Bone Form, Function, Injury, Regeneration, and Repair

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Ovid: Oncology and Basic Science

Editors: Tornetta, Paul; Einhorn, Thomas A.; Damron, Timothy A.

Title: Oncology and Basic Science, 7th Edition

> Table of Contents > Section IV – Basic Science > 19 – Bone Form, Function, Injury, Regeneration, and Repair

Bone Form, Function, Injury, Regeneration, and Repair

Alexia Hernandez-Soria

Mathias Bostrom

Bone form consists of its cellular morphology, matrix
composition, and circulation. Bone function, regeneration, and repair
integrate cellular and macroscopic remodeling, biomechanics, material
properties, metabolism, and age-related changes. Injury to bone can
occur by way of osteonecrosis and fracture. These topics are addressed
individually in this chapter.

Bone Cellular Morphology

Microscopic Bone

Microscopically, bone exists in either a woven or a lamellar form (Table 19-1).

Bone Structure

Structurally, bone is categorized as trabecular or cortical bone (Table 19-2).
Porosity and architectural characteristics differentiate the two types
of bone. These differences account for their respective material
properties. Each structural bone type may exist as either or both types
of microscopic bone, depending upon age, location, and setting (normal
vs. pathologic bone).

Trabecular bone
- Woven
- Lamellar
Cortical bone
- Compact bone: layers of lamellar bone without osteons; small animals
- Plexiform bone: layers of lamellar and woven bone; large animals experiencing rapid growth
- Haversian bone: vascular channels surrounded by lamellar bone (osteons); most complex type of cortical bone

Haversian Bone

Osteon/bone structural unit (BSU): the
major structural unit of cortical bone; contains a central
neurovascular canal surrounded by concentric lamellae

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Table 19-1 Properties of Microscopic Bone

Property	Woven Bone	Lamellar Bone
Definition	Primitive; “immature” bone	Remodeled woven bone; “mature” bone
Found in	Embryo, infant, metaphyseal region, tumors, osteogenesis imperfecta, pagetic bone	Cortical bone, trabecular bone throughout the mature skeleton (most bone after the age of 4)
Composition	Dense collagen fibers, varied mineral content	Formed by intramembranous or endochondral ossification; contains collagen fibers
Organization	Randomly arranged collagen fibers	Highly ordered; stress-oriented collagen fibers
Response to stress	Isotropic: independent of direction of applied forces	Anisotropic: mechanical behavior differs according to direction of forces; bone’s greatest strength is parallel to longitudinal axis

Table 19-2 Bone Structure

Property	Trabecular	Cortical
Description	Spongy and cancellous bone	Dense or compact bone; <30% porosity
Location	Metaphysis or epiphysis (long bone); cuboid bone (vertebrae)	Diaphysis (long bone); outer layer, “envelope,” of cuboid bone (vertebrae)
Architecture	Individual trabeculae organized into 3-D lattice of rods and rods, rods and plates, or plates and plates Rods = thin trabeculae Plates = thick trabeculae Lattices orient in response to stress.	Plexiform bone: layers of lamellar and woven bone. Contains vascular channels and allows for rapid growth and accumulation of bone. Haversian bone: arrangement of osteons surrounded by lamellae
Mechanical stress	Predominantly subjected to compressive forces	Subjected to bending, torsional, and compression forces
Porosity	50% to 90% (large spaces between trabeculae)	~10% (dependent on density of voids in architecture)
Apparent density^a	0.30 g/cm³ (std 0.10 g/cm³ ± 30%)	1.85 g/cm³ (std 0.06 g/cm³ ± 3%)
^aApparent density = mass of bone tissue/bulk volume of tissue (bulk volume = bone + bone marrow cavities); std = standard deviation

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Haversian canal: central canal of the osteon; contains cells, haversian vessels, and nerves
Volkmann’s canals: connect haversian canals of neighboring osteons
Howship’s lacunae: resorptive cavities within which reside osteoclasts
Canaliculi: channels within and between
osteons; allow communication and waste removal between developing cells
of lamellae and haversian vessels

Haversian Vessels

Most are structurally similar to
capillaries. They contain a base membrane that functions as a
selective-ion transport barrier important for Ca²⁺ and P^2- transport and response of bone to mechanical loads.
The small vessels are similar to
lymphatic vessels, which do not have a base membrane. These vessels
contain only precipitated protein.

Bone Cells

Osteoblastic Lineage

Three types of cells of osteoblastic lineage are each derived from pleuripotential mesenchymal stem cells (Table 19-3).

Osteoclastic Lineage

Osteoclasts differentiate from pleuripotential hematopoietic stem cells (Table 19-4).
Circulating monocytes develop into osteoclasts at resorption sites.

Cellular Mechanisms of Remodeling

Throughout life old bone is continually replaced by new
bone. The process of remodeling and bone formation is regulated by
cellular mechanisms of osteoblasts and osteoclasts.

Table 19-3 Properties of Osteoblastic Lineage Cells

Property

Osteoblasts

Osteocytes

Bone-Lining Cells

Morphology

Initially pleuripotential mesenchymal cells.
Round, polar, organelle-rich cells.
High endoplasmic reticulum and golgi density reflects secretory function.

Most abundant cell in mature bone.
Develop from osteoblasts embedded in lacunae; lose most cytoplasmic contents during maturation.
Defining characteristic is extensive network of processes extending through canaliculi.

Flattened, elongated cells covering bone surfaces.
Connect to osteocytes via gap junctions.

Function

Main function is to form bone.
Two stages of bone formation:

Matrix formation
Mineralization

Main function is thought to be communication.
Minimal synthetic activity when remodeling to maintain local environment.
Location and morphology ideal for responding to mechanical stress and communicating with bone-lining cells.

Function is unconfirmed.
Believed to be involved in bone formation and resorptive mechanisms.
Act
as an ion barrier between interstitial fluid and fluid in matrix,
suggesting participation in mineral homeostatic mechanisms.

Table 19-4 Properties of Osteoclasts

Property	Description
Cell lineage	Hematopoietic lineage, same as macrophages. Similar to macrophages but have distinct differences in surface receptors. Osteoclasts have about two to five nuclei and receptors for calcitonin and vitronectin (integrin αvβ3).
Morphology	Foamy, acidophilic cytoplasm. When active, are polar and have ruffled border. Generally located in groups on bone surface (forming Howship’s lacuna) or in cortical bone (making haversian canals).
Function	Active osteoclasts solubilize mineral and organic bone matrix by creating an enclosed acidic environment (“clear zone”) with H+ ions. When pH reaches ~3.5, bone resorbs. Mechanism of attachment to bone surface is not confirmed; evidence suggests communication with bone-lining cells.

Remodeling

Remodeling is the process of resorption of immature (woven) and old bone followed by the formation of new lamellar bone.
There are two forms of remodeling:
- Endochondral remodeling: converts primary
  bone to secondary bone (cartilage to trabecular bone); believed to
  decrease density of trabecular bone
- Haversian remodeling: repairs fatigue
  damage to skeleton, maintains bone mineral homeostasis, and thought to
  be necessary for maintaining viability of cells far from bone surfaces.
  Increases porosity of cortical bone, decreases width, and believed to
  decrease strength.
Both endochondral and haversian
remodeling follow the same six-stage sequence of events: resting,
activation, resorption, reversal (coupling), formation, and
mineralization. The process is regulated by mechanical and systemic
factors.

Stages of Remodeling

Resting

At any time, about 80% of human bone surface (perios-teal and endosteal) is resting.
Bone surface is lined with an endosteal
membrane and resting bone lining cells believed to be involved in bone
mineral homeostatic mechanisms.

Activation

The exact factor of activation is unknown.
In response to regulators, osteoclasts
are recruited and given access to a section of bone surface. It is
believed that a capillary extends to the surface, delivering osteoclast
precursors (monocytes).
Bone lining cells digest the endosteal
membrane before retracting to allow the osteoclasts access to the
mineralized bone (osteoclast regulation factors are summarized in Box 19-1).

Resorption

Resorption leads to formation of Howship’s lacunae in cancellous bone and cutting cones (resorptive cavities or Haversian canals) in cortical bone.
The process lasts about 14 days. The
osteoclast precursors are thought to coalesce at the bone’s surface to
form large multinucleated osteoclasts.
The osteoclasts attach to the surface, forming a “clear zone” under their ruffled border.
In a concerted mechanism, the bone surface is solubi-lized.
- Concerted mechanism: Cathepsin B and acid
  phosphatase are released in “clear zone.” Carbonic acid is reduced by
  carbonic anhydrase intracellularly. H ⁺ is released into the “clear zone” until pH reaches ~3.5 and environment is acidic enough to degrade mineralized bone.
Pyridinolines cannot be degraded by
resorption and are released into extracellular fluid. Serum and urine
levels can be measured for monitoring resorption.

Reversal/Coupling

A 28-to 35-day interval between
resorption and formation of bone, which can be noted histologically by
an absence of osteoclasts in Howship’s lacunae and cutting cones
Surfaces are lined with mononuclear cells
to prepare the surfaces for new bone formation. A glycoprotein layer
(cement line), placed over the surface, is thought to facilitate
attachment by new osteoblasts. The mechanisms by which this occurs are
not known.
- This time interval is considered the time
  when bone formation is “coupled” with resorption due to the perceived
  hormonal and cellular mechanisms of communication among the bone
  resorbing and forming cells.

Box 19-1 Osteoclast Regulation Factors

Receptor activator of NF-_K β(RANK)/receptor activator of NF-k β-ligand (RANKL)

Osteoblasts produce protein RANKL.
RANKL is received by cell surface receptor, RANK, on precursor osteoclasts.
RANK + RANKL stimulates osteoclasts’ development and bone resorption.

Osteoprotegerin (OPG)

Decoy RANKL receptor
OPG inhibits osteoclast development and increases bone mass.

Parathyroid hormone (PTH)

Stimulates number of osteoclasts found in bone
PTH is correlated with increased RANKL and decreased OPG expression.
PTH receptors are found on osteoblasts.
PTH stimulates osteoblast production of interleukin-6 (IL-6) and IL-6 stimulates osteoblast production of IGF-1.

Calcitonin

Directly inhibits bone resorption
Calcitonin receptors found on osteoclasts

Thyroid hormone

Hyperthyroidism increases bone resorption.

Vitamin A

Has been shown to stimulate resorption

Growth Factors

Resorption-stimulating growth factors:
- EGF/TGFα, PDGF, IGF-1, and FGF
  - Osteoclasts have receptors for IGF-1.
TGFβ has been shown to inhibit osteoclast formation.

Cytokines

IL-1, IL-6, and tumor necrosis factor are known to be involved in mediating osteoclast differentiation and bone resorption.

Formation and Mineralization

The two aspects of bone formation occur in this stage: matrix synthesis followed by mineralization.
The new osteoblasts deposit a new layer of unmineralized bone matrix, the osteoid seam.
The osteoid seam will reach ~70%
mineralization in 5 to 10 days and complete mineralization in about 4
months (in cortical and trabecular bone).
Bone modeling-dependent bone loss: An adult BSU will mineralize 5% less bone than it resorbed.

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Matrix Synthesis

Osteoblasts secrete many types of collagenous and non-collagenous macromolecules, which are all proteins.
The secretions include all critical structural elements for osteoid in both trabecular and cortical bone.
- The unique architecture differentiating bone types is due to the particular organization of the secreted proteins.
All proteins, and thus matrix organization, are regulated on a genetic level.
Most matrix proteins undergo some form of post-transla-tional processing, which allows matrix regulation without interfering with gene expression.
- Collagen cross-linking
- Glycosylation to produce proteoglycans and glycoproteins
- Phosphorylation: produces osteopontin, bone sialoprotein
- Vitamin K dependant -y-carboxylation: produces osteocalcin
Many proteins have specific functions related to their surface receptors or adhesion and anti-adhesion properties.
Osteoblasts secrete proteins according to matrix formation.
- Fibronectin and osteonectin are secreted early in formation.
- Osteocalcin (calcium binding protein) is secreted only after matrix is formed.

Mineralization

Mineralization is the process by which bone crystals grow and proliferate within the holes and pores of the matrix collagen fibers.
The bone crystals are composed of an analog of hydroxy-apatite (HA). The HA in matrix leads to the rigidity of bone.
Mineralization is regulated by the spaces and orientation of matrix collagen fibers (pores and holes) and by the noncollagenous matrix proteins.
The noncollagenous proteins can function both as nucleators and inhibitors of crystal formation.
There is a lag time of —14 days between
matrix formation and mineralization. The time is thought to be
regulated by noncollagenous proteins and allows matrix to “mature;”
strengthened by collagen cross-linking, resulting pyridinolines
(pyridinoline, deoxypyridinoline, hydroxylysylpyridinoline,
lysylpyridinoline).
- Due to lag time, there is always an osteoid seam between the osteoblasts and newly mineralized bone.

Regulation of Remodeling

The bone remodeling sequence is intricately controlled
by endocrine hormones as well as local paracrine and auto-crine
factors. The systemic and local factors that mediate bone formation are
listed in Box 19-2 (also see Chapter 10, Metabolic Bone Diseases).

Box 19-2 Regulators of Bone Formation

Systemic factors

Growth hormone/insulin-like growth factor
Thyroid hormone
Vitamin D
Estrogens
Glucorticoids
Parathyroid hormone

Local factors

IGF-1
Transforming growth factor beta
Bone morphogenetic protein
Fibroblast growth factors
Parathyroid hormone-related peptide
Prostaglandins
Platelet-derived growth factor (VEGF)

Transcription factors

Core binding factor (Cbfa1/Runx2)
Osterix (transcription factor for osteoblast differentiation)

Resorption Regulation

Regulating bone resorption necessarily focuses on
mediating osteoclast proliferation and activity. The exact mechanisms
of interaction remain under investigation. The roles of systemic and
local factors in osteoclast regulation are summarized in Chapter 10.

Bone Matrix Composition

Bone Composition

Inorganic/mineral phase: 60% to 70%
Organic matrix: 35% to 22%
Water: 5% to 8%

Mineral Phase

Mineral crystals are composed of an analog of calcium hydroxyapatite (HA): Ca₁₀(PO₄)₆(OH)₂
Frequent impurities include Mg² ⁺, Sr² ⁺, Na ⁺, CO₃^2-, CO₃^–, HPO₃^2-, F^–, K⁺
- Apatite crystals are small and can
  contain many impurities, which can vary depending on diet, age, tissue
  location, and health status.
- Impurities may alter physical characteristics of bone, such as solubility.
- Newly formed woven bone has smaller crystals, which may result in it being more readily absorbed.

Bone Mineralization

Two distinct phases of mineralization
- Initiation: formation of the initial mineral deposits at multiple discrete sites
  - Requires the most energy
  - Local concentration of precipitatory ions increases.
  - Formation and exposure of mineral nucleators
  - Removal and modification of mineralization inhibitors
  - Most mineral is an analog of HA.
  - Primary nucleation: initial deposition of Ca₃(PO₄)₂ crystals into collagen
- Growth: proliferation/accumulation of mineral crystals on initial deposits
  - Rapid increase in size of crystals beginning as nuclei and forming solid particles
  - Secondary nucleation: greatest growth of crystals; grow in branching pattern off surface of other smaller crystals
  - Heterogeneous apatite nucleator: foreign material with surfaces on which crystals can grow
  - Aggregation of crystals to form mineralized bone matrix

Organic Matrix Composition

Collagen: 90%
Noncollagenous proteins: 5% to 8%

Organic Phase

Mostly made up of type I collagen (~90%)
Noncollagenous matrix proteins, minor collagen types, and lipids and macromolecules compose ~10%.

Collagen

Low solubility
Consists of three polypeptide chains (two α1 chains + α2 chain), ~ 4,000 amino acids
Chains arranged in a triple helix, which is stabilized by H-bonding between hydroxyproline and other residues
Collagen molecules aligned in parallel with other collagen molecules to form a collagen fibril
Collagen fibrils bundle to form a collagen fiber.
Pores: spaces between the sides of parallel molecules in a fibril
Hole zones: gaps within fiber between ends of molecules
- Noncollagenous proteins and mineral deposits can be found in hole zones and pores.

Collagen Synthesis

Completed within the cell (post-translational processing completed intracellularly)
- Triple helix procollagen is secreted.
Postsecretory processing: Nonhelical tail of propeptide is enzymatically cleaved.
Extracellular collagen molecules are stabilized by crosslinks (bonding) between chains.
- Cross-linking is unique to extracellular collagen.
- Presence of cross-linked collagen in urine (pyridino-lines) indicates bone resorption.

Osteocalcin

Synthetic product of osteoblasts
Represents 10% to 20% of bone noncollagenous protein
Thought to play a role in attracting osteoclasts to resorption sites and in regulating bone and mineral maturation
Synthesis is enhanced by 1, 25-dihydroxy vitamin D and hindered by parathyroid hormone (PTH) and cortical steroids.

Bone Remodeling

Bone Growth

Begins with embryogenesis and continues through skeletal maturity
Intramembranous ossification
- Flat bone growth
- Osteoblasts develop directly from mesenchymal cells and form bone matrix.
Endochondral ossification
- Long bone growth
- Cartilaginous bone develops into osteocytes/hav-ersian bone and continues to remodel throughout life.

Skeletal Maturity

Bone continues to remodel and adapt its material properties to the mechanical demands placed on it throughout life.
Wolff’s Law describes mechanisms by which bone responds to mechanical stress.

Remodeling

Remodeling occurs on all bone surfaces: periosteal, end-osteal, haversian, trabecular.
Rate of cortical remodeling
- Infant: up to 50%/year
- Healthy adult: 2% to 5%/year
Trabecular remodeling is 5 to 10 times higher than cortical remodeling throughout life.
In “healthy” remodeling, bone formation and resorption are perfectly coupled so that there is no net change in bone mass.

Bone Circulation

There are three main circulatory systems in bone (Box 19-3).
A unique characteristic of the three systems is that they are interconnected, allowing one to replace another when damaged.
- Epiphyseal vessels are not interconnected until after skeletal maturity.

Biomechanics and Material Properties of Bone

Bone as a tissue has material properties, whereas each specific bone has its own structural properties. As a structure,

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bone is unique in its ability to remodel and change in response to metabolic and mechanical stresses (see Chapter 16, Biomechanics).

Box 19-3 Circulatory Systems in Bone

Nutrient blood supply

Originates from a major artery of the systemic circulation
Enters diaphysis through nutrient foramen
The number of nutrient vessels varies per bone.
Nutrient vessel enters medullary space and branches into ascending and descending arteries.
Arterioles directly penetrate the endosteal surface and supply diaphyseal regions.

Metaphyseal complex

Originates from periarticular complex (geniculate artery)
Penetrates thin bone cortices to supply metaphyseal region
Vessels anastomose with the medullary arteries and epiphyseal arteries after closure of the growth plate.

Periosteal capillaries

Supply outer layers of cortical bone where there are muscular attachments

Material Properties of Bone

The material properties of bone vary
between cortical and trabecular bone and depend additionally on
micro-structure and type of stress (Table 19-5).

Bone Metabolism and Mineral Homeostasis

Maintaining mineral homeostasis is bone’s primary
function and is essential for bone’s cellular life and in avoiding
metabolic bone diseases. Problems arise when bone formation and
resorption rates are no longer complementary, often resulting in loss
of bone mass. The primary mechanism for maintaining mineral homeostasis
involves an endocrine regulation of serum calcium concentration with
vitamin D metabolites and PTH.

Bone Metabolism

Bone metabolism is regulated by the interaction between bone cells and the endocrine system (see Chapter 10).

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Table 19-5 Mechanical Properties of Bone

Property	Cortical	Trabecular
Elastic behavior Dependent on material orientation Described by Young’s modulus (stiffness, energy absorbed) and Poisson’s ratio (strain)	Transversely isotropic. Greater bulging than metal when loaded uniaxially.	Due to varying architecture and density, trabecular bone is anistroptic in some locations and isotropic in others. Variable stiffness and strain. Generally less stiff than cortical bone, except in cranium, subchondral plates, and vertebral bodies.
Strength	Stronger in response to longitudinal and transverse compression loads than tension. loads.	Strongest in compression. Weak in tension.
Viscoelastic behavior (variability of stress/strain relationship with time)	Typical viscoelastic behavior. Ultimate strain/ductility, increases with increases in strain rate below 0.1/sec (i.e., walking to running). When strain rates exceed 0.1/sec (trauma), cortical bone becomes more brittle; ultimate strain decreases.	Modest viscoelastic behavior.
Age effects	Young’s modulus and strength properties deteriorate for men and women after age 20. Ultimate strain reduction leads to more brittle, weaker bones and high risk of fracture. Changes vary by bone location.	Preferential loss of vertical trabeculae with age. Results in new architecture and an increased susceptibility to vertebral and hip fractures. Double^a/triple^b jeopardy.
^aDouble jeopardy: weakened mechanism of fracture due to thinning and loss of trabeculae ^bTriple jeopardy: reduced resistance to failure due to few, thinner, and longer trabeculae

The regulatory mechanisms are closely related to the regulatory mechanisms of remodeling discussed above.

Calcium Homeostasis

Maintaining an extracellular/intracellular Ca²⁺ gradient is essential for cellular life.
A gradient is maintained through interactions between intestines, kidneys, and skeleton.
99% of a body’s Ca²⁺ is in the
skeleton (bone matrix, calcium salts, and within bone cells); the
remaining 1% is extraskeletal within circulating fluid.
Normal serum Ca²⁺ concentration is 9 to 10.4 mg/dL.
All Ca²⁺ is acquired from diet; absorption/excretion rates are dependent on the Ca²⁺ gradient.
- Regulation of the Ca² ⁺ gradient is intricately associated with phosphate (Pi) metabolism.
- Dietary deficiency of Ca²⁺ requires the endocrine system to find Ca²⁺ intracellularly.
- Among other mechanisms, Ca²⁺ levels are restored by increased levels of bone resorption.
- An age-related decrease in efficiency of dietary Ca² ⁺ absorption necessitates variations in minimum daily Ca²⁺ requirements with regard to age, bone growth, and healing.

Vitamin D

The primary function of vitamin D is to
enhance calcium and phosphorus absorption in the small intestine and
resorption in bone (mobilizing calcium and phosphorus).

Mechanism of Vitamin D Production

Vitamin D is absorbed from food (fatty
fish, cod-liver oil, and fortified cereals, bread, and milk) as vitamin
D3 (cholecalciferol) or from sunlight as 7-dehydrocholest-erol
(converted to D3 in skin).
Vitamin D₃ is biologically inert; it is carried to the liver by vitamin D binding proteins.
Two vitamin D 25-hydroxylases catalyze the hydrolysis of vitamin D₃ to 25-hydroxyvitamin D₃ (25(OH)D₃) in hepatic microsomes.
25(OH)D₃ (principal circulating form of vitamin D) binds to a-globulin and circulates throughout body.
In the proximal tubule and glomerulus of the kidney, 1–α-hydroxylase produces the active 25-dihydroxyvitamin D₃ (1,25(OH)₂D). PTH, calcium, and phosphate levels control 1-a-hydroxylase function.
- If PTH levels are high, or hypocalcemia or hypophosphatemia exists: 25(OH)D₃ is hydroxylated to D₃ (1,25(OH)₂D).
- If PTH levels are low, or hypercalcemia or hyperpho-sphatemia exists: 25(OH)D₃ is hydroxylated to 21, 25(OH)vitaminD₃ (24,25(OH)₂D).

Calcitonin

In bone
- Receptors: on osteoclasts
- Action: associated with osteoclast shrinkage and decreased bone
In kidney
- Actions
  - Decreased Ca²⁺ and P reabsorption
  - Increases Na⁺, K⁺, Cl^–, and H₂O secretion

Estrogen

Estrogen is an important regulator of bone formation.
During late puberty: inhibits resorption and allows epiphyseal closure
Regulatory effect on osteoblasts, osteoclasts, and other local regulatory factors remains controversial.
- Estrogen may be involved in stimulating osteoclast apoptosis.
- Estrogen deficiency may stimulate RANKL production by osteoblasts, thus increasing osteoclast activity and bone resorption.

Age-Related Bone Changes

Bone Mass

Bone grows the most during adolescence.
- Early adolescence is marked by rapid longitudinal growth and modest mineral density increases.
- When longitudinal growth slows, bone
  density increases in late adolescence until bone mass reaches its
  maximum in men and women between the ages of 25 and 40 years.
Age-related bone loss begins between ages 30 and 50 years.
- Associated with uncoupling of bone formation and resorption, especially from increased resorption rates
- Steady loss of cortical and trabecular bone (see Table 19-5)
- Ultimately trabecular mass can be reduced to 50% of its peak mass and cortical bone to 25% of peak mass.

Age-Related Bone Loss Disorders (see also Chapter 10)

Osteopenia: decrease in bone density (loss of mineral and matrix)
Osteomalacia: inadequately mineralized bone matrix (loss of mineralization)
Osteoporosis:
a skeletal disorder, independent of age or sex, characterized by
compromised bone strength predisposing to an increased risk of fracture
due to decrease in bone density (loss of mineral and matrix) (Osteoporosis treatment and prevention, diagnosis and therapy: National Institutes of Health consensus statement, 2000; 17:1)
- Osteoporosis is a factor in 70% of all fractures in patients 45 years of age and older.

Osteonecrosis

The United States sees 10,000 to 20,000 new cases of osteonecrosis every year. Osteonecrosis is the death of a segment

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of bone in situ (from lack of circulation, not disease) and is caused
by many factors that damage intraosseous vasculature. It is possible
for sufficient compensatory circulation to supply the bone segment
following vascular damage, avoiding cell death. Bone’s blood supply
varies by location, creating areas of high and low risk for
osteonecrosis.

Pathogenesis

“Osteonecrosis” is a correct description of the histopathologic process and does not suggest a specific etiology.
- Other terms for this condition: avascular necrosis, aseptic necrosis, ischemic necrosis, osteochondritis
- Osteonecrotic bone is NOT avascular; vessels are present but compromised.
Prolonged secondary effects result in collapse and joint destruction within 3 to 5 years.
- Osteonecrosis is the cause of roughly 10% of all hip replacements.
If affected area is small enough and does not involve subchondral bone, collapse and degenerative changes can be avoided.
- Early stages: hyperemia and vascular fibrous ingrowth
- Creeping substitution: revascularization of necrotic bone
- Cancellous bone: bone formation on top of the necrotic trabeculae
  - Increased density appearance on radiographs
  - No significant changes in the bone’s mechanical properties
- Cortical bone: cutting cones replace haversian bone
  - Initial osteoporosis during osteoclast removal of necrotic osteons
    - Fractures through weakened bone at 18 to 24 months
  - Late restoration of bone density: Osteoblasts begin bone formation when most of the haversian bone has been removed.
    - 2 additional years before the area’s original strength and density are restored

Factors Believed to Affect Intraosseous Blood Supply

Mechanisms

Mechanical disruption of vessels: fractures and dislocations (Box 19-4)
Occlusion of arterial vessels:
thrombosis, embolism, fat emboli, sickle-cell disease, and nitrogen
bubbles (decompression sickness)
Injury to (or pressure on) arterial walls
and capillaries: can develop from within the vessel walls (vasculitis),
or from internal or external injury
Occlusion of venous vessels: Any factor
resulting in greater vascular pressure than arterial pressure
compromises local circulation.

Traumatic Injury

Osteonecrosis is correlated with traumatic and nontraumatic causative factors (see Box 19-4).

Nontraumatic Vessel Damage

Osteonecrosis is associated with several diseases and therapies:
- Glucocorticoid administration
- Ethanol abuse
- Systemic lupus erythematosus
- Antiphospholipid antibodies
- Sickle-cell disease
- Gaucher’s disease
- Decompression disease
- Transplant
- HIV
- Legg-Calve-Perthes disease (children only)
- Slipped femoral epiphysis (children only)

Classification

There are numerous classification schema for osteonecrosis, but they are beyond the scope of this text.
Classic staging systems include those of Ficat and Steinberg.

Staging

The staging system for osteonecrosis of
the femoral head has been most recently revised by the Association of
Research into Osseous Circulation (ARCO; Table 19-6).

Diagnosis

In pathologic osteonecrosis, the necrotic bone gradually collapses, leading to joint destruction.
Symptoms do not tend to present until
long after the disease has manifested itself in the bone; thus,
diagnosis often occurs after joint degeneration.
An early diagnosis provides the opportunity to minimize the extent of damage.

Clinical Features

Most common location: anterolateral femoral head
- Other common locations: humeral head, femoral condyles, proximal tibia
- Other locations: vertebrae, small bones of hands and feet

Bilaterality: common in hips, knees, or shoulders

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Table 19-6 International Classification of Stages of Osteonecrosis

Stage	Description
0	All diagnostic studies normal, diagnosis by histology only
1	Plain radiographs and computed tomography normal, magnetic resonance imaging and biopsy positive, extent of A, B, or C (< 15%, 15% to 30%, and <30%, respectively)
2	Radiographs positive but no collapse, extent of involvement A, B, or C
3	Early flattening of dome, crescent sign, computed tomography or tomograms may be needed, extent of involvement A, B, or C, further characterization by amount of depression (mm
4	Flattening of femoral head with joint space narrowing, possible other signs of early osteoarthritis

Most common symptom: pain
- Groin pain followed by thigh and buttock pain (common in femoral head disease)
- Weight-bearing and motion-induced pain (frequent)
- Rest pain (66%)
- Night pain (33%)
- Pain in multiple joints can suggest a multifocal process (rare).
Physical findings: nonspecific
- Pain with forced internal rotation and abduction of hip
- Loss of motion
- Limp in patients with lower extremity disease

Radiologic and Imaging Features

Magnetic Resonance Imaging (MRI)

Most sensitive method of diagnosis
Replaces bone marrow pressure measurement, venography, and bone biopsy methods in most cases
Can identify changes early in disease:
- T1-weighted images: focal lesions clearly defined and heterogeneous
  - Earliest MRI indication of osteonecrosis: Single low-intensity line separates normal and ischemic bone.
- T2-weighted images: Second high-intensity line demonstrates hypervascular granulation tissue (pathognomonic double-line sign).

Radiographs

Relatively insensitive to early changes: Films can remain normal long after symptoms of disease have presented.
Recommended evaluation
- Anteroposterior films
- Frog-leg lateral films of hip: to
  evaluate the superior (anterolateral) portion of the femoral head,
  where subchondral abnormalities may be seen
Plain radiographic findings of osteonecrosis
- Earliest plain radiographic sign: mild increases in density; followed later by sclerosis and cysts
- Pathognomonic crescent sign (subchondral radiolu-cency): indicates subchondral collapse
- Late stage: collapse and change in shape of femoral head
- Final stage: joint space narrowing and degeneration in acetabulum

Technetium-99m Bone Scanning

Can be used (when there are no risk factors) when suspicious unilateral symptoms produce negative films
Scan will produce the “doughnut sign” if bone is diseased.

Treatment

Treatment of osteonecrosis remains controversial.
There are four main treatment options; all seek to preserve the joint for as long as possible.

Nonoperative Treatment

Lower extremity: bed rest, partial weight bearing with crutches, progression to weight bearing as tolerated
Upper extremity: reasonable option when treating stage 0 to III humeral head lesions
- Generally not proven effective

Surgical Treatment

Total Joint Arthroplasty

Inconsistent results
Generally less successful compared to patients with non-osteonecrosis disorders, resulting in higher rate of revision surgeries
Best option for stage IV (even less severe stages in older sedentary patients) femoral head

Vascularized Fibular Grafting

Reported results better than core decompression for selected patients
Technically difficult, adds potential donor-site morbidity

Core Decompression

Favorable for stage I, II, and III hips and stage I, II, III, and IV shoulders

Osteotomy

Technically difficult; results not uniformly reproducible

Fractures and Fracture Fixation Biology

Fracture Healing

Fractures occur with concomitant damage to marrow, cortex, periosteum, and external soft tissues. Bone self-repairs

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and restores its mechanical and anatomical integrity without leaving
scar tissue. As the bone healing process progresses, bone function is
gradually restored.

Healing Process

The two types of fracture healing are distinguished by mechanical stability and the environment surrounding a fracture.

Direct (Primary) Fracture Healing

Requisites
- Rigid stabilization to eliminate motion (usually rigid internal plate fixation)
- Bone matrix on one side of fracture must be exposed and in contact with the other fragment.
Features
- Bone heals without forming a callus (a biological splint).
- Osteoid fills gaps >200 µm between fragments.
Steps
- Resorption: Osteoclasts resorb surrounding necrotic bone and, in cutting cones, create haversian systems through the osteoid.
- Vascular ingrowth: New blood vessels
  penetrate the pathways, bringing endothelial, perivascular,
  mesenchymal, and osteoprogenitor cells, thus recreating mini-osteons.
- Bone deposition: Osteoblasts lay down new bone; takes about 18 months for bone to heal completely.

Callus Formation (Secondary Healing)

Requisite: Nonrigid fixation allows formation of fracture callus.
Features: Fracture callus typifies secondary bone healing.
- Callus serves as a splint, allowing motion and ensuring the bone’s mechanical strength as it heals.
- As bone is able to withstand more stress, the callus increases in strength (Wolff’s law).
- Clinical fracture union may be completed within months, but complete remodeling takes years to complete.
Five-stage healing process of callus formation and remodeling (Box 19-5)

Vascularity of Fractures and Fracture Healing

Not surprisingly, the vascular response to fractures
varies greatly by fracture site, extent/mechanism of damage, and
fixation method. Generally the blood flow rate changes with time
following fracture.

Immediately following fracture, the blood flow rate decreases due to damage of blood vessels.
Within hours after fracture, the flow rate increases.
Approximately 2 weeks after the fracture, the flow rate peaks.
By 12 weeks after the fracture, the flow rate reaches normal.

Biochemistry of Fracture Healing

Fracture healing has phases analogous to both intramembranous and endochondral bone formation.

Proteoglycans

Early callus formation (first week): Dermatan sulfate predominates (expressed by fibroblasts).
Cartilage formation (second week): Chondroitin-4-sulfate predominates (chondrocytes).
Premineralization preparation (third week)
- Collagenase, gelatinase, stromolysine (proteolytic enzymes) expression increases and proteoglycan concentration decreases.
- Alkaline phosphatase, IL-1, and IL-6 concentrations increase.

Collagenous Proteins

Callus formation: type II collagen—predominant structural protein for cartilage
- Peaks at 9 days, then turned off by 14 days
Condensation: type I collagen—predominant structural protein in bone
- Very low levels early on; levels increase progressively thereafter
Cell proliferation: type III collagen (fibroblasts) found on periosteal surface
- Substrate for cell proliferation and capillary growth
- Present throughout fracture healing
Minor regulatory collagens: types V, IX, XI

Noncollagenous Proteins

Fibronectin, osteonectin, osteopontin, osteocalcin

Fracture Treatment/Fixation

Fracture treatment objectives: align
fracture fragments and maintain position until fragment union is
achieved, while maintaining movement and function and avoiding
complications and extended hospitalization for the patient
Role for fracture fixation
- Not biologically necessary due to the natural splint formed by the callus in response to motion
- Immobilization devices are beneficial
  because they reduce pain, ensure proper fragment alignment, and allow
  patients earlier use of a fractured limb.

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Augmentation of Fracture Healing

Augmentation of fracture healing may be done initially
for closed comminuted fractures or later for delayed union or nonunion.
Augmentation may involve the addition of scaffolding (osteoconduction),
bone morphogenic proteins and other growth factors (osteoinduction), or
live bone cells (os-teogenesis), alone or in combination.

Osteogenic Methods

Osteogenic methods use naturally occurring grafts with living cells to promote bone regeneration.
Autogenous grafts
- Bone marrow provides only cells without scaffolding.
- Cancellous bone graft provides cells, scaffolding, and growth factors.
Fresh allogeneic grafts

Osteoconductive Methods

Osteoconductive materials serve as a
scaffold for the ingrowth of capillaries, perivascular tissues, and
osteo-progenitor cells, allowing bone formation on their surfaces.
Allograft bone
- Classification: particulate and structural forms available
- Widespread availability in developed countries
- Small risk of disease transmission
Calcium sulfate
- Composition: basic component of plaster of Paris
- Degradation within 60 days limits usefulness for load-bearing sites.
Calcium phosphate-based ceramics
- Composition: resorbable combinations of synthetic or coralline hydroxyapatite and tricalcium phosphate
- Most commonly used group of ceramic bone graft substitutes
- Relative brittleness limits load-bearing role.
Bioactive glasses
- Composition: silica-containing calcium phosphates
- Limited applications due to high modulus and brittleness
- Marketed currently in combination with
  polymethylmethacrylate as bioactive bone cement and as implant coating
  to enhance bonding with bone
Synthetic polymers
- Classifications: natural versus synthetic and degrad-able versus nondegradable
- Available examples
  - Collagen fiber with hydroxyapatite polymer-ceramic used as bone graft substitute for spine fusions
  - Resin-based products for spine fusions
  - Polylactic acid (PLA) and polyglycolic acid (PGA) degradable plates and screws
  - Poly(lactic-co-glycolic acid) compounds used as graft extenders

Osteoinductive Methods

Osteoinductive materials induce cellular development through growth factors, which leads to bone formation.
TGF-β family (transforming growth factor)
- Bone morphogenic proteins: especially BMP-2, BMP-4, BMP-7 (OP-1)
Insulin-like growth factors
Fibroblastic growth factors
Platelet-derived growth factors
Demineralized bone matrix (allograft
cocktail of growth factors and osteogenic proteins after bone mineral
removed), available in numerous preparations alone or with ceramics and
polymers

Pulsed Electromagnetic Fields

The use of electromagnetic fields to
treat nonunion is based on the discovery of electrical currents in bone
that were generated in response to normal functioning mechanical loads.
Pulsed electromagnetic fields are induced by a square wave generator (Faraday’s law).
Optimal frequency for bone growth: 15 to 30 Hz (extremely low frequency [ELF])
Commonly used clinically: high-frequency
induction waveforms 1 to 10 kHz at low frequency (1 to 100 Hz) (pulsed
electromagnetic fields [PEMF])

Ultrasound

Ultrasound is a form of mechanical energy that has been found to have a strong influence on biological activity.
- Low-intensity ultrasound does not cause heating or destruction to tissues and is noninvasive.
  - Accelerates fracture healing with short (20-min-ute) daily treatments at 30 mW/cm²
  - Utility in treating delayed unions or nonunions