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C a l c i f T i s s u e I n t (1989) 45:131-133

Calcified Tissue
International
9 1989 Springer-Verlag New York Inc.

Editorials

Some ABCs of Skeletal Pathophysiology III: Bone Balance and


the AB.BMU

Preceding editorials described general properties of The AB.BMU


skeletal mediator mechanism, that they have their
own functions and different game rules from iso- In principle, completed BMUs need not resorb and
lated cells, and that they directly underlie most form equal amounts of bone. In fact, where BMUs
skeletal disease and treatment effects. This editorial touch marrow they form less than they resorb to
describes a special function of one of the mediator leave a small net local permanent bone loss (Fig.
mechanisms that controls human bone balance, a lI). They form more than they resorb on diaphyseal
matter that bears on the pathogenesis, prevention, periosteal surfaces (Fig. 1G) and resorb and form
treatment, and research of adult-acquired human nearly equal amounts on haversian surfaces in com-
osteoporoses. 1 pact bone (Fig. 1H) [4-6].
Call that bone balance of a completed bone re-
modeling BMU the AB.BMU (delta bee per BMU)
The BMU [6]. Five of its properties affect efforts to restore
bone to adult osteoporosis patients or to study the
Between 1964 and 1973, a mediator mechanism that tissue mechanisms that cause excessive bone loss in
controls bone balance as well as some of its prop- human adults (later editorials will review further tis-
erties was discovered [1, 2]. That bone remodeling sue mechanisms that affect bone mass in children).
BMU (basic multicellular unit) turns over small (1) The AB.BMU alone directly determines whether
packets of about 0.05 mm 3 of bone per completed an adult's bone balance has a negative, zero, or
packet. A local Activation event starts its histoge- positive value (Fig. 1, bottom row), except for dis-
netic stage. In the following construction stage, eases that produce woven bone (e.g., myelofibro-
bone Resorption occurs for about a month, fol- sis, myositis ossificans) or reactivate bone forma-
lowed by Formation for about 3 more months (Fig. tion modeling drifts (e.g., Paget's disease, acromeg-
1, top and 2nd rows). When that ARF sequence aly) [3-6]. (2) The AB.BMU applies only to BMU
ends, the newly created packet of lamellar bone, that have completed their construction stage, how-
such as a secondary osteon, begins its maintenance ever long that takes [3-6]. (3) As the AB.BMU de-
stage of life, typically lasting 2-20 years. During termines the sign of the bone balance, that defines
that phase, it carries some of the physical loads on one function of the BMU [5]. (4) Because BMUs on
the bone it lies in and likely has homeostatic and trabecular and cortical-endosteal surfaces have a
other functions, including mechanical microdamage negative mean AB.BMU throughout life (Fig. 1,
detection, that do not concern us here [3]. 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-
Send reprint requests to Dr. H. M. Frost, Department of Ortho- fect spongiosa and expand the marrow cavity diam-
paedic Surgery, Southern Colorado Clinic, 2002 Lake Ave.,
Pueblo, CO 81004, USA.
eter. Bone losses in adult-acquired osteoporoses
tend to have the same distribution [3-6]. (5) Adult
1Many authorities have discussed what controls our bone bal-
ance from other viewpoints. They include, among others, L Avi- annual bone losses (normally about 0.75% of the
oli, D Baylink, C Christensen, J Haddad, R Heaney, J Jowsey, previous bone mass) equal the product of the
PJ Meunier, A Reifenstern, BL Riggs, RW Smith, S Walser, and AB.BMU for the "typical" remodeling B M U (nor-
D Whedon. 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 ficiency also have negative effects whereas calcito-
(normally about 6 x l 0 6 BMUs), a histogenetic- nin, fluoride (studied b y F Olah, L Jagstrup, L
stage feature called the "activation f r e q u e n c y " by Mosekilde), growth hormone, and estrogen (studied
bone histomorphometrists who learned how to mea- by C Anderson, C Jerome, TJ Wronski) may have
sure it in 1964 [1, 2, 7]. positive effects. The human strict A D F R osteopo-
rosis treatment experiment by Anderson et al. in
London, Ontario caused a considerably positive
Control of the A B . B M U trabecular AB.BMU [8], as the treatment's origina-
tor predicted in 1979 [9]. L a c k of appropriate stud-
What controls the number of BMUs completed an- ies leaves us ignorant of how, for example, so-
nually in a skeleton is discussed elsewhere and in matomedins, parathyroid hormone, vitamin D and
later editorials as well. The AB.BMU itself has not its metabolites, t h y r o x i n e , dietary calcium and
yet had systematic study although P Courpron, D 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
Darby, E F Eriksen, and PJ Meunier, among others, AB.BMU.
have done preliminary studies. Eriksen's are out-
standing (he had outstanding teachers in F Melsen Comment
and L Mosekilde at Aarhus). Those studies and
other evidence provide clues about its regulation. Since 1935, most authorities followed the lead of F
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 Albright and FC M c L e a n by thinking we could cure
make the AB.BMU more negative, sometimes by osteoporoses by giving agents continuously to ei-
delaying and/or nearly suppressing the formation ther depress existing osteoclasts or invigorate ex-
phase o f the B M U (some call that "uncoupling"). isting osteoblasts. That idea could be encoded as
Adrenalcortical steroids and possibly estrogen de- [6]:
H. M. Frost: ABCs of Skeletal Pathophysiology III 133

a g e n t ---> cell --* organ (I) ical BMU. Subsequent editorials will describe why
that correspondingly prolongs how long an osteo-
The idea contains the assumptions never tested porosis treatment should last to show its steady-
by experiment that agents do not act on both re- state effects on bone balance and mass.
sorption and formation, and in the same way. Yet in The AB.BMU function is a property of intact re-
that regard, hundreds of human experiments since modeling BMUs. It does not exist in current cell,
1935 failed to make the idea work. Today we prob- tissue, and organ culture systems [5] which pro-
ably understand why: the intact remodeling BMU vides one of many reasons why live animal research
couples bone resorption to formation in a way that must continue. The more such research is ad-
makes most known agents change the amounts of dressed to the above matters the sooner we can
resorption and formation in completed B M U in the master and exploit them for clinical u s e . 3
same direction if not always equally [5]. That could The fourth editorial of this series will discuss how
be encoded as: steady states happen and how that knowledge can
a g e n t ---> ( B M U / A R F ) ---> organ (2) help to design experiments and interpret their re-
suits.
Consequently, investigators must accept that cir-
H. M. Frost
culating agents do not independently regulate re-
Department of Orthopaedic Surgery
sorption or formation by remodeling BMUs [3, 6].
Southern Colorado Clinic
Drugs that affect one activity usually affect the
Pueblo, Colorado
other also. Proof lies in the clinical-pathologic fact
USA
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 References
then level off, a statement that defines the 1964- 1. Frost HM (1964) Mathematical elements of lamellar bone re-
1967 "Frost-Heaney observation" [6]. 2 Therefore, modelling. Charles C. Thomas, Springfield
controlling bone balance requires learning how to 2. Frost HM (1969) Tetracycline-based histological analysis of
control the AB.BMU. The ideas and physiology em- bone remodeling. Calcif Tissue Res 3:211-237
bodied in Anderson's ADFR experiment specifi- 3. Uhthoff H (ed) (1986) Current concepts of bone fragility.
Springer-Verlag, Berlin
cally address that problem. That idea could be en- 4. Frost HM (1988) Bone "mass" and the mechanostat. A pro-
coded as: posal. Anat Rec 219:1-9
5. Kleerekoper M, Krane SM (eds) (in press) Clinical disorders
a g e n t ---> ( B M U / A B . B M U ) ---> bone b a l a n c e effect of bone and mineral metabolism. Mary Ann Liebert, Inc., New
(3) York
6. Frost HM (1986) Intermediary organization of the skeleton.
The normal remodeling BMU finishes its ARF CRC Press, Boca Raton
sequence in about 4 months, but dynamic histomor- 7. Recker RR (ed) (1987) Bone histomorphometry. Techniques
phometric studies of bone biopsies from symptom- and interpretation. CRC Press, Boca Raton
atic osteoporosis victims show it takes them 1-5 8. Anderson C, Cape RDT, Crilly RG, Hodsman AB, Wolfe
BMJ (1983) Preliminary observations on a form of coherence
years to complete the construction stage of the typ-
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
2Brought up in many discussions at WSS Jee's annual Bone
Workshops, and also noted by C Cann, RP Heaney, H Genant,
143:227-244
R Lindsay, CC Johnston, Jr., AM Parfitt, RR Recker, BL Riggs, Received November 23, 1988, and accepted December 16, 1988.
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 3This editorial was reviewed before publication by C Anderson,
and WSS Jee, AM Parfitt, F Melsen, or H Takahashi might sup- JS Arnold, WSS Jee, RB Martin, J McAllister, RW Norrdin, and
ply copies if asked. MR Urist.