Rheumatology 2009;48:iv3–iv8 doi:10.

1093/rheumatology/kep273

Microarchitecture, the key to bone quality

Maria Luisa Brandi1

Bone has the ability to adapt its shape and size in response to mechanical loads via a process known as modelling in which bones are shaped
or reshaped by the independent action of osteoblasts and osteoclasts. Remodelling is a process that maintains mechanical integrity of the
skeleton, allowing it to selectively repair and replace damaged bone. During adulthood, bone remodelling is the dominant process; after the

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age of 40 years, the age-related decline in bone mass increases the risk of fracture, especially in women. Osteoporosis is defined as a
reduction in bone mass and an impairment of bone architecture resulting in thinning and increased cortical porosity, bone fragility and fracture
risk. As new products and methods have been developed, focusing on bone fragility, effective and sensitive non-invasive means able to
detect early changes in bone fragility process have also been developed. Due to limitations in assessing fracture risk and response to
therapy, the evaluation of bone mineral contents by bone densitometry is progressively replaced by new non-invasive and/or non-destructive
techniques able to estimate bone strength, providing structural information about the pathophysiology of bone fragility by quantitative
assessments of macro- and microstructural bone features. DXA and volumetric QCT quantify bone macrostructure, whereas high-resolution
CT, microCT, high-resolution MR and microMR assess bone microstructure. Knowledge of bone microarchitecture is a clue for understanding
osteoporosis pathophysiology and improving its diagnosis and treatment; the response of microarchitecture parameters to treatment should
allow assessment of the real efficacy of the osteoporosis therapy.

KEY WORDS: Bone modelling, Bone remodelling, Osteoporosis, Microarchitecture.

Introduction
The framework of the human body is provided by the 206 separate
bones of the skeleton. This anatomic entity contains 99% of the
total body calcium, and plays a major role in its preservation; it
also protects vital organs, contains bone marrow and is the site of
attachment of muscles and tendons.
The shape of bones results from a process known as ‘model-
ling’, whereas the process that constantly renews the bones is
known as ‘remodelling’. Bone tissue is a composite of both flexible
and rigid components: a flexible and tough extracellular matrix is
made up of type 1 collagen, proteoglycans and a number of non-
collagenous proteins; within this matrix, the rigid one, bone
mineral—predominantly hydroxyapatite—, is deposited [1]. It
also contains high amounts of growth factors and bone morpho-
genetic proteins. Bone cells are the osteoclasts, which are bone-
resorbing cells. The osteoblasts, the main function of which is to
synthesize and subsequently mineralize the osteoid, produce many
factors that regulate osteoclast development and function.
Osteocytes are terminally differentiated osteoblasts, which
become embedded in bone matrix. Osteocytes are connected to
one another and to osteoblastic cells on the bone surface by an
extensive network of canaliculi, which contain the bone extracel-
lular fluid; they act as mechanosensors in the bone, sensing phy-
sical strains and initiating the appropriate modelling or
remodelling response [1, 2].
Macroscopically, there are two types of bones: (i) the cortical
bones (compact), which constitute 80% of the skeleton and are
found in the shafts of long bones such as the femur, tibia and
radius and outer surfaces of the flat bones (skull, mandible and
scapula); and (ii) the trabecular bone (cancellous) found mainly at
the end of long bones and at the inner parts of flat bones [1]. The
relative proportions of the two types of bone vary considerably
among different skeletal sites: the cancellous: cortical bone ratio is
about 75 : 25 in the vertebra, 50 : 50 in the femoral head and 95 : 5
1
Department of Internal Medicine, University of Florence, Florence, Italy.
Submitted 4 February 2009; revised version accepted 31 July 2009.
Correspondence to: Maria Luisa Brandi, Department of Internal Medicine,
University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
E-mail: m.brandi@dmi.unifi.it
iv3
ß The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
in the shaft or diaphysis of the radius [1]. In the cortical bone, the
periosteum is the outer fibrous structure of all bones, which con-
tains the blood vessels that nourish the bone, nerve endings, osteo-
blasts and osteoclasts, and which is anchored to the bone by
Sharpey’s fibres that penetrate into the bone tissue. The endo-
steum is a membranous sheath that constitutes the inner
surface which is in direct contact with the marrow, and that also
contains blood vessels, osteoblasts and osteoclasts.
Mechanisms of bone modelling and remodelling at healthy
and postmenopausal stages
Bone modelling
A particular feature of the bone is its ability to adapt its shape and
size in response to mechanical loads. This mechanical adaptation
is generated by a process known as modelling, in which bones are
shaped or reshaped by the independent action of osteoblasts and
osteoclasts. Modelling occurs vigorously not only during growth,
but also, in the adult, in response to a mechanical load such as in
tennis players in whom the radius of the playing arm has a thicker
cortex and a larger external diameter than the contralateral radius.
Conversely, rapid bone loss may be induced by the unloading of
the skeleton during bed rest or space flight [3].
Bone modelling differs from bone remodelling, because in this
process bone formation is not coupled with prior bone resorption.
The modelling process is less frequent than the remodelling one,
but it does occur in normal subjects [4] and may be increased by
some pathological states [5, 6].
Bone remodelling
Another feature of the human bone is the process of remodelling,
a surface-based phenomenon that involves the removal of a
quantum of bone by osteoclasts followed by the deposition of
new bone by osteoblasts in the cavity formed [2]. The remodelling
process by which the bone is renewed constantly occurs through-
out life: at any one time, when 10% of the bone surfaces in the
adult skeleton are undergoing active remodelling, the remaining
90% are found to be quiescent. The duration of the remodelling
cycle is 6 months, most of this time being occupied by forma-
tion; 10% of the skeleton is renewed by remodelling each
year [2].
iv4 Maria Luisa Brandi
Quiescence/Activation
Pre-osteoclasts
Osteoclast
Resorption
Pre-osteoblasts
Inversion
FIG. 1. The bone remodelling cycle.
The remodelling process is accomplished at the level of
the ‘bone remodelling unit’, which groups the different cell
types [7–10] in four distinct phases, which are now clearly identi-
fied: quiescence/activation, resorption, reversal and formation
(Fig. 1).
The quiescence/activation phase refers to the event that
transforms a previously quiescent bone surface into a remodelling
one, involving recruitment of circulating mononucleated osteo-
clast precursors [11], penetration of the bone lining cell layer
and fusion of the mononuclear cells to form multi-nucleated
pre-osteoclasts [1].
The resorption phase refers to the osteoclastic resorption that is
regulated by local cytokines and systemic hormones [11–14].
During this phase, specific types of proton pumps and other ion
channels in the osteoclast membrane transfer hydrogen ions to the
resorbing compartment, and this acidic solution dissolves the
mineral component of the matrix while a number of lysosomal
enzymes are secreted and digest the organic phase of the matrix.
Resulting from this process, saucer-shaped resorption cavities are
created on the surface of the cancellous bone (Howship’s lacunae),
and cylindrical tunnels form within the cortex [1]. Resorption is
first accomplished by multinucleated osteoclasts and later by
mononucleated cells [1, 15, 16]. This phase concludes with
osteoclast apoptosis and is followed by reversal [1, 2, 17].
During the reversal phase, the resorption lacuna is inhabited
by mononuclear cells (monocytes, osteocytes liberated from the
bone by osteoclasts, and pre-osteoblasts recruited to initiate the
formation phase of the cycle). It is during this phase that coupling
mechanisms (resorption always followed by formation) must work
in an efficient and balanced manner. In the absence of efficient
coupling and bone balance, each remodelling transaction would
result in a net loss of bone. Bone remodelling units on the
periosteal surface of cortical bone produce a slightly positive
bone balance so that with ageing, the periosteal circumference
increases. On the other hand, remodelling units on the endosteal
surface of cortical bone are in negative balance so that the
Osteoblasts
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Formation
marrow cavity enlarges with age. In addition, the balance is
more negative on the endosteal surface than on the perisoteal
surface, which results in age-related cortical thickness decline.
The bone balance is also negative on cancellous surfaces, resulting
in an age-related gradual thinning of the trabecular plates [18]
(Fig. 2).
In the two-step formation process, the osteoblasts initially
synthesize the collagenous organic matrix, and then regulate its
mineralization by secondary nucleation on contact with pre-
existing mineral [19]. As bone formation continues, some osteo-
blasts are buried in the matrix, becoming osteocytes that maintain
intimate contact with one another and with the cells on the bone
surface, whereas others differentiate into flattened ‘lining cells’
that cover the bone surface [1]. At the end of each remodelling
cycle, a new osteon, a bone structural unit (BSU), has been created
[1]. The process of bone remodelling is equivalent in cancellous
and cortical bone.
Normal and osteoporotic bone structures
At the macroscopic level, the normal cortical bone appears dense
and solid, whereas cancellous bone is a lace-like structure of
interconnected trabecular plates and bars surrounding marrow-
filled cavities. At the light microscope level, both cortical and
cancellous bone is composed of BSUs or osteons [1]. The
normal trabecular bone is composed of internal rods or plates
that form a 3D branching lattice oriented along the lines of
stress. The trabecular interstices of the axial skeleton are the pri-
mary repository of red bone marrow, therefore trabecular bone
lies in close proximity with the marrow-derived cells that partici-
pate in bone turnover. Bone loss initially starts at the bone
surfaces; therefore, changes in bone mass occur earlier and to a
greater extent in trabecular bone than in skeleton regions that are
primarily cortical.
Osteoporosis is a systemic disease defined as a reduction
in bone mass associated with an impaired bone architecture:
disruption of trabecular continuity by trabecular perforation,
 Bone microarchitecture determines bone health
Peak
bone
Bone mass mass
Ageing
0 25
Bone balance Normal
Trabecular bone
Normal
FIG. 2. The process of age-related trabecular thinning.
Normal bone: Osteoporotic bone:
trabecular architecture trabecular architecture
FIG. 3. The importance of bone microarchitecture.
resulting in reduced connectivity of the trabecular bone structure,
increased bone fragility and increased fracture risk; and thinning
and increased porosity of the cortices occur, with the conversion
of the normal plate-like trabeculae into thinner rod-like structures
(Fig. 3) [20]. These changes result from the combination of the
increased osteoclastic activity and the reduced osteoblast function
that characterizes postmenopausal osteoporosis.
iv5
Menopause
Ageing
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50 55 60 75 Age
Decreased Decreased +++
Thinning Thinning + perforation
Evaluation of bone structure: new imaging techniques,
CT and MR
Traditional techniques
Besides conventional radiographs, bone densitometry has long
been the standard technique to assess bone mineral content
despite the fact that this technique provides important informa-
tion about osteoporotic fracture risk. Recent clinical investiga-
tions indicate that BMD only partly explains bone strength and
show limitations of BMD measurements in assessing fracture risk
and monitoring the response to therapy [21–27].
New techniques
As new products and methods have been developed by
molecular and cellular research focusing on bone fragility, it
became essential to develop effective and sensitive non-invasive
means by which early changes in the fracture repair process can
be detected [20]. New specialized non-invasive and/or non-
destructive techniques that are able to provide structural informa-
tion about local and systemic skeletal health, the propensity to
fracture and the pathophysiology of bone fragility have been
developed, enabling quantitative assessments of macro- and
microstructural bone features, and improving our ability to esti-
mate bone strength.
Quantitative assessment of bone macrostructure can be
provided by DXA and CT (Table 1), particularly volumetric
QCT (vQCT), whereas assessment of the trabecular bone micro-
structure may be obtained by high-resolution CT (hrCT),
microCT, high-resolution MR (hrMR) and microMR.
vQCT, hrCT and hrMR are generally applicable in vivo,
whereas microCT and microMR are principally used in vitro
[21]. These currently available advanced imaging modalities help
to investigate bone fragility and to define the skeletal response to
innovative therapies and assess the biomechanical relation-
ships [20]. QCT allows separate analysis of the trabecular and
cortical compartments. The analysis of cortical bone, in
particular at the hip, is important to estimate fracture risk, and
this technique has been utilized in several clinical trials [28, 29].
MicroCT is a technique particularly adapted to 3D analysis of
human iliac crest bone biopsies, investigating evolution of
trabecular structure under treatment (Fig. 4).
Despite the progress made with these techniques, certain issues
remain, such as the important balances between spatial resolution
and sampling size, or between signal-to-noise and radiation dose
iv6
TABLE 1. Overview of CT techniques to determine BMD and bone architecture
vQCT
In plane pixel size >0.3  0.3 mm2
Slice thickness >1 mm
Equipment Whole-body clinical scanners; dedicated
peripheral scanners
Skeletal location Spine, hip, forearm, tibia
Subjects/samples Human in vivo
Applications BMD/bone macrostructure/FEM
Techniques with a voxel size <1 mm are typically called microscopy. FEM: finite element microscopy model.
(A)
Placebo
FIG. 4. 3D microCT: microstructure of transiliac bone biopsies from two post-menopausal women after 36 months of strontium ranelate therapy. (A) Placebo and (B)
strontium ranelate therapy. Reproduced from Journal of Bone and Mineral Research 2008;23:215–22 with permission of the American Society for Bone and Mineral
Research.
or acquisition time, which need to be considered further, as do the
complexity and expense of the methods vs their availability and
accessibility. The relative merits of these sophisticated imaging
techniques must be weighed with respect to their applications as
diagnostic procedures, requiring high accuracy or reliability, com-
pared with their monitoring applications, requiring high precision
or reproducibility [21].
Evaluations of bone microarchitecture and strength
Fundamentally, a fracture occurs when the external force (or load)
applied to a bone exceeds its strength. Whether or not a bone will
be able to resist the fracture [22] depends on the amount of bone
present, the spatial distribution of the bone mass, the cortical and
trabecular microarchitecture and the intrinsic properties of each of
the bone components. Imaging techniques that can measure one
or more of the determinants of bone strength may enhance clinical
management of osteoporosis and enhance new drug development
[22]. Several novel non-invasive techniques for the assessment of
bone quality and strength are currently being investigated in clin-
ical studies. They aim to quantify various determinants of bone
strength such as 3D bone geometry, volumetric bone density,
microarchitecture and properties of the bone matrix [22]. Finite
element analysis, by combining bone geometry with material char-
acteristics to predict bone strength, holds promise as a biomecha-
nically based technique for fracture assessment, and imaging
modalities capable of assessing trabecular architecture may be
Maria Luisa Brandi
hrCT microCT
0.1  0.1–0.3  0.3 mm2 Isotropic
0.2–1 mm 1–100 mm3
Whole-body clinical scanners; dedicated Dedicated microCT scanners
peripheral scanners
Spine, forearm Human biopsies: iliac crest, animals and
specimens: various
Human in vivo/human biopsies/bone specimen Laboratory animals in vivo and in vitro, bone
specimen
Bone macrostructure/trabecular microstructure Trabecular and cortical microstructure/microFEM
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(B)
Strontium ranelate
particularly useful in assessing subtle treatment-based changes in
bone strength [22]. Finite element methods are becoming increas-
ingly popular for quantifying the elastic and failure properties of
trabecular bone [30].
Few methods are currently clinically validated to assess and
monitor the evolution of microarchitecture in bone diseases. The
most developed studies relate to microarchitectural measurements
obtained by bone histomorphometry with the use of new algo-
rithms, which can assess 2D various characteristics of
the trabeculae, such as thickness and connectivity [31].
Histomorphometry or quantitative histology is the analysis of
histological sections of bone resorption parameters, formation
and structure. This modality is the gold standard for assessing
bone because it is the only method available for the direct in
situ analysis of bone cells and their activities [32] (Table 2).
It has been shown that microarchitecture parameters should be
obtained by using several independent techniques; microCT,
micro-MRI and synchrotron also allow the measurement of 3D
trabecular microarchitecture in a non-destructive way on bone
specimens [30]. The methods of MR and microCT image analysis
are reliable, but preferably should be used in combination as to
obtain valid conclusions [33].
The ability to assess the risk of fracture, evaluate new therapies,
predict implant success and assess the influence of bone remodel-
ling disorders requires specific measurement of local bone
micromechanical properties. To assess these properties, two new
methods are used: (i) nano-indentation is a reliable method for
 Bone microarchitecture determines bone health iv7

TABLE 2. Standardized nomenclature of histomorphometric parameters, from the ASBMR (the American Society of Bone and Mineral Research)

Key measurements in bone histomorphometry

Parameters of bone structure Abrreviation, unit Description

Parameters expressing the amount of bone
Cancellous bone volume Cn-BV/TV, % The percentage of spongy bone tissue including mineralized bone and osteoid
Total bone volume BV/Tt.CV, % This is an estimate of bone mass
Cortical width Ct.Wi, mm The thickness of the cortices
Wall thickness W.Th, mm The width of complete trabecular bone
Parameters reflecting trabecular bone microarchitecture
a
Trabecular thickness Tb.Th, mm The width of the trabeculae
Trabecular separationa Tb.Sp, mm The distance between trabeculae

a
Trabecular number
Parameters of bone formation
Static parameters
Osteoid volume
Osteoid surface
Osteoid thickness
Dynamic parameters
Mineral apposition rate
Mineralizing surfaces
Derived parameters
b
Bone formation rate
Adjusted apposition rate
Formation period
Mineralization lag time
Activation frequency
Bone resorption parameters
Eroded surface
Osteoclast number
Erosion depth
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Tb.N, mm The density of trabeculae
OV/BV, % The fraction of trabecular tissue that is not calcified
OS/BS, % The percentage of total trabecular surface covered with osteoid
O.Th, mm The average width of osteoid seams
MAR, mm/day It expresses the rate of progression of the mineralization front
dLS/BS, % The extent of double, single or total tetracycline labelled surfaces expressed as a percentage of
sLS/BS, % total trabecular bone surfaces
LS/BS, %
Cn-BFR/BS, mm3 mm2/day The amount of mineralized bone made per unit of trabecular bone per day
Aj.AR, mm/day The amount of mineralized bone made per day per unit of osteoid-covered surface
FP, days The mean time needed to build a new bone structural unit
Mlt, days The mean interval between the deposition of osteoid and the mineralization
Cn-BFR/W.Th, per year Number of bone multi-cellular units born per year represents the probability that a new cycle of
bone remodelling will start on the bone surface
ES/BS, % The percentage of trabecular bone surface eroded
N.Oc/BS Number per millimetre of trabecular surface
E.De, mm Derived from the number of eroded lamellae in each resorption cavity and the lamellar thickness

This table has been reproduced with permission from Current Medicine Group 2009ß from: Rizzoli R, The atlas of postmenopausal osteoporosis, 3rd edition. London: Current Medicine Group.
The table from ‘The atlas of postmenopausal osteoporosis’ was adapted from Parfitt MA, Drezner MK, Glorieux FH et al. Bone histomorphometry: standardization of nomenclature, symbols, and units.
Bone Miner Res 1987;2:595–610. aCalculated from the trabecular bone area, volume and the length of the bone marrow interface. bCalculated from the mean apposition rate and the mineralizing
surfaces.

assessing the intrinsic micromechanical properties of single BSUs
such as the hardness and modulus of dry and wet bone tissue, with
a high spatial resolution [34–36]. This technique contributes to
the current understanding of structure–function relationships
throughout the trabecular bone structural hierarchy [37, 38].
(ii) The three-point bending test is also used to evaluate the
mechanical properties of bone. The bone is placed in the
material-testing machine on two supports and load is applied on
the middle of the bone shaft [39, 40].
Implications
Fractures that result from osteoporosis are a major and growing
concern for public health systems. As the population ages, the
number of fractures worldwide will double or triple in the next
50 years [22]. The ability of a bone to resist fracture (or ‘whole
bone strength’) depends not only on the bone mass but also on its
spatial distribution (macro- and microarchitecture), and the
intrinsic properties of the materials that constitute the bone [41].
Quantitative assessment of macro- and microstructural bone
features improve our ability to estimate bone strength. Thus,
knowledge of bone microarchitecture appears to be clue for
understanding the pathophysiology of osteoporosis and improv-
ing both its diagnosis and its treatment. The response of micro-
architecture parameters to treatment should allow assessment of
the real efficacy of a treatment for osteoporosis. Another clue is a
computer-driven fracture risk assessment (FRAX) tool that
has been developed by WHO to evaluate fracture risk of patients.
It is based on individual patient models that incorporate the risks
associated with clinical risk factors as well as BMD at femoral
neck. The FRAX algorithms give the 10-year probability of
fractures [42].
Elderly women have the highest prevalence of osteoporosis and
the highest risk of falling, making them likely to experience osteo-
porotic fractures. However, early treatment of osteoporotic
women, as early as at menopause, should maximize the efficacy
of the long-term osteoporosis therapy and prevent the devastating
consequences known to occur at an older age. Since anti-
resorptive treatments, such as bisphosphonates, also strongly
decrease bone formation by a coupling effect besides fixing
osteoporosis-induced bone loss, and since anabolic treatments,
such as PTH, increase bone resorption by the same effect, a new
generation agent, strontium ranelate, seems to be characterized by
a dual mechanism of action which increases bone formation and
decreases bone resorption with a net improvement in the two main
components of bone strength, BMD and bone quality (bone
microarchitecture, its intrinsic properties and its geometry, i.e.
its shape and dimensions).
Rheumatology key messages
 Osteoporosis is defined as a reduction in bone mass associated
with impaired bone microarchitecture.
 Ability of bone to resist fracture depends on its spatial distribution
and intrinsic material properties.
 Response of microarchitecture parameters to treatment allows
assessment of the real efficacy of an osteoporosis drug.
Acknowledgements
Technical editing assistance for the preparation of this manuscript
was provided by Mediscript. This assistance was funded by
Servier.
iv8 Maria Luisa Brandi
Supplement: This paper forms part of the supplement entitled
‘Improvement of bone microarchitecture: the foundation for a
better protection against osteoporotic fractures’. This supplement
was supported by an unrestricted grant from Servier.
Disclosure statement: M.L.B. is a consultant for and has received
honoraria and grant/research support from MSD, Procter &
Gamble, Servier, Nycomed, Glaxo, NPS and Amgen.
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