Calcium, Phosphate, and Magnesium in Bone Disease Lecture PDF

Calcium, phosphate, magnesium and bone disease Pixabay.com Calcium 1. Functions of Calcium The most abundant mineral in the body Structural Neuromuscular Enzymatic Signaling Pixabay.com 1.1 Forms of Calcium Vast majority (...

Calcium, phosphate, magnesium and bone disease Pixabay.com Calcium 1. Functions of Calcium The most abundant mineral in the body Structural Neuromuscular Enzymatic Signaling Pixabay.com 1.1 Forms of Calcium Vast majority (99%) found in bone 1% in ECF Calcium balance is maintained between the bone, extracellular fluid and the kidneys Extracellular total [Ca] is tightly controlled: 2.2-2.6 mmol/L In plasma (1%) exists mostly: Bound to albumin (45%) Binding is H+ dependent Ionized (free) – biologically active Parathyroid hormone (PTH) keeps free [Ca] constant - homeostasis 1.2 Calcium/Albumin Binding is Dependent on [H+] Binding decreases in acidosis Increased free [Ca] Binding increases in alkalosis Decreased free [Ca] ❖Free calcium is the active form Pixabay.com 1.3 Which Calcium to Measure in Clinical Situations? Total calcium (bound + free) measurement in serum Easy, cheap and reproducible Changes in [albumin] can change the total [Ca] Decreased albumin, decreased total [Ca] Albumin must be measured when [Ca] is measured Pixabay.com Patients with a low albumin have total serum calcium lower than the reference values, yet have normal unbound/ionized calcium “Adjusted calcium” is utilized In cases in which albumin is low Calculate what total [Ca] would be if albumin was normal Adjusted [Ca] (mmol/L)= total measured calcium + 0.02 (47 – albumin) 1.4 Parathyroid Glands Four glands (2-6) adjacent the thyroid gland Affect calcium homeostasis but not metabolism Produce PTH (interacts with vitamin D) to increase calcium levels Regulation occurs by calcium binding to parathyroid chief cells Calcium, magnesium and phosphate levels affect PTH levels Normal calcium levels, low magnesium – mildly PTH stimulation Decreased calcium and magnesium – decreased PTH Increased phosphate levels lead to decreased calcium- increased PTH 1.5 Hormonal Regulation of Calcium Review Question: How does PTH regulate calcium? Why is clinically important to measure vitamin D? Disorders of Calcium Hypercalcemia 1.6 Hypercalcemia The most common causes include: ❖Primary hyperparathyroidism ❖Hypercalcemia of malignancy 1.6.1 Primary Hyperparathyroidism Common endocrine disorder that is caused by adenomas, hyperplasia, and carcinomas Most common in post menopausal women Body attempts to regulate calcium levels Often due to a parathyroid adenoma Increased PTH levels – not responsive to plasma calcium levels Hypercalcemia and hypophosphatemia occur Most individuals with primary hyperparathyroidism are asymptomatic Calcium stability Symptoms: muscle weakness, fatigue, bradycardia, confusion, etc. 1.6.2 Hypercalcemia Associated with Malignancy The most common cause of hypercalcemia in a hospital population Usually due to PTH related protein (PTHrP) production by a tumour Homology with PTH Not detected in PTH assay Abnormal laboratory tests: PTH typically undetectable Phosphate very low Urine calcium very high (hypercalciuria) Vitamin D low Calcidiol to calcitriol conversion dysregulated Pixabay.com ❖ Hypercalcemia – Clinical features Neurological and psychiatric features Lethargy, confusion, irritability, depression Gastrointestinal problems Anorexia, abdominal pain, nausea, vomiting, constipation Renal features Thirst, polyuria, renal calculi Bone pain Pixabay.com Cardiac arrythmias Pixabay.com ❖ Hypercalcemia – Rare Causes Calcium therapy Excess of vitamin D ingestion Thiazide diuretics (Excretion of sodium) Granulomatous diseases (synthesis of vit. D) Immobilization (paraplegia-increased bone resorption) Familial benign hypercalcemia (FBH) Genetic mutations in calcium-sensing receptor Pixabay.com Reduced receptor sensitivity Normal PTH levels with hypercalcemia ❖ Hypercalcemia - Treatment Urgent when total serum [Ca] > 3.5 mmol/L Intravenous saline to restore glomerular filtration rate Pixabay.com Hypercalcemia inhibits reabsorption of sodium Loss of sodium, loss of water Parenteral bisphosphonates (zoledronic acid and pamidronate) Best calcium-lowering effects (inhibit osteoclast activity) Treatment of choice in patients with hypercalcemia of malignancy Hypocalcemia 1.7 Hypocalcemia Causes include: Renal disease and low albumin (90% of cases) Vitamin D deficiency Malnutrition, malabsorption Hypoparathyroidism Magnesium deficiency “Hungry bone” syndrome Follows parathyroidectomy for severe hyperparathyroidism Followed by rapid remineralization of bone (low PTH) ❖ Hypocalcemia – Clinical Features Neurologic features Tingling, tetany, and mental changes Cardiovascular disorders Hypotension, arrhythmias Test for neuromuscular irritability -muscle spasm/cramps ❖ Hypocalcemia - Treatment Treat the cause of hypocalcemia Oral calcium supplements (often combined with Vitamin D) Mild disorders Calcitriol (more potent form of vitamin D) Hypoparathyroidism or severe renal disease Pixabay.com Essential Minerals: Phosphate and Magnesium 2. Phosphate Abundant anion in body (intracellular and extracellular anion) Mineral strength, component of nucleic acid, buffer Important in phosphorylation and dephosphorylation of enzymes Much phosphate is in bone (around 80%) Changes accompany calcium deposition or resorption of bone Phosphate concentration in ECF is controlled by the kidney Increased excretion by PTH Inverse relationship with calcium 2.1 Hyperphosphatemia Increased concentrates of phosphate Causes Renal failure (most common) Hypoparathyroidism Redistribution (cell damage) Acidosis (buffer) Pseudohypoparathyroidism Genetic disorder Tissue resistance to PTH 2.2 Hypophosphatemia Severe hypophosphatemia (99%) Important sources Important for enzyme activation, glycolysis, oxidative metabolism, and transmembrane transport of K+ and Ca+2 Important interactions exist among Mg+2, K+ and Ca+2 Influences the secretion and action of PTH Severe hypomagnesemia ✓It may lead to hypoparathyroidism ✓Refractory hypocalcemia ✓Unresponsive to medical interventions (PTH is low) 3.1 Magnesium Homeostasis Around 30% of dietary magnesium is absorbed in the small intestine and distributed to tissues Largely controlled by the kidneys Hypermagnesemia – Uncommon (renal failure, antiacids) Hypomagnesemia – Magnesium deficiency in serum Symptoms similar to hypocalcemia Impaired neuromuscular function Muscle weakness Tremor 3.2 Hypomagnesemia – Causes Commonly associated with nutritional insufficiency NVD and intestinal losses Other causes Osmotic diuresis Prolonged use of diuretics Prolonged nasogastric suction Cytotoxic therapy (impairs kidney reabsorption of Mg+2) Use of proton pump inhibitors 3.3 Hypomagnesemia – Diagnosis Repeated [Mg] less than 0.7 mmol/L = intracellular depletion Measurement in serum or plasma (RI: 0.70 - 1.00 mmol/L ) A variety of oral, intramuscular and intravenous supplementation regimens have been proposed Oral supplementation of magnesium salts usually lead to diarrhea Administration of magnesium salt is contraindicated in cases of significant renal impairment Patients with established diarrhea and malabsorption, a parenteral supplementation 4. Metabolic Bone Disease Disorders of bone structure and/or function Calcium (and phosphate) levels may be normal Hypercalcemia or hypocalcemia may not be associated with marked bone changes Main metabolic bone diseases: Osteoporosis Osteomalacia and rickets Paget’s disease X- linked hypophosphatemia (XLH) Pixabay.com 4.1 Bone Turnover (metabolism) Bone is constantly broken down and re-formed (bone remodeling) Osteoblasts and osteoclasts Biochemical markers may help assessment of disease extension and treatment monitoring Urinary hydroxyproline (breakdown of collagen) Gelatine consumption makes it unreliable Deoxypyridinoline (collagen product; specific to bone) Alkaline phosphatase (ALP) – commonly utilized Increased with increased activity of osteoblasts Not specific to bone Osteocalcin (sensitive indicator of osteoblastic activity) Synthesized by osteoblasts Some is found in plasma  4.2 Osteoporosis The most common bone disorder Major cause of morbidity and mortality in the elderly Bone turnover is disturbed in favour of resorption Characteristics: Low bone mineral density (BMD) Deterioration of the microarchitecture of bone tissue Increased susceptibility to fracture Risk factors: Age and menopause (non modifiable risk factors) Family history Genetic factors Sex hormone deficiencies Diet Smoking Sedentary life style Previous fracture Alcohol Immobility 4.3 Osteoporosis – Diagnosis and Treatment Clinical history Risk factors Measurement of bone density (bone scan) Essential for diagnosis Biochemical markers of bone turnover Limited used in osteoporosis Help select and monitor treatment Treatment Oral bisphosphonates Pixabay.com Inhibit osteoclastic function 4.4 Osteomalacia and Rickets Defective/inadequate bone mineralization Osteomalacia- adults Rickets- children (deformities in growing bones) Primarily due to vitamin D deficiency Inadequate ingestion of vitamin D Limited exposure to sunlight Laboratory considerations Serum 25-hydroxycholecalciferol (calcidiol) Severe osteomalacia ✓ Low serum calcium ✓ Increase in PTH ✓ Increase in renal excretion of phosphate ✓ Low serum phosphate ✓ Increase serum ALP Symptoms : muscle aches and bone pain 4.5 Paget’s Disease of Bone Increased osteoclastic activity Common in the elderly Increased osteoblastic activity (disorganized) ✓ “plastic” bone, deformities Causes Viral, genetics? Commonly asymptomatic Laboratory considerations No disturbance in serum calcium levels Serum ALP- very high Urinary hydroxyproline - elevated Pixabay.com 4.6 X-Linked Hypophosphatemia (XLH) Rare genetic disorder Excess phosphate excretion by kidneys Decreased absorption of phosphate in intestines Low levels of phosphate in serum Pixabay.com Consequences: Rickets, osteomalacia, short stature, bone and joint pain, dental problems Treatment Phosphate and active vitamin D (calcitriol) supplementation ❖ Calcium Disorders or Bone Disease – Biochemistry testing ❖First-line tests in serum: Calcium Albumin Phosphate ALP ❖Follow-up tests: PTH Magnesium 25-hydroxycholecalciferol Urine calcium excretion Specific markers of bone turnover (e.g., deoxypyridinoline) Skeletal Muscle Disorders 5. Skeletal Muscle Disorders (Myopathies) Conditions that lead to muscle weakness/atrophy Causes Congenital (muscular dystrophies) Infections Damage due to anoxia, toxins or drugs Muscle denervation Lack of energy-producing molecules Severe electrolyte imbalance Severe damage to muscle cells lead to leaking of contents (rhabdomyolysis) Myoglobin Creatine kinase (CK) 5.1 Rhabdomyolysis Rapid destruction of skeletal muscle cells often as a result of muscle injury Release of large quantities of myoglobin It may be toxic (lead to AKI) Causes Medications Heatstroke Alcohol and drug use Symptoms Muscle weakness, muscle pain, and dark urine Pixabay.com Complications Renal failure and disseminated intravascular coagulation (widespread blood clotting) Electrolyte abnormalities (due to damaged cells) Hyperkalemia, hyperphosphatemia and hypocalcemia ❖ Rhabdomyolysis – Investigation and Treatment Increased serum total CK levels (very high) Investigation and monitoring Urea and electrolytes Screens for alcohol and drugs of abuse Urine or plasma myoglobin? Limited usefulness Too sensitive marker ❖Treatment Pixabay.com Cardiac monitoring Control of hyperkalemia, hyperphosphatemia and hypocalcemia Hemodialysis