeps
evolving to account for new evidence and ideas (and “devils”), so it could provide a kind of gold standard in such
matters for years to come.
The author thanks the staffs of Pueblo’s Southern Colorado Clinic, Parkview Episcopal Hospital, and St. Mary
Corwin Hospital for their time producing this and related
articles, and David Gavin and Ralph Scott for the drawings. Thanks also to the orthopaedic surgeons trained at
Henry Ford Hospital between 1957–1973 for their spontaneous assistance in a time of great troubles. Other colleagues who have offered perceptive comments and advice
regarding matters discussed in this article include: J.S.
Arnold, D.B. Burr, Z.F.G. Jaworski, W.S.S. Jee, R.B. Martin, A.M. Parfitt, E.L. Radin, R.R. Recker, H.E. Takahashi, M.R. Urist, and C. Woodard.
Abendroth K, Hubscher J, Rosler O. 1998. Increase in bone mineral
density by using GALILEO 2000 muscle-stimulation-machine (abstr). Bone F374;S499.
Aegerter E, Kirkpatrick JA. 1975. Orthopaedic diseases. Philadelphia:
WB Saunders Co.
Aho AJ, Ekfors T, Dean PB, Aro HT, Ahonen A, Nikkanen V. 1994.
Incorporation and clinical results of large allografts of the extremities and pelvis. Clin Orthop Rel Res 307:200 –213.
Albright F, Reifenstein EC Jr. 1948. The parathyroid glands and
metabolic bone disease. Selected studies. Baltimore: Williams and
Wilkins Co.
Alexander R McN. 1984. Optimum strength for bones liable to fatigue
and accidental failure. J Theor Biol 109:621– 636.
Arnold JS, Frost HM, Buss RO. 1971. The osteocyte as a bone pump.
Clin Orthop 78:47–55.
Bak B, Jorgensen PH, Andreassen TT. 1991. The stimulating effect of
growth hormone on fracture healing is dependent on onset and
duration of administration. Clin Orthop Rel Res 264:295–299.
Banu MJ, Orhii PB, Mejia W, McCarter RJM, Mosekilde L, Thomsen
JS, Kalu DN. 1999. Analysis of the effects of growth hormone,
voluntary exercise, and food restriction on diaphyseal bone in female F344 rats. Bone 25:479 – 480.
Barnes GL, Kostenuik PJ, Gerstenfeld LC, Einhorn TA. 1999. Growth
factor regulation of fracture repair. J Bone Miner Res 14:1805–
Barzel US, editor. 1979. Osteoporosis. New York: Grune and Stratton.
Bauer TW, Hirokawa K. 1995. Osteolysis: A generic problem. Orthop
Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J,
Bunnell TJ, Tricker R, Shirazi A, Casaburi R. 1996. The effects of
supraphysiologic doses of testosterone on muscle size and strength
in normal men. N Eng J Med 335:1–7.
Bilezikian JP, Raisz LG, Rodan GA. 1996. Principles of bone biology.
Orlando, FL: Academic Press.
Blenman PR, Carter DR, Beaupre GS. 1989. Role of mechanical loading in the progressive ossification of a fracture callus. J Orthop Res
7:398 – 407.
Blount WP. 1955. Fractures in children. Baltimore: Williams and
Bollerslev J. 1989. Autosomal dominant osteopetrosis: Bone metabolism and epidemiological, clinical and hormonal aspects. Endocr
Rev 10:45– 67.
Borgens RR. 1984. Endogenous ion currents traverse intact and damaged bone. Science 225:478 – 482.
Brand R, Claes L. 1989. Book review: the law of bone remodelling.
J Biomech 185–187.
Brand RA, Rubin CT. 1987. Fracture healing. In: Albright JA, Brand
RA, editors. The scientific basis of orthopaedics, 2nd ed. Norwalk,
CT: Appleton and Lange, p 325–346.
Branemark PI. 1988. Tooth replacement by oral endoprostheses: Clinical aspects. J Dent Educ 52:821– 823.
Bronner F. 1994. Calcium and osteoporosis. Am J Clin Nutr 60:831–
Brown W, Haglund K. 1995. Landmarks. J NIH Res 7:54 –59.
Buckwalter JA, Woo S L-Y, Goldberg VM, Hadley EC, Booth F,
Oregema TR, Eyre DR. 1993. Soft tissue aging and musculoskeletal
function. J Bone Jt Surg 75A:1533–1548.
Burchardt H. 1983. The biology of bone graft repair. Clin Orthop
174:28 –37.
Burr DB. 1997. Muscle strength, bone mass, and age-related bone
loss. J Bone Miner Res 12:1547–1551.
Burr DB. 1998. The mechanical behavior of cortical bone in vivo. J Jpn
Soc Bone Morphom 8:1–7.
Burr DB, Martin RB. 1992. Mechanisms of bone adaptation to the
mechanical environment. Triangle (Sandoz) 31:59 –76.
Burr DB, Stafford T. 1990. Validity of the bulk staining technique to
separate artifactual from in vivo microdamage. Clin Orthop Rel Res
Burr DB, Martin RB, Radin EL. 1983. Threshold values for the
production of fatigue microdamage in bone in vivo. Orth Res Soc
Abstr 69.
Burr DB, Milgrom C, Fyrhie D, Forwood M, Nyska M, Finestone A,
Saiag E, Simkin A. 1995. Human in vivo tibial strains during
vigorous activity. Orthop Res Soc Abstr 20:202.
Burr DB, Forwood MR, Fyrhie DP, Martin RB, Schaffler MB, Turner
CH. 1997. Bone microdamage and skeletal fragility in osteoporotic
and stress fractures. J Bone Miner Res 12:6 –15.
Canalis E. 1993. Regulation of bone remodeling. In: Favus MJ, editor.
Primer on the metabolic bone diseases and disorders of mineral
metabolism. New York: Raven Press, p 33–37.
Caplan AI, Dennis JE. 1996. Mesenchymal stem cells: Progenitors,
progeny, pathways. J Bone Miner Metab 14:193–201.
Carter DR. 1984. Mechanical loading histories and cortical bone remodeling. Calc Tiss Int Suppl 36:19 –24.
Carter DR, Wong M. 1990. Mechanical stresses in joint morphogenesis and maintenance. In: Mow VC, Ratcliffe A, Woo SL-Y, editors.
Biomechanics of diarthrodial joints, vol II. New York: SpringerVerlag, p 155–174.
Carter DR, Blenman PR, Beaupre GS. 1988. Correlations between
mechanical stress history and tissue differentiation in initial fracture healing. J Orthop Res 6:736 –748.
Chamay A, Tschantz P. 1972. Mechanical influences on bone remodeling. Experimental research on Wolff’s Law. J Biomech 3: 173–180.
Chen M-M, Yeh JK, Aloia JF. 1995. Skeletal alterations in hypophysectomized rats: II. A histomorphometric study on tibial cortical
bone. Anat Rec 241:513–518.
Chow JWM, Badve S, Chambers TJ. 1993. Bone formation is not
coupled to bone resorption in a site-specific manner in adult rats.
Anat Rec 236:366 –372.
Christiansen C, Christensen MS, Transbol I. 1981. Bone mass in
postmenopausal women after withdrawal of estrogen/gestagen replacement therapy. Lancet 1:459 – 461.
Claes L, Wilke H-J, Augat P, Suger G, Fleischman W. 1994. The
influence of fracture gap size and stability on bone healing. ORS
Abstr 19:203.
Cohn DV, Fujita T, Potts JTJr, Talmage RV. 1984. Endocrine control
of bone and calcium metabolism. Amsterdam: Excerpta Medica.
Cook SD, Ryaby JP, McCabe J, Frey JJ, Heckman JD, Kristiansen
TK. 1997. Acceleration of tibia and distal radius fracture healing in
patients who smoke. Clin Orthop Rel Res 337;198 –207.
Cozen L. 1990. Knock-knee deformity in children: Congenital and
acquired. Clin Orthop Rel Res 258:191–203.
Crowninshield RD, Johnston RC, Andrews JG, Brand RA. 1978. A
biomechanical investigation of the human hip. J Biomech 11:75– 85.
Cruess RL. 1982. The musculoskeletal system. Embryology, biochemistry and physiology. Edinburgh: Churchill Livingstone.
Currey JD. 1984. The mechanical adaptations of bones. Princeton:
Princeton University Press.
Damjanov I, Linder J. 1996. Anderson’s pathology, vols I, II. St. Louis:
Mosby-Year Book, Inc.
Deng H-W, Chen W-M, Recker S, Stegman MR, Li J-L, Davies KM,
Zhou Y, Deng H, Heaney R, Recker RR. 2000. Genetic determination of Colle’s fractures and differential bone mass in women with
and without Colle’s fracture. J Bone Miner Res 15:1243–1252.
de Palma L, Tulli A, Macccauro G, Sabetta SP, del Torto M. 1994.
Fracture callus in osteopetrosis. Clin Orthop Rel Res 308:85– 89.
Devas M. 1975. Stress Fractures. Churchill-Livingston, London.
Dickinson MH, Farley CT, Full RJ, Koehl MAR, Kram R, Lehman S.
2000. How animals move: An integrative view. Science 288:100 –
Dickman S. 1997. No bone about a genetic switch for bone growth.
Science 276:1502.
Dietz FR, Mathews KD. 1996. Update on the genetic bases of disorders with orthopaedic manifestations. J Bone Jt Surg 78A:1583–
Dimar JR, Campbell M, Glassman SD, Puno RM, Johnson JR. 1995.
Idiopathic juvenile osteoporosis. Am J Orthop 24:865– 869.
Doyle F, Brown J, Lachance C. 1970. Relation between bone mass and
muscle weight. Lancet 1:391–393.
Doyle LD. 1993. Bone changes in total hip replacement. Tech Orthop
4:1– 8.
Duncan H, Frame B, Arnstein AR, Frost HM. 1973. Migratory osteolysis of the lower extremities. Ann Int Med 66: 1165–1173.
Duncan RL, Turner CH. 1995. Mechanostransduction and the functional response of bone to mechanical strain. Calc Tiss Int 57:344 –
Eastell R, Cedel SL, Wahner HW, Riggs BL, Melton LJ. 1991. Classification of vertebral fractures. J Bone Miner Res 6:207–215.
El Haj AJ. 1990 Biomechanical bone cell signalling: is there a grapevine? J Zool (Lond) 220:689 – 693.
English TA, Kilvington M. 1979. In vivo records of hip loads using a
femoral implant with telemetric output. J Biomech Engin 1:111–
Enlow DH. 1963 Principles of bone remodeling. Springfield, MA:
Charles C Thomas.
Erben RG. 1996 Trabecular and endocortical bone surfaces in the rat:
modeling or remodeling? Anat Rec 246:39 – 46.
Erben RG, Eberle J, Stahr K, Goldberg M. 2000. Androgen deficiency
induces high turnover osteopenia in aged male rats: A sequential
histomorphometric study. J Bone Miner Res 15:1085–1098.
Evans FG. 1957. Stress and strain in bones. Springfield, MA: Charles
C Thomas.
Evans RA. 1987. Is there a need for whole body physiology? Bone
Miner 2:243–244.
Faulkner JA, Brooks SV, Zerva E. 1990 Skeletal muscle weakness and
fatigue in old age: underlying mechanisms. In: Cristofalo VJ, Law-
ton MP, editors. Annual review of gerontology and geriatrics. New
York: Springer-Verlag, p 147–166.
Favus MJ. 1999 Primer on the metabolic bone diseases and disorders
of mineral metabolism, 4th ed. Philadelphia: Lippincott-Williams
and Wilkins, p 1–502.
Fazzalari NL, Forwood MR, Manthey BA, Smith K, Kolesik P. 1998.
Three-dimensional confocal images of microdamage in cancellous
bone. Bone 23:373–378.
Ferretti JL. 1997. Biomechanical properties of bone. In: Genant HK,
Gugliemi G, Jergas M, editors. Osteoporosis and bone densitometry.
Berlin: Springer-Verlag, p 143–161.
Ferretti JL. 1999. Peripheral, quantitative computed tomography
(pQCT) for evaluating structural and mechanical properties of
small bone. In: An YH, Draughn RA, editors. Practi cal guide for
mechanical testing of bone. Boca Raton, FL: CRC Press, p 1–25.
Ferretti JL, Frost HM, Gasser JA, High WB, Jee WSS, Jerome C,
Mosekilde L, Thompson DD. 1995. Perspectives: On osteoporosis
research: Its focus and some insights of a new paradigm. Calc Tiss
Int 57:399 – 404.
Ferretti JL, Frost HM, Schiessl H. 1998a. On new opportunities for
absorptiometry. J Clin Densitom 1:41–53.
Ferretti JL, Capozza RP, Cointry GR, Garcia SL, Plotkin H, Avlarez
P, Figueira ML, Zanchetta JR. 1998b. Gender-related differences in
the relationship between densitometric values of whole-body bone
mineral content and lean body mass in humans between 2 and 87
years of age. Bone 22:683– 690.
Fleisch H. 1995. Bisphosphonates in bone disease. From the laboratory to the patient. London: Parthenon Publishing Group.
Flieger J, Karachalios T, Khadaldi L, Rapton P, Lyritis G. 1998.
Mechanical stimulation in the form of vibration prevents postmenopausal bone loss in ovariectomized rats. 63:510 –514.
Flora L, Hassing GS, Parfitt AM, Villanueva AR. 1981. Comparative
skeletal effects of two diphosphonate drugs. In: Deluca HF, Frost
HM, Jee WSS, Johnston CC Jr, Parfitt AM, editors. Osteoporosis.
Baltimore: University Park Press, p 389 – 407.
Forwood MR, Parker AW. 1989. Microdamage in response to repetitive torsional loading in the rat tibia. Calc Tiss Int 45:47–53.
Forwood MR, Turner CH. 1995. Skeletal adaptations to mechanical
usage: Results from tibial loading studies in rats. Bone 17 (Suppl.):
Freeman MAR, Todd RC, Pirie CJ. 1974. The role of fatigue in the
pathogenesis of senile femoral neck fracture. J Bone Jt Surg 56B:
898 –905.
Frost HM. 1960. Presence of microscopic cracks in vivo in bone. Henry
Ford Hosp Med Bull 8:27–35.
Frost HM. 1964. Laws of bone structure. Springfield, MA: Charles C
Frost HM. 1969. Tetracycline-based histological analysis of bone remodeling. Calc Tiss Res 3:211–237.
Frost HM. 1983. The regional acceleratory phenomenon: a review.
Henry Ford Hosp Med J 31:3–9.
Frost HM. 1986. Intermediary organization of the skeleton, vols I,II.
Boca Raton: CRC Press.
Frost HM. 1987a. Osteogenesis imperfecta. The setpoint proposal.
Clin Orthop Rel Res 216:280 –297.
Frost HM. 1987b. The mechanostat: A proposed pathogenetic mechanism of osteoporoses and the bone mass effects of mechanical and
nonmechanical agents. Bone Miner 2:73– 85.
Frost HM. 1989a. Transient-steady state phenomena in microdamage
physiology: A proposed algorithm for lamellar bone. Calc Tiss Int
Frost HM. 1989b. The biology of fracture healing. Clin Orthop Rel Res
Part I:248:283–293; Part II:248:294 –309.
Frost HM. 1990a. Structural adaptations to mechanical usage
(SATMU):1. Redefining Wolff’s Law: The bone modeling problem.
Anat Rec 226:403– 413.
Frost HM. 1990b. Structural adaptations to mechanical usage
(SATMU):2. Redefining Wolff’s Law: The bone remodeling problem.
Anat Rec 226:414 – 422.
Frost HM. 1992a. Perspectives: Bone’s mechanical usage windows.
Bone Miner 19:257–271.
Frost HM. 1992b. Perspectives on artificial joint design. J Long-Term
Eff Med Impl 2:9 –35.
Frost HM. 1993. Wolff’s Law: an “MGS” derivation of Gamma in the
Three-Way Rule for mechanically controlled lamellar bone modeling drifts. Bone Miner 22:117–127.
Frost HM. 1995. Introduction to a new skeletal physiology, Vols I, II.
Pueblo, CO: The Pajaro Group, Inc. ***
Frost HM. 1996. Perspectives: A proposed general model for the
mechanostat (suggestions from a new paradigm). Anat Rec 244:
139 –147.
Frost HM. 1997a. Osteoporoses: their nature, and therapeutic targets
(Insights from a new paradigm). In: Whitfield JF, Morely P, editors.
Anabolic treatments for osteoporosis. Boca Raton: CRC Press, p
Frost HM. 1997b. Biomechanical control of knee alignment. Clin
Orthop Rel Res 335:335–342.
Frost HM. 1997c. Perspectives: On increased fractures during the
human adolescent growth spurt. summary of a new vital-biomechanical explanation. J Bone Miner Metabol 15:115–121.
Frost HM. 1997d. Strain and other mechanical influences on bone
strength and maintenance. Curr Op Orthop 8:60–70.
Frost HM. 1998a. Changing concepts in skeletal physiology: Wolff’s
Law, the mechanostat and the “Utah Paradigm.” J Hum Biol 10:
599 – 605.
Frost HM. 1998b. On rho, a marrow mediator and estrogen: Their
roles in bone strength and “mass” in human females, osteopenias
and osteoporoses (insights from a new paradigm). J Bone Miner
Metab 16:113–123.
Frost HM. 1998c. Some vital biomechanics of bone grafting and loadbearing implants in dental and maxillofacial surgery: A brief tutorial. In: Jensen OT, editor. The sinus bone graft. Chicago: Quintessence Publishing Co, Inc., p 17–29.
Frost HM. 1999a. Joint anatomy, design and arthroses: insights of the
Utah paradigm. Anat Rec 255:162–174.
Frost HM. 1999b. Why does bone in aging adults become unresponsive to vigorous physical activities? A review based on insights of a
new paradigm. J Bone Miner Metab 17:90 –97.
Frost HM. 2000a. Why the ISMNI and the Utah pardigm? Their role
in skeletal and extraskeletal disorders. J Musculskel Interact 1:29 –
Frost HM. 2000b. The author’s personal observation(s) during 50
years as an orthopaedic surgeon, teacher, researcher and amateur
pathologist, and of a matter others must have observed too so it
need not be original to the author. However, it did not previously
seem important or relevant enough to deserve formal study and
Frost HM. 2000c. Does bone design intend to minimize fatigue failures? A case for the affirmative. J Bone Miner Metab 18:278 –262.
Frost HM, Jee WSS. 1994. Perspectives: A vital biomechanical model
of the endochondral ossification mechanism. Anat Rec 240:435–
Frost HM, Schönau E. 2000. The “muscle-bone unit” in children and
adolescents: A 1999 overview. J Ped Endocrinol Metab 13:571–590.
Fukada E, Yasuda J. 1957. On the piezoelectric effect of bone.
J Physiol Soc Japan 12:1158 –1160.
Gallagher JC. 1990. The pathogenesis of osteoporosis. Bone Min
Garland DE, Foulkes GD, Adkins RH, Stewart CA, Yakura JS. 1994.
Regional osteoporosis following incomplete spinal injury. Contemp
Orthop 28:134 –142.
Garn S. 1970. The earlier gain and later loss of cortical bone. Springfield, MA: Charles C Thomas.
Gasser JA. 1999. Modulation of strain sensing: A new approach for
the treatment of osteoporosis. In: Lyritis GP, editor. Musculoskeletal Interactions, vol II. Athens: Hylonome Editions, p 77– 82.
Gegenbaur C. 1867. Uber die Bildung des knochengewebes. Jena Z
Med Naturwiss 1:343–369.
Goldring SR, Goldring MB. 1996. Cytokines and skeletal physiology.
Clin Orthop Rel Res 324:13–23.
Gowen M. 1992. Cytokines and bone metabolism. Boca Raton: CRC
Greenspan SL, Myers ER, Maitland LA, Resnick NM, Hayes WC.
1994. Fall severity and bone mineral density as risk factors for hip
fracture in ambulatory elderly. J Am Med Assn 271:128 –133.
Gross TS, Edwards JL, McLeod KJ, Rubin CT. 1997. Strain gradients
correlate with sites of periosteal bone foration. J. Bone Miner Res
Guralnik JM, Ferrucci L, Simonsick EM, Salive MB, Wallace RB.
1995. Lower-extremity function in persons over the age of 70 years
as a predictor of subsequent disability. N E J Med 332:556 –561.
Habal MB, Reddi AH. 1992. Bone grafting: from basic science to
clinical application. New York: WB Saunders Co.
Halioua L, Anderson JB. 1989. Lifetime calcium intake and physical
activity habits: independent and combined effects on the radial
bone of healthy premenopausal Caucasian women. Am J Clin Nutr
49:534 –541.
Hall BK. 1991. Historical overview of studies on bone growth and
repair. In: Bone, vol 6. Boca Raton: CRC Press, p 1–247.
Hamilton HW, Gorczyca J. 1995. Low friction arthroplasty at 10 to 20
years. Clin Orthop Rel Res 318:160 –166.
Hanafusa S, Matsusue Y, Yasunaga T, Yamamuro T, Oka M, Shikinami Y, Ikada Y. 1995. Biodegradable plate fixation of rabbit femoral shaft osteotomies. Clin Orthop Rel Res 315:262–271.
Hanes RW, Mohidden A. 1965. Handbook of human embryology.
Baltimore: Williams and Wilkins Co.
Harris SA, Tau KR, Turner RT, Spelsberg TC. 1996. Estrogens and
progestins. In: Bilezikian JP, Raisz LG, Rodan GA, editors. Principles of bone biology. New York: Academic Press, p 507–530.
Heaney RP. 1990. Nutritional factors in bone health in elderly
subjects: Methodological and contextual problems. Am J Clin Nutr
Heaney RP. 1993. Is there a role for bone quality in fragility fractures?
Calc Tiss Int 53 Suppl):3– 6.
Heaney RP. 1994. The bone-remodeling transient: Implications for
the interpretation of clinical studies of bone mass change. J Bone
Miner Res 9:1515–1523.
Heckman JD, Ryaby JP, McCabe J, Frey JJ, Kilcoyne RF. 1994.
Acceleration of tibial fracture-healing by non-invasive, low intensity pulsed ultrasound. J Bone Jt Surg 76A:26 –34.
Heinonen A, Sievanen H, Kannus P, Oja P, Vuori I. 1995. Effects of
unilateral strength training and detraining on bone mineral mass
and estimated mechanical characteristics of the upper limb bones in
young women. J Bone Miner Res 11:490 –501.
Hernandez JA, Serrano S, Marinoso ML, Aubia J, Lloreta J, Marrugat
J, Diez A. 1995. Bone growth and modeling changes induced by
periosteal stripping in the rat. Clin Orthop Rel Res 320:211–219.
High WB. 1988. Effects of orally administered prostaglandin on cortical bone turnover in dogs: A histomorphometric study. Bone
Huffer WE. 1988. Morphology and biochemistry of bone remodeling:
possible control by vitamin D, parathyroid hormone, and other
substances. Lab Invest 59:418 – 442.
Inzucchi SE, Robbins RJ. 1994. (Clinical Review 61) Effects of growth
hormone on human bone biology. J Clin Endocrinol Metab 79:691–
Jaffe H. 1958. Tumors and tumorous conditions of the bones and
joints. Philadelphia: Lea and Febiger.
Jaffe H. 1972. Metabolic, degenerative and inflammatory diseases of
bones and joints. Philadelphia: Lea and Febiger.
Jaffurs D, Evans CH. 1998. The human genome project: implications
for the treatment of musculoskeletal disorders. J Am Acad Orthop
Surg 6:1–14.
Jansson M. 1920. On bone formation. its relation to tension and
pressure. London: Longmans.
Jasty M, Bragdon C, Jiranek W, Chandler H, Maloney W, Harris WH.
1994. Etiology of osteolysis around porous-coated cementless total
hip arthroplasties. Clin Orthop Rel Res 308:111–126.
Jaworski ZFG. 1984. Lamellar bone turnover system and its effector
organ. Calc Tiss Int Suppl 36:46 –55.
Jaworski ZFG, Meunier PJ, Frost HM. 1972. Observations on two
types of resorption cavities in human lamellar cortical bone. Clin
Orthop 83:279 –285.
Jee WSS. 1989. The skeletal tissues. In: Weiss L, editor. Cell and
tissue biology. a textbook of histology. Baltimore: Urban and
Schwartzenberg, p 211–259.
Jee WSS. 1995. Proceedings of the International Conference on Animal Models in the Prevention and Treatment of Osteopenia. Bone
17(Suppl):1– 466.
Jee WSS. 1999. The interactions of muscles and skeletal tissue. In:
Lyritis GP, editor. Musculoskeletal Interactions, vol II. Athens:
Hylonome Editions, p 35– 46.
Jee WSS. 2000. Principles in bone physiology. J Musculoskel Interact
1:9 –11.
Jee WSS, Frost HM. 1992. Skeletal adaptations during growth. In:
Triangle (Sandoz) 31:77– 88.
Jee WSS, Li XJ. 1990. Adaptation of cancellous bone to overloading in
the adult rat: A single photon absorptiometry and histomorphometry study. Anat Rec 227:418 – 426.
Jee WSS, Li XJ, Schaffler MB. 1991. Adaptation of diaphyseal structure with aging and increased mechanical loading in the adult rat.
A densitometric, histomorphometric and biomechanical study. Anat
Rec 230:332–338.
Jergensen HE, Heller M, Genant HK. 1990. Signal variability in
magnetic resonance imaging of femoral head osteonecrosis. Clin
Orthop Rel Res 253:137–149.
Jiang Y, Zhao J, Rosen C, Gensens P, Genant H. 1999. Perspctives on
bone mechanical properties and adaptive response to mechanical
loading. J Clin Densitom 2:422– 433.
Joseph KN, Kane HA, Milner RS, Steg NL, Williamson MB, Bowen
JR. 1992. Orthopedic aspects of the Marfan syndrome. Clin Orthop
Rel Res 277:251–261.
Judex S, Gross TS, Zernicke RF. 1997. Strain gradients correlate with
sites of exercise-inducd bone-forming surfaces in the adult skeleton.
J Bone Miner Res 12:1737–1745.
Kalu DN, Banu J, Wang I. 2000. How cancellous and cortical bones
adapt to loading and growth hormone. J Musculoskel Interact 1:46 –
Kanis JA. 1994. Assessment of fracture risk and its application to
screening for postmenopausal osteoporosis: synopsis of a WHO report. Osteoporosis Int 4:368 –381.
Kannus P, Sievanen H, Vuori L. 1996. Physical loading, exercise and
bone. Bone 18(Suppl 1):1–3.
Karlsson M, Johnell O, Obrant K. 1993. Bone mineral density in
weight lifters. Calc Tiss Int 52:212–215.
Kelly PJ. 1990. Reaction of the circulatory system to injury and
regeneration. Clin Orthop Rel Res 254:275–288.
Kenwright J, Goodship AE. 1989. Controlled mechanical stimulation
in the treatment of tibial fractures. Clin Orthop Rel Res 241:36 – 47.
Key LL, Ries W. 1996. Osteopetrosis. In: Bilezikian JP, Raisz LG,
Rodan GA, editors. Principles of bone biology. New York: Academic
Press, p 941–950.
Kimmel D. 1993 A paradigm for skeletal strength homeostasis. J Bone
Miner Res 8(Suppl 2):515–522.
Kiratli BJ. 1996. Immobilization osteopenia. In: Marcus R, Feldman
D, Kelsey J, editors. Osteoporosis. Orlando, FL: Academic Press, p
833– 850.
Koch JC. 1917. The laws of bone architecture. Am J Anat 21:177–298.
Kozin F. 1993. Reflex sympathetic dystrophy syndrome and transient
regional osteoporosis. In: Schumacher HR, Kippel JH, Koopman
WJ, editors. Primer on rheumatic diseases, 10th ed. The Arthritis
Foundation, p 288 –290.
Kuhlencordt F, Bartelheimer H. 1981. Handbuch der Inneren Medizen, vol. VI. Heidelberg: Springer-Verlag.
Langloh ND, Hunder GG, Riggs BL, Kelley PJ. 1973. Transient painful osteoporoses of the lower extremities. J Bone Jt Surg 55A:1188 –
Lanyon LE. 1996. Using functional loading to influence bone mass
and architecture: Objectives, mechanisms, and relationship with
estrogen of the mechanically adaptive process in bone. Bone 18
(Suppl 1):37– 43.
Larsson L, Grimby G, Karlsson J. 1979. Muscle strength and speed of
movement in relation to age and muscle morphology. J Appl Phys
Ther 46:451– 456.
Lauritzen JB. 1996. Hip fractures: Incidence, risk factors, energy
absorption and prevention. Bone 18:65S–75S.
Lavine LS, Grodzinski AJ. 1987. Electrical stimulation of bone.
J Bone Jt Surg 69A:626 – 670.
Lee WTK, Leung SSF, Leung DMY. 1996. A follow-up study on the
effects of calcium-supplement withdrawal and puberty on bone
acquisition of children. Am J Cllin Nutr 64:71–77.
Lewis FT. 1906. Stohr’s histology, 6th U.S. ed. Philadelphia: P Blakiston’s Son and Co.
Li XJ, Jee WSS. 1991. Adaptation of diaphyseal structure to aging
and decreased mechanical loading in the adult rat. A densitometric
and histomorphometric study. Anat Rec 229:291–297.
Li XJ, Jee WSS, Chow S-Y, Woodbury DM. 1990. Adaptation of
cancellous bone to aging and immobilization in the rat. A single
photon absorptiometry and histomorphometry study. Anat Rec 227:
Lu T-W, Taylor SJG, O’Connor JJ, Walker PS. 1997. Influence of
muscle activity on the forces in the femur: an in vivo study. J
Bimech 30:1101–1106.
Luck JV. 1950. Bone and joint diseases. Springfield, MA: Charles C
Ma YF, Ke HZ, Jee WSS. 1994. Prostaglandin E2 adds bone to a
cancellous bone site with a closed growth plate and low bone turnover in ovariectomized rats. Bone 15:137–146.
Maddox J. 1999. The unexpected science to come. Sci Am 281:62– 67.
Mailis A, Onman R, Pham D. 1992. Transient migratory osteoporosis:
a variant of reflex sympathetic dystrophy? Report of 3 cases and
literature review. J Rheumatol 19:758 –764.
Manolagas SC, Jilka RL. 1995. Bone marrow, cytokines, and bone
remodeling: emerging insights into the pathophysiology of osteoporosis. N Engl J Med 332:305–311.
Marcus R, Feldman D, Kelsey J. 1996. Osteoporosis. Orlando, FL:
Academic Press.
Markey KI. 1987. Stress fractures. Clin Sports Med 6:405– 425.
Marotti G, Palazzini S, Palumbo C, Ferretti M. 1996. Ultrastructural
evidence of the existence of a dendritic network throughout the cells
of the osteogenic lineage: the novel concept of wiring, and volume
transmission in bone. Bone 19(Suppl 3) 151.
Mashiba T, Jirano T, Turner CH, Forwood MR, Johonston CC Jr, Burr
DB. 2000. Suppressed bone turnover by bisphosphonates increases
microdamage accumulation and reduces some biomechanical properties of bone. J Bone Miner Res 15:613– 620.
Martin RB. 1987. Osteonal remodeling in response to screw implantation in the canine femur. J Orthop Res 5:445– 454.
Martin RB. 1995. Mathematical model for repair of fatigue damage
and stress fracture in osteonal bone. J Orthop Res 13:309 –316.
Martin RB. 2000. Towards a unifying theory of bone remodeling. Bone
26:1– 6.
Martin RB, Burr DB, Sharkey NA. 1998. Skeletal tissue mechanics.
New York: Springer-Verlag.
Mayr E. 1961. Cause and effect in biology. Science 134:1501–1506.
Mayr E. 2000. Darwin’s influence on modern thought. Sci Am 283:
78 – 83.
McLean FC, Urist MR. 1961. Bone, 2nd. ed. Chicago: University of
Chicago Press.
Micklesfield LK, Lambert EV, Fataar AB, Noakes TD, Myburgh KH.
1995. Bone mineral density in mature premenopausal ultramarathon runners. Med Sci Sports Exerc 27:688 – 696.
Mori S, Burr DB. 1993. Increased intracortical remodeling following
fatigue damage. Bone 14:103–109.
Moseley JR, Lanyon LE. 1998. Strain rate as a controlling influence
on adaptive modeling in response to dynamic loading of the ulna in
growing male rats. Bone 23:313–318.
Muller W. 1926. Bone physiology. Zeitshr fur Orthopad Chir
Mundy GR. 1996. Regulation of bone formation by bone morphogenetic proteins and other growth factors. Clin Orthop Rel Res 324:
24 –28.
Murray M, Gardner G, Mollinger L, Sepic S. 1980. Strength of isometric and isokinetic contractions: Knee muscles of men aged 20 to
86. Phys Ther 60:412– 419.
Nguyen TV, Eisman JA. 2000. Genetics of fracture: challenges and
opportunities. J Bone Miner Res 15:1253–1256.
Nielsen SP. 2000. The fallacy of BMD: A critical review of the diagnostic use of dual X-ray absorptiometry. Clin Rheumatol 19:174 –
Nilsson BE, Andersson SM, Hardtrup T, Westlin NE. 1978. Ballet
dancing and weight lifting: effects on BMC. Am J Roentgen 131:
Nishizawa Y, Koyama H, Shoji T, Aratani H, Hagiwara S, Miki T,
Morii H. 1991. Obesity as a determinant of regional bone mineral
density. J Nutr Sci Vitaminol 37:S65–S70.
Nordin BEC. 1987. The definition and diagnosis of osteoporosis. Calcif
Tiss Int 40:57–58.
Nordin BEC, Heaney RP. 1990. Calcium supplementation of the diet:
Justified by present evidence. Br Med J 300:1056 –1060.
Norimatsu H, Vander Wiel CJ, Talmage RV. 1979. Morphological
support of a role for cells lining bone surfaces in maintenance of
plasma calcium concentration. Clin Orthop Rel Res 138:254 –262.
O’Connor JA, Lanyon LE, MacFie H. 1982. The influence of strain
rate on adaptive bone remodeling. J Biomech 15:767–781.
Ogle GD, Moore B, Lu PW, Craighead A, Briody JN, Cowell CT. 1994
Changes in body composition and bone density after discontinuation of growth hormone therapy in adolescence: an intermim report.
Acta Paediatr (Suppl 399):3–7.
Okuyama K, Sato K, Abe E, Murai H, Shimada Y, Inaba H, Kamata
S, Nagata H. 1995. Influence of bone mineral density on the mechanical stability of transpedicle screwing. In: Takahashi HE, editor. Spinal disorders in growth and aging. Tokyo: Springer-Verlag,
p 197–203.
Overstall PW, Exton-Smith AN, Imms FJ, Johnson AL. 1997. Falls in
the elderly related to postural imbalance. Br Med J 1:261–264.
Parfitt AM. 1980. Morphologic basis of bone mineral measurements:
Transient and steady state effects of treatment in osteoporosis. Min
Elec Metab 4:273–287.
Parfitt AM. 1993. Calcium homeostasis. In: Mundy GR, Martin TJ,
editors. Handbook of experimental pharmacology, vol 107. Berlin:
Springer-Verlag, p 1– 65.
Parfitt AM. 1995. Problems in the application of in vitro systems to
the study of human bone remodeling. Calcif Tiss Int 56(Suppl
Parfitt AM. 1997. Review of “primer on the metabolic bone diseases
and disorders of mineral metabolism, 3rd ed. Trends Endocrinol
Metab 8:331–332.
Parfitt AM, Mundy GR, Roodman GD, Hughes DE, Boyce B. 1996. A
new model for the regulation of bone resorption, with particular
reference to the effects of bisphosphonates. J Bone Miner Res 11:
150 –159.
Pattin CA, Caler WE, Carter DR. 1996. Cyclic mechanical property
degradation during fatigue loading of cortical bone. J Biomech
29:69 –79.
Pauwels F. 1986. Biomechanics of the locomotor apparatus. Berlin:
Podenphant J, Engel U. 1998. Regional variations in histomorphometric bone dynamics from the skeleton of an osteoporotic woman.
Calcif Tiss Int 40:184 –188.
Pritchett JW. 1995. Femoral bone loss following hip replacement. Clin
Orthop Rel Res 314:156 –161.
Putschar WGJ. 1960. General pathology of the musculoskeletal system. In: Buchner F, Letterer E, Roulet F, editors. Handbuch der
Allgemeinen Pathologie. Berlin: Springer-Verlag, p 361– 488.
Raab-Cullen DM, Kimmel DB, Akhter MP, Recker RR. 1996. External
loading of the aged and young rat tibia at similar strains causes a
similar bone response. Orth Res Soc Abstr 129.
Rahn BA. 1982. Bone healing: histologic and physiologic concepts. In:
Sumner-Smith G, editor. Bone in clinical orthopaedics.
Philadelphia: W.B. Saunders, p 335–386.
Raisz LG. 1988. Hormonal regulation of bone growth and remodelling.
Ciba Found Symp 136:226 –238.
Rasch PJ, Burke RK. 1963. Kinesiology and applied anatomy.
Philadelphia: Lea and Febiger.
Rasmussen H, Bordier P. 1974. The physiological and cellular basis of
metabolic bone disease. Baltimore: Williams and Wilkins.
Recker RR. 1983. Bone histomorphometry. techniques and interpretation. Boca Raton: CRC Press.
Recker RR, Heaney RP. 1985. The effect of milk supplements on
calcium metabolism, bone metabolism and calcium balance. Am J
Clin Nutr 41:254 –263.
Reilly DT, Burstein AH. 1991. The mechanical properties of cortical
bone. J Bone Jt Surg 56A:1001–1021.
Rhinelnander FW, Wilson JW. 1982. Blood supply to developing,
mature and healing bone. In: Sumner-Smith G, editor. Bone in
clinical orthopaedics. Philadelphai: WB Saunders Co, p 81–158.
Ridley M. 2000. Genome: the autobiography of a species in 23 chapters. New York: HarperCollins.
Riggs BL, Melton LJ. 1995. Osteoporosis. Etiology, diagnosis and
treatment, 2nd ed. Hagerstown, MD: Lippincott-Raven Publishers.
Riggs B, Khosla S, Melton J. 1998. A unitary model for involutional
osteoporosis: Estrogen deficiency causes both Type I and Type II
osteoporosis in postmenopausal women and contributes to bone loss
in aging men. J Bone Miner Res 13:763–773.
Ring PA, Ward BCH. 1958. Paralytic bone lengthening following
poliomyelitis. Lancet 2:551–553.
Rittweger J, Gunga HC, Felsenberg D, Kirsch KA. 1999. Muscle and
bone: aging and space. J Gravit Physiol 6:P133–P136
Rockwood CA Jr, Green DP. 1991. Fractures in children, 3rd ed, vol 3.
Philadelphia,: JB Lippincott.
Rockwood CA Jr, Green DP. 1997. Fractures in Adults, 4th ed., vols I,
II. Hagerstown, MD: Lippincott-Raven.
Rodan GA. 1997. Bone mass homeostasis and bisphosphonate action.
Bone 20:1– 4.
Roesler H. 1987. The history of some fundamental concepts in bone
biomechanics. J Biomech 20:1025–1034.
Romer AS. 1966. Vertebrate paleontology, 3rd. ed. Chicago: University of Chicago Press.
Roux W. 1895. Gesammel Abhandlungen uber die Entwicklungsmechanik der Organismen. Leipzig: Engelmann.
Rubin C, McLeod K. 1995. Endogenous control of bone morphology via
frequency specific, low magnitude functional strain. In: Odgaard A,
Weinans H, editors. Bone structure and remodelng. London: World
Scientific, p 79 – 89.
Rubin CT, McLeod KJ. 1994. Promotion of bony ingrowth by frequency-specific, low-amplitude mechanical strain. Clin Orthop Rel Res
Rubinacci A, Benelli FD, Borgo E, Villa I. 2000. Bone as an ion
exchange system: evidence for a pump-leak mechanism devoted to
maintenance of high bone K⫹. Am J Physiol Endocrinol Metab
Runge M. 1997. Die multifaktorielle Genese von Gehstörungen, Stürzen und Hüftfrakturen im Alter. Zeits Gerontol Geriat 30:267–275.
Runge M, Rehfeld G, Resnicek E. 2000. Balance training and exercise
in geriatric patients. J Musculoskel Interact 1:54 –58.
Schaffler MB, Choi K, Milgrom C. 1995. Aging and matrix microdamage accumulation in human compact bone. Bone 17:521–525.
Schiano A, Elsinger J, Acquaviva PC. 1976. Les Algodystrophies.
Paris: Armour-Montagu.
Schiessl H, Willnecker J. 1999. Muscle cross sectional area and bone
cross sectional area in the lower leg measured with peripheral
computed tomography. In: Lyritis GP, editor. Musculoskeletal interactions, vol II. Athens: Hylonome Editions, p 47–52.
Schiessl H, Frost HM, Jee WSS. 1998. Perspectives: Estrogen and
bone-muscle strength and “mass” relationships. Bone 22:1– 6.
Schönau E. 1996 Paediatric osteology. New trends and diagnostic
possibilities. Amsterdam: Elsevier Science.
Schönau E, Westermann F, Mokow E, Scheidhauer K, Werhahn E,
Stabrey A, Müller-Berghaus J. 1998. The functional muscle-boneunit in health and disease. In: Schönau E, Matkovic V, editors.
paediatric osteology. prevention of osteoporosis: a paediatric task?
Amsterdam: Excerpta Medica, p 191–202.
Schroll M, Petti E, Avlund K. 1999. Postural balance, its sensorymotor correlates and self-reported functional ability in 75-year old
men and women; A cross-sectional comparative study. In: Lyritis
GP, editor. Musculoskeletal interactions. Athens: Hylonome Editions, p 53– 66.
Seeforf KS. 1949. Osteogenesis Imperfecta. Aarhus: University of
Aarhus Press.
Seeman E. 1997. From density to structure: Growing up and growing
old on the surfaces of bone. J Bone Miner Res 12:509 –521.
Sherman MS, Phemister DB. 1947. The pathology of ununited fractures of the femoral neck of the femur. J Bone Jt Surg 29A:19 – 40.
Shih MS, Norrdin RW. 1985. Regional acceleration of remodeling
during healing of bone defects in Beagles of various ages. Bone
Shires R, Avioli LV, Bergfeld MA, Fallon MD, Slatopolski E, Teitelbaum SL. 1980. Effects of semistarvation on skeletal homeostasis.
Emdocrinology 107:1530 –1535.
Sievanen H, Heinonen A, Kannus F. 1996. Adaptation of bone to
altered loading environment: A biomechanical approach using Xray absorptiometric data from the patella of a young woman. Bone
Sillence DO, Senn A, Danks DM. 1979 Genetic diversity in osteogenesis imperfecta. J Med Genet 16:101–116.
Skerry TM. 1997 Perspectives: mechanical loading and bone. What
sort of exercise is beneficial to the skeleton? Bone 20:179 –181.
Slemenda CW, Reister TK, Hui SL, Miller JZ, Christian JC, Johnston
CC. 1994 Influences on skeletal mineralization in children and
adolescents: Evidence for varying effects of sexual maturation and
physical activity. J Pediatr 125:201–207.
Smith EL, Gilligan C. 1989. Mechanical forces and bone. Bone Miner
Res 6:139 –173.
Smith EL, Gilligan C, McAdam M, Ensign CP, Smith PE. 1989.
Deterring bone loss by exercise intervention in premenopausal
women and postmenopausal women. Calc Tiss Int 44:312–321.
Snapper I. 1957. Bone disease in medical practice. New York: Grune
and Stratton.
Snow-Harter C, Bouxsein ML, Lewis BT. 1990 Muscle strength as a
predictor of bone mineral density in young women. J Bone Miner
Res 5:589 –595.
Stanisaljevic S. 1964 Dysplasia and treatment of congenital hip pathology in the newborn. Baltimore: Williams and Wilkins.
Stanulis-Praeger BM. 1989 Cellular senescence revisted: a review.
Mech Age Dev 38:1– 48.
Steinhagen-Thiessen E, Borchelt M. 1996. Medikation und Funktionalität im Alter. In: Mayer K, Baltes PH, editors. Die Berliner Altersstudie. Berlin: Akademie Verlag, p 151–183.
Sumner DR, Andriacchi TF. 1996. Adpatation to differential loading:
Comparison of growth-related changes in cross-sectional properties
of the human femur and humerus. Bone 19:121–126.
Taaffe DR, Snow-Harter C, Connolly DA, Robinson TL, Brown MD,
Marcus R. 1995. Differential effects of swimming versus weightbearing activity on bone mineral status of eumenorrheic athletes.
J Bone Miner Res 10:586 –593.
Takahashi HE. 1995. Spinal disorders in growth and aging. Tokyo:
Takahashi HE. 1999. Mechanical loading of bones and joints. Tokyo:
Takahashi HE, Tanizawa T, Hori M, Uzawa T. 1991. Effect of intermittent administration of human parathyroid hormone (1-34) on
experimental osteopenia of rats induced by ovariectomy. In: Jee
WSS, editor. The rat model for bone biology studies. Cells Mater
(Suppl 1):113–118.
Tang LY, Cullen DM, Yee, JA, Jee WSS, Kimmel DB. 1997. Prostaglandin E-2 increases the skeletal response to mechanical loading.
J Bone Miner Res 12:276 –282.
Tate MLK, Niederer P, Knothe U. 1998. In vivo tracer transport
through the lacunocanalicular system of rat bone in an environment devoid of mechanical loading. Bone 22:107–117.
Thompson D’Arcy W. 1917. On growth and form. Cambridge: University of Cambridge Press (Dover reprint).
Tinetti ME, Baker DI, McAvay G. 1994. A multifactorial intervention
to reduce the risk of falling among elderly people living in the
community. N Eng J Med 331:821– 827.
Torrance AG, Mosley JR, Suswillo RFL, Lanyon LE. 1994. Noninvasive loading of the rat ulna in vivo induces a strain-related modeling
response uncomplicated by trauma or periosteal pressure. Calc Tiss
Int 54:241–247.
Treharne RW. 1981. Review of Wolff’s Law and its proposed means of
operation. Orthop Rev 10:35– 47.
Tsuji S, Katsukawa F, Onishi S, Yamazaki H. 1996. Period of adolescence during which exercise maximizes bone mass in young women.
J Bone Miner Metabol 14:89 –95.
Turner RT, Riggs BL, Spelsberg TC. 1994. Skeletal effects of estrogen.
Endocrin Rev 15:275–300.
Tylavsky FA, Anderson JJB. 1988. Dietary factors in bone health of
elderly lactoovovegetarian and omnivorous women. Am J Clin Nutr
48:842– 849.
Ullman M, Oldfors A. 1989. Effects of growth hormone on skeletal
muscle. I. Studies on normal adult rats. Acta Physiol Scand 135:
Umemura Y, Ishiko T, Yamauchi T, Kurono M, Mashiko S. 1997. Five
jumps per day increase bone mass and breaking force in rats.
J Bone Miner Res 12:1480 –1485.
Urist MR. 1960. Observations bearing on the problem of osteoporosis.
In: Nicolsen J, editor. Bone as a tissue. New York: McGraw-Hill Co,
p 18 – 45.
Urist MR. 1995. The first three decades of bone morphogenetic protein
research. Osteologie 4:207–223.
van der Perre G, Lowet G. 1996. In vivo assessment of bone mineral
properties by vibration and ultrasonic wave propagation analysis.
Bone (Suppl 1)18:29 –33.
Vaughn VC, KcKay RJ, Nelson WE. 1975. Nelson textbook of pediatrics, 10th ed. Philadelphia: WB Saunders Co.
Verborgt O, Gibson GI, Schaffler MB. 2000. Loss of osteocyte integrity
in association with microdamage, bone remodeling after fatigue
damage in vivo. J Bone Min Res 15:60 – 67.
Vernon-Roberts B, Pirie CJ. 1973. Healing trabecular microfractures
in the bodies of lumbar vertebrae. Ann Rheum Dis 32:406 – 412.
Vico L, Chappard D, Alexandre C, Palle S, Minaire P, Reffat G,
Novikov VE, Bakulin AV. 1987. Effects of weightlessness on bone
mass and osteoclast number in pregnant rats after a five-day space
flight (Cosmos 1514). Bone 8:95–103.
Weinmann JP, Sicher H. 1955. Bone and bones, 2nd ed. St. Louis: CV
Mosby Co.
Welten DC, Kemper HCG, Post GB, VanMechelen WQ, Twisk J, Lips
P, Teule GI. 1994. Weight-bearing activity during youth is a more
important factor for peak bone mass than calcium intake. J Bone
Min Res 9:1089 –1096.
Whedon GD. 1984. Disuse osteoporosis: physiological aspects. Calc
Tiss Int Suppl 36:146 –150.
Wiley JJ, McIntyre MW. 1980. Fracture patterns in pediatric patients. In: Uhthoff HK, editor. Current concepts of bone fragility.
Berlin: Springer-Verlag, p 159 –165.
Wilhelm G, Felsenberg D, Bogusch G, Willnecker J, Thaten I, Gummert P. 1999. Biomechanical examinations for validation of the
Bone Strength Strain Index SSI, calculated by peripheral quantitative computed tomography. In: Lyritis GP, editor. Musculoskeletal interactions, vol II. Athens: Holonome Edtions, p 105–110.
Wittich A, Mautalen CA, Oliveri MB, Bagur A, Somoza F, Rotemberg
E. 1998. Professional football (soccer) players have a markedly
greater skeletal mineral content, density and size than age- and
BMI-matched controls. Calc Tiss Int 63:112–117.
Wolff J. 1892. Das Gesetz der Transformation der Knochen. Berlin: A
Hirschwald (Springer-Verlag published an excellent English translation of this monograph in 1986).
Wolff JW, White AA, Panjabi MM, Southwick WO. 1981. Comparison
of cyclic loading versus constant compression in the treatment of
long-bone fractures. J Bone Jt Surg 63A:805– 810.
Woo SL-Y, Kuei SC, Amiel D, Gomez MA, Hayes WC, White FC,
Akeson WH. 1981. The effect of prolonged physical training on the
properties of long bone. J Bone Jt Surg 63A:780 –787.
Wood BP. 1987. Infant ribs: Generalized periosteal reaction resulting
from vibrator chest physiotherapy. Radiology 162:811– 812.
Woodard JC. 1991. Morphology of fracture nonunion and osteomyelitis. Vet Clin N Am 21:813– 844.
Worton R. 1995. Muscular dystrophies: diseases of the dystrophinglycoprotein complex. Science 270:755–757.
Wronski TJ, Dann LM, Scott KS, Crooke LR. 1989. Endocrine and
pharmacological suppressors of bone turnover protect against osteopenia in ovariectomized rats. Endocrinology 125:810 – 816.
Wronski TJ, Dann LM, Qi H, Yen C-F. 1993. Skeletal effects of
withdrawal of estrogen and diphosphonate treatment in ovariectomzed rats. Calc Tiss Int 53:210 –216.
Wunder CC, Welch RC, Cook KM. 1979. Femur strength as influenced
by growth, bone length and gravity with the male rat. J Biomech
Yamada H. 1970. Strength of biological materials. Baltimore: Williams and Wilkins Co.
Yao W, Jee WSS, Chen J, Liu H, Ta CS, Cui L, Zhou H, Setterberg RB,
Frost HM. 2000. Making rats rise to erect bipedal stance for feeding
partially prevented orchidectomy-induced bone loss and added bone
to intact rats. J Bone Miner Res 15:1158 –1168.
Yeh JK, Chen MM, Aloia JF. 1995. Skeletal alterations in hypophysectomizd rats. I. A histomorphometric study in tibial cancellous
bone. Anat Rec 241:505–512.
Zanchetta JR, Plotkin H, Alvarez-Figueira ML. 1995. Bone mass in
children: Normative values for the 2–20 year-old population. Bone
As some terms have vague or even different meanings in
the medical literature, the intended meaning of some
terms in this article are listed below. (*: The scientifically
correct meaning in 2000 AD.)
architecture: the size, shape, and orientation of a
bone, the amounts of bone tissue in it, and the arrangement of that tissue in anatomical space.
BMU: the Basic Multicellular Unit of bone remodeling
(Jee, 1989)*. In 3 or more months and in a stereotyped,
biologically-coupled Activation 3 Resorption 3 Formation or “ARF” sequence, it turns over ⬇ 0.05 mm3 of
bone. The resulting new packet of bone was called a
bone structural unit (BSU) by Jaworski (1984). When a
BMU makes less bone than it resorbs, that “disuse
mode” tends to remove bone permanently, but only for
bone next to or close to marrow. When it resorbs and
makes equal amounts of bone, that “conservation mode”
turns bone over without net gains or losses. Completed
BMUs do not seem to make more bone than they resorb
so they do not increase bone “mass.” Healthy adult
humans may create and complete about 3 million BMUs
annually, but in disease and other circumstances that
can change more than five times (Frost, 1995).
bone “density”: since the true physical density of bone
as a material varies little with age, sex, and species,
“density” as absorptiometrists use the term only provides an estimate of the amount of bone in the path of
one or more X-ray beams as a bone-mineral equivalent
(here one can assume gamma rays and X-rays are the
same). While many still think otherwise, true bone density is normal in most osteoporoses and osteopenias
(Seeman, 1997). When in quotes in this article, “density”
has its meaning in absorptiometry.
bone “mass”: the amount of bone tissue in a bone or
skeleton, preferably viewed as a volume minus the volume of the soft tissues in the marrow cavity. In absorptiometry, it does not mean mass as used in physics.
When in quotes in this article, it has the absorptiometric meaning.
DEXA: dual energy X-ray absorptiometry. Often also
written as “DXA.”
disuse: bones need some criterion to recognize this.
When a bone’s peak strains down-shift into or below the
remodeling threshold region in Figure 3, for that bone
that would signal the existence of disuse, no matter how
small or big the bone (Frost, 2000a). In such situations,
disuse-mode remodeling usually removes bone next to
marrow. “Disuse” would be the relationship between a
bone’s strength and the size of its usual peak loads and
the strains they cause. The relationship between those
TABLE 4. Conversion factors and symbols for units
Symbols for units
N ⫽ Newton
kg ⫽ kilogram
cm ⫽ centimeter
mpa ⫽ megapascal
M ⫽ meter
in ⫽ inch
psi ⫽ pounds per square inch
mm ⫽ millimeter
lb ⫽ pound
Approximate strain-stress equivalents for normal lamellar cortical bonea (loaded in compression parallel to
the grain)
50–100 microstrain corresponds to ⬇ 1–2 mpa, ⬇ 140–280 psi, 0.2 kg/mm2
1,000 microstrain corresponds to ⬇ 20 mpa, ⬇ 2,800 psi, ⬇ 2 kg/mm2
3,000 microstrain corresponds to ⬇ 60 mpa, ⬇ 8,500 psi, ⬇ 6.1 kg/mm2
25,000 microstrain corresponds to ⬇ 120 mpa, ⬇ 17,000 psi, ⬇ 12.2 kg/mm2
Bone’s ultimate strength is a range centered near 25,000 microstrain, 120 mpa, or 17,000 psi
Some English-metric conversionsa
1 kg ⫽ 2.2 lb ⫽ 9.8 N. 1 N ⫽ 0.225 lb ⫽ 0.102 kg. 1 million N ⫽ 224,000 lb.
1 mpa ⫽ 1 million N/M2 ⫽ 145 psi ⫽ 1 N/mm2 ⫽ 0.102 kg/mm2. 1 kg/cm2 ⫽ 14.2 psi.
1 kg/mm2 ⫽ 9.8 mpa ⫽ 1,420 psi. 120 mpa ⫽ 17,400 psi ⫽ 12.2 kg/mm2. 60 mpa ⫽ 8,700 psi ⫽ 6.1 kg/mm2. 20 mpa ⫽
2,800 psi ⫽ 2.04 kg/mm2. 1 M2 ⫽ 1,550 in2.
1 in2 ⫽ 6.45 cm2.
Values to two or three place accuracy. Taken from Frost (1998a), Yamada (1970), and The Merck Index, 11th ed. (1989).
strains and the remodeling threshold would provide a
natural criterion for “recognizing” disuse.
disuse-pattern osteopenia: as a steady state, an osteopenia in which endocortical bone loss expanded the
marrow cavity, loss of trabecular bone reduced its
amount, cortical porosity remains essentially normal,
and outside bone diameter does not decrease, or may
even increase a bit. The reduced outside bone diameter
in some children’s osteopenias usually reflects failure of
modeling to increase it instead of an effect of periosteal
bone loss. In steady-state osteopenias, surface-referent
bone tissue dynamics tend to be normal for the subject’s
age (Recker, 1983).
drifts: see “modeling” below, and Figure 1.
effector cells: here, differentiated osteoblasts and osteoclasts but not their precursor or other cells. The
effector cells directly make or resorb bone, so by that
definition osteocytes would not be effector cells.
mechanical competence: the state in which bones
endure voluntary physical activities for life without developing spontaneous fractures. Sometimes called “biomechanical competence.” The antonym, “mechanical incompetence,” means the state in which voluntary
physical activities (not injuries) do cause spontaneous
fractures; modeling and/or remodeling disorders would
usually cause it.
microdamage: microscopic physical damage in a structural material due to materials fatigue (Martin et al.,
1989)*. To increase the fatigue life of inanimate structures, engineers usually add more structural material.
But skeletons can detect and repair limited amounts of
fatigue damage to keep it from accumulating, so they only
need enough strength to keep strains below the level that
could cause larger amounts. Presumably they could carry
loads that cause smaller amounts indefinitely.
microdamage threshold: the strain range above
which new microdamage begins to escape repair and
accumulate (MESp in Fig. 3). It seems to center near
3,000 microstrain, which corresponds to a stress of
about 60 megapascals. Pattin et al. (1996) found that as
the loads that originally cause strains in the 2,000 microstrain range only double to cause 4,000 microstrain,
the resulting fatigue damage increases over 500 times.
modeling: the biologic processes that produce function-
ally purposeful sizes, shapes and organization to all
skeletal organs (Jee, 1989)*. Mostly independent resorption and formation modeling drifts do it in bones.
Normally it fits bones to their voluntary mechanical
usage to keep that usage from breaking them. That is
done by making a bone strong enough to keep its typical
peak strains from exceeding bone’s modeling threshold.
modeling threshold: the genetically-determined Minimum Effective Strain range (or equivalent Stimulus;
MESm in Fig. 3) for mechanically controlled bone modeling. Where strains exceed it modeling turns on; where
strains stay below it modeling turns off. It seems to center
near 1,000 microstrain in most young adults, which corresponds to a stress of about 20 megapascals (Table 4).
muscle strength: the maximum momentary contractile force exerted by a muscle can be expressed in Newtons or kiloponds (the attraction of earth’s gravity for a
mass of one kilogram) (Dickinson et al., 2000; Murray et
al., 1980)*. Or muscle strength can be measured as the
peak torque in Newton-meters produced by muscle
forces across joints like the hip, elbow, knee, and fingers. That differs from endurance, which concerns how
long and often submaximal muscle forces can be exerted, as in marathon running*. It differs from mechanical work or energy, which can be expressed in Newtonmeters, Joules, or kilowatt-hours*. It differs from
muscle power, which concerns how rapidly mechanical
work is done and is usually expressed in Newtonmeters/sec, Joules/sec, or watts (one Joule/sec ⫽ one
watt)*. Since bones seem to adapt their strength and
stiffness to the typical peak momentary loads they
carry, accounting for these distinctions can minimize
errors in interpreting and discussing mechanical usage
effects on bone strength and “mass.”
osteopenia: here, less whole-bone strength than usual
for most healthy people of the same age, height, weight,
sex, and race. Also less bone strength than before in the
same person. It need not represent a disease nor stem
from an intrinsic bone disorder. Affected bones would
break more easily. In clinical work, probably the commonest cause of an osteopenia is chronic muscle weakness. But it is currently and usually expressed in terms
of reduced bone “mass” as evaluated by DEXA.
osteoporosis: defining this was debated for decades (Nor-
din, 1987; Urist, 1960). The currently accepted 1994 WHO
“standard” for diagnosing an “osteoporosis” consisted of a
bone mineral “density” or content over 2.5 standard deviations below the applicable norm (Kanis, 1994). Some
suggested an “osteopenia” consists of a reduction in bone
“mass” between 1.0 and 2.4 standard deviations below the
applicable norm. That idea does not depend on the osteopenia’s pathogenesis, yet effective treatment should depend on it. Reviews published after 1985 show many authors find the “Type I, Type II” terms confusing (Riggs et
al., 1998). The pathogenetically-based terms in Part III of
this text would supplement older ones. In this text, without quotes the term signifies any osteopenia in which
voluntary activities (not trauma) cause spontaneous fractures. When in quotes, it would have the above absorptiometric meaning,
remodeling: turnover of bone in small packets by BMUs
(Jee, 1989)*. Pre-1964 literature did not distinguish it
from modeling and lumped them together as “remodeling.”
While drifts and BMUs seem to create and use the same
kinds of osteoblasts and osteoclasts to do their work, in
different parts of the same bone at the same time the
‘blasts and ’clasts in drifts and BMUs can even respond
oppositely to the same stimulus (Chen et al., 1995; Yeh et
al., 1995). Since locally increased remodeling increases
local bone formation, scintigrams (“bone scans”) usually
show increased local uptake of the bone-seeking radioactive tracer, usually technetium.
remodeling space: increased BMU creations also increase the number of temporary holes in a bone and
excavations on its surfaces. That causes a temporary
bone loss called the remodeling space. It is temporary
because when BMU creations return to normal, the
existing holes refill with bone (because of the ARF sequence in BMUs) (Parfitt, 1980). Since increased bone
formation accompanies increased remodeling and an
increased remodeling space, that can help bone scans
(scintograms) with radioactive bone-seeking agents to
locate skeletal pathology when ordinary X-rays appear
normal (Jergensen et al., 1990).
remodeling threshold: the genetically-determined
Minimum Effective Strain range (or equivalent Stimulus; MESr in Fig. 3) that helps to control the switching
of BMU-based remodeling between its conservation and
disuse modes. When strains exceed it, completed BMUs
begin to make and resorb equal amounts of bone to
provide conservation-mode remodeling. When strains
stay below it, completed BMUs next to marrow make
less bone than they resorb to provide the disuse-mode
remodeling that mainly affects trabecular and endocortical bone. This threshold may center near 50 –100 microstrain, which would correspond to a tension or compression stress of ⬇ 1–2 megapascals. One might also
define the threshold as the region just to the left of the
“adapted window” in Figure 3, which could put the
corresponding threshold strain range in the 400 – 600
microstrain region.
resorption: different meanings of this term in the literature cause some confusion. Some authors use it to
mean net bone loss, and in that sense discuss “antiresorption agents.” While often called antiresorption
agents, estrogen and bisphosphonates really depress
BMU creations (Fleisch, 1995; Jee, 1995). At first, that
decreases global resorption, but due to the ARF sequence in the BMU, an equal decrease in global bone
formation usually and eventually follows, so these are
really “antiremodeling agents.” This text uses resorption to mean bone resorption by osteoclasts. It refers to
net losses of bone as such and separately.
strain: the deformation or change in dimensions and/or
shape caused by a load on any structure or structural
material*. It includes stretching, shortening, twisting,
and/or bending. Loads always cause strains, even if very
small ones, and three kinds occur: compression, tension,
and shear. Biomechanicians can express strain in microstrain units (millionths of a 100% strain), where
1,000 microstrain in compression would shorten a bone
by 0.1% of its original length, 10,000 microstrain would
shorten it by 1% of that length, and 100,000 microstrain
would shorten it by 10% of that length (and break it).
Strain emerges as an important signalling mechanism
in controlling a skeleton’s structural adaptations to its
mechanical usage.
strength: the load or strain that, when applied once,
usually fractures a bone (also the “ultimate strength”;
Fx in Fig. 3)*. Normal lamellar bone’s fracture strength
expressed as a strain is a range centered near 25,000
microstrain (somewhat lower in adults and higher in
rapidly growing mammals). That corresponds to a
change from 100% of its original length to 97.5% of that
length under compression, or to 102.5% of it under tension (Table 4).
strength-safety factor: when defined as how much
stronger a bone is than needed to carry the typical
largest voluntary loads on it, this factor would equal the
ultimate strength divided by the modeling threshold
when both are expressed as stresses. From Table 4 and
in young adults, that would equal 120 mpa ⫼ 20 mpa ⫽
6. Since the modeling threshold determines the largest
allowed bone strain or stress, when that threshold lies
below the ultimate strength it creates the safety factor.
Bones cannot foresee and adapt their strength to future
injuries, so they must adapt to past and present voluntary physical activities instead, whether the activities
are subnormal, normal, or supranormal.
“supranormal” exercise: here, high-force muscular
activities that cause the largest momentary voluntary
loads on bones. Examples include weight lifting and highacceleration sports like soccer and US-style football.
typical peak strains: visualize a histogram that plots
the sizes of a bone’s strains (or loads) on the vertical axis,
and on the horizontal axis the number of times dynamic
strains of a given size occurred during, say, a week. The
strains large enough to turn modeling on would be the
largest ones in that histogram, but would comprise fewer
than 0.01% of all strain events in that week. For example,
each systolic pulse in the marrow cavity is a loading event
on a hollow bone like the femur. In a week it would carry
over 725,000 corresponding strains, of which only ⬇ 50
from peak muscle forces might be large enough to reach or
exceed bone’s modeling threshold. The bone would adapt
its strength and “mass” to those ⬇ 50 events and pay little
attention to all others. While some controversy affected
this feature, the different bone strengths of long distance
runners and weight lifters strongly suggest it is true. It
would also be an obligatory effect of a modeling threshold’s
existence, which led me to infer that threshold’s existence
before in vivo strain studies verified its existence (Frost,
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