Bone Structure and Function

Bone is a complex organ composed of multiple specialized tissues (osseous, periosteum/
endosteum, and bone marrow) that act synergistically and serve multiple functions.
Definition
Lang and Lindhe 2015. Clinical Periodontology and Implant Dentistry, Sixth Edition.

• Development of bone
• Microstructure of bone
• Composition of bone
• Formation of osteoblasts
• Mineralisation of bone
• Formation of osteoclasts
• Resorption of bone
• Macrostructure of bone
• Volume changes in bone
• Bone healing
Presentation outline

Derivatives of the branchial arch system
Ten Cate 2013. Oral Histology 8th Edition

Intramembranous - clavicle, mandible, maxilla and skull
Endochondral- mandibular condyle, long bones and vertebrae
Ossification

Endochondral ossification
http://teambone.com/education-basic/basic-biology-of-bone/

The Growth Plate
The growth plate is divided into
multiple zones. These zones include
the reserve zone, proliferative zone,
and the hypertrophic zone. The
reserve zone is the area closest to the
secondary center of ossification. It has
epiphyseal vessels the pass through
this area but do not provide it with
oxygen and keeps the oxygen tension
low in this area. It has no known
function with respect to longitudinal
growth.
Endochondral ossification

Development of the mandible

Spread of mandibular ossification away
from Meckel’s cartilage at the lingula
Development of the mandible

Development of the maxilla

Development of the maxilla
• Primary palate from the frontonasal and medial nasal processes
• Secondary palate from three outgrowths; the nasal septum that grows downward
from the frontonasal process along the midline, and two palatine shelves or
processes
• Commences between 7 and 8 weeks of gestation and completes around the 3rd
month.

Mature or adult bones, whether compact
or trabecular, are histologically identical in
that they consist of microscopic layers or
lamellae.
Three distinct types of layering are
recognized: circumferential, concentric, and
interstitial
Microstructure of bone

Endosteum
The fibrous,
non‐mineralized lining of
the medullary cavity is
the endosteum.
Osteoblasts form in the
endosteum and begin
the formation of
endosteal bone.

Hierarchical structure of bone
Launey et al 2010. On the mechanistic origin of bone.
A actinomycetemcomitans size: ~1 μm
~50mm
~100 μm
~50 μm

Hierarchical structure of bone
Launey et al 2010. On the mechanistic origin of bone.
~10 μm
~1 μm
~300nm
~1nm
Hydroxyapatite:
~ 25 nm in length,
~ 15 nm in width,
~ 2–5 nm in thickness.
Endotoxin size: ~2.5nm

Nanci A 2013. Ten Cate’s Oral Histology. 8th Ed. Mosby
Bone cells

Osteoblasts and osteocytes
Lindhe 2015. Clinical Periodontology. 6th Ed

Cell communication in bone
• Local strain gradients provide the information that
guides osteoclasts and osteoblasts during bone
remodeling.
• This information is sensed by the osteocyte network, as
reduced or increased canalicular fluid flow.
• The osteocyte network then signals to the osteoclasts
and osteoblasts on the bone surface, thereby recruiting
them to resorb or produce bone matrix.
New cell communication system Involved in the coupling of
bone formation and bone resorption.
• expression of ephrin B2 and its receptor ephrin B4
(EphB4) in osteoclasts and osteoblasts, respectively, and
have revealed that ephrinB2-EphB4 bidirectional
signalling links the suppression of osteoclast
differentiation to the stimulation of bone formation.

• Early studies noted that direct, noxious mechanical stimulation of the periosteum
produced painful percepts in human subjects (Inman and Saunders, 1944), and indeed
some more recent literature highlights the prevailing opinion that pain from bone is
generally not perceived unless the periosteum is involved.
• However, injection of irritants into the medullary cavity is also very painful, as is
needle aspiration of bone marrow, and this pain is distinct from that associated with
disruption of the periosteum. Thus, it appears that both the periosteum and the
marrow cavity of bones must be innervated by primary afferent neurons capable of
transducing and transmitting nociceptive information.
• There are many studies that have reported the existence of primary afferent neurons
that innervate bone, and it has become clear that most of these sensory neurons have
a morphology and molecular phenotype consistent with a role in nociception.
• Some of these nerve fibres were in close apposition with blood vessels
Physiology of bone pain.
Nencini and Ivanusic 2016

Composition of bone

Skeleton (storage), gut (uptake), kidney (secretion).
Parathyroid hormone (PTH): Action = Ca increase in circulation
• stimulates bone resorption (osteoclasts)
• stimulates renal reabsorption of Ca
• stimulates synthesis of active vitamin D
Calcitonin (CT): Action = Ca decrease in circulation
• counteracts all PTH actions
1,25-dihydroxyvitamin D: Action = Ca (& Pi) increase in circulation
• stimulates Ca and Pi uptake from food (through gut)
Fibroblast Growth Factor, FGF23: Action = Pi decrease in circulation
• reduces renal reabsorption of Pi, inhibits synthesis active 1,25 vitamin D
Bone - calcium and phosphate metabolism

1. Collagen Type 1
• major organic bone component
• basic structural unit is a triple helix
molecule.
• crosslinks between the chains and
between the molecules give
collagen its strength.
2. Non collagenous bone proteins
PROTEINS OF BONE MATRIX

Non collagenous bone proteins: bone formation role/function
Protein Bone formation function
Bone specific alkaline
phosphatase (BAP)
Osteoblastic enzyme involved in bone formation
(probably plays a role in bone matrix maturation)
Osteonectin Binds calcium and is involved in regulation of mineralization
Osteocalcin (OC) or
Bone gla protein
Binds calcium and attracts osteoclasts.
Major structural protein of the bone matrix.
Bone Sialoprotein
(BSP)
Its role has been associated with mineral crystal formation.
Major structural protein of the bone matrix.
Matrix gla protein
(MGP)
Binds calcium. In bone, its production is increased by vitamin
D. Found in in bone, heart, kidney and lung.
Proteoglycans Role is unclear.

Non collagenous bone proteins: bone resorption role/function
Protein Bone resorption function
Tartrate resistant isoenzyme
acid phosphatase (TRAP5b)
Synthesized by active osteoclasts. TRAP5b catalyzes the
formation of reactive oxygen species (ROS), that degrade
bone matrix products in resorbing osteoclasts.
Cathepsin K Main osteoclastic protease, responsible for bulk
degradation of Type I Collagen.
Matrix Metalloproteinases
(MMPs)
MMP-2, -9, -13, -14 participate in the degradation of the
collagenous bone matrix, resulting in epitope ICTP
(carboxyterminal telopeptide of type I collagen).
Lysozymal enzymes Enzymes secreted by the osteoclasts
Responsible for mineral dissolution in an acid
environment
Calcitonin receptor Osteoclastic receptor for calcitonin
Inhibitor of osteoclast activity.

Protein Bone resorption function
RANK (NF-κB ) Osteoclastic receptor for sRANKL
sRANKL Soluble Receptor Activator of Nuclear Factor (NF)-
κB Ligand.
Binds to RANK and is the main stimulatory factor
for the formation of mature osteoclasts.
OPG (Osteoprotegerin)
OCIF (Osteoclast Inhibiting Factor)
OBF (Osteoclast Binding Factor)
Key factor in inhibition of osteoclast differentiation
and activity.
Binds and acts as decoy receptor for sRANKL.
Osteopontin Cell-binding protein, synthesized by osteoblasts,
that anchors osteoclasts to mineralized matrix.
Sclerostin Synthesized by osteocytes, inhibits bone formation
by regulating osteoblast function and promoting
osteoblast apoptosis.
Non collagenous bone proteins: bone resorption role/ function

Source of pluripotent mesenchymal stem cells
• bone lining cells
• inner cellular layer of the periosteum
• pericytes in the walls of smallest blood vessels (Corselli et al. 2010).
Osteoblast differentiation

Osteoblast differentiation

MAJOR SIGNALING PATHWAYS
• Wnt pathway (been shown to control the differentiation of both osteoblasts and
osteoclasts)
• TGF-β/BMP superfamily
• notch signaling (cell fate division and homeostatic maintenance, the notch
pathway is believed to be important in osteogenesis because of notch1–BMP-2
interactions that promote osteogenic differentiation)
• hedgehog proteins (plays a role in many embryonic processes and also is involved
with the maintenance of stem cells in adults)
• fibroblast growth factors
TRANSCRIPTION PATHWAYS
• Runt-related transcription factor 2/core-binding factor alpha 1 (Runx2/cbfα-1)
• osterix
Mesenchymal stem cells differentiate into mature osteoblasts
Seitz et al 2013. Repair and Grafting of Bone. Plastic surgery

Receptor signaling typically leads to the formation or modification of biochemical
intermediates and/ or activation of enzymes, and ultimately to the generation of active
transcription factors that enter the nucleus and alter gene expression. Gene expression
is the process in which information from a gene is used by the cell to produce a
functional product, typically a protein (functional messenger RNA (mRNA)).

Signal transduction. Wikipedia. https://en.wikipedia.org/wiki/Signal_transduction. Assessed 25 Feb 2017

Response to a signal. Khan academy. www.khanacademy.org. Assessed 25 Feb 2017
The mRNA leaves the
nucleus and enters the
cytosol. There, it directs
synthesis of a protein,
indicating which amino
acids should be added to
the chain. This step is
called translation

Three distinct periods of osteoblast phenotype development
1. proliferation
2. maturation and extra-cellular matrix synthesis
3. matrix mineralization.
Mineralisation

Proliferation
• express genes that support proliferation and several genes encoding for
extracellular matrix proteins, such as type I collagen and fibronectin.
• BMP-2 and BMP-5 play a significant role in increasing alkaline phosphatase
activity, osteocalcin synthesis and parathyroid hormone (PTH) responsiveness.
Maturation and extra-cellular matrix synthesis
• The active bone-matrix-secreting osteoblasts are cuboidal cells, with a large Golgi
apparatus and an abundant rough endoplasmic reticulum, and are provided with
regions of plasma membrane specialized in the trafficking and secretion of
vesicles that facilitate the deposition of bone matrix
• high synthesis of alkaline phosphatase,
• osteoblasts synthesize several proteins that are associated with the mineralized
matrix in vivo , including sialoprotein, osteopontin and osteocalcin
Mineralisation
• cellular levels of alkaline phosphatase mRNA decline
• 50%–70% of mature osteoblasts undergo apoptosis
• the remainder can differentiate into lining cells or osteocytes or transdifferentiate
into cells that deposit chondroid bone

Bone formation stimulators & inhibitors
Protein Stimulation Inhibition
Systemic PTH
PTHrP
Sex-steroids (Estrogen, Testosterone)
Growth hormone
IGF-1
Thyroid hormone
Leptin
Glucocorticoids
β-2 adrenergic
Leptin
Serotonin
Local Transforming growth factor-ß
BMP-2
Platelet-derived growth factors
Endothelial growth factor (EGF)
Vascular EGF
IGF-1
Fibroblast growth factors (FGF-2)
Prostaglandins
Wnt-LRP5/6
Sclerostin
Noggin
Interleukin-1ß,7
Interferon- Ƴ
Tumor necrosis factors
Dickkopfs (DKK-1)

Osteoclast differentiation

TRAP, tartrate-resistant acid phosphatase
Osteoclast differentiation

1. Attachment of osteoclasts to the mineralized surface of bone via integrins
2. Creation of a sealed acidic microenvironment (resorption pit) through action of the
proton pump, which demineralizes bone and exposes the organic matrix
3. Degradation of the exposed matrix by the action of released enzymes, such as acid
phosphatase and cathepsin B
4. Endocytosis at the ruffled border of organic degradation products
5. Translocation of degradation products in transport vesicles and extracellular release
along the membrane opposite the ruffled border (transcytosis)
Osteoclast Cell
• Responsible for mineral dissolution (by acid environment and lysozymal enzyme
action below ruffled border).
• Responsible for collagen break down (Cathepsin K and MMP pathways).
Osteoclasts- sequence of resorptive events

Risteli et al 2012 Bone and mineral metabolism
RANKL stimulates osteoclast activation by inducing secretion of protons and lytic
enzymes into a sealed resorption vacuole formed between the basal surface of the
osteoclast and the bone surface. Acidification of the vacuole leads to activation of
tartrate- resistant acid phosphatase (TRACP) and cathepsin K (Cat K)
Bone resorption

Bone resorption stimulators & inhibitors
Protein Stimulation Inhibition
Systemic PTH
PTHrP
1,25 (OH2)D3
Thyroid hormone
β-2 adrenergic
Calcitonin
Sex steroids (Estrogen, Testosterone)
Local RANKL
Macrophage-CSF
Granulocyte macrophage-CSF
Interleukin-1,6,7,11,15,17
Interferon-Ƴ
Tumor necrosis factor-α (TNF-α)
Fibroblast growth factors
Prostaglandins
Osteoprotegerin (OPG)
Transforming growth factor-ß (TGF-β)
Interferon-Ƴ
Interleukin-4,10, 13,18
Interleukin-1 receptor antagonist

Bone remodelling timeline
https://pharmaceuticalintelligence.com/tag/bone-mineral-density/

• (A and B). Remodeling of bone in a multicellular bone unit starts with osteoblastic
activation of osteoclast differentiation, fusion, and activation. When resorption
lacunae are formed, the osteoclasts leave the area and mononucleated cells of
uncertain origin appear and “clean up” the organic matrix remnants left by the
osteoclast, also possibly forming the cement line (dotted line) at the bottom of the
lacunae
• (C). During the resorption process, coupling factors, including insulin-like growth
factor–I and transforming growth factor–β, are released from the bone-extracellular
matrix, and these growth factors contribute to the recruitment of osteoblasts to the
resorption lacunae and their activation.
• (D). The osteoblasts will then fill the lacunae with new bone; when the same amount
of bone is formed as is being resorbed, the remodeling process is finished, and the
mineralized extracellular matrix will be covered by osteoid and a single-cell layer of
osteoblasts
The bone- remodelling cycle
https://pharmaceuticalintelligence.com/tag/bone-mineral-density/

The alveolar process forms with the eruption of teeth and growth of the jaws
After tooth extraction, the alveolar process gradually resorbs
The alveolar process
Beagle 2013. Surgical Essentials of Immediate Implant Dentistry. John Wiley & Sons, Inc

Alveolar process
Antonio Nanci. Ten Cate's Oral Histology, 8th Edition. Elsevier Canada
Cortical plate (buccal and lingual)
Alveolar bone (bone lining the alveolus)
Spongiosa (trabecular bone)

Bundle bone
Haversian
system of
trabecular
bone
Bundle bone
Sharpeys
fibres
PDL Cementum
• The aspect of bone which lines the tooth socket is also referred to as the bundle
bone.
• The extrinsic collagen fiber bundles of the periodontal ligament (PDL) embed into
this area of bone. The bundle bone usually exhibits a course-fibered texture and
contains fewer intrinsic collagen fibrils than that in lamellar bone (Avery, 1994).

Facial bone (buccal plate) thickness in the maxillary anterior region
Facial bone
(bundle bone and cortical plate)

CBCT of the maxillary lateral incisor
Bundle bone
Width of bundle bone varies between 0.1 mm and 0.4 mm
(Schroeder 1986).
When the buccal bone plate is ≤ 0.5mm it may be solely
comprised of bundle bone.
Since bundle bone is a tooth dependent structure, the loss
of teeth will result in the loss of bundle bone
Chen & Darby 2016. The relationship between facial bone wall defects and dimensional alterations of the ridge
following flapless tooth extraction in the anterior maxilla. Clin Oral Implants Res.

Horizontal or buccolingual ridge reduction
• approximately 5 to 7 mm (almost 50% of the initial ridge width)
• reduction occurs over a period of 6 to 12 months
• most of the changes occur during the first 2 months (Chen and Darby 2016)
(short window to place implants).
Vertical or apicocoronal height reduction
• 2.0 to 4.5 mm
Dimensional changes of the extraction socket
Al-Sabbagh & Kutkut 2015. Immediate Implant Placement. Dent Clin N Am
Chen & Darby 2016. The relationship between facial bone wall defects and dimensional alterations of the ridge
following flapless tooth extraction in the anterior maxilla. Clin Oral Implants Res.

Based on the volume of remaining
mineralized bone, the edentulous
sites may, according to Lekholm and
Zarb (1985), be classified into five
different groups.
In groups A and B, substantial
amounts of the ridge still remain,
whereas in groups C, D, and E, only
minute amounts of hard tissue
remain.
Evaluation of bone volume
Lekholm and Zarb 1985

Qualitative evaluation of bone quality
Lekholm and Zarb 1985

• First 24 hours are characterized by the formation of a blood clot in the socket
• 2–3 days the blood clot is gradually replaced with granulation tissue
• 4–5 days, the epithelium from the margins of the soft tissue starts to proliferate
to cover the granulation tissue in the socket.
• 1 week after extraction, the socket contains granulation tissue and young
connective tissue, and osteoid formation is ongoing in the apical portion of the
socket.
• After 3 weeks, the socket contains connective tissue and there are signs of
mineralization of the osteoid. The epithelium covers the wound.
• After 6 weeks of healing, bone formation in the socket is pronounced and
trabeculae of newly formed bone can be seen.
• the process by which woven bone was replaced by lamellar bone and marrow,
that is remodeling, was slow and exhibited great individual variation and may take
years to be completed.
Wound healing following tooth extraction
Trombelli et al 2008. Modeling and remodeling of human extraction sockets.

• The mechanisms of healing and incorporation of autogenous bone grafts are
universal, irrespective of the donor site.
• Autogenous bone grafts are comprised of cortical or cancellous bone (or both)
• The factors affecting the healing of bone are the
• amount of cellular marrow transplanted with the bone graft,
• the vascularity of the tissue bed and
• the attainment of graft stability
Autogenous bone grafts and their healing
Marx, RE 2007. Bone and bone graft healing. Oral Maxillofacial Surg Clin N Am

• During the 1st week, platelets are responsible for regulating bone regeneration.
The platelets secrete several growth factors, namely –PDGF; TGFβ-1 and EGF.
• Most osteocytes within the autogenous bone grafts die off, as they are encased in
a mineral matrix and the harvesting of the graft disrupts their delicate canalicular
blood supply . However, those osteocytes (in their lacunae) situated within 0.3
mm of a perfusion surface appear to survive.
• New bone formation occurs by the process of osteogenesis, which is induced by
the surviving osteoblasts and marrow stem cells within the autogenous bone.
These cells are open to the local environment and survive by oxygen and
nutritional diffusion (plasmatic circulation) until the graft becomes revascularized
by capillary ingrowth.
• By day 3, capillaries are seen to penetrate into the graft and osteocompetent cells
undergo proliferation.
Healing of cancellous bone grafts

• By day 7, the platelets are exhausted and contribute little to further healing.
Macrophages are attracted to the site by the initial hypoxic state in the area, as
well as by chemotaxis by the platelets. The macrophages also secrete growth
factors until the graft is fully vascularized between day 14 and 21.
• The vascularization of the graft provides oxygen and nutrients to the
osteocompetent cells, which then synthesize and secrete osteoid.
• During the process of revascularization, osteoclasts also arrive from the
circulation. The osteoclasts resorb the mineral matrix (this includes mineral matrix
surrounding the osteocytes) and allow the release of growth factors (BMP and
IGF-1 and 2), which induce osteoinduction and allows maturation of the graft.
• Cancellous bone grafts are initially weaker due to their spongy, trabecular
architecture, however these grafts continue to gain strength.
Healing of cancellous bone grafts

• Large cortical block bone grafts with their compact architecture, form new bone
mainly through the processes of osteoinduction and osteoconduction from the
adjacent bone margins.
• Cortical grafts require significant resorption by osteoclasts, before osteoblasts
commence new bone formation – this process is referred to as “creeping
substitution”.
• Cortical bone grafts are strong initially, but weaken overtime – before regaining
strength. There is also a significant loss in dimension as a result of the resorption
process that takes place.
• Cortical grafts require proper fixation and have a high risk of sequestration in
contaminated areas.
Healing of cortical block bone grafts
Buser, D 2009. 20 Years of Guided Bone Regeneration in Implant Dentistry

• Bone is a complex organ composed of multiple specialized tissues serve multiple
functions.
• Except for the condylar and coronoid processes, the rest of the maxillofacial
structure undergoes intramembranous ossification.
• Bone is composed mainly of inorganic hydroxyapatite and it plays a major role in
calcium homeostasis.
• The balance of serum ionized calcium blood concentration results from a complex
interaction between parathyroid hormone (PTH), vitamin D, and calcitonin.
• The bone remodeling cycle involves a complex series of sequential steps that
involves osteoclasts in the “resorption” phase followed by a “reversal” phase and
finally a “formation” phase that involves osteoblasts, which lay down matrix.
• Remodeling of bone is slow and exhibited great individual variation and may take
years to be completed.
• Sound knowledge of bone anatomy, physiology and wound healing are essential
for surgeons to perform successful periodontal and implant surgical procedures.
Conclusion

Bone Structure and Function

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