C a l c i f T i s s u e I n t (1989) 45:131-133
Calcified Tissue
Editorials
Some ABCs of Skeletal Pathophysiology III: Bone Balance and
the AB.BMU
Preceding editorials described general properties of
skeletal mediator mechanism, that they have their
own functions and different game rules from iso-
lated cells, and that they directly underlie most
skeletal disease and treatment effects. This editorial
describes a special function of one of the mediator
mechanisms that controls human bone balance, a
matter that bears on the pathogenesis, prevention,
treatment, and research of adult-acquired human
osteoporoses. 1
The BMU
Between 1964 and 1973, a mediator mechanism that
controls bone balance as well as some of its prop-
erties was discovered [1, 2]. That bone remodeling
BMU (basic multicellular unit) turns over small
packets of about 0.05 mm 3 of bone per completed
packet. A local Activation event starts its histoge-
netic stage. In the following construction stage,
bone Resorption occurs for about a month, fol-
lowed by Formation for about 3 more months (Fig.
1, top and 2nd rows). When that ARF sequence
ends, the newly created packet of lamellar bone,
such as a secondary osteon, begins its maintenance
stage of life, typically lasting 2-20 years. During
that phase, it carries some of the physical loads on
the bone it lies in and likely has homeostatic and
other functions, including mechanical microdamage
detection, that do not concern us here [3].
Send reprint requests to Dr. H. M. Frost, Department of Ortho-
paedic Surgery, Southern Colorado Clinic, 2002 Lake Ave.,
Pueblo, CO 81004, USA.
1Many authorities have discussed what controls our bone bal-
ance from other viewpoints. They include, among others, L Avi-
oli, D Baylink, C Christensen, J Haddad, R Heaney, J Jowsey,
PJ Meunier, A Reifenstern, BL Riggs, RW Smith, S Walser, and
D Whedon.
International
9 1989 Springer-Verlag New York Inc.
The AB.BMU
In principle, completed BMUs need not resorb and
form equal amounts of bone. In fact, where BMUs
touch marrow they form less than they resorb to
leave a small net local permanent bone loss (Fig.
lI). They form more than they resorb on diaphyseal
periosteal surfaces (Fig. 1G) and resorb and form
nearly equal amounts on haversian surfaces in com-
pact bone (Fig. 1H) [4-6].
Call that bone balance of a completed bone re-
modeling BMU the AB.BMU (delta bee per BMU)
[6]. Five of its properties affect efforts to restore
bone to adult osteoporosis patients or to study the
tissue mechanisms that cause excessive bone loss in
human adults (later editorials will review further tis-
sue mechanisms that affect bone mass in children).
(1) The AB.BMU alone directly determines whether
an adult's bone balance has a negative, zero, or
positive value (Fig. 1, bottom row), except for dis-
eases that produce woven bone (e.g., myelofibro-
sis, myositis ossificans) or reactivate bone forma-
tion modeling drifts (e.g., Paget's disease, acromeg-
aly) [3-6]. (2) The AB.BMU applies only to BMU
that have completed their construction stage, how-
ever long that takes [3-6]. (3) As the AB.BMU de-
termines the sign of the bone balance, that defines
one function of the BMU [5]. (4) Because BMUs on
trabecular and cortical-endosteal surfaces have a
negative mean AB.BMU throughout life (Fig. 1,
bottom right) and have not yet shown a positive one
there (excepting in Anderson's experiment quoted
shortly), our normal annual bone losses usually af-
fect spongiosa and expand the marrow cavity diam-
eter. Bone losses in adult-acquired osteoporoses
tend to have the same distribution [3-6]. (5) Adult
annual bone losses (normally about 0.75% of the
previous bone mass) equal the product of the
AB.BMU for the "typical" remodeling B M U (nor-
mally about -0.003 mm 3 bone/BMU) times how
132 H.M. Frost: ABCs of Skeletal Pathophysiology III

A a c

Time )

_ _ _..~-

~ B 9 BMU= (+) ~B.BMU = (0) AB.BMU = ( - )

t )
Fig. 1. Top row: The ARF sequence of remodeling BMU on a trabecular surface. Second row: the scales are changed to bring out the
relative amounts of resorption and formation in a completed BMU. TMrd row: net excess (13)and loss (I) of bone in completed BMU.
Bottom row: The effect on local bone balance and mass of a series of BMU with the AB.BMU value directly above (reprinted by
permission: HM Frost, Intermediary organization of the skeleton, CRC Press, Boca Raton, 1986).

many such BMUs are completed during the year
(normally about 6 x l 0 6 BMUs), a histogenetic-
stage feature called the "activation f r e q u e n c y " by
bone histomorphometrists who learned how to mea-
sure it in 1964 [1, 2, 7].
Control of the A B . B M U
What controls the number of BMUs completed an-
nually in a skeleton is discussed elsewhere and in
later editorials as well. The AB.BMU itself has not
yet had systematic study although P Courpron, D
Darby, E F Eriksen, and PJ Meunier, among others,
have done preliminary studies. Eriksen's are out-
standing (he had outstanding teachers in F Melsen
and L Mosekilde at Aarhus). Those studies and
other evidence provide clues about its regulation.
D e c r e a s i n g l y vigorous m e c h a n i c a l usage can
make the AB.BMU more negative, sometimes by
delaying and/or nearly suppressing the formation
phase o f the B M U (some call that "uncoupling").
Adrenalcortical steroids and possibly estrogen de-
ficiency also have negative effects whereas calcito-
nin, fluoride (studied b y F Olah, L Jagstrup, L
Mosekilde), growth hormone, and estrogen (studied
by C Anderson, C Jerome, TJ Wronski) may have
positive effects. The human strict A D F R osteopo-
rosis treatment experiment by Anderson et al. in
London, Ontario caused a considerably positive
trabecular AB.BMU [8], as the treatment's origina-
tor predicted in 1979 [9]. L a c k of appropriate stud-
ies leaves us ignorant of how, for example, so-
matomedins, parathyroid hormone, vitamin D and
its metabolites, t h y r o x i n e , dietary calcium and
p h o s p h a t e , and v a r i o u s c y t o k i n e s a f f e c t the
AB.BMU.
Comment
Since 1935, most authorities followed the lead of F
Albright and FC M c L e a n by thinking we could cure
osteoporoses by giving agents continuously to ei-
ther depress existing osteoclasts or invigorate ex-
isting osteoblasts. That idea could be encoded as
[6]:
H. M. Frost: ABCs of Skeletal Pathophysiology III
a g e n t ---> cell --* organ (I)
The idea contains the assumptions never tested
by experiment that agents do not act on both re-
sorption and formation, and in the same way. Yet in
that regard, hundreds of human experiments since
1935 failed to make the idea work. Today we prob-
ably understand why: the intact remodeling BMU
couples bone resorption to formation in a way that
makes most known agents change the amounts of
resorption and formation in completed B M U in the
same direction if not always equally [5]. That could
be encoded as:
a g e n t ---> ( B M U / A R F ) ---> organ (2)
Consequently, investigators must accept that cir-
culating agents do not independently regulate re-
sorption or formation by remodeling BMUs [3, 6].
Drugs that affect one activity usually affect the
other also. Proof lies in the clinical-pathologic fact
that no known continuously given drug or other
agent ever made whole skeletons lose or gain bone
without limit. They lose or gain up to a point and
then level off, a statement that defines the 1964-
1967 "Frost-Heaney observation" [6]. 2 Therefore,
controlling bone balance requires learning how to
control the AB.BMU. The ideas and physiology em-
bodied in Anderson's ADFR experiment specifi-
cally address that problem. That idea could be en-
coded as:
a g e n t ---> ( B M U / A B . B M U ) ---> bone b a l a n c e effect
(3)
The normal remodeling BMU finishes its ARF
sequence in about 4 months, but dynamic histomor-
phometric studies of bone biopsies from symptom-
atic osteoporosis victims show it takes them 1-5
years to complete the construction stage of the typ-
2Brought up in many discussions at WSS Jee's annual Bone
Workshops, and also noted by C Cann, RP Heaney, H Genant,
R Lindsay, CC Johnston, Jr., AM Parfitt, RR Recker, BL Riggs,
and R Talmage. See also Orthop Clin North Am 12:1981, and
Clin Orthop Rel Res 200:1985. A flier explaining the Frost-
Heaney observation was distributed at the I987 Bone Workshop
and WSS Jee, AM Parfitt, F Melsen, or H Takahashi might sup-
ply copies if asked.
133
ical BMU. Subsequent editorials will describe why
that correspondingly prolongs how long an osteo-
porosis treatment should last to show its steady-
state effects on bone balance and mass.
The AB.BMU function is a property of intact re-
modeling BMUs. It does not exist in current cell,
tissue, and organ culture systems [5] which pro-
vides one of many reasons why live animal research
must continue. The more such research is ad-
dressed to the above matters the sooner we can
master and exploit them for clinical u s e . 3
The fourth editorial of this series will discuss how
steady states happen and how that knowledge can
help to design experiments and interpret their re-
suits.
H. M. Frost
Department of Orthopaedic Surgery
Southern Colorado Clinic
Pueblo, Colorado
USA
References
1. Frost HM (1964) Mathematical elements of lamellar bone re-
modelling. Charles C. Thomas, Springfield
2. Frost HM (1969) Tetracycline-based histological analysis of
bone remodeling. Calcif Tissue Res 3:211-237
3. Uhthoff H (ed) (1986) Current concepts of bone fragility.
Springer-Verlag, Berlin
4. Frost HM (1988) Bone "mass" and the mechanostat. A pro-
posal. Anat Rec 219:1-9
5. Kleerekoper M, Krane SM (eds) (in press) Clinical disorders
of bone and mineral metabolism. Mary Ann Liebert, Inc., New
York
6. Frost HM (1986) Intermediary organization of the skeleton.
CRC Press, Boca Raton
7. Recker RR (ed) (1987) Bone histomorphometry. Techniques
and interpretation. CRC Press, Boca Raton
8. Anderson C, Cape RDT, Crilly RG, Hodsman AB, Wolfe
BMJ (1983) Preliminary observations on a form of coherence
therapy for osteoporosis. Calcif Tissue Int 36:341-343
9. Frost HM (1979) Treatment of osteoporoses by manipulation
of coherent bone cell populations. Clin Orthop Rel Res
143:227-244
Received November 23, 1988, and accepted December 16, 1988.
3This editorial was reviewed before publication by C Anderson,
JS Arnold, WSS Jee, RB Martin, J McAllister, RW Norrdin, and
MR Urist.