Calcium and Its Functions

Calcium

• Most abundant mineral in the body
• Plays structural, neuromuscular, enzymatic, and signaling roles
• 99% of calcium is found in bone, 1% in extracellular fluid (ECF)
• Calcium balance is maintained between bone, ECF, and kidneys
• Extracellular total calcium levels are tightly controlled: 2.2-2.6 mmol/L
• In plasma, calcium exists mainly bound to albumin (45%) and as free ionized calcium (55%)
• Free ionized calcium is biologically active and is regulated by parathyroid hormone (PTH)

Calcium/Albumin Binding is Dependent on H+

• Binding decreases in acidosis, leading to increased free calcium
• Binding increases in alkalosis, leading to decreased free calcium

Parathyroid Glands

• Four glands located near the thyroid gland
• Regulate calcium homeostasis but not metabolism
• Produce PTH which interacts with vitamin D to increase calcium levels
• Calcium, magnesium, and phosphate levels affect PTH levels:
  • Normal calcium levels, low magnesium: mild PTH stimulation
  • Decreased calcium and magnesium: decreased PTH
  • Increased phosphate levels: decreased calcium and increased PTH

Hypercalcemia

• Most common causes include primary hyperparathyroidism and hypercalcemia of malignancy

Primary Hyperparathyroidism

• Common endocrine disorder caused by adenomas, hyperplasia, and carcinomas
• Most common in postmenopausal women
• Often due to a parathyroid adenoma, resulting in increased PTH levels
• Hypercalcemia and hypophosphatemia occur
• Most individuals are asymptomatic due to calcium stability
• Symptoms include muscle weakness, fatigue, bradycardia, confusion, etc.

Hypercalcemia Associated with Malignancy

• Most common cause of hypercalcemia in hospitalized patients
• Usually due to PTH-related protein (PTHrP) production by a tumor
• PTH is often undetectable in laboratory tests
• Other abnormal lab findings: very low phosphate, very high urine calcium, and low vitamin D
• Clinical features include neurological, gastrointestinal, renal, cardiac, and bone symptoms

Hypercalcemia - Rare Causes

• Calcium therapy
• Excess vitamin D ingestion
• Thiazide diuretics (Excretion of sodium)
• Granulomatous diseases (synthesis of vit. D)

Phosphate

• Abundant anion in the body
• Important component of nucleic acids, mineral strength, and buffer
• Plays key roles in phosphorylation and dephosphorylation of enzymes
• 80% of phosphate is found in bone
• Concentrations in ECF are controlled by the kidneys, with increased excretion by PTH

Hyperphosphatemia

• Increased phosphate concentrations
• Most common cause is renal failure
• Other causes: hypoparathyroidism, cell damage (redistribution), acidosis (buffer), and pseudohypoparathyroidism (genetic disorder causing resistance to PTH)

Hypophosphatemia

• Important for enzyme activation, glycolysis, oxidative metabolism, and transmembrane transport of K+ and Ca+2
• Influences secretion and action of PTH
• Severe hypomagnesemia can lead to hypoparathyroidism and refractory hypocalcemia

Magnesium Homeostasis

• Around 30% of dietary magnesium is absorbed in the small intestine and distributed to tissues
• Largely controlled by the kidneys
• Hypermagnesemia is uncommon, often associated with renal failure or antiacid use
• Hypomagnesemia (magnesium deficiency in serum) has symptoms similar to hypocalcemia, including impaired neuromuscular function and muscle weakness

Hypomagnesemia - Causes

• Commonly associated with nutritional insufficiency
• Other causes: osmotic diuresis, prolonged diuretic use, nasogastric suction, cytotoxic therapy, and proton pump inhibitors

Hypomagnesemia - Diagnosis and Treatment

• Repeated magnesium levels below 0.7 mmol/L indicate intracellular depletion
• Supplementation is available in oral, intramuscular, and intravenous forms
• Oral supplementation often leads to diarrhea
• Parenteral supplementation is necessary in patients with diarrhea or malabsorption

Metabolic Bone Disease

• Disorders of bone structure and function
• Calcium and phosphate levels may be normal, and hypercalcemia or hypocalcemia may not be associated with marked bone changes
• Main types: osteoporosis, osteomalacia/rickets, Paget's disease, and X-linked hypophosphatemia (XLH)

Bone Turnover (metabolism)

• Bone is constantly broken down and reformed (bone remodeling) by osteoblasts and osteoclasts
• Biochemical markers help assess disease and monitor treatment:
  • Urinary hydroxyproline (collagen breakdown)
  • Deoxypyridinoline (specific collagen product)
  • Alkaline phosphatase (ALP)
  • Osteocalcin (sensitive indicator of osteoblastic activity)

Osteoporosis

• Most common bone disorder
• Major cause of morbidity and mortality in the elderly
• Bone turnover favors resorption
• Characterized by low bone mineral density (BMD) and deterioration of bone microarchitecture
• Increased susceptibility to fracture

Osteoporosis - Risk Factors

• Non-modifiable: age, menopause, family history, genetic factors
• Modifiable: diet, smoking, sedentary lifestyle, previous fracture, sex hormone deficiencies, alcohol, immobility

Osteoporosis - Diagnosis and Treatment

• Clinical history and risk factor assessment
• Bone density measurement (bone scan) is essential for diagnosis
• Treatment includes oral bisphosphonates to inhibit osteoclastic function

Osteomalacia and Rickets

• Defective or inadequate bone mineralization
• Osteomalacia affects adults, while rickets affects children (deformities in growing bones)
• Primarily due to vitamin D deficiency (inadequate ingestion or sun exposure)

Osteomalacia and Rickets - Laboratory Considerations

• Low serum calcium
• Increased PTH
• Increased renal phosphate excretion
• Low serum phosphate
• Increased serum ALP
• Symptoms include muscle aches and bone pain

Paget’s Disease of Bone

• Increased osteoclastic and osteoblastic activity (disorganized)
• Common in the elderly
• Causes may be viral or genetic
• Often asymptomatic

Paget’s Disease of Bone - Laboratory Considerations

• No disturbance in serum calcium levels
• Very high serum ALP
• Elevated urinary hydroxyproline

X-Linked Hypophosphatemia (XLH)

• Rare genetic disorder
• Excess phosphate excretion by kidneys
• Decreased phosphate absorption in intestines
• Low phosphate levels in serum

X-Linked Hypophosphatemia (XLH) - Consequences

• Rickets, osteomalacia, short stature, bone/joint pain, and dental problems
• Treatment includes phosphate and active vitamin D supplementation

Calcium Disorders or Bone Disease - Biochemistry Testing

• First line serum tests: calcium, albumin, phosphate, ALP
• Follow-up tests: PTH, magnesium, 25-hydroxycholecalciferol, urine calcium excretion, specific markers of bone turnover

Skeletal Muscle Disorders (Myopathies)

• Conditions leading to muscle weakness or atrophy
• Causes: congenital (muscular dystrophies), infections, anoxia, toxins, drugs, muscle denervation, lack of energy molecules, severe electrolyte imbalance
• Severe damage to muscle cells leads to rhabdomyolysis, releasing myoglobin and creatine kinase (CK)

Rhabdomyolysis

• Rapid destruction of skeletal muscle cells, often due to injury
• Releases large quantities of myoglobin, which can be toxic to the kidneys
• Causes: medications, heatstroke, alcohol & drug use
• Symptoms: muscle weakness, muscle pain, dark urine
• Complications: renal failure, disseminated intravascular coagulation, electrolyte abnormalities (hyperkalemia, hyperphosphatemia, and hypocalcemia)

Rhabdomyolysis - Investigation and Treatment

• Increased serum total CK levels
• Monitoring of urea, electrolytes, alcohol and drug of abuse
• Treatment: cardiac monitoring, electrolyte correction, hemodialysis