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1 Basic Science ofBone andCartilage Metabolism
9
Fig. 1.14 Schematic
demonstrates the
vascular supply to bone,
with the main blood
supply originating from
the nutrient arteries,
which penetrate the
deeper medullary bone,
and the lower-pressure
periosteal blood supply,
which enables direct
perfusion of the more
peripheral cortical bone.
(From “The Key Role of
the Blood Supply to
Bone”, Bone Research,
2013)
central sinus
central artery
bone
emissary vein
Cartilage
Cartilage, like bone, is a connective tissue. Its
histologic organization, however, is far less structured. There exist four histologic types of cartilage, each serving a different function:
1. Hyaline cartilage covers the ends of long
bones and provides a smooth, frictionless surface for articulation in a diarthrodial (synoviallined) joint.
2. Fibrocartilage is typically found in certain
non-diarthrodial joints such as the pubic
symphysis. It is also located at the margins
of certain diarthrodial joints, forming structures such as the glenoid labrum and acetabular labrum. Following injury to hyaline
cartilage, repair of the chondral defect is
typically accomplished in the form of
brocartilage.
3. Elastic cartilage is found in certain areas
where resilience is important. Examples
include the tip of the nose and the ear lobe.
4. Physeal cartilage is found in the physis.
periosteal artery
Medullary sinuses
& hemopoietic niches
nutrient artery
The most important of the four, hyaline cartilage, is a relatively aneural, avascular, and hypocellular connective tissue. By weight, it is 70%
water. The remaining 30% is composed of ground
substance and cells, known as chondrocytes. The
ground substance of hyaline cartilage is composed primarily of type II collagen and GAGs.
Collagen endows the cartilage with tensile
strength and GAGs are critical for resiliency.
Chondrocytes are found in individual lacunae,
where they maintain healthy cartilage by actively
synthesizing new ground substance components
(Fig.1.15).
The cartilage is grossly organized into multiple layers: tangential (most supercial), transitional, radial, and calcied (Fig. 1.16).
Distinguishing these layers is the shape of the
chondrocytes, orientation of the collagen brils,
and percentage of GAGs, with more supercial
layers providing tensile strength, and deeper layers accounting for more compressive strength.
The chondral layer receives the bulk of its
nutrition not only from the vasculature of the
subchondral bone below it, but mostly by diffusion from the synovial uid it is bathed in.
10
Fig. 1.15 Chondrocyte cells, with abundant
endoplasmic reticulum, necessary for actively
secreting their collagen- rich matrix. (From
Junqueira’s Basic Histology, Chapter 7, Figure7-7)
Fig. 1.16 Articular, or
hyaline cartilage, caps
the end of bones
entering diarthrodial
joints. As can be seen,
collagen bers run
parallel to the articular
surface, supercially,
gradually changing their
orientation with depth to
become perpendicular at
the junction with the
underlying subchondral
bone. This specic
orientation imparts
tension strength
supercially, and
compressive strength
deep. (From Junqueira’s
Basic Histology, Chapter
8, Figure8-23)
M. J. Kelly and J. N. Delahay
Proteoglycan aggregates ll the space between
the individual collagen bers in the cartilage tissue, which allows for inow and outow of a
small amount of water between this space and the
synovial uid. This action produces a biomechanical spring, and with changes in pressure
(joint motion and loading), constant movement
of water between the tissues results. This pro-
Normal Bone
Matrix
=>
Osteoporosis Osteomalacia
Matrix
Matrix
1 Basic Science ofBone andCartilage Metabolism
11
vides essential nutrition to the articular cartilage
and permits the interchange of oxygen and metabolic waste. Additionally, when healthy, articular
cartilage can take on a fully hydrated state, providing an almost frictionless bearing, hence minimizing wear on the articular surface.
Abnormal Bone Development
andMetabolism
Most skeletal diseases are the result of disruption
of normal bone growth and development, breakdown of bone once it has been normally formed,
or alteration of the normal mechanisms of bone
formation or bone resorption. The etiologies of
the pathologic states, as one would expect, are
quite varied, but the nal manifestations within
the musculoskeletal system frequently show striking similarities.
As one considers the etiology of skeletal disease, it is helpful to rst group the possible differential diagnoses by disease category. This
permits one to develop a comprehensive list of
possible diagnoses that may explain the ndings
manifested by the skeleton. The seven disease
categories are perhaps best organized using the
acronym “VITAMIN.”
V—vascular
I—infection
T—tumor
A—arthritis
M—metabolic bone disease
I—injury (trauma)
N—neurodevelopmental
changes and, therefore, will be highlighted in
greater detail in the ensuing chapters.
Metabolic Bone Disease
Disease processes affecting bone often can be
understood as a change in the relationship of
bone formation and bone resorption. It is therefore important to understand this relationship. By
doing so the net effect on the skeleton be
appreciated.
The relationship (ratio) of mineral to matrix
may be affected in abnormal metabolic states. For
example, osteoporosis is a loss of bone mass, but
there is an equivalent loss of matrix and mineral;
therefore, the ratio remains normal. In contrast,
osteomalacia is a relative loss of mineral resulting
in a predominance of matrix; thus, a decrease in
bone mass is accompanied by a decrease in the
ratio of mineral to matrix (Fig.1.17).
Serum calcium level is rarely representative of
skeletal activity. Considering that more than 95%
of the body’s calcium is stored in bone apatite, it is
understandable that the ~180mg of ionized plasma
calcium represents just the “tip of the iceberg.”
While peripheral sampling of the serum calcium
provides only a remote clue to the true content of
skeletal apatite, it does provide a convenient way to
think about and classify metabolic bone disease.
MINERAL
MINERAL
MINERAL
The remainder of this chapter will focus on
these diagnostic groups and the way in which
they affect the skeleton. Specic emphasis will
be placed on generalized afictions of the skeleton. In that light, certain disease categories are
more likely to adversely affect the skeleton in a
generalized fashion; specically vascular, metabolic, systemic arthritis, and neurodevelopmental
etiologies. The others—infection, injury, and
tumor—are more likely to produce localized
MATRIX
Mineral
Fig. 1.17 Ratio of mineral to matrix in normal bone and in
certain disease states. In osteoporosis, the ratio remains constant and equivalent to normal bone, despite an overall
decrease in bone mass. In osteomalacia, there is not only an
overall decrease in bone mass, but also a decrease in the ratio
of mineral to matrix as a result of skeletal demineralization
MATRIX
Mineral
MATRIX
Mineral
12
N Engl J Med. 1986;314:1676
100
Age in years
% bone
M. J. Kelly and J. N. Delahay
Eucalcemic States: Osteoporosis
As mentioned, osteoporosis is a predominance of
bone resorption over bone formation, with the net
effect being bone loss (Fig.1.18).
There is a parallel loss of mineral and matrix,
so their ratio remains normal. Essentially, osteoporosis is a decrease in bone mass with an
increase in cortical porosity and in diaphyseal
bone diameter. This latter phenomenon is an
attempt by the body to use what limited bone
there is to disperse it as far as possible from the
neutral axis of the long bone. Mechanically, this
Cortical
60 70
Trabecular
Mean ± 2 S.E.
80 90
80
60
40
20
0
020304050
Fig. 1.18 The relative decrease in cortical and trabecular
bone with age in apparently normal persons. Note the
relatively rapid loss early in life in trabecular bone and
comparatively little loss at this age in cortical bone. The
situation is reversed after age 55. (From Jowsey
J. Metabolic Diseases of Bone. Philadelphia, PA:
Saunders; 1977. Reprinted with permission)
increases the torsional rigidity of the bone.
Numerous etiologies of osteoporosis have been
identied, with the most common causes being
postmenopausal, senile, and a long list of secondary causes (endocrinopathies, nutritional deciencies, side effects of medications including
anti-convulsants and glucocorticoids, alcoholism, prolonged immobilization, and more). The
most clinically relevant of those listed is the postmenopausal type, which occurs shortly after the
withdrawal of estrogen (naturally or surgically),
and brings along with it a host of predictable biological changes. This diagnosis is classically referenced against senile osteoporosis, a disease of
aging, thus one that affects a slightly older population (Fig.1.19).
No matter the etiology, the primary pathology
remains a quantitative, not qualitative disorder of
bone.
With osteoporosis, the new patient will present with a history of pain and/or recurrent fractures. Occasionally, they will complain of early
satiety because of abdominal compression resulting from loss of height of the vertebral column
(Fig.1.20).
Similarly, with increasing kyphosis in the thoracic region, they may experience some shortness
of breath. On examination, one can nd the
prominent dowager’s hump, barrel chest, protuberant abdomen, and generalized bone pain with
percussion tenderness.
Fig. 1.19 Types of
involutional
osteoporosis. (Source:
Modied from Riggs
BL, Melton LJ
III.Involutional
osteoporosis. N Engl J
Med 1986;314:1676)
Type 1
(Postmenopausal) Type 2 (Senile)
Age (years)
Sex ratio (M/F)
Type of bone loss
Fracture site
Main causes
Calcium absorption
(1,25-OH)
Parathyroid function
Source: Modified from Riggs BL, Melton LJ III. Involutional osteoporosis.
-vitamin D
2
synthesis from
25-(OH) Vitamin D
50–75
1:6
Trabecular
Vertebrae (crush)
Distal radius
Menopause
Decreased
Secondary
decrease
Decreased Increased
Over 70
1:2
Trabecular and cortical
Ver tical (multiple wedge)
Hip
Aging
Decreased
Primary decrease
1 Basic Science ofBone andCartilage Metabolism
13
Classically, once changes are noticeable radiographically, it has been estimated that the bone
density has already decreased by 30% or more.
Today, however, Dual-energy X-ray absorptiometry (DEXA) scanning allows accurate and reproducible measures of bone mineral density of the
spine and the hip. While it requires a minimal
amount of radiation to obtain, it remains quite
accurate in its goals. Because DEXA has become
so mainstream, we now have population-based
normal values that allow comparison of an individual’s bone density. The difference is expressed
as a T score, which represents the number of
standard deviations below that of normal, young
controls (25–30 year old women, who display
peak bone mass). Of note, while the T score is
calculated as bone mineral density compared to
young controls, the Z score, another used term, is
bone mineral density compared to patients of
similar age and sex. The denitions based on T
scores are as follows:
Fig. 1.20 The osteoporotic spine. There exists a relative
density of the vertebral body endplates with resorption of
the trabeculae of the spongy bone. Anterior wedging and
end plate compression are present, due to weakness of the
vertebral body end plates. (From Orthopedic Imaging: A
Practical Approach. 7E. 2021. Chapter 27, Figure27.7)
The yearly cost of this disease in dollars, as
well as the associated pain and suffering to the
patient, is overwhelming. And once fractures
start, this condition is associated with a 15–20%
increase in mortality, in addition to the aforementioned reduced quality of life related to the associated morbidity. And this is not a rare condition,
with recent data suggesting over 1.5 million
osteoporotic fractures occurring annually in the
USA alone, with compression fractures of the
vertebral body, and fractures of the proximal
femur, distal radius, and proximal humerus leading the charge. However, until recently, it was
quite challenging to quantify bone mass, and thus
diagnose this condition reliably.
Typically, a crude estimate of bone density
determined by plain radiographs has been used to
extrapolate to the amount of bone previously lost.
Normal: 0 to −1
Osteopenia: −1 to −2.5
Osteoporosis: < −2.5
An unfortunate result of mainstream DEXA)
scanning has been to adulterate the use of the
term “osteopenia.” For many years, this term was
dened as a generalized decrease in radiographic
bone density. As such, it was non pejorative and
did not speak to a specic metabolic bone disease. In its present accepted context, the implication of using the term “osteopenia” is to imply a
mild form of osteoporosis. This was certainly not
the original connotation of the term. Diseases
other than osteoporosis, such as hyperthyroidism
and multiple myeloma, are characterized by
observed generalized decreases in radiographic
bone density, hence osteopenia, and are not necessarily just “mild” forms of a different
condition.
Once this condition is diagnosed, treatment
must ensue, for limitation of bone loss and prevention of fractures is the most prudent approach
to patient care. Prophylactic treatment regimens
include lifestyle modications and vitamin supplementation. Regular weight-bearing exercise
14
(walking or jogging, not swimming, which
many older patients prefer) and supplemental
calcium and vitamin D administration is standard recommendation. Pharmacological treatment is considered for postmenopausal women
or men over 50years old with a history of osteoporotic fracture, or with osteoporosis diagnosed
on DEXA scan.
The classic pharmacological agent used in the
treatment of postmenopausal osteoporosis was
estrogen substitutes. While its efcacy in maintaining skeletal mass is beyond question, its complication prole, including its relation to breast
and cervical cancer, heart disease, and venous
thromboembolic events (VTE) made its regular
use somewhat controversial. In light of this complication prole, other therapeutic regimens were
developed and have since been popularized. We
will highlight them individually below.
1. Without doubt, the most commonly used
agents are the bisphosphonates. Structurally
similar to naturally occurring pyrophosphates, they are taken up by osteoclasts,
accumulate at sites of bone turnover, and
behave as potent inhibitors of bone resorption. It has been said that bisphosphonates are
able to “freeze the skeleton” and have been
shown to reduce rates of osteoporotic fractures upwards of 50%. While they carry the
rare, suspected complications of osteonecrosis of the jaw and atypical subtrochanteric
femur fractures in patients on these medications long term, they are clearly rst-line
treatment for this condition and have been a
major pharmacological advancement in the
eld of orthopedics (Fig.1.21).
2. Teriparatide is a synthetic form of parathyroid
hormone (PTH), which has a direct agonist
effect on osteoblasts, thus increasing bone
mineral density. Of note, this may at rst seem
counterintuitive, as the elevated levels of PTH
in hyperparathyroidism in fact reduce bone
formation in this condition. However, it seems
that PTH’s effect on bone differs based on
dosing and pattern of exposure, and when
given as a low-dose, daily subcutaneous injection, it does demonstrate a (paradoxical) effect
M. J. Kelly and J. N. Delahay
Fig. 1.21 Classic atypical femur fracture in a patient on
bisphosphonate medications for extended duration. Note
the fracture characteristics, with lateral cortical thickening, and a transverse, non-comminuted fracture line.
(From Rockwood and Green’s Fractures in Adults, 9e,
Tornetta. Chapter 55, Figure55-1)
as a bone-forming agent. Its niche indication
at this time appears to be in preventing
junctional kyphosis in those patients undergoing spinal fusion operations.
3. Denosumab is a monoclonal antibody with
signicant pharmacologic promise. It works
against the RANK-ligand molecule in the
RANK/RANK-ligand/OPG system, effectively mimicking OPG, and thus protecting
the bone.
4. While selective estrogen receptor modulators
(SERMs) may be less prescribed now than in
the recent past, with the popularization of the
bisphosphonate drugs, Raloxifene still has its
place in treatment. This drug behaves as an
agonist on estrogen receptors in the bone, yet
antagonizes estrogen receipts in the breast,
thus reducing breast cancer risk, while also
improving bone mineral density. Its downsides—hot ashes, and a strict contraindication with a VTE history.
5. Calcitonin is the last pharmacologic option to
be discussed. A naturally occurring polypeptide hormone, it acts as a direct inhibitor of
1 Basic Science ofBone andCartilage Metabolism
osteoclasts, decreasing bony resorption.
Interestingly, it is administered largely in the
form of a nasal spray, and its major use now is
in decreasing pain associated with vertebral
compression fractures.
Hypercalcemic States: Hyperparathyroidism
The effect of PTH on bone is the same whether it
is released as a result of a parathyroid adenoma
(primary hyperparathyroidism) or by one of several secondary causes. In an attempt to increase
serum calcium concentration, PTH stimulates
osteoclastic activity, causing an intense resorption of bone. The cavities resulting from this
osteoclastic activity ll with vascular brous tissue, resulting in the classic “osteitis brosa cystica.” As the cavities coalesce, they form a single
large cyst called a “brown tumor,” named for the
hemosiderin staining one sees within (Fig.1.22).
Without doubt, the most common cause of
secondary parathyroid hyperplasia in today’s
world is chronic renal disease, which causes
hypovitaminosis D, calcium wasting by way of
the kidneys, and a resultant hyperparathyroidism.
15
Fig. 1.22 Brown tumors in the bilateral tibiae of a patient
with primary hyperparathyroidism. (From Orthopedic
Imaging: A Practical Approach. 7E. 2021. Chapter 28,
Figure28.8)
Hypocalcemic States: Rickets
andOsteomalacia
The same underlying mechanism accounts for
rickets and osteomalacia: faulty mineralization of
bone matrix, which results in the presence of
unmineralized osteoid about bony trabeculae.
The lack of mineral required for adequate mineralization can be due to a number of different etiologies: nutritional deciencies, malabsorption
states, lack of exposure to ultraviolet light, and
renal disease are some of the more common.
Notably, if the failure of mineralization
impacts the skeleton prior to physeal closure, the
result is rickets. The affected patient will demonstrate the characteristic hallmarks of the disease:
bowlegs, frontal bossing, ricketic rosary, and
knobby joints (Fig. 1.23). All of these ndings
are due to the presence of large masses of unmin-
eralized osteoid. In addition, abnormalities of the
physis and abnormal physeal growth can be
anticipated.
If the process impacts the skeleton after physeal closure, the disease that results is osteomalacia. In the adult, these areas of unmineralized
osteoid present as radiographic lucent areas in
the bone, frequently referred to a Looser’s lines
(Fig. 1.24). In addition, the bones themselves
tend to be somewhat malleable and can bow
under load.
Renal Osteodystrophy
Renal osteodystrophy encompasses the skeletal
changes that result from long-standing renal disease. These changes are truly a “collage” of the
other metabolic bone diseases. To understand the
pathogenesis of renal osteodystrophy is to under-
16
ab
Fig. 1.23 Child with
Rickets. (a) XR of the
hand shows widened
growth plates. (b) There
are irregularly widened
physes via the zone of
provisional calcication.
(From Orthopedic
Imaging: A Practical
Approach. 7E. 2021.
Chapter 27,
Figure27.11)
M. J. Kelly and J. N. Delahay
Fig. 1.24 Osteomalacia caused by malabsorption
syndrome. Left scapula demonstrates a radiolucent
cleft, known as a pseudofracture, or Loosers lines.
These lines appear at sites in which stress fractures
would occur. In normal individuals, the removed
bone in the area of stress fractures is replaced by
normal osteons. In persons with osteomalacia, the
removed bone is replaced with abnormal osteoid,
which fails to mineralize and leaves a linear
radiolucency that may persist for years. (From
Orthopedic Imaging: A Practical Approach. 7E.
2021. Chapter 27, Figure27.15)
PO
Re
←
Ca
PTH
←
1 Basic Science ofBone andCartilage Metabolism
17
Fig. 1.25 Pathogenesis
of renal osteodystrophy
4
tention
(PO4)s
Maintain
solubility product
stand the basis of all of the metabolic afictions
of the skeleton (Fig.1.25).
Chronic uremia allows a two-fold drive to
depress the serum calcium. First, the kidney is
unable to excrete phosphate; hence the serum
phosphate level rises. The serum calcium level is
then of necessity driven down to maintain the
xed solubility product. Coincidentally, since the
absence of a functional renal parenchyma stops
the output of signicant amounts of activated vitamin D, intestinal absorption of calcium is retarded,
further depressing serum calcium. This dual
mechanism profoundly depresses serum calcium,
mandating the secondary parathyroid hyperplasia
as previously discussed. The changes in the bone
reect the metabolic drives. The vitamin D deciency is demonstrated by the presence of unmineralized osteoid. And the elevated levels of PTH
cause the aforementioned osteitis brosis cystica.
Unique to this syndrome, hyperphosphatemia
results in a diffuse osteosclerosis (Fig.1.26).
Uremia
(Ca)s
←
←
Fig. 1.26 Pelvic radiograph of patient with long- standing
renal osteodystrophy due to renal failure in the setting of
posterior urethral valves. Sclerotic changes as well as cystic defects in the proximal femora are evident. (From
Orthopedic Imaging: A Practical Approach. 6E. 2015.
Greenspan, Adam, chapter 26, Figure27.16)
Renal
parenchymal
damage
Vit. D synthesis
←
Absorption of
←
Osteogenesis Imperfecta
Sick Cell Syndromes
Osteogenesis imperfecta (OI), also known as
brittle bone disease, is a spectrum of disorders
The underlying mechanism seen in these conditions is a qualitative, functional decit in a specic cell population—despite the fact that the
population is quantitatively normal.
that have a hallmark feature—bone fragility. OI
is typied by the impotence of the osteoblasts;
they are unable to manufacture and secrete nor-
mal collagen. Ossication is, therefore, abnormal
18
ab
M. J. Kelly and J. N. Delahay
(due to insufcient osteoid production) and
results in inferior quality bone (Fig.1.27).
Clinically and radiographically, there is
marked cortical thinning and attenuation of the
diaphyseal caliber. The long bones, because of
their altered anatomy, are at very high risk for
fracture, often requiring multiple orthopedic
operations by a very young age (Fig.1.28).
Upwards of 90% of patients with OI have a
traceable genetic mutation in collagen (specically the COL1A1 or COL1A2 genes), and there
is signicant phenotypic heterogeneity.
Individuals can be affected mildly, severely, or
even fatally in the perinatal period. In an effort to
accommodate the variations in phenotype, the
Sillence classication has been adopted by most
authors. Four specic types, all transmitted in an
autosomal dominant fashion, were described in
the original classication.
Type I is the most common form and the mildest
clinically. This is the only quantitative disor-
der in collagen (i.e., not enough made). These
patients demonstrate the classic ndings of
blue sclera, long bone fractures after the age
of walking, and a relatively normal life
expectancy.
Type II is the lethal form of the disease. A qual-
itative disorder of collagen similar to types
III and IV, these children are usually stillborn or die shortly after birth, usually due to
respiratory failure or intracranial hemorrhage.
Type III is the severe nonlethal form, character-
ized by sclera of normal color, multiple birth
fractures, and signicant long-term deformity
and disability.
Type IV is the intermediate form, with variable
manifestations. Notably, it is the least common of the rst four types.
The Sillence classication has since been
modied to include types ve through seven.
These three types in fact do not have a type one
collagen mutation, but manifest with a similar
phenotype and have abnormal bone when viewed
microscopically.
Osteopetrosis
Known as a sclerosing bone condition, osteopetrosis results from the failure of the osteoclasts to
remove primary spongiosa bone. This latter osseous
Fig. 1.27 (a, b) Marked
degree of spinal
deformity in a young
patient with severe
osteogenesis imperfecta.
(From Lovell and
Winter’s Pediatric
Orthopaedics, Chapter 6,
Figure19)