Lecture 9.1 - Calcium metabolism

Calcium in the Body

• An adult human contains approximately 1000g of calcium, with 99% of it stored in bones as hydroxyapatite crystals.
• The skeleton provides structural support, acts as a major reserve of calcium, helps buffer serum levels, and releases/uptakes calcium phosphate into/from the interstitium.
• Approximately 300-600mg of calcium is exchanged between bone and extracellular fluid (ECF) daily.

Plasma Calcium Levels

• Serum total calcium levels range from 2.2-2.6 mmol/L, with free ionized calcium levels closely regulated to 1.0-1.3 mmol/L.
• The biologically active free ionized calcium is distributed among three interconvertible fractions.
• Only a small fraction (<1%) of the total body calcium is present in ECF.

Regulation of Calcium and Phosphate

• Three hormones are involved in regulating calcium and phosphate levels: parathyroid hormone (PTH), calcitriol, and calcitonin.
• PTH is the main acute regulator of calcium, produced by the parathyroid glands, which are located on the posterior surface of the thyroid gland.

Parathyroid Hormone (PTH)

• PTH has no serum binding protein and is synthesized as a straight chain polypeptide hormone (pro-pre-hormone, 115AA long) that is cleaved to 84AA.
• PTH synthesis is regulated at both transcriptional and post-transcriptional levels, with low serum calcium levels up-regulating gene transcription and high serum calcium levels down-regulating it.
• PTH has a half-life of 4 minutes and is continually synthesized, but little is stored.

Calcium-Sensing Receptor (CaSR) and PTH

• The CaSR controls the release of PTH, which targets the kidney, gut, and bone, and has physiological effects on calcium levels.

Bone Remodeling and Calcium Balance

• The skeleton has two primary functions: providing structural support and maintaining serum calcium concentration, with the latter being the priority.
• Bone deposition involves osteoblasts producing collagen matrix, which is mineralized by hydroxyapatite, while bone reabsorption involves osteoclasts producing an acid microenvironment that dissolves hydroxyapatite.
• Bone is dynamic, with a two-step process of bone remodeling involving bone breakdown and reformation.

Actions of PTH on Bone

• PTH stimulates osteolysis by inducing osteoblastic cells to synthesize and secrete cytokines, which stimulate differentiation and activity in osteoclasts and protect them from apoptosis.
• PTH decreases osteoblast activity, exposing the bony surface to osteoclasts, leading to reabsorption of mineralized bone and release of Pi and Ca2+ into ECF.

Calcitriol (Vitamin D)

• Calcitriol is the hormonally active metabolite of vitamin D, produced from calcidiol in the kidney.
• Vitamin D is formed in the skin upon sunlight exposure, and dietary intake is typically 1000mg/d, with only 30% absorbed through a paracellular uptake.

Calcitriol's Actions on Bone, Gut, and Kidney

• Calcitriol stimulates the transcellular uptake of calcium from the gut, increases bone resorption, and decreases the loss of calcium in the urine.

Feedback Regulation of Serum Calcium

• Elevated calcium levels prevent C-1 hydroxylation, while PTH stimulates C-1 hydroxylation to form calcitriol.

Overview of Calcium Regulation

• Calcium regulation involves a feedback loop between serum calcium levels, PTH, and calcitriol.

Disorders of Calcium Balance

• Hypocalcaemia can lead to hyper-excitability of the neuromuscular junction, muscle spasms, paralysis, and convulsions.
• Chronic hypercalcaemia can cause renal calculi, kidney damage, constipation, dehydration, tiredness, and depression.
• Hypercalcaemia can also cause lethargy, depression, constipation, renal calculi, frequent urination, nausea, and cardiac arrhythmias.

Hypercalcaemia and Malignancy

• Some malignancies can alter calcium homeostasis indirectly via various endocrine factors.
• Hypercalcaemia is commonly seen in breast cancer, squamous cell lung cancer, myeloma, and genito-urinary cancers.