The document provides an in-depth overview of bone tissue, including its types, composition, and cellular components, as well as the regulators of bone metabolism like calcium, phosphate, and various hormones. It discusses the roles of osteoclasts, osteoblasts, and osteocytes in bone health and the impacts of hormonal regulation, particularly from parathyroid hormone and vitamin D. Additionally, it highlights potential disorders related to bone metabolism and the implications for orthodontics.

1. Dr. Miliya Parveen

2. CONTENTS :
1. Introduction
2. Types of bone tissue
3. Composition of bone
4. Cells of bone
5. Regulators of bone metabolism
6. Calcium and phosphate balance
a) Calcium and phosphate
b) Parathyroid hormone
c) Calcitonin
d) Vitamin D
e) Fibroblast growth factor
7. Growth hormone and IGF-1
8. Thyroid hormone
9. Estrogens, progesterone and
androgens
10. Cortisol and related
glucocorticoids
11. Disorders of bone metabolism
12. Orthodontic considerations
13. Conclusion
14. References

3. INTRODUCTION :
• Bone is a dynamic, highly specialized, highly vascular and constantly
changing connective tissue.
• Main function - provide a mechanical support for
muscular activity, physical protection to the tissues
and internal organs and to act as a repository for the
systemic mineral homeostasis.
• Bone tissue also serves as a mineral bank that can
be drawn upon in times of need.

4. TYPES OF BONE TISSUE :
Based on texture of
cross sections
Compact bone
Dense/Cortical bone
Spongy bone
Trabecular/Cancellous
Based on matrix
arrangement
Woven bone
(primary bone tissue)
Lamellar bone
(secondary bone
tissue)
Based on maturity
Immature bone
(primary)
Mature bone
(secondary)
Based on
developmental
origin
Intramembranous
(mesenchymal)
Intracartilaginous
(endochondral)

5. Composite Bone
• Formed by the deposition of lamellar bone
within a woven bone lattice - cancellous
compaction.
• Quickest means of producing relatively
strong bone.
• Important intermediary type of bone in the
physiologic response to orthodontic loading
Bundle Bone
• Functional adaptation of lamellar structure to allow attachment of tendons
and ligaments.
• Perpendicular striations, called Sharpey fibers - major distinguishing
characteristics of bundle bone.
• Distinct layers of bundle bone usually are seen adjacent to the PDL.
and predominant osseous tissue for stabilization during the early process of
retention or postoperative healing.

6. COMPOSITION OF BONE:
• Consists of ground substance or matrix
in which are embedded fibers and is
impregnated with bone salts.
• The intercellular material is composed
largely of glycosaminoglycans,
metabolites, water and ions - ground
substance.
• Water constitutes about one-fifth of
the weight of the matrix in mature
bone; organic material forms 30-40
percent and mineral salts 60-70 percent
of the dry weight.

7. CELLS OF BONE :
1. OSTEOCLASTS -
- large cells that dissolve the bone.
- come from the bone marrow and are related to white blood cells.
- formed from two or more cells that fuse together, so the osteoclasts
usually have more than one nucleus
- found on the surface of the bone mineral next to the dissolving bone.
- involved in bone resorption (forming depressions known as
Howship’s lacunae) and remodelling in response to growth or
changing mechanical stresses upon the skeleton
- also participate in the long-term maintenance of blood calcium
homeostasis

8. 2. OSTEOBLASTS –
- cells that form new bone
- come from the bone marrow and have only one nucleus.
- Osteoblasts work in teams to build bone
- produce new bone called "osteoid" made of bone collagen and other
protein
- control calcium and mineral deposition
- found on the surface of the new bone
- when finished filling in a cavity, the cells become flat and look like
pancakes, lining the surface of the bone→ LINING CELLS
- regulate passage of calcium into and out of the bone, and respond to
hormones by making special proteins that activate the osteoclasts.

9. 3. OSTEOCYTES -
- cells inside the bone
- also come from osteoblasts
- some of the osteoblasts turn into osteocytes while the new bone
is being formed, and the osteocytes then get surrounded by new
bone
- not isolated, however, because they send out long branches that
connect to the other osteocytes
- can sense pressures or cracks in the bone and help to direct
where osteoclasts will dissolve the bone.
- maintains mineral conc. of matrix

10. REGULATORS OF BONE METABOLISM :
1. Calcium and phosphate balance
a) Calcium and phosphate
b) Parathyroid hormone
c) Calcitonin
d) Vitamin D
e) Fibroblast growth factor
2. Growth hormone and IGF-1
3. Thyroid hormone
4. Estrogens, progesterone and androgens
5. Cortisol and related glucocorticoids
6. Mechanical strain

11. CALCIUM AND PHOSPHATE BALANCE :
• LOCATION –
- Most abundant among the minerals in the body.
- The total content of calcium in an adult is about 1 to 1.5kg (1.5% body
weight)
- As much as 99% of it is in the bones and teeth and a small fraction of
found outside the skeletal tissue.
- Normal Serum Calcium level is “9-11 mg/dl”
1. CALCIUM :-

12. • FUNCTIONS –
a) mineralization of bone
b) cell proliferation
c) cellular secretion
d) stability and permeability of
cell membranes
e) blood clotting
f) neural transmission
g) neuromuscular function
h) muscle contraction
(including cardiac muscle)

13. • FORMS OF CALCIUM –
- In bone,
A normal 70 kg adult contains between 700 and 1000 g of calcium
with over 99% in the skeleton in the form of hydroxyapatite
- In serum,
i. Ionized Calcium:
About 45-50% of total serum calcium is present in the ionized form
(physiologically active) as Ca2+ ions. Ionized calcium is freely
exchangeable between the soft tissues, ECF and blood.
ii. Protein Bound Calcium:
Nearly 45-50% of total serum calcium is bound to protein (Albumin)
iii.Calcium Salts:
About 5-10% of calcium is present in the form of salts ie. bound with
citrate, bicarbonate and phosphate.

14. • REGULATION OF CALCIUM –
I. Absorption from the digestive tract
II. Resorption from bone
III. Resorption in the kidneys

15. a) Active, transcellular absorption
-occurs only in the duodenum when calcium intake has been low
- involves import of calcium into the enterocyte, transport across the cell,
and export into extracellular fluid and blood
- only a limited amount of calcium can be absorbed
- at low levels of calcium intake, the active transport is extremely
important, because it can absorb a very high percentage of small amounts
of calcium.
b) Passive, paracellular absorption
-occurs in the jejunum and ileum, when dietary calcium levels have been
moderate or high
- ionized calcium diffuses through tight junctions into blood
- depends on having higher concentrations of free calcium in the
intestinal lumen than in blood
- Passive calcium transport is simply diffusion across the intestinal
mucosa.
I. Absorption from the digestive tract -

17. II. Resorption from bone -
ECF contains about 1000mg of calcium which is in equilibrium with
calcium present in the bones and exchange between them occurs in two
ways.
a) Rapid exchange:
- Occurs between ECF and smaller (1% of total bony content) readily
exchangeable pool of bone calcium.
- A large amount of calcium (about 20,000mg) per day moves in and out
of the readily exchangeable pool.
b) Slow exchange:
- Occurs between the ECF and larger (99% of total bone content) pool
of stable calcium.
- This exchange is the one concerned with bone remodelling by constant
interplay of bone resorption and deposition.

19. III. Resorption in the kidneys –
• The amount of calcium excreted in the urine
usually ranges from 100 to 200 mg per 24 hours
while 98%–99% of the filtered load of calcium is
reabsorbed by the renal tubules.
• Calcium absorption proceeds through both an
active, transcellular pathway and by a passive
paracellular pathway.
• Vitamin D and parathyroid hormone (PTH) help regulate how
much calcium is absorbed and how much calcium the kidneys eliminate.
Healthy kidneys turn vitamin D into an active hormone (calcitriol), which
helps increase calcium absorption from the intestines into the blood.

20. • DIETARY REQUIREMENT –
− 2000 mg/day for lactating women
− 1500 mg/day for pregnant women,
postmenopausal woman, and
patients with a healing bone fracture
− 1300 mg/day for adolescents and
young adults
− 750 mg/day for adults
− 600 mg/day for children

21. • DYSFUNCTION –
1. Hypocalcemia –
- Serum ionized calcium falls below 1.16 mmol/L
(true hypocalcemia).
- The hallmark of acute hypocalcemia is
neuromuscular irritability - perioral numbness and
carpodedal spasms of the hands and feet.
- Seizures may be the only presenting symptom of
hypocalcemia. Patients may also present with
lethargy and altered mental status.
- Tetany usually only occurs when the total serum
calcium level falls below 7.0 mg/dL which
corresponds to an ionized calcium of 1.1 mmol/L.

23. 2. Hypercalcemia –
- Serum level of ionized (free), not total,
calcium increases.
- When the total serum calcium level is
>10.5 mg/dL or the ionized calcium level
is > 5.6 mg/dL (1.4 mmol/L).
- Elevations can lead to diffuse
precipitation of calcium phosphate in
tissues, leading to widespread organ
dysfunction and damage.
-The two most common causes of
hypercalcemia are primary
hyperparathyroidism and malignancy.

24. 2. PHOSPHATE :-
• LOCATION –
− In bone, combined with Calcium (86%)
− In blood and extracelluar fluid (0.08%)
− In soft tissues, intracellular phosphate (14%) is organic
(phospholipids, phosphoprotiens, etc)
− Normal Serum Phosphate level is “2.5-4.5 mg/dl”
• FUNCTION –
- key component of bone mineral
- important in enzyme systems and
molecular interactions
- maintains pH of body fluid

25. • FORMS OF PHOSPHATE –
- bone
majority is hydroxyapatite
- serum
mostly inorganic phosphate (H2PO4-)
• REGULATION –
- plasma phosphate is mostly unbound and reabsorbed by the kidney
- may be excreted in urine
- calcium and phosphate have a reciprocal relationship
- elevated serum phosphate can lead to increased release of PTH and
bone resorption
• DIETARY INTAKE –
1000 - 1500 mg/day

26. 2. PARATHYROID HORMONE :-
• STRUCTURE –
84 amino acid peptide
• ORIGIN –
synthesized and secreted from chief cells in the four parathyroid glands

27. • NET EFFECT –
- increases serum calcium
- decreases serum phosphate
• MECHANISM –
I. On bone,
- PTH stimulates osteoblasts to secrete IL-1, IL-6 and other cytokines
to activate osteoclasts and increase resorption of bone
- Increases osteoblast production of M-CSF (macrophage colony-
stimulating factor) and RANKL, which increases number of osteoclasts.
- Inhibits production of OPG, thus also increasing osteoclast number.

28. - In the bone marrow, two molecules that induce differentiation and
proliferation of more osteoclasts: M-CSF (macrophage colony-stimulating
factor) and RANKL.
- M-CSF and RANKL encounter precursor cells which express RANK
(receptor-activator of NFκB), a transmembrane protein.
- RANK functions as receptor for RANKL. As precursor cell RANK is
trimerized by osteoblast-emitted RANKL, the precursor cells differentiate
first to osteoclast precursors and then to mature osteoclasts.
- Osteoblasts secrete a further protein, osteoprotegerin (OPG). This is
called a decoy receptor to neutralize RANKL acting as its inhibitor.
- Thus, the formation rate of osteoclasts depends on the relative amounts of
RANKL and OPG produced by osteoblasts. While PTH induces expression
of M-CSF and RANKL, it inhibits production of OPG, cranking up the
generation of osteoclasts.

29. II. On kidney,
- Stimulates enzymatic conversion of vitamin D3 into its active
hormone form which:
a) increases reabsorption of Ca in kidney (increasing serum Ca)
b) increases excretion of PO4- from kidney (decreasing serum
phosphate)
- Stimulates release of calcitriol (VD3) which inturn causes intestines
to absorb more calcium
III. On intestine,
- No direct action
- Indirectly increase Ca
absorption by activating 1,25-
(OH)2-vitamin D3

30. • DYSFUNCTION –
1. Hypoparathyroidism -
Rare and almost always by excessive surgical removal of parathyroid
tissue during thyroid or parathyroid surgery.
2. Hyperparathyroidism -
a) Primary hyperparathyroidism → parathyroid adenoma or cancer.
- High PTH and high calcium level.
b) Secondary hyperparathyroidism →chronic renal failure , low calcium and
high phosphate.
- Parathyroid glands persistently produce PTH to maintain calcium level
- High PTH and low calcium.
c) Tertiary hyperparathyroidism → bypass the compensatory mechanism.
- Develops a high PTH level, leads to hypercalcemia.
- High PTH and high calcium levels.

32. 3. CALCITONIN :-
• STRUCTURE –
- 32 amino-acid peptide hormone
• ORIGIN –
- produced by clear cells in the parafollicles of the thyroid gland
(C cells)
-stimulated by increases in the serum calcium concentration
- also stimulated by gastrointestinal hormones such as gastrin.
• NET EFFECT –
- opposes the action of the parathyroid hormone
- limited help in regulating blood calcium and phosphate levels
- inhibit number and activity of osteoclasts

33. • FUNCTION –
- primary role of calcitonin is skeletal
conservation
I. In bone,
- it inhibits osteoclastic bone resorption
by decreasing number and activity of
osteoclasts as they have receptors for
calcitonin
II. On intestines, inhibits Vitamin D induced resorption of calcium.
III. On kidney, increases resorption of phosphate and inhibits calcium
reabsorption
- Inc. serum Ca > secretion of calcitonin > inhibition of osteoclasts
> dec. Ca (transiently)

34. 4. VITAMIN D :-
• STRUCTURE –
- fat soluble secosteroid (steroid with a
'broken ring')
• ORIGIN –
- produced by skin when exposed to sunlight
(UV B-generated Vitamin D)
- dietary intake (lipid-soluble vitamin D3)
- enters the circulation bound to vitamin D–
binding protein
-active metabolite 1,25-(OH)2-
vitamin D3 formed by two hydroxylations in
the liver and kidney, respectively which then
enters the target cell, and binds to the vitamin D
receptor (VDR)

35. • NET EFFECT –
-Vitamin D allows body to absorb calcium
- maintains normal serum calcium levels by activating osteoclasts
for bone resorption and increasing intestinal absorption of
calcium (increase serum Ca++)
- promotes the mineralization of osteoid matrix
• FUNCTION –
I. On intestine,
- central target organ in this respect is the duodenum.
- calcitriol induces several proteins that enhance absorption of
Ca2+ from food
- calcitriol also enhances phosphate absorption in the small
intestine.

36. II. In kidney,
- Action of vitamin D parallels that of PTH
- Increases reabsorption of Ca2+ in the distal tubule,
although effect is weaker.
- Contrary to PTH, vitamin D also enhances reabsorption
of phosphate: both ions are required to promote bone
mineralization.
III. In bone,
- Indirect effect → vitamin D raises Ca and phosphate
concentrations above their solubility product, inducing
their precipitation in osteoid.
- Direct effect → receptor-mediated activation of
osteoblast and osteoclast precursors enhancing bone
turnover and Ca2+ mobilization.

37. • DIETARY REQUIREMENTS –
- Vitamin D under age 50 — 400 to 800 IU
- Vitamin D over age 50 — 800 to 1,000 IU

38. • DYSFUNCTION –
1. Vitamin D deficiency –
a) In children → Rickets
- Rickets is a rare disease that
causes the bones to become soft
and bend.
- Presents as bowing of the legs.
- Occurs in children between 6
months to 2 years of age.
- Affects long bones.
- Lack of calcium causes failure of mineralization
- Resulting into formation of cartilagenous form of bone.

39. b) In adults → osteomalacia.
- Causes weak bones, bone pain, and
muscle weakness.
- Only the flat bones and diaphysis of long
bones are affected
- Seen in patients with low dietary intake
and little exposure to sunlight or due to
malabsorption
- Prone for fractures of bones.
- Severe periodontitis
c) In the elderly → osteopenia, osteoporosis and falls risk
d) Vitamin D deficiency may even contribute to obesity, diabetes,
hypertension, depression, fibromyalgia, chronic fatigue syndrome,
neuro-degenerative diseases including Alzheimer’s disease and cancers.

40. 2. Vitamin D toxicity –
- nausea, vomiting, poor appetite, constipation, weakness, and weight
loss.
- Excess vitamin D can also damage the kidneys.
- Too much vitamin D also raises the level of calcium in your blood.
- High levels of blood calcium (hypercalcemia) can cause confusion,
disorientation, and problems with heart rhythm.
3. Phenytoin (dilantin), the anticonvulsant drug causes impaired
metabolism of vitamin D.
- Resulting vitamin D deficiency leads to hypocalcaemia,
hypophosphatemia, secondary hyperparathyroidism all of which
contribute to increased bone loss.
- It directly decreases calcium absorption leading to hypocalcaemia.
- Also causes vitamin K deficiency

42. 5. FIBROBLAST GROWTH FACTOR-23 (FGF23) :-
-FGF23 is a bone-derived phosphate and vitamin D-regulating hormone.
- Produced by osteocytes and osteoblasts in response to 1,25-
dihydroxyvitamin D and dietary phospate loading.
- The main function of FGF23 seems to be regulation of phosphate
concentration in plasma.
- Increases renal phosphate excretion by reducing the number of
Na/phosphate cotransporters in the apical membrane of the proximal
tubule.
- It counters PTH by inhibiting 1α-hydroxylation of vitamin D. It thus
lowers active vitamin D, which in turn reduces uptake of Ca via the
intestines.
- FGF-23 acts as a counter-regulatory hormone to mitigate vitamin D
toxicity

43. GROWTH HORMONE :
• STRUCTURE –
It is a 191 amino acid protein produced by somatotrophs in the anterior
pituitary under control of the hypothalamus
• ORIGIN –
GH secretion is stimulated by GH releasing hormone (GHRH),
inhibited by somatostatin. GH is secreted in short bursts of pulses only
during sleep or during exercise
• NET EFFECT –
Growth hormone (GH) is essential for longitudinal bone growth.

44. • FUNCTION –
- increases serum calcium by increased
absorption in intestine and decreasing
urinary excretion
- GH stimulates hepatocytes to secrete
insulin-like growth factor-1 (IGF-1) into
the blood.
- In bone, part of it is embedded by
mineralization, together with other growth
factors like TGFβ and PDGF (transforming
growth factor β and platelet-derived
growth factor) creating a reservoir of
growth factors that is only activated in case
of bone resorption .

45. -Thyroid hormones are required for
skeletal development and establishment
of peak bone mass.
- Hypothyroidism in children results in
growth retardation with delayed skeletal
development, whereas thyrotoxicosis
accelerates bone maturation.
THYROID HORMONE :
- In adults, T(3) regulates bone turnover and bone mineral density, and
normal euthyroid status is essential to maintain optimal bone strength.
- But thyrotoxicosis is an important and established cause of secondary
osteoporosis, and an increased risk of fracture

46. - In hypogonadism, lack of these hormones results in osteoporosis.
- Overproduction of androgens or estrogens during childhood initially
accelerates growth but results in early epiphyseal closure with reduced
final height.
1. ESTROGEN-
- Estrogens reduce the number and activity of osteoclasts.
- Part of this effect is mediated via the RANK system.
- The result is a decrease in the rate of osteoclast generation.
- By the same and other mechanisms, activity levels and lifespan of existing
osteoclasts are reduced.
- Estrogens reduce bone resorption.
- Postmenopausal osteoporosis starts with a decrease in estrogen
concentrations.
SEX HORMONES :

47. 2. PROGESTERONE –
- Drives RANKL expression and osteoclast formation.
- Peaks during pregnancy to release Calcium from the mother's bones to
help calcify the bones of the fetus.

48. 3. FOLLICLE STIMULATING HORMONE (FSH) –
- The hormone stimulating estrogen production, has a direct effect on
bone
- Stimulates osteoclast activity, an effect that would counter that of
thyrotropin.
4. ANDROGEN –
- In males, androgen levels come down only at a later age.
- Male osteoporosis manifests itself at least ten years later then in
females.
- Also in males, androgens are being converted to estrogens by the
enzyme aromatase, expressed in fatty tissue.
- bone-protective effect of androgens might in fact be due to
estrogens.

49. - Glucocorticoids affect bone formation
as well as bone resorption.
- Inhibits osteoblast function but also
reduces the life span of osteoblasts.
- Glucocorticoids simultaneously induce
RANKL and inhibit OPG production in
osteoblasts which increases the number
and activity of osteoclasts.
- Effects on both sides of the coin
therefore strongly promote osteoporosis.
CORTISOL & RELATED GLUCOCORTICOIDS:

50. DISORDERS OF BONE METABOLISM :
1. Osteoporosis
a) Primary osteoporosis
b) Secondary osteoporosis
2. Rickets and osteomalacia
3. Bone resorption in the context of inflammatory disease
4. Paget's disease of bone (osteitis deformans)
5. Bone metastasis

51. Primary or idiopathic osteoporosis –
- Most common form of the disease
- Main symptoms of osteoporosis are bone fractures
- In women, net resorption accelerates with menopause due to the fall in
estrogens.
- Factors that contribute to the negative net effect:
a) Decrease in estrogen and androgen concentrations
b) Reduced physical activity
c) Insufficient vitamin D and calcium intake
d) Reduced UV exposure, resulting in decreased vitamin D
e) Reduced renal function secondary to other causes
OSTEOPOROSIS :

52. ORTHODONTIC CONSIDERATIONS :
Role of calcium metabolism in orthodontic tooth
movement –
- Orthodontic tooth movement is a unique process
in which a solid object (tooth) is made to move
through a solid medium (bone)
- Whenever force is applied over a tooth surface,
it results in formation of :
a) Area of pressure (same direction)
b) Area of tension (opposite direction)

53. Parathyroid hormone:
- Acts through osteoclasts for increasing the plasma calcium level.
- Causes bone resorption and so tooth movement is favoured
Calcitriol:
- Calcitriol along with PTH increases the plasma calcium level.
- But as opposed to PTH, it has its action both on bone deposition and
resorption but mainly on bone deposition.
- As a result, it does not favour tooth movement in orthodontics.
Calcitonin:
- Increases the deposition of calcium into the bone through osteoblast.
- It also suppresses the activity of osteoclasts
- As a result it increases the bone mass and doesn’t favour orthodontic
treatment.

54. Bone metabolism is a continual cycle of bone growth and resorption
that is carefully orchestrated by the dynamic relationship between
osteoclasts, osteoblasts and an array of hormonal and regulatory
influences. The complete process is still to be understood and the
practical applications to be further discovered.
CONCLUSION :

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4. Textbook of physiology – A.K.Jain
5. Effect of altered bone metabolism on orthodontic tooth movement - Dr. Midgett et al(
AJODO vol 80 sept 1981)
6. Normal Bone Metabolism - Evan Watts, Orthobullets
7. VIVO Pathophysiology – Endocrine Control of Calcium and Phosphate Homeostasis -
Richard Bowen
8. Mohamed AM. An overview of bone cells and their regulating factors of
differentiation. Malays J Med Sci. 2008;15(1):4–12.
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154,12 (2013): 4469-82. doi:10.1210/en.2013-1627
10. Shaker JL, Deftos L. Calcium and Phosphate Homeostasis. [Updated 2018 Jan 19]. In:
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REFFERNCES :