Bone metabolism

1. BONE METABOLISM
• The main functions of bone are
 Mechanical – for locomotion
 Protective - for organs
 Metabolic - as a reserve for minerals Ca and PO₄
• Bones are composed of cortical and trabecular bone
• Cortical (compact) bone is 80-90% mineral by volume and
constitutes 80% of the skeleton
• Its function is primarily mechanical and protective
• Trabecular bone constitutes the remaining 20% of the
skeleton
• Trabecular or cancellous bone is spongy and 15-20%
mineralized and is more metabolically active

2. • Bone is composed of an extracellular mineralized matrix
with a smaller cellular fraction
• The organic matrix is primarily type I collagen (90%) with
lesser amounts of noncollagenous proteins including
osteocalcin
• The organic matrix is mineralized by deposition of inorganic
calcium and phosphate and in small, imperfect
hydroxyapatite crystal
• Osteoclasts and osteoblasts, the two main bone cells , are
located on surfaces undergoing bone resorption and
formation, respectively
• Osteoclasts resorb bone whereas osteoblasts participate in
the synthesis of new bone

3. • Continuous turnover or remodeling of bone
occurs enabling bone to repair damage and
adjust strength
• Bone remodeling does not occur at random, but
instead in discrete packets known as bone
remodeling units
• Bone resorption and bone formation are coupled
• The remodeling cycle is divided into activation,
resorption, reversal, formation and resting
phases

4. • Circulating osteoclast precursors are recruited,
proliferate, and fuse to form osteoclasts
• These giant multinucleated cells resorb bone by
producing hydrogen ions to mobilize minerals and
lysosomal enzymes to digest the organic matrix
• Deep foldings of plasma membrane (ruffled border) are
in contact with the bone surface, forming the bone-
resorbing compartment
• After resorption ceases, a cement line is deposited in
the resorption cavity, probably by mononucleated cells
• Stromal lining cells differentiate to osteoblasts

5. • Osteoblasts form bone by synthesizing the
organic matrix, including type I collagen, and
participating in the mineralization of the
newly synthesized matrix
• Remodeling is followed by a quiescent phase
• An estimated 10-30% of the skeleton is
remodeled each year

6. • Bone growth and turnover is influenced by the
metabolism of :
 Calcium
 Phosphate
 Magnesium and a number of hormones and the
primary one are:
 PTH and
 1,25 – dihydrovitamin D
• In addition, a large number of other hormones and
factors are involved in bone formation and resorption
including:

7.  Thyroid hormones
 Estrogens
 Androgens
 Cortisol
 Insulin
 Growth hormone
 Insulin-like growth factors(IGF-I and IGF-II)
 Transforming growth factor β (TGF-β)
 Fibroblast growth factor (FGF) and
 Platelet-derived growth factor (PDGF)

8. • A number of cytokines, including interleukin (IL) – 1 , 4 , 6 and
11, macrophage and granulocyte/macrophage colony-
stimulating factors
• These including tumour necrosis factor (TNFα) alter bone
remodeling primarily by stimulating resorption
• Bone contains nearly all of the calcium (99%), most of the
phosphate (85%), and much of the magnesium (55%) of the
body
• The concentration of the calcium phosphate and magnesium
is dependent on the net effect of bone remodeling, intestinal
absorption and renal excretion
• PTH and the 1,25-dihydroxyvitamin D are principal hormones
regulating these processes

9. HORMONES REGULATING MINERAL METABOLISM
• PTH and 1, 25 – dihydroxyvitamin D are the
primary hormones regulating bones and
mineral metabolism
• Calcitonin has pharmacological actions, but a
physiological role has not been established
• PTHrP is the principal mediator of humoral
hypercalcaemia of malignancy

10. PARATHYROID HORMONE
• Synthesized and secreted by the parathyroid gland
• The glands are composed of chief and oxyphil cells; the
chief cells synthesize, store and secrete PTH
• Concentration of PTH in plasma is determined by its
synthesis by the glands and its metabolism and
clearance by the liver and kidneys
• PTH acts directly on bone and kidneys and indirectly on
intestine to regulate the concentration of calcium and
phosphate in plasma

11. • The concentration of free calcium in blood or
extracellular fluid is the primary acute physiological
regulator of PTH synthesis, metabolism and excretion
• An increase in extracellular free calcium inhibits PTH
synthesis and secretion and increases PTH metabolism
• An inverse sigmoidal relationship exists between PTH
secretion and free calcium
• Maximal secretion and suppression are attained with
mild hypocalcaemia and mild hypercalcaemia

12. • 1, 25 dihydroxyvitamin D, phosphate and
magnesium also influence synthesis and secretion
of PTH
• 1,25 dihydroxyvit D interacts with vitamin D
receptors in the parathyroid glands to chronically
suppress PTH synthesis by suppressing PTH gene
transcription
• Hyperphosphatemia and hypophosphatemia
increase and decrease PTH synthesis and
secretion, respectively

13. • Chronic severe hypomagnesaemia (as occurs
in alcoholism) has been associated with
impaired PTH secretion
• Whereas acute hypomagnesaemia may
stimulate secretion
• Hypomagnesaemia suppresses PTH secretion
via the calcium-sensing receptor, although not
as effectively as calcium

14. BIOLOGICAL ACTIONS OF PTH
• PTH influences both calcium and phosphate
homeostasis directly through its action on bone and
kidney and indirectly on the intestine through active
vitamin D
• PTH exerts its actions by interacting with PTH/ PTHrP
receptors located in the plasma membrane of target
cells
• This interaction leads to generation of cAMP activation
of kinases, phosphorylation of proteins, increased
entry of calcium, stimulated phospholipase C activity
and secretion of lysosomal proteins

15. • In the kidneys, PTH
1) Induces 25-hydroxyvitamin D- 1α – hydroxylase,
increasing production of 1,25(OH)₂D
This stimulates intestinal absorption of both
calcium and phosphate
2) Increases calcium reabsorption in the distal
convoluted tubule of the nephron
3) Decreases reabsorption of phosphate by the
proximal tubule and

16. • 4) Inhibits Na+-H+ antiporter activity, which
favours a mild hyperchloremic metabolic acidosis
in hyperparathyroid states
• Effects of PTH on bone are complex, as evidenced
by its stimulation of bone resorption or bone
formation,
• Which will depend on the concentration of PTH
and the duration of exposure
• Chronic exposure to high concentrations of PTH
leads to increased bone resorption

17. • PTH acts directly by altering the activity or
numbers of osteoblasts and indirectly on
osteoclasts
• Bone resorption a prompt effect, is important for
the maintenance of calcium homeostasis
• Integration of the direct effects of PTH on bone
and kidney and indirect effects on intestine
through vitamin D result in alterations in calcium
and phosphate concentrations in serum and urine

18. • In serum free and total calcium are increased
but concentration of phosphate is decreased
• In urine, inorganic phosphate and cAMP
concentration increase
• In the absence of disease, increase in serum
calcium reduces PTH secretion through a
negative-feedback loop, maintaining
homeostasis

19. METABOLISM AND CIRCULATING HETEROGENEITY
• PTH circulates as biologically active intact hormone and
• The carboxyl (C) – terminal fragments containing the
midregion and the C-terminal aminoacids, but lacking
the biologically active amino (N)-terminal region
• Its heterogeneity is a consequence of
1) The excretion of both the intact hormone and C
terminal fragments by the parathyroids
2) Peripheral metabolism of intact hormone by the liver
and the kidney and to C-terminal fragments and

20. • 3) Renal clearance of intact hormone and the C-
terminal fragments
• In the parathyroids , secretion of the intact PTH is
increased by hypocalcaemia and greatly reduced
or absent in hypercalcaemia
• Secretion of C-terminal fragments persists in
hypercalcaemia
• Biologically active intact PTH is rapidly cleared
from plasma by metabolism to C-terminal
fragments by the liver and the kidneys and
clearance of intact PTH by the kidneys

21. • Circulating immunoreactive PTH is composed primarily
of “inactive” C-terminal fragments and secondarily of
intact hormone
• Although the exact length of circulating C-terminal
fragments is uncertain, fragments consisting of the
middle and carboxyl regions of the molecule (34-84,
36-84) have been frequently reported
• These fragments are devoid of the N-terminal region
and classical PTH biological activity and were
considered to be inactive degradation products

22. • C-terminal fragments are cleared by
glomerular filtration and have a half-life of less
than 1 hour
• The half-life and circulating concentration is
increased significantly in individuals with
impaired renal function
• Generally 5-25% of the total immunoreactive
PTH is intact hormone, and 75-95% is C-
terminal fragments

23. REFERENCE RANGES
• Reference ranges vary with the method
• Typical reference intervals are
Intact PTH (first generation) 10-65 pg/ml (1.1-
6.8pmol/L)
PTH (1-84) (second generation) : 6-40 pg/ml
(0.6-4.2pmol/L)
• Interpretation of PTH concentrations should
consider the patient’s calcium concentration
at the time of sampling

24. • The upper limit of the reference interval may
be inappropriately high because of the
prevalence of vitamin D insufficiency and mild
hyperparathyroidism in the reference group
• Intact PTH concentrations vary with age and
are low and normal during pregnancy, lower in
fetuses and umbilical cord blood
• It is increased in the first few days of life in
respose to neonatal hypocalcaemia

25. • Concentrations in children and adolescents are
similar if not identical to those in adults
• In healthy adults, circulating intact PTH increases
with age
• The overall circadian rhythm is characterized by a
nocturnal rise a fact that it is secreted in a
pulsatile fashion
• Measurement should be done more than once to
prevent misinterpretation of the parathyroid
status because of episodic secretion

26. INTERPRETATION OF PTH RESULTS
• PTH is one of the most important tests for the
differential diagnosis of hypocalcaemia
• Intact PTH is elevated in most patients with primary
hyperparathyroidism
• Levels are below normal or in the lower half of the
reference interval in most patients with nonparathyroid
hypercalcaemia including hypercalcaemia –associated
malignancy
• In patients with stable hypercalcaemia, PTH in the half
of the reference interval is inappropriately high and
suggestive of primary hyperparathyroidism

27. • Patients with hypercalcaemia and malignancy and
have elevated PTH suggests coexisting
hyperparathyroidism and malignancy since
ectopic PTH secretion is extremely rare
• Hypercalcaemia in malignancy is usually
associated with bone metastasis and/or
production of PTHrP
• Subnormal or low normal PTH is observed
inpatients with hypoparathyroidism
• Levels are inappropriately low for patients with
hypocalcaemia

28. • In secondary hyperparathyroidism, PTH is increased before total or
free calcium becomes abnormally low
• This is consequence of homeostatic mechanisms for maintenance
of serum calcium
• Consequently, PTH is more sensitive than calcium in identifying
secondary hyperparathyroidism
• In patients with end-stage renal disease, measurement of PTH is
useful in
 Assessing parathyroid function
 Estimating bone turn-over
 Improving management
• Patients with high bone – turnover because of secondary
hyperparathyroidism (advanced osteitis fibrosa) have the highest
PTH concentrations

29. • Patients with low bone - turnover, dynamic bone
disease, including osteomalacia have the lowest
concentrations
• Intermediate concentrations are seen in low bone –
turnover adynamic (aplastic) disease and early osteitis
fibrosa
• Considerable overlap in intact PTH levels are apparent
in the various forms of renal osteodystrophy
• PTH levels may also be altered in
hyperthyroidism,hypothroidism and with lithium
carbonate treatment

30. • PTH is decreased and inversely correlated with
T3 in hyperthyroid patients
• Serum PTH increases in patients who become
hypothyroid after radioactive iodine treatment
and decreases with replacement therapy