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Bone Histology and
Histopathology for Clinicians
A Primer
Stephen F. Hodgson M.D., M.A.C.E, F.A.C.P.
Bart L. Clarke M.D., F.A.C.E., F.A.C.P.
Robert Wermers M.D., F.A.C.E.
Theresa Hefferan, Ph.D.
Michael Yaszemski. M.D., Ph.D.
Presented By
Mayo Clinic
Divisions of Endocrinology
and Orthopedic Research
and
The American College
of Endocrinology
Supported by an Educational Grant from:
The American
College of Endocrinology
The authors acknowledge the many
valuable contributions of others
•
•
•
•
•
•
•
•
•
Julie Burgess
Glenda Evans
Dr. Lorraine Fitzpatrick
Dr. Hunter Heath
Dr. Dan Hurley
Donna Jewison
Dr. Ann Kearns
Dr. Kurt Kennel
Dr. Sundeep Khosla
•
•
•
•
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Dr. Rajiv Kumar
Dr. James McCarthy
Dr. B.L. Riggs
Dr. Jean Sibonga
Peter Steiner,
Illustration & Design
• Dr. Peter Tebben
• Dr. Robert Tiegs
• Dr. Russell Turner
Bone Histology and
Histopathology for Clinicians©
This presentation provides basic
instruction in bone histology, and in the
histopathology of metabolic bone
diseases and related disorders. It was
prepared primarily for endocrine fellows,
endocrinologists, osteologists, and other
physicians and scientists interested in
metabolic and related bone diseases.
©2007 Mayo Foundation for Medical Education and Research and licensed to
The American College of Endocrinology.
• Normal Bone Microanatomy and
Histology
• Bone Cells and Bone
Remodeling
• Basic Bone Histomorphometry
Normal Bone Microanatomy
Cortical
bone
Cancellous
bone
From Gray’s Anatomy
All bones of the human skeleton, though widely variable in function and
shape, share a common anatomic organization. Grossly, they are
composed of dense outer cortical bone which encloses an irregular
medullary space containing cancellous bone, bone that is composed of
branching networks of interconnecting bony trabecular elements.
Normal Bone Microanatomy
Cortical
bone
Cancellous
bone
Undecalcified transiliac bone biopsies (right) are considered to be
representative of all skeletal bone and are suitable for examining,
measuring, and analyzing the microscopic features of cortical and
cancellous bone. Also, with the appropriate use of absorbable
fluorochrome agents, the dynamic changes that occur in bone can be
assessed.
Normal Bone Microanatomy
Variable cortical
thickness
Trabecular orientation differs
Note that cortical thickness varies within individual bones. Also, note that
trabeculae in the vertebral body are oriented vertically along lines of
mechanical stress, whereas in the ilium they appear to be randomly
oriented and are therefore said to be isotropic.
Anatomic Features of a Normal
Transiliac Bone Biopsy
Cortex
Hematopoietic
and fatty marrow
7.5
mm
Trabeculae
Normal Bone Microanatomy
Differential Tissue Stains
Mineralized bone
Unmineralized bone
A number of differential stains can be used to examine undecalcified
tissue. Toluidine Blue stain (left) and Goldner Trichrome stain (right)
will be used throughout this presentation, except as otherwise indicated.
Each stain has characteristics that favor, or disfavor, its use. Either may
be used for histomorphometric analysis.
Normal Bone Microanatomy and Histology
Cortical Bone
Cortical bone forms a relatively thick and dense outer wall and makes up
about 80% of total skeletal mass.
Normal Bone Microanatomy and Histology
Periosteum
The outer cortical surface is enveloped in the periosteum, a connective
tissue covering that contains cells that maintain, change, and repair the
external cortical surface.
Normal Bone Microanatomy and Histology
Periosteum
The periosteum also contains blood vessels, sensory nerves, and dense
fibrous tissue that is contiguous with the connective tissue elements of
tendons, ligaments, and joint capsules
Cortex
Periosteum
Normal Bone Microanatomy and Histology
Bone Structural Units (BSU)
Both cortical and trabecular bones are composed of an assembly of
individual bone structural units (BSU), also called osteons, each of which
represents the structural end result of a focus of bone renewal (remodeling).
Architecturally, cortical and trabecular BSUs are distinct. In cortical bone
(left), BSUs may appear in cross section as concentric rings (lamellae),
forming cylindrical - shaped structures. In cancellous bone (right), the
lamellae are flat and appear stacked in saucer shaped depressions.
Normal Bone Microanatomy and Histology
Cancellous Bone
Cancellous bone accounts for the remaining 20% of skeletal mass and
consists of interconnecting trabecular plates that share the medullary
space with hematopoietic and fatty marrow.
Normal Bone Microanatomy and Histology
Endosteum
The inactive or resting trabecular surface is covered by a thin endosteum which, like
the contiguous cortical endosteum, has widely spaced flat lining cells that are
believed to have osteogenic potential, and form a barrier between marrow and bone.
Lining cells
Endosteum
Normal Bone Microanatomy and Histology
Cortical BSUs
Cortical BSUs are laminated bony cylinders (seen in cross section above) that
have central (Haversian) canals enclosing vascular structures, nerves, and a thin
membranous lining (cortical endosteum) containing flat, inactive appearing lining
cells. Cortical BSUs arise from Haversian and other communicating channels
called Volkman’s canals. They are about 0.4 mm in width and are several mm in
length. They are oriented in a branching pattern and lie perpendicular to the long
access of bone.
(Cortex above (left) under incandescent and (right) polarized light)
Cortical (Haversian) BSU
Viewed in cross section under Polarized light
Trabecular BSUs
Trabecular BSUs are laminated saucer-shaped structures that, though appearing
somewhat variable in two-dimensional view, contain a relatively uniform volume of
bone, each BSU representing a “quantum” of bone.
Bone Cells and Bone Remodeling
All normal adult human bone undergoes renewal and
repair through a process called bone remodeling.
Teams of bone resorbing and bone forming cells
form basic multicellular units (BMU) that function at
discrete sites throughout the skeleton in a highly
coordinated sequence of cellular activity. At any
given remodeling site, bone resorption always
precedes bone formation, resulting in the removal
and subsequent replacement of a quantum of bone
at each site.
Under normal steady state conditions, the amount
of bone removed is precisely replaced and there is
no net change in bone mass. Only bone architecture
is changed.
Bone Remodeling
Sequence of Bone Cell Activity
The sequential events of the bone remodeling cycle are
driven by an evolution of cellular events that occurs over a
time period of three to six months:
• Activation – a quiescent bone surface becomes
populated with cells that have been recruited from
osteoclast precursors and are destined to become bone
resorbing osteoclasts
• Resorption – osteoclasts mature and remove a finite
quantum of mineralized bone
• Reversal – osteoclast activity and numbers decline and
are replaced by pre-osteoblasts (bone forming cell
precursors)
• Formation – preosteoblasts become mature osteoblasts
and secrete bone matrix, which subsequently undergoes
mineralization
Bone Remodeling
Activation
Lining cells produce
collagenase, which exposes
the mineralized bone surface
for bone resorption
Bone Remodeling
Resorption
(Mineralized bone)
Osteoclast
Sealed
micro-environment
Ruffled membrane
(Marrow)
Cells
derivedsurface
from circulating
mononuclear
phagocyte
are recruited
The basal
of the osteoclast
is rich
in HCl precursors
and cathepsin
transferto
become
boneand
resorbing
pre-osteoclasts,
which cannot be visually identified by
organelles
is called
the ruffled membrane.
standard microscopy. Pre-osteoclasts mature to become osteoclasts and attach
to the exposed mineralized bone surface, to form an isolated and sealed microenvironment that is rich in both HCl and lysozomal enzymes (cathepsin).
Bone Remodeling
Resorption
Resorption (Howship’s) lacunae
Mature osteoclasts move over the surface, removing mineral and organic
components of mature bone simultaneously, leaving serrated footprints, or
Howship’s lacunae, on the surface
Osteoclasts
Morphology
Osteoclasts
Acid Phos (+)osteoclasts
Osteoclasts have variable morphology. Though often appearing as large
multinuclear cells, they may be small, appear mononuclear, and, except
for their characteristic location within resorption lacunae, can be difficult to
distinguish from fibroblasts, osteoblasts, and other cells. Positive
identification may be made using acid phosphatase stains (right).
Osteoclasts
Variations
Osteoclasts
Prevalence
In normal bone (left), osteoclasts are encountered infrequently, only about
three being identified per 100 mm of trabecular surface, and therefore
may be absent from an entire section.
Under some pathologic conditions (e.g., above right) the number, size,
and activity of osteoclasts may increase.
Biochemical Effects of Bone Remodeling
Markers of Bone Resorption
Osteoclastic resorption of mineralized bone releases minerals in support of
mineral homeostasis, and products of collagenous protein degradation, including
the inter- and intramolecular collagen cross links, into the circulation. The
relative concentrations of cross links in blood or urine reflect the degree of bone
resorbing activity and are considered to be “markers” of bone resorption.
Bone Remodeling
Reversal
Preosteoblasts
As the resorptive phase wanes and is replaced by the reversal phase, resorption
lacunae become populated by mononuclear pre-osteoblasts (cells that may be
derived from recruited monocytes and circulating bone-forming cell precursors).
Preosteoblasts are destined to become bone-forming osteoblasts. Osteoclasts
ultimately undergo cell death, or apoptosis.
Reversal
Pre-Osteoblast Maturation
Preosteoblasts
Osteoblasts
Preosteoblasts (left) can be visually identified by their proximity to the resorption
surface, clear cytoplasm, single nuclei, and (+)stain for alkaline phosphatase.
They mature into osteoblasts (right), which appear as mononuclear cells with
prominent nucleoli and deeply stained cytoplasm. Osteoblasts form a cellular
monolayer on the resorption surface previously abandoned by osteoclasts.
Bone Remodeling
Bone Formation
Unmineralized osteoid
Osteoblasts secrete type I collagen, called osteoid, from their basal
surfaces onto the previously resorbed surface. Osteoid forms the organic
matrix of bone.
Bone Formation
Osteoblasts – Effects of Cell Age
…but flatten as they complete
bone formation to eventually
become lining cells
Young osteoblasts appear
cuboidal and robust…
Type I Collagen
Type I collagen is a triple helical structure
composed of two α1 chains and one α2 chain.
Collagen α chains are characterized by Gly-X-Y
repeating triplets where X and Y are usually proline
and hydroxyproline, respectively.
Type I collagen is synthesized in a procollagen
form which undergoes post-translational
hydroxylation and glycosylation of selective
residues. It further undergoes removal of terminal
sequences before being secreted in its mature
form from the basilar surface of osteoblasts into
the underlying extra cellular space.
Bone Formation
Osteoblasts Become Osteocytes
Some osteoblasts become
entrapped in osteoid to
become osteocytes
Osteocytes
As bone mineralizes, osteocytes tend to
become pyknotic but retain metabolic
responsiveness to PTH and other stimuli
Bone Formation
Osteocytic Canaliculi
Osteocytes retain communication
with the surface and with other cells
through a system of microtubules
called canaliculi
Bone Formation
Reversal Line
Osteoblasts secrete collagen matrix
directly on the resorption lacunar
surface. The resulting scalloped
interface between old bone and new
matrix is called the Reversal, or
Cement Line
Bone Formation
Lamellar Bone
Under normal conditions, collagen molecules establish covalent C-to-N cross
links that result in both end-to-end and side-to-side alignment, forming mats of
aligned and interconnected collagen molecules. Collagen mats periodically
alternate their spatial orientation 90°, resulting in the layered or lamellar
configuration seen in normal BSUs.
Bone Formation
Woven Bone
Under conditions of rapid
turnover, e.g., normal
growth, fracture healing,
or under some pathologic
conditions as illustrated,
osteoid is deposited in
disorganized fashion
and is called woven
bone in contrast to
lamellar bone.
Woven bone
Lamellar bone
Biochemical Effects of Bone Remodeling
Markers of Bone Formation
Osteoblasts secrete collagenous and noncollagenous proteins into circulation,
including the C and N-terminal fragments of procollagen, alkaline phosphatase,
and osteocalcin. Concentrations of these products in serum and urine serve as
“markers” of bone formation and turnover.
Bone Formation
Reversal Line
The reversal line defines the limit of bone
erosion and the original site of bone
formation.
Bone Formation
Reversal Line
The persistence of a serrated interface
indicates that mineral deposition has not
begun at this location.
Mineralization of Osteoid
The Mineralization Front
Ten to fifteen days following secretion, osteoid undergoes maturational
changes that prepare it for the initial deposition of calcium phosphate
crystals.
This occurs along an interface between mineralized and unmineralized bone,
called the mineralization front.
Mineralization of Osteoid
The Mineralization Front
Mineralization front
Reversal line
As early mineralization proceeds, the serrated reversal line becomes obscured
and the mineralization front becomes a smooth linear interface. When a
flurorochrome labeling agent, such as tetracycline, is present, it becomes
incorporated into the mineralization front, leaving a clear linear record of the
precise site where mineralization was occurring during tetracycline exposure.
Mineralization of Osteoid
Fluorescent Labeling With Tetracycline:
Fluorescence Microscopy
Label #1
#2
Old Mineralized bone
New mineralized bone
Marrow
Tetracycline is usually administered on two occasions separated by an interval of
several days. The presence of well-resolved double labels indicates that normal
bone mineralization was actively occurring over the labeling interval.
Mineralization of Osteoid
Fluorescent Labeling With Tetracycline:
Fluorescence Microscopy
Single label
Osteocytic lacunae
and canaliculi
The presence of a single label indicates that mineralization was occurring during
only one labeling period.
Note that osteocytic lacunae and canaliculi are visible under fluorescence.
Normal Iliac Bone Biopsy From a
33-year-old Woman
Recent double tetracycline labeling has resulted in multiple double- and
single-fluorescent labels on the surfaces of trabeculae, marking the
location of active bone mineralization.
Normal Iliac Bone Biopsy From a
33-year-old Woman
Fluorescent bands deep within mineralized trabeculae indicate previous
incidental tetracycline exposure.
Cancellous Bone Remodeling
The Bone Remodeling Compartment (BRC)
BRC
Between the BMU and bone marrow is a structure called the bone
remodeling compartment (BRC).
Cancellous Bone Remodeling
The Bone Remodeling Compartment (BRC)
Lining cells
The BRC is lined by sinusoidal vascular structures
whose marrow interface is made up of lining cells that
form a canopy over the remodeling site.
Cancellous Bone Remodeling
The Bone Remodeling Compartment (BRC)
BRC
The BRC is thought to be a component of the BMU providing a local
environment for regional cell signaling and the coordination of the
coupling of formation to resorption.
Cancellous Bone Remodeling
Though the remodeling cycle begins with osteoclastic resorption ands ends with
osteoblastic formation and mineralization, osteoclasts and osteoblasts are
otherwise simultaneously present in different regions of the same BMU during
most of the active remodeling cycle.
Cancellous Bone Remodeling
Sequence
Early osteoblastic
formation
New
mineralized
bone
Mineralization front
Reversal line
Osteoclastic
resorption
Lead by osteoclastic resorption, the BMU moves across the surface of
cancellous bone. Resorption is succeeded by formation, which eventually
becomes new mineralized bone.
Cancellous Bone Remodeling
Sequence
Osteoblasts flatten
to ultimately form
inactive lining cells.
Cancellous Bone Remodeling
Remodeling Space
Increases
The remodeling
in remodeling
space (RS)refers
space (turnover)
to that volume
are associated
of bone with
that has
an
increasing
undergonetendency
resorptionfor
orfracturing.
will undergo
It’sformation
size is a limiting
and mineralization,
factor for
and
increasing
which therefore
bone does
massnot
with
contribute
drugs that
to reduce
mineralized
turnover
bone
(eg.
mass. The RS is
Bisphosphonates)
directly related to bone turnover, and represents the skeleton’s potential
for increasing bone volume, mass, and strength.
Cancellous and Cortical Bone Remodeling
Cancellous BMU
Cortical BMU
Cancellous bone remodeling (left) occurs over a trabecular surface, whereas
cortical remodeling (right) occurs within a cylinder. Bone cell function and the
sequence of cell activities are otherwise similar.
Cancellous bone remodeling units occur in greater numbers, causing the
cancellous bone turnover rate to be about tenfold that of cortical bone.
Cortical Bone Remodeling
Osteoclasts
Cutting cone
Cortical BRUs originate from Haversian or Volkman’s canals, where
osteoclasts excavate a resorption cavity called a cutting cone, which
extends in a linear path through the cortex, forming a resorption tunnel.
Cortical Bone Remodeling
Osteoblasts forming
ostoid
Closing cone
Reversal zone
Behind the advancing cutting cone is an irregular area somewhat devoid of
active cells, the reversal zone, followed by an elongated tapering tunnel lined
by osteoid and osteoblasts, which circumferentially refill the resorption tunnel,
the closing cone.
Cortical Bone Remodeling
Formation, Longitudinal, and Cross-Sectional Views
#2
#1
Fluorochrome labeling with tetracyclene (right) documents the
circumferential closure of a cortical BMU (osteon).
Cortical Bone Remodeling
Completed Haversian canal
Forming Haversian canal
Bone formation eventually terminates, leaving a central Haversian canal which
contains blood vessels, lymphatics, and connective tissue, elements that are
contiguous with those of the periosteum, endosteum, and bone marrow.
Haversian Remodeling of Cortical Bone*
Bone formation
(osteoblasts)
Resorption
(osteoclast)
Haversian canal
Cutting cone
Remodeled cortex
Cortical Bone Remodeling
A complete cortical remodeling cycle requires from six to nine months.
Circumferential closure at any point requires about three months.
Basic Bone Histomorphometry
Stereologic Basis
The measurement and analysis of bone structure and bone
remodeling is called bone histomorphometry. It is usually
performed on cancellous bone from transiliac biopsies.
The isotropic (randomly oriented) nature of trabeculae in
iliac bone is assumed, and allows two-dimensional
measurements (area) to be converted to, and expressed as,
three-dimensional (volume) measurements. This is a
fundamental stereologic principle used in
histomorphometry.
Isotropy also implies that structures are viewed and
measured at some random degree of obliquity. Therefore, a
correction factor for obliquity (4/π) is used in all thickness
measurements.*
*For detailed discussion, see Recker, RR. Bone Histomorphometry:
Techniques and Interpretation, CRC Press, 1983.
Basic Bone Histomorphometry
Using computer graphics,
multiple fields of known
medullary area/volume are
analyzed. Bone tissue volume
(TV) is the sum of field
volumes
All trabeculae within each field
are graphically outlined and
trabecular bone volume
(Tb.V), and total trabecular
bone surface (Tb.S) are
determined.
Basic Bone Histomorphometry
Using computer graphics,
multiple fields of known
medullary area/volume are
analyzed. Bone tissue volume
(TV) is the sum of field
volumes
All trabeculae within each field
are graphically outlined and
trabecular bone volume
(Tb.v), and total trabecular
bone surface (Tb.S) are
determined.
Bone Histomorphometry
Trabecular Bone Volume (Tb.V)
Trabecular bone volume,
(Tb.V) is the relative volume
of total cancellous bone
measured (TV), expressed
as %, that is occupied by
trabeculae.
Tb.V is about 20% in women
and 22% in men.
Tb.Vis related to cancellous
bone mass. It declines with
age and with bone loss
Bone Histomorphometry
Trabecular Bone Volume (Tb.V)
Note
Tb.V is also commonly
referred to as
Bone Volume / Total
Volume, or
BV/TV
Bone Histomorphometry
Surface Classification
Total bone (trabecular) surfaces
(Tb.S) are measured, subclassified
by type, and each type of surface
expressed as % of Tb.S, or as % of
a specific surface type:
Resorbing surface (RS)
Osteoid surface (OS)
Osteoblast surface(Ob.s)
(as % osteoid surface)
Bone Histomorphometry
Trabecular Separation (Tb.Sp)
Trabecular Separation Tb.Sp is the mean distance in mm between
trabeculae (measured by integrated computer graphics)
Tb.Sp is a measure of trabecular connectivity
Tb.Sp increases with trabecular bone loss
Bone Histomorphometry
Trabecular Thickness (Tb.Th)
Tb.Th = 1/Tb.S
Mean trabecular thickness, (Tb.Th) is a measure of trabecular structure and is
calculated as the reciprocal of Tb.S
Tb.Th is reduced by aging and osteoporosis.
Bone Histomorphometry
Trabecular Number (Tb.N)
Trabecular number (Tb.N). The number of trabeculae present per lineal mm
Tb.N is calculated as Trabecular bone volume/Trabecular Thickness
Tb.N is a measure of trabecular connectivity
Tb.N decreases with bone loss
Bone Histomotphometry
Cortical Thickness (Ct.Th)
In the ileum, average combined cortical width (Ct.Th) in women and men is about
820 µm and 915 µm, respectively. Ct.Th correlates with dual photon
absorptiometric (DPX) measurements of bone density.
Bone Histomorphometry
Mineral Apposition Rate
(MAR)
MAR =
Interlabel distance
Label interval
The average distance between visible labels, divided by the labeling interval, is the mineral
apposition rate (MAR) in µm/day, the avarage rate at which new bone mineral is being
added on any actively forming surface. MAR is the basic measurement and calculation on
which all dynamic estimates of bone formation are based. It is usually expressed as the
adjusted appositional rate ((Aj.Ar) or MAR (MS/BS ) – see next slide
Bone Histomorphometry
Mineralizing Surfaces (MS)
Total mineralizing surfaces (MS) include all double and ½ of single-labeled
surfaces. MS is expressed relative to total bone surface or, MS = total labeled
surface / BS
Bone Histomorphometry
Mineralizing Surface (MS)
MS is used in the calculations for bone formation rates, (BFR), activation
frequency (Ac.F), and mineralization lag time (MLT).
Bone Histomorphometry
Osteoid Thickness (O.Th)
Osteoid thickness (O.Th) is the mean thickness, in µm, of osteoid seams on
cancellous surfaces.
Bone Histomorphometry
Osteoid Thickness (O.Th)
O.Th is normally <12.5 µm. Increased O.Th suggests abnormal mineralization
(osteomalacia).
Bone Histomorphometry
Mineralization Lag Time (MLT)
Secretion
Mineralization
The time interval between osteoid secretion and its subsequent mineralization, in
days, is known as the mineralization lag time (MLT).
Bone Histomorphometry
Mineralization Lag Time
MLT is a measure of mineralization competence and is normally less than 22 days
in women and 27 days in men.
Bone Histomorphometry
Mineralization Lag Time (MLT)
MLT is calculated
as:
O.Th
MAR
x
MS
Os
Bone Histomorphometry
Activation: Activation Frequency (Ac.f)
The average time that it takes for a new remodeling cycle to begin on any
point on a cancellous surface is called the activation frequency (Ac.f).
Ac.f is a measure of bone turnover and is expressed in years.
Bone Histomorphometry
Wall Thickness (W.Th)
W.Th=
Average thickness of BSU
Wall thickness is the average thickness of trabecular BSU.
(W.Th) is used to assess the overall balance between resorption
and formation.
Bone Histomorphometry
Bone Formation Rates
Bone formation rates (BFR/BV and BFR/BS) are the
calculated rates at which cancellous bone surface
and bone volume are being replaced annually.
They are derived from estimates of:
Mineral Appositional Rate (MAR), (interlabel distance
(4/π) (labeling interval) in µm/Day x 365.
Relative Mineralizing Surface (MS),
Bone Surfaces (BS) or Bone Volume (BV)
or
BFR = MAR(MS/BS)
BFR= MAR(MS/BV)
Bone Histomorphometry
Bone Formation Rates
Bone formation rates are expressed as:
BFR/BV in (mm³/mm³/yr)
BFR/BS in (mm³/mm²/yr)
Alternatively, BFR/BS can be derived as:
BFR/BS = Ac.f x W.Th
Bone Histomorphometry
Normal Mean Values
Parameter
Female mean Male mean
Cortical thickness (Ct.Th)
823 µm
915 µm
Cancellous bone volume (BV/TV) 21.8%
19.7%
Osteoid thickness (O.Th)
12.3 µm
11.1 µm
Osteiod surface (OS)
8.4%
6.5%
Osteoblast/osteoid
interface (Ob.s/OS)
22.1%
14.4%
Osteoclasts/trabecular
surface(N.Oc/BS)
3.0/100 mm 3.5/100 mm
Eroded surface (ES)
2.3%
1.5%
Single labled surface (sL.S)
2.3%
2.4%
Double labeled surface (dL.S)
6.2%
3.0%
Bone Histomorphometry
Normal Mean Values
Parameter
Female mean Male mean
Wall Thickness (W.Th)
Mineral Apposition Rate (MAR)
49.8 µm
0.88 µm/d
0.89 µm/d
Bone formation Rate
Surface (BFR/BS) (mm³/mm²/yr)
0.019
0.009
Volume (BFR/BV) (mm³/mm³/yr)
0.250
0.131
Mineralization Lag Time (M.Lt)
21.1 d
27.6 d
Activation Frequency (Ac.f)
0.42 y
Bone Histology and
Histopathology for Clinicians
End part I