Bone metabolism. Calcium homeostasis. Hypercalcemia and hypocalcemia. Markers of bone formation and resorption

1. Bone Metabolism
Dr. Subhash Kumar Das
Resident
Department of Orthopaedics
SBH

2. Objectives
• Composition of bone
• Calcium and phosphorus homeostasis
• Hypercalcemia and Hypocalcemia
• Markers of bone remodelling
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3. What is bone
composed of ??

4. • Cells :
Osteoblasts- Bone forming cells.
Osteocytes – maintain bone. Constitute 90% of cells
in mature skeleton.
Osteoclasts- These cells helps in bone resorption.
• Matrix:
Organic matrix= mainly type I collagen fibers
Inorganic matrix= calcium, magnesium, phosphate,
carbonate, chloride, fluride and citrate.

5. • Inorganic content give rigidity to the bone
• Organic content give the elasticity to the bone.
• Lack of inorganic content- soft
bone(rickets/osteomalacia)
• Lack of organic content- brittle bone (OI/lobstein
syndrome)

6. Calcium and
phosphate
homeostasis

7. Why do we need
calcium ??

8. 8
• For bones
• For neurotransmission to muscle contraction
• The cell cycle ( mitotis promoting factors, kinase)

9. 9

10. • Bone is like a reservoir for blood calcium(99%)
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11. 3 main players
• Thers are 3 main players in the control of
blood calcium levels
1. Vitamin D ( calcitriol)
2. Parathyroid hormone
3. Calcitonin
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13. ACTIONOFCALCITRIOLONTHEINTESTINE
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14. ON BONE:
CALCITRIOL   n. & activity of osteoblasts;
also  secretion of ALP by osteoblasts 
mineralization of bone
• Mineralization of bones
Calcitriol Osteoblast   Ca uptake for
deposition as calcium phosphate.
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ON KIDNEY:
Calcitriol   excretion and  reabsorption of Ca & P
  plasma Ca & P

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Secretion of PTH is under negative feedback regulation by S Ca
Low S Ca→ ↑PTH secretion
1. Action on Bone - demineralization or decalcification of bone by
osteoclasts (bone resorption)
 Quantitatively most important action.
2. Action on Kidney - ↑ Ca reabsorption in DCT → ↑ S Ca
 Most rapid but quantitatively less imp as compared to action on bone
(PTH at PCT ↓ses PO4 reabsorption →↑U excretion→ ↓ S phosphate)
3. Action via Calcitriol - by activation of activity of 1 α-hydroxylase →
on intestine, bone, kidney → ↑ S Ca
PTH - parathyroid glands → ↑ S Ca

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 Secreted by- parafollicular cells of Thyroid
 Calcitonin action on calcium is antagonistic to
that of PTH
1. Calcitonin promotes calcification by
increasing activity of osteoblasts [v/s PTH-
decalcification]
2. Calcitonin ↓ses bone resorption by osteoclasts
[v/s PTH- ↑ bone resorption by osteoclasts]
3. Calcitonin ↑ses Ca excretion in urine [v/s PTH- ↑
Ca reabsorption by DCT]
Calcitonin

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S Ca Calcitonin &  PTH
 S Ca   Calcitonin & PTH
 demineralization & effect on kidney & PTH via 1α
hydroxylase
 S Ca

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Low pH
↓
Increased secretion of PTH
↓
Increased urinary excretion of
phosphate
↓
Increased net acid excretion by
increased buffering of
excreting H+ ions
Effect of pH on
Calcium/Phosphate
Metabolism:

20. Hypercalcemia and
Hypocalcemia

21. Hypercalcemia
Symptoms: Polyuria, dehydration, confusion, depression, fatigue,
nausea/vomiting, anorexia, abdominal pain, and renal stones.
Signs: Diminished reflexes, short QT interval on ECG.
Etiologies:
1. Increased GI Absorption of Calcium:
 Milk-alkali syndrome
 Elevated Calcitriol: causes-
»Vitamin D excess
• Chronic granulomatous diseases – mc in sarcoidosis
• Excessive vitamin D intake
• Acromegaly (
• Lymphoma
» Elevated PTH [by ↑ing 1 α-hydroxylase ]
» Hypophosphatemia [by ↑ing 1 α-hydroxylase ] 21

22. 2. Increased Calcium Loss From Bone:
• Increased Bone Resorption
• Elevated PTH
• Primary hyperparathyroidism
• Adenoma (80%)
• Hyperplasia (15%)
• Carcinoma (<5)
• Acidemia
• Malignancy (Hypercalcemia in malignancy is a grave
prognostic factor: Median survival = 1-6 months)
• Increased bone turnover
• Immobilization
• Hyperthyroidism
• Hypervitaminosis A / retinoic acid
• Paget’s disease of bone 22

23. 3. Decreased Bone Mineralization:
• Aluminum intoxication – seen in end-stage renal disease.
• Elevated PTH (see above)
4. Decreased Urinary Calcium Excretion:
• Thiazide diuretics
• Familial hypocalciuric hypercalcemia
• Elevated calcitriol (see above)
5. Pseudohypercalcemia (due to increased protein
binding of calcium in hyperprotiein states)
• Severe dehydration (due to concentration of albumin)
• Multiple Myeloma
• In ambulatory patients, 90% of cases will be due to
hyperparathyroidism.
• In hospitalized patients, 65% of cases will be due to
malignancy.
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24. Hypocalcemia
Symptoms: Irritability, muscle cramps, depression, psychosis, bronchospasm,
and seizures.
Signs: Increased reflexes, prolonged QT interval on ECG (the only cause of a
prolonged QT with a normal duration of the T wave itself)
• Chvostek’s sign – Tapping of the facial nerve induces contractions of the facial muscles
• Trousseau’s sign – Inflation of a blood pressure cuff induces carpal spasm
Etiologies:
A. Decreased GI Absorption of Calcium
• Poor dietary intake of calcium
• Decreased GI absorption with normal dietary intake
B. Decreased calcitriol
1. Vitamin D deficiency
• Poor dietary intake
• Inadequate sunlight exposure- purda, burka etc
• Malabsorption syndromes
• Drugs – drug which increased activity of the P-450 system, increases
inactivation of vitamin D. isoniazid, theophylline, rifampin, and
anticonvulsants.
• Nephrotic syndrome – Due to loss of vitamin D binding protein in the
urine
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25. Hypocalcemia cont…
2. Decreased conversion of vitamin D to calcitriol
• Liver failure
• Renal failure
• Low PTH
• Hyperphosphatemia
• Vitamin D dependent rickets,
C. Vitamin D resistance
Hereditary vitamin D resistant rickets (formerly called vitamin D
dependent rickets, type 2)
D. Increased Bone Mineralization
• Low PTH
• PTH resistance
• Hungry bones syndrome – The rapid mineralization of bones
following parathyroidectomy
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26. E. Decreased Bone Resorption
– Low PTH
– PTH resistance
– Decreased calcitriol
F. Increased Urinary Excretion of Calcium
1. Low PTH (hypoparathyroidism)-
a. Post-Thyroidectomy complication (most common cause)
b. Post I131 therapy for Graves disease or thyroid cancer
c. Autoimmune hypoparathyroidis
d. Congenital hypoparathyroidism
i. Autosomal dominant hypocalcemia.
ii. DiGeorge Syndrome
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2. PTH Resistance
3. Deficiency of calcitriol

27. What are markers
of Bone
Remodeling ??

28. Markers of Bone Remodeling
Formation
Markers(serum)
• Total ALP
• Bone ALP
• Osteocalcin (OC)
• C-terminal propeptide
of protocollagen type I
(PICP)
• N-terminal propeptide
of protocollagen type I
(PINP)
Resorption
Markers(serum)
• Tartrate resistant acid
phosphatase (TRAP)
• C-terminal telopeptide
of collagen type I
(ICTP)
• N-terminal telopeptide
of collagen type I (NTX)
• β-CrossLaps (β-CTX) 28

29. Urine
• Urinary excretion of
calcium
• Hydroxyproline
• Pirydinolin (Pir)
• Deoxypirydinolin (Dpir)
• C-terminal telopeptide
of collagen type I (ICTP)
• N-terminal telopeptide
of collagen type I (NTX)
• α-CrossLaps (α-CTX)
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30. Formation Markers
• Alkaline phosphatase activity is derived from various
tissues such as the liver, bone, placenta, etc.
• Bone and liver isoforms are the most common (90%).
• Both are found in the same proportion in the healthy
individual and differ in glycosylation patterns, and there
is a cross-activity of 10%–20%, according to studies with
monoclonal antibodies.
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31. Serum osteocalcin
• Osteocalcin is a small protein (49 amino acids) .
• Synthesized by mature osteoblasts , odontoblasts , and
hypertrophic chondrocytes .
• Major advantages -considered a specific marker of osteoblast
function, as its levels correlate with the bone formation rate.
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32. Procollagen type 1
• Procollagen type 1 contains N- and C-terminal extensions,
which are removed by specific proteases during conversion of
procollagen to collagen.
• Antibodies are used to detect the P1CP and P1NP by ELISA or
radioimmunoassay.
• Measurement of P1NP appears to be a more sensitive marker
of bone formation rate in osteoporosis.
• Because type I collagen is the main product of synthesis of the
osteoblast, the amino-termina carboxy propeptides would,
theoretically, be the ideal marker of bone formation.
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33. Resorption Markers
• Historically, urinary calcium was the first test used to assess
bone resorption.
• However, the fact that it is influenced by various factors, such
as calcium intake, intestinal absorption and renal threshold of
excretion of calcium, makes its determination a test with low
sensitivity and specificity, and is currently unused.
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34. Carboxyterminal (ICTP, CTX) and amino-terminal
(NTX) telopeptides of collagen
• They have shown a significant correlation with BMD in
postmenopausal women.
• considered the most clinically useful markers of bone
resorption currently available.
Tartrate-resistant acid phosphatase
• Is a lysosomal enzyme not only involved in osteoclast bone
degradation but is also present in other tissues.
• It is poorly specific, and together with the methodological
difficulty in identifying it, currently makes it of little use.
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35. Clinical Utility of Biomarkers
in Osteoporosis
• assessment of therapeutic response.
• Predicting risk of fracture and bone loss and their correlation
with BMD.
• Prediction of bone mass.
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36. Limitations on the Use of
Markers
• However, one cannot ignore the fact that markers of bone
turnover show a marked variability, both analytical and
biological.
• The causes of variability : age, sex, ethnicity, fracture repair,
renal and hepatic function, other associated diseases, and so
on.
• It is important to determine the time of sample collection
according to the circadian rhythm of each marker.
• Some markers in particular are heavily influenced by food, as
is the case with serum CTX.
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