Normal bone metabolism, calcium metabolism, phosphate metabolism, calcium balance, phosphate balance, bone markers

1. Bone Metabolism
Presenter- Dr Binod Chaudhary
1st year Resident
Department of Orthopaedics, PoAHS

2. Contents
• Composition of bone
• Distribution of calcium and phosphate in human body
• Serum calcium and phosphate measurement
• Dietary sources and requirements of calcium and phosphate
• Calcium and phosphate absorption and excretion
• Calcium and phosphate homeostasis
• Hormonal control of calcium and phosphate ion concentration
• Hypercalcemia and hypocalcemia
• Bone health
• Calcium supplements

3. COMPOSITION OF BONE

4. CALCIUM METABOLISM
Why do we need calcium?

5. DISTRIBUTION OF CALCIUM IN THE HUMAN
BODY
• Calcium constitutes 2% of the body weight- approx. 1.2 kg
• 0.1% is in the extracellular fluid
• 1% in the cells
• More than 99% stored in bones
Distribution of Serum Calcium
Ionized (or free)
calcium
Calcium bound to
albumin
Calcium complexed
with citrate, sulfate,
or phosphate
45%
40%
15%

6. Serum calcium measurements
• Normal serum calcium concentration is 8.6-10.3 mg/dL
(2.15-2.54 mmol/L).
• Normal ionized calcium concentration is 4.4-5.2 mg/dL.
• In general, measuring total serum calcium is sufficient.
• However, this can be misleading in certain situations.
• Thus, measurement of ionized calcium is the gold standard
for assessing calcium status.

7. • Conditions in which total calcium can change without
affecting ionized calcium:
– Hypoalbuminemia (decreased total calcium)
– Hyperalbuminemia (increased total calcium)
– Multiple myeloma (increased total calcium)
• Conditions in which ionized calcium can change without
affecting total calcium:
– Acid-base disorders (increased pH leads to decreased
ionized calcium)
– Hyperphosphatemia (decreased ionized calcium)
– Hyperparathyroidism (increased ionized calcium)

8. Bone: A reservoir for blood calcium(99%)

9. Dietary sources of calcium
1. Food
• Dairy products: milk, yogurt and cheese
• Vegetables, grains, legumes, fruit
• Meat, fish, eggs
• Fortified foods- orange juice, other beverages, and ready-to-eat
cereals
2. Dietary supplements
• Calcium carbonate and
• Calcium citrate

10. Foods rich in calcium

11. Dietary requirements
ELEMENTAL CALCIUM PER
DAY
Children 600 mg
Adolescents and young adults (10-25 yrs) 1300mg
Adults ages 25050 yrs 750 mg
Over age 50 years 1200-1500 mg
Pregnant women 1500 mg
Lactating women 2000 mg
Post menopausal women and the patient with
healing fractures
1500 mg

12. CALCIUM ABSORPTION AND EXCRETION
• Absorbed in the duodenum by active transport
(transcellular pathway).
– Requires ATP and calcium binding protein
– Regulated by 1,25-(OH)2D3
• Absorbed in the jejunum by passive diffusion
(paracellular pathway)
• Average daily consumption is about 1000 mg, of
which 350 mg is absorbed and the rest (650 mg)
is excreted in feces.
• Further 250 mg is secreted in GI secretions and
excreted in feces, thus 90% (900 mg/day) is
excreted in feces.

13. CALCIUM ABSORPTION AND EXCRETION
• Absorption is inhibited by:
– Excessive intake of phosphates (in soft drinks)
– Oxalates (in tea and coffee)
– Fats
– Certain drugs such as corticosteroids
– Intestinal malabsorption disorders
• 98% of filtered calcium is absorbed by the kidneys (60% in PCT).
• Approx. 100 mg is excreted daily in urine in the steady state.
• Approx. 400-500 mg of calcium is released from bone everyday and
the same amount is deposited.

15. Phosphate
• In human body Phosphorus is present as Phosphate (compounds
containing the phosphate ion, PO4
---)
• Role of phosphate:

16. Phosphates
Distribution
Total phosphorus
500-800 gm
80%-90% 10%-20%
Bones
Teeth
RBC
Plasma
Normal plasma levels
2.5-4.5 mg/dl
Organic
0.5-1 mg/dl
Inorganic
Adults: 3-4 mg/dl
Children: 5-6 mg/dl

17. Phosphates
• Daily requirements
– Adults: 800 mg
– Pregnancy, lactation and children: 1200 mg
– Infants: 240 mg
• Sources of phosphate
• Rich (milk, meat, fish, poultry, eggs)
• Moderate (cereals, pulses, nuts, legumes)
• Reabsorbed by the kidney (proximal tubule)
• Phosphate may be excreted in urine

18. Calcium and Phosphate Homeostasis
There are 3 main players in the control of blood calcium levels
1. Vitamin D (Calcitriol)
2. Parathyroid hormone
3. Calcitonin

20. VITAMIN D(CALCITRIOL)
• Has potent effect to increase calcium absorption from intestinal tract,
bone deposition and bone resorption.
• Cholecalciferol is formed in the skin
• Cholecalciferol is converted to 25-Hydroxycholecalciferol in the liver
• Formation of 1,25-Dihydroxycholecalciferol in the kidneys
• Calcium ion concentration controls the formation of 1,25-
Dihydroxycholecalciferol

21. Actions of Vitamin D
In Intestine:
• Two major mechanisms for calcium absorption
Between cells(paracellular):
passive
quantitative significance when intake is high
Through cells
active
influenced by calcitriol
calbindin: acts as an intracellular sink to reduce the microvilli[Ca]

22. On Bone:
Calcitriol → ↑no. and activity of osteoblasts; also ↑secretion of
ALP by osteoblasts → mineralization of bone
Mineralization of bones:
Calcitriol → Osteoblast → ↑Ca uptake for deposition as calcium
phosphate
On kidney:
calcitriol → ↓excretion and ↑reabsorption of Ca and P →
↑plasma Ca and P

23. VITAMIN D DEFICIENCY
• Deficiency leads to osteomalacia in adults and rickets in children.
• Decreased vitamin D, decreased serum calcium and phosphate,
increased PTH and ALP seen.
• Causes of vitamin D deficiency:
– Inadequate dietary intake
– Intestinal malabsorption
– Lack of sunlight exposure
– Impaired 25-hydroxylation in liver disease
– Impaired 1-alfa hydroxylation in renal disease

24. RICKETS
• Defective mineralization of cartilagenous growth plate, causing chondrocytes to pile up
irregularly, increase in width of growth plate, poor mineralization of the zone of
calcification and sparse bone formation in the zone of ossification.
• Clinical features:
– Tetany or convulsions
– Bow legs (genu varum)
– Bead-like costochondral junctions (rachitic rosary)
– Craniotabes (soft skull)
– Harrison’s sulcus (lateral indentation of the chest)
• X-ray:
– Epiphyseal widening and metaphyseal cupping/fraying
– Bowing of the diaphysis

26. OSTEOMALACIA
• Defective mineralization of osteoid due to deficiency of vitamin D.
• Increased bone fragility and fracture risk.
• Clinical features:
– Bone pain
– Muscle weakness
– Waddling gait
• X-ray:
– Looser zone, a thin transverse band of rarefaction in an otherwise normal-
looking bone
– Vertebral fractures may show characteristic biconcave appearance
– Champagne glass pelvis

28. PTH- Parathyroid glands
• Secretion of PTH is under negative feedback regulation by S Ca.
Low S Ca → ↑ PTH secretion
Action on Bone- Demineralization or decalcification of bone by
osteoclasts (bone resorption)
• Quantitatively most important action
Action on kidney- ↑Ca reabsorption in DCT→↑S Ca
• Most rapid but quantitatively less important as compared to action on bone
(PTH at PCT→decreases PO4 reabsorption→↑U excretion →decreases S
phosphate)
 Action via Calcitriol- By activation of activity of 1α-hydroxylase→on
intestine, bone and kidney →↑S Ca

30. HYPOPARATHYROIDISM
• Low PTH levels with decreased serum calcium and increased
serum phosphate.
• Causes:
• Hypoparathyroidism most commonly follows thyroidectomy
• Autoimmune disease
• Magnesium deficiency
• DiGeorge syndrome
• Pseudohypoparathyroidism
• Rare genetic disorder caused by impaired peripheral sensitivity to PTH
• PTH normal or high
• Albright’s hereditary osteodystrophy (short stature, short 4th and 5th
metacarpals and mild mental retardation)

31. HYPERPARATHYROIDISM
• Increased PTH levels with increased serum calcium and decreased serum
phosphate.
• Types:
• Primary (usually due to an adenoma or hyperplasia).
• Secondary (due to persistent hypocalcemia leading to parathyroid hyperplasia).
• Tertiary (when secondary hyperplasia leads to autonomous overactivity).
• Treatment:
• Adequate hydration and decreased calcium intake
• Parathyroidectomy for primary hyperparathyroidism

32. RENAL OSTEODYSTROPHY
• Is a form of metabolic bone disease seen in patients with chronic
renal insufficiency characterized by bone mineralization deficiency
due to electrolyte and endocrine abnormalities.
• The dominant picture may be that of secondary hyperparathyroidism
(due to phosphate retention, hypocalcemia, and diminished
production of vit D3), osteoporosis, osteomalacia, - or in advance
cases- a combination of these.
• The effects may be superimposed with postmenopausal osteoporosis,
glucocorticoid medication or aluminium retention in dialysis fluids

33. PATHOPHYSIOLOGY
CHRONIC KIDNEY DISEASE
DECREASED TUBULAR FILTRATION DECREASED GLOMERULAR FILTRATION
HYPERPHOSPHATEMIA
DECREASED SYNTHESIS OF ACTIVE FORM OF VIT D
HYPOCALCEMIA
SECONDARY HYPERPARATHYROIDISM
LEECHING OF CALCIUM FROM BONES TO COMPENSATE FOR SERUM HYPOCALCEMIA
DYSTROPHIC BONE WHICH IS SUSCEPTIBLE TO PATHOLOGIC FRACTURES

34. • Clinical features
• Weakness
• Bone pain
• Pathological fracture
• Skeletal deformity
• Symptoms of hpocalcemia
Treatment
• Treat the underlying renal condition.

35. Calcitonin
• 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 ↓bone resorption by osteoclasts[v/s PTH- ↑bone
resorption by osteoclasts]
3. Calcitonin ↑Ca excretion in urine[v/s PTH-↑Ca reabsorption by
DCT]

36. ↑S Ca→ ↑Calcitonin and ↓PTH
↓S Ca→ ↓Calcitonin and ↑PTH→demineralization & effect on kidney
& PTH via 1α hydroxylase→↑S Ca

37. Hormonal control of calcium ion
concentration

38. Hormonal Regulation of [Ca++]

39. Other hormones affecting bone metabolism
Estrogen
prevents bone loss by inhibiting bone resorption (also decreases
bone formation)
Corticosteroids
increases bone loss
decreases gut absorption of Ca by ↓binding proteins
↓bone formation(cancellous>cortical) by inhibiting collagen
synthesis
do not affect mineralisation

40. Thyroid hormones
affect bone resorption>bone formation
regulates skeletal growth at the physis.
Growth hormone
positive Ca balance

41. Disorders in Calcium Homeostasis
Hypercalcemia
S. Ca >10.5 mg/dl
Hyporcalcemia
S. Ca <8.5 mg/dl

42. Hypercalcemia
Symptoms- polyuria, polydipsia, nephrolithiasis, confusion, depression,
fatigue, nausea/vomiting, anorexia, abdominal pain
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, excessive vitamin D intake,
acromegaly, lymphoma)
• Elevated PTH (by increasing 1 α hydroxylase)
• Hypophosphatemia (by increasing 1 α hydroxylase)

43. 2. Increased Calcium loss from Bone
• Increased bone resorption
• Elevated PTH (primary hyperparathyroidism, adenoma,
hyperplasia, carcinoma)
• Acidemia
• Malignancy
 Increased bone turnover
 Immobilization
 Hyperthyroidism
 Hypervitaminosis A/ retinoic acid
 Paget’s disease of bone

44. 3. Decreased Bone Mineralization
• Aluminium intoxication- seen in end stage renal failure
• Elevated PTH
4. Decreased urinary calcium excretion
• Thiazide diuretics
• Familial hypocalciuric hypercalcemia
• Elevated calcitriol
5. Pseudohypercalcemia
• Severe dehydration
• Multiple myeloma

45. Hypocalcemia
Symptoms- irritability, muscle cramps, depression, psychosis, bronchospasm and
seizures
Signs- increased reflexes, prolonged QT interval on ECG
Chovstek’s sign: tapping of the facial nerve induces contraction of the facial muscles
Trousseau’s sign: inflation of blood pressure cuff induces carpal muscle spasm
Etiologies:
1. Decreased GI Absorption of Calcium
• Poor dietary intake of calcium
• Decreased GI absorption with normal dietary intake
2. Decreased calcitriol: causes
• Vitamin D deficiency (poor dietary intake, inadequate sunlight exposure, malabsorpton syn,
nephrotic syndrome)
• Decreased convertion of vitamin D to calcitriol (liver/kidney failure, low PTH)

46. 3. Vitamin D resistance
• Hereditary vitamin D resistant rickets
4. Increased bone mineralization
• Low PTH
• PTH resistance
• Hungry bone syndrome: the rapid mineralization of bones following
parathyroidectomy.
5. Decreased bone resorption
• Low PTH
• PTH resistance
6. Increased urinary excretion of calcium

47. Markers of Bone Remodeling
• Formation markers
• Alkaline phosphatase
• Serum osteocalcin
• Procollagen type 1
• Resorption markers
• Carboxyterminal (ICTP,CTX) and amino-terminal (NTX) telopeptides of
collagen
• Tartarate-resistant acid phosphatase

48. BONE HEALTH
• Calcium and vitamin D are important
for bone health because they can:
– Help keep bones strong
– Prevent bones from breaking easily,
especially in the spine
• People who do not have healthy bones can develop
osteoporosis.
• Eating enough calcium and vitamin D is important in
preventing osteoporosis and reducing bone loss, thus
decreasing the risk of fractures.

49. CALCIUM SUPPLEMENTS
• Calcium carbonate
– Effective and least expensive
– Best absorbed with a low-iron meal
– May not be well absorbed in patients taking PPI
• Calcium citrate
– Well absorbed in fasting state as well as with a meal
• Calcium doses above 500 mg are not absorbed well, so large
doses of supplements should be taken in divided doses.
• Calcium supplements don’t replace other osteoporosis
treatments such as hormone replacement and

50. References
• Miller’s Review of Orthopaedics, 8th edition
• Apley & Solomon’s System of Orthopaedics and Trauma,
10th edition
• Guyton and Hall Textbook of Medical Physiology, 12th
edition
• Netter’s Concise Orthopaedic Anatomy 2nd Edition

51. Thank you