Bone Modelling And Remodelling

· Bone remodeling is a lifelong process wherein old bone is removed from the skeleton (a sub- process called bone resorption), and new bone is added (a sub-process called ossification or bone formation).

·  Remodelling involves continuous removal of discrete packets of old bone, replacement of these packets with newly synthesized proteinaceous matrix, and subsequent mineralization of the matrix to form new bone.

· These processes also control the reshaping or replacement of bone during growth and following injuries like fractures but also microdamage.

·   Remodelling responds also to functional demands of the mechanical loading.

·  As a result, bone is added where needed and removed where it is not required.

·  This process is essential in the maintenance of bone strength and mineral homeostasis.

· The skeleton is a metabolically active organ that undergoes continuous remodeling throughout life.

·  This remodeling is necessary both to maintain the structural integrity of the skeleton and to subserve its metabolic functions as a storehouse of calcium and phosphorus.

·  The balance between bone resorption and bone deposition is determined by the activities of these two principle cell types, namely, osteoclasts and osteoblasts.

·   Osteoblasts and osteoclasts, coupled together via paracrine cell signaling, are referred to as bone remodeling units.

·    In the young skeleton, the amount of resorbed bone is proportional to the newly formed.

·    For this reason, it is referred to as a balanced process, linked in both space and time under normal conditions.

·   The average lifespan of each remodeled unit in humans is 2–8 months, the greater part of this time being taken up by bone formation.

·  Bone remodeling occurs throughout life, but only up to the third decade is the balance positive.

·  It is precisely in the third decade when the bone mass is at its maximum, and this is maintained with small variations until the age of 50.

·     From then on, resorption predominates and the bone mass begins to decrease.

·   Bone remodeling increases in perimenopausal and early postmenopausal women and then slows with further aging but continues at a faster rate than in premenopausal women.

Mediators of Remodeling

1.    Osteoclasts

·       Osteoclasts are the only cells that are known to be capable of resorbing bone.

·       They are typically multinucleated.

·    Osteoclasts are derived from mononuclear precursor cells of the monocyte-macrophage lineage.

·  Bone resorption depends on osteoclast secretion of hydrogen ions and cathepsin K enzyme.

·   H+ ions acidify the resorption compartment beneath osteoclasts to dissolve the mineral component of bone matrix, whereas cathepsin K digests the proteinaceous matrix, which is mostly composed of type I collagen.

·     Osteoclasts bind to bone matrix via integrin receptors in the osteoclast membrane linking to bone matrix peptides.

·  They digest the organic matrix, resulting in formation of saucer-shaped Howship’s lacunae on the surface of trabecular bone and Haversian canals in cortical bone.

·   The resorption is completed by mononuclear cells after the multinucleated osteoclasts undergo apoptosis.

2.    Osteoblasts

·   Osteoblasts can be stimulated to increase bone mass through increased secretion of osteoid and by inhibiting the ability of osteoclasts to break down osseous tissue.

·  Bone building through increased formation of osteoid is stimulated by the secretion of growth hormone by the pituitary, the thyroid hormone and the sex hormones (estrogens and androgens).

3.    RANK

·   The cell surface receptor called RANK (for receptor activator of NFkB) prods osteoclast precursor cells to develop into fully differentiated osteoclasts when RANK is activated by its cognate partner RANK ligand (RANKL).

·   RANKL and macrophage CSF (M-CSF) are two cytokines that are critical for osteoclast formation.

·       Both RANKL and M-CSF are produced mainly by marrow stromal cells and osteoblasts

·       Osteoclastogenesis requires the presence of stromal cells and osteoblasts in bone marrow

·      Osteoprotegerin is another protein released by osteoblasts that acts as a decoy to prevent RANK and RANKL from coming in contact.

·   Osteoblast precursors express a molecule called TRANCE, or osteoclast differentiation factor, which can activate cells of the osteoclast lineage by interacting with a receptor called RANK.

4.    Osteoprotegerin

·   Osteoprotegerin (OPG), also known as osteoclast inhibiting factor (OCIF) or osteoclast binding factor (OBF), is a key factor inhibiting the differentiation and activation of osteoclasts, and is, therefore, essential for bone resorption.

· Osteoprotegerin inhibits the binding of RANK to RANKL and thus inhibits the recruitment, proliferation, and activation of osteoclasts.

·  Abnormalties in the balance of OPGL/RANK/OPG system lead to the increased bone resorption that underlies the bone damage of postmenopausal osteoporosis, Paget’s disease, bone loss in metastatic cancers, and rheumatoid arthritis.

·   The boundary between the old and new bone is distinguished in an hematoxylin and eosin section by a blue (basophilic) line called a Cement Line or reversal line.

5.     Paracrine Cell Signaling

·       At various stages throughout this process of remodeling, the precursors, osteoclasts, and osteoblasts communicate with each other through the release of various “signaling” molecules.

·       Osteoclasts are apparently activated by “signals” from osteoblasts.

·     For example, osteoblasts have receptors for PTH, whereas osteoclasts do not, and PTH-induced osteoclastic bone resorption is said not to occur in the absence of osteoblasts.

·    The action of osteoblasts and osteoclasts is controlled by a number of chemical factors which either promote or inhibit the activity of the bone remodeling cells, controlling the rate at which bone is made, destroyed, or changed in shape.

·       The cells also use paracrine signaling to control the activity of each other.

Remodeling Phases

1.     Quiescence

•    The bone surface is covered by a layer of thin flattened lining cells which arise by terminal transformation of osteoblasts, which have lost the ability to synthesize collagen.
•      Between the lining cells, bone is a layer of osteoid like unmineralized connective tissue, whose function appears to be protection of the bone surface from osteoclastic resorption.

2.     Activation

•   The lining cells of quiescent area are stimulated to digest the unmineralized connective tissue overlying the bone, they then retract to expose the mineralized bone surface which is chemotactic for osteoclasts precursor cells which undergo fusion into osteoclasts, when they reach the bone surface.

3.     Resorption

•      Osteoclast resorbs the bone producing Howship’s lacuna in trabecular bone or cutting cone in cortical bone.

4.     Reversal

•    This is the period between completion of resorption and the start of formation at a particular location.
•      The surface is smoothened out by mononuclear cells.
•       The mechanism of coupling of bone formation and bone resorption is unclear.

5.     Formation

•    Soon after the cement substance has been deposited, the newly formed osteoblasts began to deposit a layer of unmineralized bone matrix which is referred as osteoid seam.
•       Thus, collagen cross-linking occurs and later mineralize in one week.

6.     Mineralization

•     The process begins 30 days after deposition of the osteoid, ending at 90 days in the trabecular and at 130 days in the cortical bone.
•       The quiescent or “at rest” phase then begins again.

·       When the cycle is completed, the amount of bone formed should equal the amount of bone resorbed.

Phases of bone remodeling: FIGà     

a.     quiescent phase where flat bone lining cells are seen lining the endosteal membrane

b.     showing activation phase characterized by cell retraction with resultant membrane resorption

c.     shows activated osteoclasts resorbing the underlying bone

d.     shows formation phase where the osteoclasts are replaced by osteoblasts with underlying new osteoid matrix

e.      shows mineralization of osteoid matrix

f.      shows formation of bone structure unit with progression to quiescent phase

Regulatory Factors in Bone Remodeling

·       The balance between bone resorption and formation is influenced by such interrelated factors as genetic, mechanical, vascular, nutritional, hormonal, and local.

A. Systemic Regulation of Bone Remodeling

1.    Genetic Factors

·       These are important in determining the maximum bone mass, since between 60 and 80 % of this bone mass is genetically determined.

2.    Mechanical Factors

·       Remodeling is regulated by mechanical loading, allowing bone to adapt its structure in response to the mechanical demands.

3.    Vascular/Nerve Factors


·   Vascularization is fundamental for normal bone development, supplying blood cells, oxygen, minerals, ions, glucose, hormones, and growth factors.

·       Innervation is necessary for normal bone physiology.

·      In osteopenia and the bone fragility present in patients with neurological disorders, and also in the decreased bone density in de-nerved mandibles.


4.    Nutritional Factors

·       A minimum amount of calcium is needed for mineralization

·       1,200 mg/day to the age of 25, not less than 1 g/day from 25 to 45, and following menopause should be at least 1,500 mg/day.

·       Likewise, it is known that toxic habits such as smoking, caffeine, alcohol, and excess salt constitute risk factors for osteopenia.

5.    Hormonal Factors


·       Thus, the hormones that regulate bone metabolism are as follows:

·       Decrease bone resorption 
– Calcitonin 
– Estrogens

·       Increase bone resorption

–      PTH/PTHrP

–      Glucocorticoids

–      Thyroid hormones

–      High-dose vitamin D

·       Increase bone formation

–      Growth hormone

–      Vitamin D metabolites

–      Androgens

–      Insulin

–      Low-dose PTH/PTHrP

–      Progestogens

·       Decrease bone formation – Glucocorticoids

B. Local Regulators of Bone Remodeling

·       Bone remodeling is also regulated by local factors, among which principally growth factors and cytokines, and recently, the bone matrix proteins have been implicated as modulators of other local factors.

·       Bone cells also play an important role in the production of prostaglandins and nitric oxide, as well as cytokines and growth factors.

·       The important local factors acting on the skeleton are as follows and are tabulated in Table

	Stimulate bone formation	Stimulate bone resorption	Inhibit bone resorpn
Growth factors	BMP-2, BMP-4, BMP-6, BMP-7, IGF-I, IGF-II TGF-b, FGF, and PDGF	TNF, EGF, PDGF, FGF, M-CSF, and GM-CSF
Cytokines	IL-4,IL-13, IFN, and OPG	IL-1, IL-6, IL-8, IL-11, PGE2, PGE1, PGG2, PGI2, and PGH2	IFN-y IL-4