IN THE NAME OF GOD
Calcium and bone metabolism
Types of bones
Cortical (75%) Trabecular (25%)
• Outer layer • Surrounded by cortical
• Compact and dense layer
• Has layers of • Spongy
mineralized collagen, • Mostly in axial skeleton
mainly in long bones of (vertebrae & pelvic
the limbs. region) -More active
metabolically
• More rapidly depleted
of Ca in Ca deficiency
Bone: a dynamic tissue
Bone is constantly made and reabsorbed
(life long process).
• This involves several types of bone cells.
• “Osteoblast” secrete collagen to form
“matrix”. This matrix becomes
“calcified” with time.
• “Osteoblast” activity is affected by
PTH, calcitriol and estrogen among
other hormones
Osteoblast lineage
“Osteoclast” are the other type of bone
cells.
• These “resorb” previously formed
bone.
• Osteoclast respond to hormones PTH,
calcitonin, and calcitriol.
• “Osteoclast” help to maintain normal
blood Ca levels when Ca intake is low.
Calcium
• Ca is the most abundant cation of the
body, approximately 1 kg in a 70 kg man.
• 99% of calcium found in the body is in
bones and teeth.
• The other 1% of body’s calcium is
distributed between extracellular fluids and
various soft tissues.
Food Sources:
• Milk and milk products
• Dark green leafy vegetables
• Tofu and sardines with bones
Absorbtion of Ca
• Trans cellular: primarily in the
duodenum and proximal juejenomis
energy requiring, and regulated by
vitamin D.
• Para cellular:The other process is non-
saturable and inactive, calcium is
absorbed between cells rather than
through them.
Dietary Factors Affecting Ca
Absorption Enhancers:
• Acidic medium
• Lactose
• Vitamin D
• Need for Ca
• Animal Proteins
Inhibitors:
• Fiber and phytate (also bind Fe and Zn)
• Non-fermentable fibers: Cellulose
•
• Oxalate : chelates calcium (spinach)
• Magnesium : competes with calcium for absorption
• Phosphorus
• Unabsorbed fatty acids : can interfere with calcium
absorption.
• The absorption in adult averages
approximately 30% (20-50%).
• Absorption is more efficient if the
intake of calcium is < 200 mg/day.
• The efficiency of Ca absorption also
depends on the “physiological state”:
Increase absorption:
• Children absorb up to 75% dietary Ca.
• Pregnancy and lactation increase Ca
absorption (approximately a 50%
increase).
• Decrease absorption:
• With age, vitamin D regulated Ca
absorption decreases due to decreased
efficiency in the calcitriol production in
response to PTH.
• Estrogen deficiency at menopause
also decreases vitamin D mediated Ca
absorption
Calcium transportation in
the blood :
• Free (ionized) calcium (50%). This is
the functional calcium.
• Bound to proteins, mainly albumin
(40%)
• Complexed with sulfate, citrate or
phosphate (10%)
Calcium Functions
• Bone Mineralization:
99% of total Ca is in bones and teeth.
60 - 66 % of bone weight is due to
minerals, as hydroxyapatite and
calcium phosphate.
Other Roles of Calcium
• Approximately 1 % of Ca++ is in:
• intracellular space and
• “extracellularly” in blood plasma.
• In plasma:
• Only ionized calcium (Ca2+) is active,
thus various functions of Ca are
performed by less than 1/2 of 1% of
total body Ca.
Intracellular Calcium:
• Ionized “intracellular”
• calcium is maintained at a very low concentration
of 100 mmol/L (0.0001 of the concentration of
extracellular fluids).
• The concentration of intracellular calcium is
tightly regulated
Role of Plasma and intracellular
Ca
• It is essential for:
• Blood clotting (with vitamin K)
• Nerve conduction
• Muscle contraction
• Enzyme regulation
• Cofactor for many enzymes,
e.g.,pyruvate kinase, glycogen
synthase
Regulation of Calcium
Concentrations
Calcium concentration is regulated both
“intra” and “extracellularly”.
Three hormones are involved in Ca
homeostasis:
• PTH
• calcitonin
• calcitriol (1,25 (OH)2D3)
PTH
increases extracellular plasma Ca
concentration by:
• Increasing resorption of Ca from the bones.
• Increases “resorption” of Ca by the kidney, and
decrease renal loss
• Increasing the rate of calcitriol formation in the
kidney.
• Low Ca concentration in plasma stimulate
PTH secretion.
Calcitriol
• Increases absorption of Ca
from the G.I tract.
Calcitonin
• Decreases the blood calcium concentration by
inhibiting osteoclast activity and by decreased
Ca mobilization from the bones.
PHOSPHORUS
• 85% of the 600 g of body phosphorus is present
in bone mineral,
• phosphorus is also a major intracellular
constituent, both as the free anion(s) and as a
component of numerous organophosphate
compounds including structural proteins,
enzymes, transcription factors,carbohydrate and
lipid intermediates,
• high-energy stores (ATP,creatine phosphate),
and nucleic acids.
Regulation of P
Concentrations
• PTH
• Calcitriol
PTH
• PTH is the major known hormonal
regulator of renal phosphate excretion
• PTH increases renal phosphate excretion
• The proximal tubule is the principal site at
which renal phosphate reabsorption is
regulated.
Calcitriol
• Promotes P absorption from the intestine
and kidneys.
• Low serum phosphate directly stimulates
renal proximal tubular synthesis of
1,25(OH)2D.
Parathyroid hormone (PTH)
• A peptide hormone
from the
parathyroid glands.
• There are usually 4
of these,
associated with
thyroid gland.
PTH secretion:
• Stimulated directly by low plasma calcium
• Inhibited by high plasma calcium
Effects of PTH
• Increase serum Ca concentration
• Decrease serum P concentration
Renal effects:
• stimulates calcium resorption
• causes increased phosphate excretion
• increases production of 1,25(OH)2 vit d
Bone effects
• stimulates bone resorption
• Inhibition of osteoblasts
• Release of osteoclast activating factor
so PTH increases resorption and slows
building
PTHrp
Parathyroid hormone-related protein (PTHrP) is
a proteinaceous hormone and a member of
the parathyroid hormone family
secreted by mesenchymal stem cells.such
as brain, pancreas, heart, lung, mammary tissue,
placenta, endothelial cells, and smooth muscle.
• It is occasionally secreted by cancer cells
(for example, breast cancer, certain types
of lung cancer including squamous-cell
lung carcinoma).
• However, it also has normal functions
in bone, teeth, vascular tissues and other
tissues.
VITAMIN D
Sources of Vitamin D3
• SKIN
• Action of sunlight (ultraviolet light)
converts 7-dehydrocholesterol to vitamin
D3
• DIET
• Vitamin D3 is found in fish and eggs. In
some countriese, it is added to margarine
or oil.
Vitamin D3
Vitamin D3 is inactive
two hydroxylation reactions is needed to
activate Vitamin D3
• The first reaction is in the liver: not
regulated.
• The second reaction is in the kidneys, by 1
alpha hydroxylase enzyme that is
regulated by PTH.
Actions of calcitriol
• Increases absorbance of dietary
calcium and phosphate.
• In bone increases number of
osteoclasts.
Raises plasma calcium & P
Calcitonin
• Made in parafollicular cells of thyroid
• Acts to lower plasma calcium by inhibiting
osteoclasts and increasing calcium
excretion in urine.
• Stimulated by high plasma calcium
• Patients with excess of calcitonin have
normal plasma calcium and normal bone
structure.
• Patients with no calcitonin also have no
symptoms
Summary 1
If plasma calcium is high
PTH secretion decreases so:
• Less activation of vitamin D3 and less
uptake of calcium from gut
• Bone resorption inhibited so more bone
building happens
• Less Ca resorption in kidney so excess
calcium is lost in urine.
Summary 2
If plasma calcium is low:
PTH increases so:
• Less Ca lost in urine
• More D3 activated so more Ca
absorbed in gut
• Bone resorption stimulated
Disorders of parathyroid hormone
• 1. Hypoparathyroidism
• Uncommon but very serious.
• Leads rapidly to hypocalcaemia, tetany
and death
• 2. Hyperparathyroidism
• Primary: tumour of parathyroid
• Secondary: hypersecretion to compensate
for chronically low serum calcium
- Hypercalcaemia
- Renal calculi (kidney stones)
- Bone disease
Causes of Impaired
Vitamin D Action
Vitamin D deficiency
➢Impaired cutaneous production
➢Dietary absence
➢Malabsorption
Accelerated loss of vitamin D
➢Increased metabolism
(barbiturates,phenytoin, rifampin)
➢Impaired enterohepatic circulation
Impaired 25-hydroxylation
➢Liver disease
➢ Isoniazid
Impaired 1-hydroxylation
Hypoparathyroidism
➢Renal failure
➢Ketoconazole
➢1-hydroxylase mutation
➢Oncogenic osteomalacia
➢X-linked hypophosphatemic rickets
Target organ resistance
➢Vitamin D receptor mutation
➢ Phenytoin
Clinical finding
• Mild to moderate vitamin D deficiency is
asymptomatic
• whereas long-standing vitamin D
deficiency results in hypocalcemia
• secondary hyperparathyroidism
• impaired mineralization of the skeleton
(osteopenia on x-ray or decreased bone
mineral density)
• proximal myopathy.
DIAGNOSIS OF VITAMIN D
DEFICIENCY, RICKETS, AND
OSTEOMALACIA
The most specific screening test for vitamin
D deficiency in otherwise healthy
individuals is a serum 25(OH)D level. (<15
ng/mL)
