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J Musculoskelet Neuronal Interact 2008; 8(1):2-9
it has been proposed that increased bone turnover (i.e., rapid
bone remodeling resulting in negative balance in the bone
multicellular unit) would underlie a loss in bone strength and
lead to higher susceptibility to fractures through deteriorat-
ed bone microarchitecture, a trait that cannot be captured by
the BMD measurement
11
. However, as fascinating as this
approach might be – filling the information gap in the frac-
ture prediction not revealed by BMD – there are fundamen-
tal concerns that need to be elaborated. To begin with, we
need to comprehend the complex interrelationship between
BMD, bone strength, and fractures (bone fragility).
While there is indeed a high correlation (up to 0.9 or even
more) between BMD and bone strength in laboratory test-
ing, one should recall that:
1) Correlation does not mean straight agreement but only
group-level association between these two measures; and,
the wider the range in these variables, the stronger the
group correlation despite unacceptably large individual
differences. This means that in two individuals with the
same BMD, the actual bone strength can differ consider-
ably, even tens of percents.
2) The high correlation between BMD and bone strength
has been obtained in in vitro measurements, whereas in a
real clinical setting, BMD measurements on individual
patients are subject to sizable inaccuracies and substan-
tial uncertainty.
3) Susceptibility to fractures ("bone fragility") is attributable
not only to declined bone strength but especially to
extraskeletal etiological factors of fractures (falling).
What is BMD?
Given the strong association between DXA-derived areal
BMD and bone strength in cadaver biomechanical experi-
ments, it is tempting to conclude that BMD is a valid meas-
ure of bone strength. However, considerable inconsistency
between DXA-derived "density" and actual whole bone
Hylonome
Only reasonable theory and well-defined concepts can
underpin the knowledge on which new scientific applications
and procedures (e.g., evidence-based treatments) can be
built. Otherwise, any new concept or method, irrespective of
its potential, may remain loose and not transferred into the
form of truly working knowledge and useful applications.
The common notion that DXA-derived BMD would rep-
resent a valid predictor of bone strength is based on high
correlation (r values up to 0.9 or even more) between these
two variables in controlled laboratory experiments.
However, when large multicenter clinical trials on the effects
of antiresorptive bisphosphonate therapy (alendronate and
risendronate) or selective estrogen receptor modulator ther-
apy (raloxifene)
1,2
reported consistently greater reductions in
fracture incidence than could be anticipated from changes in
BMD, speculations on possible additional effects of antire-
sorptive treatment on something yet unknown, called "Bone
Quality", were inspired
2-7
. "Bone Quality" was defined as
"The sum total of characteristics of the bone that influence
the bone’s resistance to fracture", suggesting that BMD and
"Bone Quality" together would independently account for
bone fragility in totality (Figures 1A and 1B).
The "Bone Quality" concept has since been embraced
among the clinical osteoporosis community, as it seems to
offer a panacea for the clinical paradox that while clinical
BMD measurements can predict the relative fracture risk at
the population level, the predictive value of BMD in individ-
ual patients remains quite marginal; one will fracture but
another will not, despite similar BMD values
8-10
. Accordingly,
Bone quality: Emperor’s new clothes
T.L.N. Järvinen
1,2
, P. Kannus
2,3
, H. Sievänen
3
1
Department of Surgery and the Institute of Medical Technology, University of Tampere, Tampere, Finland;
2
Division of Orthopaedics and Traumatology, Department of Trauma, Musculoskeletal Surgery and Rehabilitation,
Tampere University Hospital, Tampere, Finland;
3
Bone Research Group, UKK-Institute, Tampere, Finland
Keywords: Aging, Bone Density, Bone Remodeling, Clinical Trials, Diphosphonates, Osteoporosis, Risk Factors
Black Forest Forum
May 10-13, 2007
Castle Bad Liebenzell, Germany
The authors have no conflict of interest.
Corresponding author: Teppo Järvinen, M.D., Ph.D., University of Tampere,
Department of Surgery, 33 014 University of Tampere, Tampere, Finland
E-mail: teppo.jarvinen@uta.fi
Accepted 1 June 2007
T.L.N. Järvinen et al.: Bone Quality - an impasse
3
strength arises from the fact that the DXA measurement is
"planar" by nature; that is, DXA scans the three-dimension-
al structure of bone only from one direction (as if it were a
two-dimensional sheet). Accordingly, DXA-derived BMD
does not directly represent a volumetric density of any kind,
but rather is an ambiguous, lumped parameter depending
strongly on volumetric bone mineral apparent density
(BMAD) and bone size (i.e., the larger the bone, the higher
the BMD at given BMAD)
12-15
and also on the scan projec-
tion (i.e., the thicker the bone in the scan direction, the high-
er the BMD at given BMAD and bone size)
16-19
. In fact,
BMD reflects nothing but the mean thickness of bone min-
eral within the given bone region without knowledge of the
true spatial bone mineral distribution in the depth direction
– at its best (Figure 2).
The other crucial limitation of DXA pertains to its inher-
ent inaccuracy which arises from the "two-component
assumption" of the method. In short, taking bone material as
the first component, DXA assumes that the composition and
distribution of all extra- and intraosseus soft tissues and
other body constituents within the scanned region constitute
an absorptiometrically homogeneous second "component".
Not surprisingly, this two-component model does not mirror
true anatomy, and thus, DXA-derived BMD is inherently
Figure 1. Schematic representation of associations between different factors underlying bone strength and fragility. Traditionally it was sim-
plistically believed that the DXA-derived areal BMD, given the strong correlation between BMD and bone strength in biomechanical exper-
iments of cadaver bones (r values up to 0.9 or even more), would represent a valid measure of whole bone strength (Figure 1A). Later it
was observed in several large multicenter clinical drug trials that the reductions in fracture incidence and BMD are inconsistent indicating
that BMD alone is not enough, but BMD together with "Bone Quality" would independently account for bone fragility in totality (Figure
1B). However, given the physical ambiguity of both of these factors
15,48
, it is obvious that BMD and most of the alleged quality characteris-
tics, measurable in vivo, are largely inseparable (Figure 1C). Finally, it must be underscored that an elderly person's bone fracture depends
on not only whole bone strength but especially fall-induced external loading, the latter, in fact, accounting much more for the fragility frac-
tures than bone strength (Figure 1D). Fall biomechanics and the concomitant bone loading is the major determinant of these fractures. For
example, over 90% of hip fractures are a direct consequence of falling
37,58
. Of note, this schematic presentation is not an exhaustive descrip-
tion of all possible factors underlying bone strength, bone fragility, and their interactions but is intended to illustrate the complexity that
needs to be taken into account when assessing skeletal fragility in general.
T.L.N. Järvinen et al.: Bone Quality - an impasse
4
inaccurate, either under- or overestimating true BMD to
some indeterminate extent in any given patient, the actual
magnitude of this error ranging as high as 20 to 50%
19-23
. The
adverse effect of these inaccuracies on the validity of BMD
as a measure of whole bone strength of an individual is
shown in many biomechanical studies and on the BMD
measurement per se in careful cadaver studies (Table 1).
BMD – a valid surrogate of whole bone strength?
Since BMD depends on bone cross-sectional size (
~
load-
bearing area) and apparent density (
~
indicator of bone tis-
sue strength), it is, in principle, mechanically plausible why
BMD is a relatively good surrogate of bone strength in a lab-
oratory setting. On the other hand, this dual nature of BMD
also complicates its precise interpretation
15
. Obviously,
BMD reflects the amount of bone mass, and bone mass in
itself cannot be indicative of actual bone structure, whereas
many structural particulars (i.e., overall bone size, cortical
thickness and porosity, trabecular thickness and number,
mineralization) contribute directly to bone mass. This simply
means that BMD and most of the structural (alleged quali-
ty) characteristics, measurable in vivo, are largely inseparable
(Figure 1C). In other words, BMD is virtually an average
measure of almost everything within the measured bone site,
but nothing specifically. Accordingly, there is not much left
for subtle structural particulars to account for in the statisti-
cal sense. So, why don’t we ask what would the bone mass
add if we knew the bone structure? At the moment, the par-
adigm is upside down.
Bone Quality – the newly introduced concept
As of today, we do not have a universally accepted meas-
urement or indicator of "Bone Quality" (neither a single
measure nor a combination of different bone parameters),
or a unit for bone quality, or even a criterion for "good or bad
Figure 2. Schematic representation of the meaning of common DXA parameters. Bone is a three-dimensional structure, made of a given
amount of bone mineral (BMC). In the primary BMD measurement, the information describing the bone structure is reduced into a single
value, BMD. In essence, BMD denotes the mean thickness of bone mineral (x), as if the BMC measured within the region-of-interest (ROI)
was of uniform true material density (Ú) and further tightly and evenly packed into a box whose length (L) corresponds to that of the ROI
and width (W) to the mean bone width within the ROI. Note that BMC is a more reasonable measure of bone structure than BMD, since
it denotes the cross-sectional area occupied by bone mineral. Since DXA measurement is subject to inherent inaccuracies
19,20,22,23
, there is
always uncertainty regarding the true amount of BMC within the ROI.
Table 1. Correlation (r) between the DXA-derived BMD as
obtained in in situ (all soft tissues intact) and ex situ (water bath)
measurements of cadaver bones and the failure strength of lumbar
vertebrae and femoral neck.
DXA site In situ Ex situ Ref.
Lateral spine 0.45 0.71
49
0.91
50
0.83
51
AP spine 0.48 0.51
49
0.53
52
0.72 0.77
51
Femoral neck 0.64
49
0.84
53
0.96
54
0.89
55
0.82-0.84
56
0.94
16
0.95
57
T.L.N. Järvinen et al.: Bone Quality - an impasse
5
bone quality". According to the Webster’s dictionary, the
word "quality" is defined as: 1) any of the features that make
something what it is; characteristics element; attribute, 2)
basic nature; character; kind, 3) the degree of excellence
which a thing possesses, or 4) excellence; superiority. In busi-
ness and industry, the concept "quality" has been classically
defined as "fitness for use"
24
or "conformance to require-
ments"
25
. Coupling the arguments behind the "Bone Quality"
concept with different definitions of quality, one is inherent-
ly left with the impression that a good quality of bone equates
to good bone strength, or even as broadly as high resistance
to fractures.
Bone Strength = BMD+Bone Quality?
At present, "Bone Quality" denotes an obscure term
incorporating a pool of various non-BMD indices of bone
strength. Needless to say, it is impossible to measure direct-
ly the bone strength in patients in vivo, whereas in pre-clini-
cal animal experiments the bone strength can be measured.
Then, if "Bone Quality" had accounted independently for the
bone fragility (as implied by several clinical fracture
59
preven-
tion studies), we should have observed the similar discor-
dance between the changes in bone mineral density or mass
and bone strength in numerous well-controlled preclinical
studies. However, the discrepancy is not there! In fact, the
effects of bisphosphonates on bone strength have been per-
fectly commensurate with changes in bone mass in virtually
life-long animal experiments of different species
26-32
.
Bone fragility (Resistance to fractures)=
BMD+Bone Quality?
More recently, the term "Bone Quality" has been defined
as broadly as: "Bone quality recognizes the unpredicted por-
tion of fracture risk with respect to the predicting variables"
33
.
In essence, this "extended definition of Bone Quality" not
only suggests that together BMD and "Bone Quality" would
independently account for bone fragility in totality, but also
implies that the bones are primarily designed and adapted to
resist fractures. However, there are major conceptual flaws
in this approach, too.
First, while the high correlation between BMD and bone
strength in the laboratory setting, as well as the increased rel-
ative risk of osteoporotic fractures among patients with low
BMD, are indeed established, one should keep in mind that
at various skeletal sites the overall proportion of elderly peo-
ple's fractures attributable to low BMD remains modest
(ranging from <10% to 44%)
9
. In other words, more than
50% of fragility fractures occur in the population which is
not classified as osteoporotic in the sense of the current
WHO operational definition of osteoporosis (i.e., BMD 2.5
standard deviations or more below the young sex-matched
adult reference level). In this respect, we have to recall that
BMD in itself is only a modest risk factor of fractures - some
85% of the contribution to the rise in fracture risk with age
is unrelated to BMD
34
.
According to several well-designed studies on risk factors of
fractures among elderly people
35-43
, falling with its determi-
nants - not the BMD-based osteoporosis - has been shown to
be the strongest single risk factor for a fracture, and when a
person falls, the type and severity of falling (fall height and
energy; fall direction; fall mechanics; anatomical site of the
impact; and energy absorption capacity and impact force atten-
uation of the body-landing surface complex) are crucial in
determining whether or not a fracture occurs
35-40
. Compared
with the modest association between BMD and risk of frac-
ture, the relative risk of hip fracture for a sideways fall is about
5, and if the fall impacts directly the greater trochanter of the
proximal femur, the relative risk rises up to 30
37,41,42
. Similar
results have been obtained for upper extremity fractures
35,43
.
With this in mind, it is quite utopian to envision that a purely
bone-derived measure (such as BMD or bone turnover mark-
ers) alone could explain the occurrence of fractures, as implied
by the broadest definitions of "Bone Quality" at present.
Now, regarding the notion that bones would primarily be
designed and adapted to resist fractures one should recall the
following facts. The human skeleton is basically and contin-
ually adapted to habitual locomotive loadings (Figure 3A),
and is particularly fit for endurance running
44
, but not to
loadings caused by falls onto the ground (or by other similar
trauma-related events) that cause fractures
45
. Clearly, there
is a tradeoff between the bone strength and other factors,
including the metabolic pressure to keep the weight of these
locomotive organs light. In support of this, there is over-
whelming evidence that the variation in the apparent
strength of human bones is attributable to variations in the
loading environment the bones are subjected to during daily
habitual activities
45,46
. As regards the capacity of the skeleton
to resist fracture during accidents one must distinguish
between two situations: whether the loading experienced
during a traumatic incident is just a magnification of the
loading experienced during habitual activities (but in this
case just exceeding the bone's capacity to withstand the load-
ing) (Figure 3B), or the loading and its direction are com-
pletely different from that the bones are customarily adapt-
ed to. In many cases of older adults' fractures (even those of
vertebrae that are commonly considered "spontaneous"),
they are indeed different (Figure 3C)
45
.
Are we hostages to the ambiguous BMD?
Since the whole bone strength provides the ultimate
measure of bone mechanical competence, the clinical osteo-
porosis paradox seems to simply stem from our inherent
inability to determine the actual bone strength or fragility of
an individual in vivo. We should not remain hostages to the
ambiguous BMD and cursorily reduce the bone fragility into
two seemingly independent factors: 1) The familiar/conven-
tional BMD, and 2) the new and fascinating "Bone Quality"
denoting the vague provisions of (all) non-BMD factors,
T.L.N. Järvinen et al.: Bone Quality - an impasse
6
which together would perfectly explain the bone fragility
(Figure 1B).
As a properly defined concept, the "Bone Quality" should
equate nothing but the capacity of bones to withstand a wide
range of loading without breaking. Because bone structure is
the ultimate determinant of whole bone mechanical compe-
tence and pertains to the endpoint of all interim biochemical
processes within the bone tissue
47
, the adequately compre-
hensive in vivo assessment of the bone structure is what we
should pursue.
"We measure things because we CAN. Accordingly, it is cru-
cial to fully understand the context of one's measurements."
Anonymous
Bone Quality – An empty term
We can assess the whole bone strength quite well in a lab-
oratory setting. In real life, our abilities to do so are much
more limited. Nevertheless, the mere inability to do so with
actual patients in vivo cannot be taken as a justification to
introduce new, obscure and ill-defined terms that are antici-
pated to fill the bill. Launching a new ambiguous concept
with loose attachment to the actual clinical problem will not
facilitate its solution – on the contrary, it can cause confusion
and exacerbate the situation at its worst. Prediction of a frac-
ture of an individual (or any other medical event, such as
heart attack or stroke) will be a formidable task given the
Figure 3. Analogous to automobiles designed to run on their wheels, the human skeleton is adapted to bipedal gait and the resulting habit-
ual locomotive loadings (Figure 3A). In terms of safety, the design of the cars is optimized to keep the drivers and passengers in the cock-
pit intact during collisions from the typical directions of impact, the front-rear directions (Figure 3B). However, a considerably smaller force
can cause profound damage to the cockpit if subjected from atypical (unforeseen) direction (Figure 3C). Similarly, the capacity of the skele-
ton to resist fracture during accidents is generally good when the loading experienced during a traumatic incident is a moderate magnifica-
tion of the loading experienced during habitual activities (i.e., within the inherent safety margin of bone), except in some cases exceeding
the bones' capacity to withstand the loading without breaking (Figure 3B). However, in many cases of older adults' fractures, the loading is
completely different from that the bones are customarily adapted to (Figure 3C). Originally published in
48
.
T.L.N. Järvinen et al.: Bone Quality - an impasse
7
overwhelming dominance of chance over all measurable
"risk factors". No matter how sophisticated methods we use
and how hard we try, the life of an individual is often just too
complicated to be predicted and it will always run its own,
largely unforeseen paths.
Taken together, we see that the term "Bone Quality" is an
empty term
48
– identical to Emperor’s new clothes in the
famous fairy tale – and thus, should be abandoned. If it really
must be used, the term "Bone Quality" should, as said, refer
only to the capacity of bones to withstand a wide range of load-
ing without breaking. And, for such capacity we already have a
proper term or the whole bone strength
47
. Our real challenge
will be to reliably estimate the whole bone strength in vivo.
Acknowledgements
The study was supported by the Competitive Research Funding of the
Pirkanmaa Hospital District, the Research Council for Physical Education
and Sports, Ministry of Education, Academy of Finland, and the AO Re-
search Fund, Switzerland.
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