Calcium, Phosphate, Magnesium and Bone Disease

Calcium, Phosphate, Magnesium and Bone Disease

• Calcium is the most abundant mineral in the body, and its functions include structural support, neuromuscular activity, enzymatic roles, and signaling.
• The vast majority (99%) of calcium is stored in bone. Only 1% is present in extracellular fluid (ECF).
• Calcium balance is maintained among bone, extracellular fluid, and the kidneys.
• Extracellular calcium is tightly controlled at 2.2-2.6 mmol/L.
• Plasma calcium exists primarily bound to albumin (45%), but the free, ionized form is biologically active. Binding to albumin is dependent on H+.
• Parathyroid hormone (PTH) regulates the free calcium concentration, ensuring homeostasis.
• Calcium binding to albumin decreases in acidosis and increases in alkalosis, thus affecting the level of free calcium.

Calcium/Albumin Binding

• Binding of calcium to albumin is dependent on the concentration of hydrogen ions ([H+]).
• In acidosis, albumin's binding to calcium decreases, increasing the free calcium concentration.
• In alkalosis, albumin's binding to calcium increases, decreasing the free calcium concentration.
• Free calcium is the biologically active form.

Which Calcium to Measure Clinically?

• Total calcium (bound and free) measurements are easy, cheap, and readily reproducible.
• However, albumin levels can alter total calcium measurements.
• Decreased albumin leads to decreased total calcium values.
• Albumin levels must be considered and measured alongside calcium to get a true picture.
• An adjusted calcium calculation can provide a more accurate value, factoring in albumin levels. Adjusted [Ca] (mmol/L) = (total measured calcium) + 0.02 (47 - albumin).

Parathyroid Glands

• Four parathyroid glands, located next to the thyroid gland, regulate calcium homeostasis, not calcium metabolism.
• Production of parathyroid hormone (PTH) is regulated by calcium binding to parathyroid chief cells.
• Calcium, magnesium, and phosphate levels all influence PTH levels.
• Normal calcium and low magnesium lead to mild increases in PTH.
• Low calcium and/or magnesium levels decrease PTH levels.
• High phosphate levels lead to decreased calcium and increased PTH.

Hormonal Regulation of Calcium

• Parathyroid hormone (PTH) regulates calcium levels primarily through bone resorption, renal calcium reabsorption, and Vitamin D activation.
• Parathyroid hormone (PTH) also stimulates vitamin D (1,25-dihydroxycholecalciferol). Vitamin D influences the absorption of calcium and phosphate.
• Vitamin D is crucial clinically as it plays a major role in calcium absorption and bone health.

Hypercalcemia

• Primary hyperparathyroidism, often caused by parathyroid adenomas, is among the most frequent causes.
• This condition stems from issues with responsiveness to calcium. PTH levels are elevated, regardless of calcium levels.
• Hypercalcemia of malignancy is also common, usually resulting from parathyroid hormone-related protein production by tumors, rather than PTH.
• Hypercalcemia causes problems in the nervous system, gut, kidneys and heart.

Primary Hyperparathyroidism

• Primary hyperparathyroidism arises from abnormalities such as adenomas, hyperplasia, or carcinomas in the parathyroid glands.
• A common occurrence in post-menopausal women, body attempts to regulate calcium levels by increasing PTH.
• PTHA is often not responsive to normal plasma calcium values.
• Symptoms such as muscle weakness, fatigue, bradycardia, and confusion may occur.

Hypercalcemia Associated with Malignancy

• Malignant tumors may secrete PTH-related peptide (PTHrP) which mimics the action of PTH.
• This results in elevated calcium and a decrease in phosphate levels.
• PTHrP is not detected by standard PTH assays.
• High levels of calcium may be excreted in the urine.
• Vitamin D metabolites may also be dysregulated.

Hypercalcemia - Clinical Features

• Hypercalcemia affects neurological functions, causing lethargy, confusion, and irritability.
• Gastrointestinal symptoms such as anorexia (loss of appetite), abdominal pain, nausea, vomiting, and constipation can also occur.
• Impaired renal function may also present with thirst, polyuria (increased frequency of urination), and renal calculi (kidney stones).
• Bone pain is also possible.
• Cardiac arrhythmias result from dysfunction in normal heart rate.

Hypercalcemia - Rare Causes

• Excessive vitamin D intake
• Medications, such as thiazide diuretics (excretion of sodium) are also causes.
• Granulomatous diseases can trigger vitamin D synthesis which causes hypercalcemia.
• Immobility (e.g., paraplegia) can lead to increased bone resorption resulting in hypercalcemia.
• Familial benign hypercalcemia is due to mutations in calcium-sensing receptors causing reduced receptor sensitivity and normal PTH levels with hypercalcemia.

Hypercalcemia - Treatment

• For total serum calcium over 3.5 mmol/L, intravenous saline is required to improve glomerular filtration rate.
• The loss of sodium and water is managed through proper hydration
• Parenteral bisphosphonates (e.g., zoledronic acid, pamidronate) are best for inducing calcium reduction by inhibiting osteoclast activity.

Hypocalcemia

• Causes of hypocalcemia often include renal disease, low albumin, Vitamin D deficiency, malnutrition, malabsorption, hypoparathyroidism, or magnesium deficiency.
• Hungry bone syndrome can occur after parathyroid removal due to rapid remineralization of bones. PTH is very low in this condition.

Hypocalcemia - Clinical Features

• Symptoms of hypocalcemia may include tingling and tetany in the body and mental changes.
• Cardiovascular disorders can arise, including hypotension and arrhythmias.

Hypocalcemia - Treatment

• Treatment strategy involves addressing the underlying cause of hypocalcemia.
• Oral calcium supplements (with vitamin D) are used for mild cases.
• For severe conditions, a more potent form of Vitamin D (e.g., calcitriol) is utilized, typically in cases of hypoparathyroidism, or severe renal disease.

Phosphate

• Phosphate is an abundant anion that is crucial for skeletal support, nucleic acid function, and enzymatic reactions.
• Most phosphate is found within bone, about 80%.
• Phosphate presence in extracellular fluid (ECF) is regulated by the kidney (excretion of phosphate).
• Phosphate and calcium have an inverse relationship.

Hyperphosphatemia

• Causes of elevated phosphate include renal failure, hypoparathyroidism, cell damage, or acidosis (buffering).

Hypophosphatemia

• Hyperparathyroidism, diabetic ketoacidosis (DKA) treatment (insulin and phosphate shift) , alkalosis (especially respiratory), 'hungry bone syndrome', and congenital renal phosphate reabsorption defects are possible causes of low phosphate.

Magnesium

• Magnesium is the second most abundant intracellular cation (~99%). Important for enzyme activity, glycolysis, and oxidative metabolism.
• Key interactions occur between Mg, K, and Calcium.
• Magnesium influences parathyroid hormone (PTH) secretion and action.

Magnesium Homeostasis

• Approximately 30% of dietary magnesium is absorbed in the small intestine and distributed to tissues.
• The kidneys play a large role in its regulation.
• Both hypermagnesemia (uncommon, often related to renal failure or antacids) and hypomagnesemia (more common) are possible.
• Symptoms mimicking hypocalcemia are possible in cases of hypomagnesemia.

Hypomagnesemia - Causes

• Nutritional inadequacy and gastrointestinal losses are common causes.
• Osmotic diuresis, prolonged diuretic use, prolonged nasogastric suction, and cytotoxic therapies (kidney magnesium reabsorption interference) can also contribute.
• Similarly, use of proton pump inhibitors can also cause issues with magnesium depletion.

Hypomagnesemia - Diagnosis

• Hypomagnesemia, diagnosed based on serum [Mg] below 0.7 mmol/L (often associated with intracellular depletion).
• Use serum [Mg] to properly assess levels.
• Various oral, intramuscular, and intravenous magnesium supplementation approaches are available.
• Oral magnesium supplementation can have diarrhea as a side effect.

Metabolic Bone Disease

• Metabolic bone diseases involve disorders of bone structure and function, sometimes even when calcium/phosphate levels are normal. - Examples include osteoporosis, osteomalacia, rickets, and Paget's disease.
• X-linked hypophosphatemia is also a metabolic bone disease.

Bone Turnover (Metabolism)

• Bone is constantly broken down and re-formed via osteoblasts and osteoclasts.
• Biochemical markers like urinary hydroxyproline, deoxypyridinoline, and alkaline phosphatase (ALP) assist in assessing disease and treatment outcomes.

Osteoporosis

• The most frequent bone disorder among the elderly, osteoporosis is characterized by low bone mineral density (BMD) and deterioration of bone tissue microarchitecture.
• Increased risk of fracture is a key feature.
• Age, menopause, genetics, diet, sedentary lifestyle, and prior fractures are common risk factors.

Osteoporosis - Diagnosis and Treatment

• Bone density measurement (bone scan crucial) is essential for diagnosing osteoporosis.
• Biochemical markers of bone turnover, while not routinely used for diagnosis, are helpful in guiding treatment decisions.
• Treatment often involves oral bisphosphonates to curb osteoclastic activity.

Osteomalacia and Rickets

• Issues with bone mineralization are the core features.
• Osteomalacia affects adults; rickets, children (deformities commonly present).
• Insufficient or defective vitamin D is often the culprit.
• Reduced sunlight exposure can cause this condition, as well as insufficient vitamin D consumption.
• Laboratory markers, like calcidiol, serum calcium, phosphate, PTH, and ALP levels, aid in diagnosis and monitoring of treatment.
• Muscle weakness and bone pain are common symptoms.

Paget's Disease of Bone

• Paget's disease is a condition characterized by increased osteoclastic activity in the elderly.
• The process involves increased/disorganized osteoblastic activity resulting in "plastic" bone, sometimes with deformities.
• Typically asymptomatic with no immediate disturbance to serum calcium levels.
• High levels of serum alkaline phosphatase (ALP) and urinary hydroxyproline are often observed.

X-Linked Hypophosphatemia (XLH)

• A rare genetic disorder involving excess phosphate excretion by the kidneys and diminished phosphate absorption from the intestines.
• Leads to low phosphate in the blood, impacting bone formation (rickets/osteomalacia), causing stunted growth, and potential bone and joint pain.
• Phosphate supplementation and active vitamin D medications help manage symptoms.

Calcium Disorders/Bone Disease - Biochemistry Testing

• Initial serum tests (calcium, albumin, phosphate, alkaline phosphatase – ALP) provide basic information.
• Follow-up testing (PTH, magnesium, vitamin D metabolites) will help diagnosis cause of irregularities
• Assessment of bone turnover via biochemical markers (deoxypyridinoline) further refines diagnosis and treatment monitoring.

Skeletal Muscle Disorders (Myopathies)

• Conditions affecting muscle strength or structure due to genetic factors, viral infections, drugs, trauma, and metabolic imbalances.

Rhabdomyolysis

• Rapid skeletal muscle breakdown resulting from various causes(medications, heatstroke, trauma, drug abuse).
• Myoglobin release into the bloodstream is problematic, causing acute kidney injury and potential electrolyte imbalances (hyperkalemia, hyperphosphatemia, hypocalcemia).

Rhabdomyolysis - Investigation and Treatment

• Rhabdomyolysis diagnosis is confirmed by high serum creatine kinase (CK).
• Further investigation includes blood tests for urea, electrolytes, and markers for possible causative factors (alcohol/drug use).
• Treatment involves cardiac monitoring and intervention to prevent potentially lethal electrolyte imbalances. Dialysis, if needed, is used to manage kidney dysfunction.

This quiz explores the critical roles of calcium, phosphate, and magnesium in bone health and disease. It covers calcium's functions, storage, and the impact of pH on calcium binding to albumin. Additionally, it highlights the regulation of calcium levels by parathyroid hormone and the balance among bone, kidneys, and extracellular fluid.