MS8 Medical Biochemistry
Spring 2025
Bone Health
Instructor: Dr. Sunil Kumar Boda
Assistant Professor
Department of Medical Science & Technology
IIT Madras
E-mail: sunilboda@iitm.ac.in; bsunilkumarpsn@gmail.com
Calcium Homeostasis
Calcium in ECF << Calcium in bone
Calcium in bone is not static. Some bone is resorbed each day
and the calcium returned to the ECF. To maintain calcium
balance, an equal amount of bone formation takes place.
Calcium homeostasis is modulated by hormones -
Parathyroid hormone (PTH) –
• PTH is secreted from the parathyroid glands in response to
a low unbound plasma calcium.
• PTH causes bone resorption and promotes calcium
resorption in the renal tubules, preventing loss in the
urine.
1,25-dihydroxycholecalciferol (1,25 DHCC)
• DHCC maintains intestinal calcium absorption.
• This sterol hormone is formed from vitamin D
(cholecalciferol), following hydroxylation in the liver and
kidney.
• But, hydroxylation in the kidney is PTH-dependent, and so Normal calcium balance:
even the absorption of calcium from the gut relies (albeit Calcium is exchanged each day, in the amounts shown, between
indirectly) on PTH. the extracellular fluid (ECF) and the gut, bone and kidney.
Calcium – Unbound/ ionized and protein-bound
Total serum calcium in a healthy person ~ 2.4 mmol/L
About half of serum calcium is bound to protein, mostly to albumin.
Calcium binding to albumin is pH-dependent i.e., it is decreased in acidosis
as albumin becomes positively charged and increased under alkalosis.
Unbound or free calcium is called ionized calcium.
This biologically active fraction of calcium in plasma is required for nerve
function, membrane permeability, muscle contraction and glandular
secretion.
Parathyroid hormone (PTH) keeps the unbound/ ionized calcium
concentration constant.
Lab tests routinely measure total calcium (bound + unbound) in serum.
If albumin ↓↓, then bound calcium ↓↓ and total calcium also ↓↓.
But, homeostatic mechanisms for regulating plasma calcium respond to
the unbound/ionised fraction, not to the total calcium.
The effect of parathyroid hormone (PTH) in restoring a low plasma calcium
to normal.
PTH also promotes renal tubular excretion of phosphate.
1,25 DHCC: 1,25-dihydroxycholecalciferol
Hypocalcemia
Hypocalcemic – low calcium in blood serum
Patients with a low albumin have low total serum calcium, yet have normal unbound/ionized calcium.
To circumvent this problem of labeling patients with low albumin as hypocalcaemic, ‘adjusted calcium’ is used.
‘Adjusted calcium’ measures total calcium and albumin and, if the albumin is abnormal (usually low), it calculates what the total
calcium would be if the albumin was normal.
𝐴𝑑𝑗𝑢𝑠𝑡𝑒𝑑 𝑐𝑎𝑙𝑐𝑖𝑢𝑚(𝑚𝑚𝑜𝑙/𝐿) = 𝑇𝑜𝑡𝑎𝑙 𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑 𝑐𝑎𝑙𝑐𝑖𝑢𝑚 + 0.02(47 − 𝐴𝑙𝑏𝑢𝑚𝑖𝑛)
Causes of Hypocalcemia –
• Vitamin D deficiency – malabsorption or low exposure to
sunlight can cause rickets in children and osteomalacia in
adults
• Hypoparathyroidism – autoimmune or postsurgical removal
• Magnesium deficiency – Mg2+ needed for PTH synthesis
• Renal disease - kidneys fail to synthesize 1,25 DHCC
• Hungry bone syndrome –post-operative fall in PTH
following parathyroidectomy
• Pseudohypoparathyroidism – end-organ resistance/ failure
of target tissue receptors to respond to secreted PTH
• Rare causes – acute pancreatitis, acute rhabdomyolysis,
ethylene glycol poisoning or bone marrow transplantation.
Hypocalcemia
Treatment -
• Oral calcium supplements (often in combination with
vitamin D) are prescribed for mild disorders.
• Hypoparathyroidism or severe renal disease requires more
potent forms of vitamin D – 1α-hydroxycholecalciferol, or
calcitriol.
Hypercalcemia
Hypercalcemia – high blood serum calcium concentration
Clinical features – renal calculi, cardiac arrhythmias, GI problems
(nausea, constipation, abdominal pain) neurological and psychiatric
features (depression, irritability, etc.)
Common causes –
• Primary Hyperparathyroidism – parathyroid hormone (PTH) is not responding to feedback control by plasma calcium
• Hypercalcemia associated with malignancy - some tumours secrete a protein called parathyroid hormone-related peptide
(PTHrP), which has PTH-like properties, causing hypercalcemia
Treatment of hypercalcemia of malignancy with palmidronate
Classic subperiosteal resorption in a patient with severe
• Hypercalcaemia (serum calcium > 3.5 mmol/L) inhibits
primary hyperparathyroidism. (A) Radiograph shows
proximal tubular reabsorption of sodium; as a result,
resorption in the phalanges. (B) Same finger 5 months after
patients are dehydrated due to loss of sodium and water.
removal of parathyroid adenoma.
• Parenteral bisphosphonates (zoledronic acid and
pamidronate) and denosumab have best calcium-lowering If hypercalcaemia is not detected early, the high circulating
effects and are used to treat hypercalcaemia of malignancy parathyroid hormone (PTH) causes a characteristic pattern of
• Diuretics to increase calcium excretion - not recommended bone resorption, known as osteitis fibrosa cystica.
Metabolic bone disease
Main metabolic bone diseases are:
• Osteoporosis – bone resorption → porous bone due to decreased
bone mass & density
• Osteomalacia and rickets –
➢ Vitamin D deficiency and limited light exposure lead to defective or
inadequate bone mineralization
➢ Vitamin D status can be assessed by measuring main circulating
metabolite, 25-hydroxycholecalciferol, in serum..
➢ Vitamin D deficiency causes serum calcium to fall, resulting in an
appropriate increase in parathyroid hormone (PTH) secretion
(secondary hyperparathyroidism). PTH increases renal excretion of
phosphate. Elevated serum alkaline phosphatase activity by
osteoblasts tries to compensate for the resulting bone loss.
➢ Patients usually present with muscle aches and bone pain, which Bone Remodeling
respond to high-dose vitamin D supplementation.
• Paget’s disease - common in the elderly and characterized by
increased osteoclastic activity → increased bone resorption.
Osteoblastic activity repairs resorbed bone, but the new bone is more
‘plastic’, i.e. malleable, than normal bone as it is laid down in a
disorganised way.
Serum alkaline phosphatase is very high, and urinary hydroxyproline
excretion is elevated. Bone biopsy showing normal (left) and osteomalacic bone (right)
Biochemical profiles in bone diseases
Disease Profile
Bone metastases • Calcium may be high, low or normal
• Phosphate may be high, low or normal
• Parathyroid hormone (PTH) is usually low
• Alkaline phosphatase (ALP) may be elevated or normal
Osteomalacia/rickets • Calcium will tend to be low or may be clearly decreased
• PTH will be elevated
• 25-hydroxycholecalciferol will be decreased if the disease
is due to vitamin D deficiency
Paget’s disease • Calcium is normal
• ALP is significantly elevated
Osteoporosis • Biochemistry is complex and unremarkable
Renal osteodystrophy • Calcium is decreased; phosphate is high
• PTH is very high
Primary • Calcium is elevated
hyperparathyroidism • Phosphate is low or normal
• PTH is increased, or clearly detectable and thus
‘inappropriate’ to the hypercalcaemia
Main steps of metabolism of vitamin D
PTH, parathyroid hormone
