Bone Physiology and Metabolism

• The lecture covers bone growth and calcium homeostasis, focusing on the regulation of calcium ion concentration in extracellular fluid.
• Calcium homeostasis is influenced by dietary absorption, urinary excretion, and bone remodeling.
• Bones store 99% of the body's calcium, acting as a reservoir.
• Calcium levels impact conditions like osteoporosis and bone fractures.

Bone Physiology

• Bone serves as structural support, protects organs, provides muscle attachment sites, and acts as a mineral reservoir for calcium and phosphorus.
• Bones contain 99% of the body's calcium and 85% of its phosphorus.
• Normal calcium levels range from 8.5-10.5 mg/dL, while phosphorus levels range from 2.7-4.6 mg/dL.
• Cortical bone is dense, strong, and makes up 80% of bone mass.
• Trabecular bone is spongy, metabolically active, and found in vertebrae and long bone ends.
• Collagen provides flexibility, while minerals offer stiffness and strength, both crucial for preventing fractures.
• Bone strength depends on bone composition, mass, and microarchitecture.
• Peak bone strength occurs between ages 18 and 25.
• Modifiable factors include calcium/vitamin D levels, exercise, lifestyle, hormonal status, diseases, and medications.
• Bone mineral density (BMD) is a major indicator of fracture risk; a 10% decrease can increase fracture risk by 1.5 to 3 times.
• Bone loss occurs when bone resorption exceeds formation, starting in the 30s and 40s.
• Older adults experience accelerated remodeling and reduced bone formation, leading to bone loss.
• Bone strength is a better predictor of fracture risk than bone mineral density alone.

Bone Remodeling

• Bone remodeling continues throughout life, with approximately 1 to 2 million tiny bone sections remodeling at any given time.
• The goals of bone remodeling are to balance bone resorption and formation, maintain calcium levels, and strengthen bone.
• Remodeling is triggered by micro-damage repair, calcium homeostasis support, and impact exercises.
• Bone remodeling maintains normal serum calcium levels and replaces existing bone matrix with new bone matrix.

Key Players in Bone Remodeling

• Hematopoietic stem cells are precursors to osteoclasts.
• Mesenchymal stem cells are precursors to osteoblasts.
• Osteoclasts are bone-resorbing cells that break down bone.
• Osteoblasts are bone-forming cells that build bone.
• Osteocytes are former osteoblasts within the bone matrix that trigger remodeling.
• Lining cells trigger new remodeling cycles.
• RANKL, emitted by osteoblasts/osteocytes, stimulates osteoclast activation and bone adherence.
• OPG, emitted by osteoblasts, acts as a decoy to prevent bone resorption.

Steps of Bone Remodeling

• Initiation: Lining cells or osteocytes signal due to triggers such as microfractures or calcium needs.
• Osteoclast Differentiation: Osteoblasts emit cytokines, and hematopoietic stem cells differentiate into osteoclasts.
• Resorption: Activated osteoclasts begin bone resorption.
• Osteoblast Differentiation: Osteoclasts produce cytokines that elicit osteoblast differentiation from mesenchymal stem cells.
• Bone Formation: Mature osteoblasts inhibit osteoclast activity and form and mineralize the bone.
• Quiescence: Bone formation stops; osteoblasts become lining cells and osteocytes, entering a resting phase.

RANK, RANKL, and OPG

• RANK is a receptor on osteoclast surfaces.
• RANKL binds to RANK, promoting osteoclast formation, function, and survival.
• OPG binds to RANKL, preventing it from binding to RANK and inhibiting osteoclast formation and bone resorption.

Calcium Homeostasis and Hormones

• Vitamin D and parathyroid hormone maintain calcium in the extracellular fluid.
• Calcium absorption occurs in the gastrointestinal tract (30-35%) and renal system.
• Absorption decreases to 10-15% with low vitamin D levels.
• Vitamin D and parathyroid hormone increase plasma calcium levels, while calcitonin decreases them.

Vitamin D

• Sources include UV light absorption and plant/animal sources.
• Vitamin D2 (ergocalciferol) comes from plants, while Vitamin D3 (cholecalciferol) comes from animals.
• Parathyroid hormone stimulates vitamin D conversion to its active form, 1,25-dihydroxyvitamin D3 (calcitriol).
• Vitamin D levels are measured by assessing the precursor, 25-hydroxy vitamin D (calcidiol).
• Calcium absorption uses both a passive paracellular pathway (between cells) and an active pathway (through cells, influenced by calcitriol using calbindin transporter).

Kidney's Role in Calcium Homeostasis

• Inadequate calcitriol leads to decreased calcium absorption and hypocalcemia.
• Hypocalcemia stimulates secondary hyperparathyroidism, treated with vitamin D, calcium supplements, and cinacalcet.
• Cinacalcet inhibits parathyroid hormone secretion.
• Calcium reabsorption occurs in the proximal convoluted tubule (60-70%), thick ascending limb of loop of Henle (20%), and distal convoluted tubule/collecting duct (15%).
• About 98% of filtered calcium is reabsorbed by the kidneys.

Parathyroid Hormone

• Parathyroid hormone secretion is stimulated by hypocalcemia.
• Mechanisms to increase calcium levels include stimulating release from bone, decreasing urinary loss via kidney reabsorption, and indirectly stimulating absorption in the small intestine by stimulating vitamin D activation.
• Parathyroid glands are located at the dorsal side of the thyroid.
• Rapid effects include stimulating osteoblasts to pump calcium ions out of the fluid surrounding the bone.
• Activates bone resorption through osteoclasts.
• Stimulates osteoblasts to express a signaling molecule that activates osteoclasts.

Parathyroid Hormone Summary

• Released in response to low calcium levels.
• Moves calcium from bone into blood.
• Increases calcium uptake in the kidneys.
• Stimulates conversion of vitamin D to its active form.
• Increases calcium uptake in the GI tract.
• Ultimately increases plasma calcium levels.
• Responds to low extracellular calcium within minutes via calcium receptors.
• Indirectly activates osteoclasts by binding to osteoblasts.
• Promotes reabsorption of calcium in urine.
• Promotes activation of vitamin D in the kidney.

Calcitonin

• Produced by parafollicular cells of the thyroid gland in response to high blood calcium.
• Receptors are found in the bones and kidneys.
• Lowers circulating calcium and phosphate levels.
• Inhibits bone resorption by inhibiting osteoclast activity.
• Increases calcium excretion in urine.

Disorders of Bone and Calcium Homeostasis

• Hypocalcemia is low calcium levels below 8.5 mg/dL.
• Hypercalcemia is high calcium levels above 10.5 mg/dL.
• Osteogenesis imperfecta is a genetic disease with easy bone fractures.
• Paget's disease is a chronic disorder with enlarged, weakened bones.
• Primary/Secondary Hyperparathyroidism affects calcium regulation and bones.
• Renal osteodystrophy causes biochemical abnormalities and skeletal manifestations in chronic kidney disease.
• Rickets is softening of bones in children due to vitamin D deficiency.

Interpretation of Lab Results

• 99% of calcium is stored in bones and teeth; less than 1% is in extracellular fluid.
• Extracellular calcium is 50% ionized, 40% bound (90% to albumin), and 10% bound to other anions.
• Corrected calcium formula = measured serum calcium + 0.8 * (4 - serum albumin)
• Hypocalcemia causes: hypoparathyroidism, vitamin D deficiency, renal disease.
• Symptoms of hypocalcemia (CATS): convulsions, arrhythmias, tetany, stridor/spasms.
• Hypercalcemia causes: hyperparathyroidism, malignancy.
• Symptoms of hypercalcemia: painful bones, renal stones, abdominal groans, psychic moans, excessive thirst, frequent urination, nausea, vomiting, constipation, bone pain, muscle weakness, confusion, lethargy, fatigue.

Osteoporosis

• Skeletal disorder with compromised bone strength, predisposing to fracture.
• Risk factors include low bone mineral density, being female, advanced age, Asian heritage, history of fragility fracture, osteoporotic fracture in a first-degree relative, low BMI, premature menopause, chronic steroid use, tobacco/excessive alcohol use, low calcium/physical activity/vitamin D, recent falls, and cognitive/vision impairment.
• After menopause, estrogen deficiency leads to bone loss by increasing osteoclast activity.
• Age-related osteoporosis involves accelerated bone turnover and decreased osteoblast formation.
• Types of Osteoporosis in Men: Primary (age-related/senile or idiopathic) and Secondary (lifestyle, diseases, medications).
• Secondary Causes of Osteoporosis: Endocrine/hormonal, gastrointestinal, disorders of calcium balance, inflammatory disorders, chronic illnesses, genetic factors.
• Medications that decrease bone mineral density: Furosemide, anti-retroviral therapies, anti-convulsant therapies (phenytoin, carbamazepine), aromatase inhibitors, SGLT2 inhibitors (canagliflozin), Heparin, Medroxyprogesterone, and Proton pump inhibitors (PPIs).
• Bone mineral density is measured using a dual-energy X-ray absorptiometry (DXA) scan of hip and spine.
• Hip BMD is the single best predictor of hip fracture.
• T-score compares patient's BMD to a healthy 20-29 year old same-sex white referenced patient.
  • Above -1: Normal bone mass
  • -1 to -2.4: Osteopenia (pre-osteoporosis)
  • Below -2.5: Osteoporosis
• Risk of subsequent fracture is high after an initial vertebral fracture.

Pharmacist's Role

• Counsel on risk reduction.
• Encourage adequate daily intake of calcium and vitamin D.
• Advise on optimal calcium absorption (with food).
• Recommend calcium citrate for elderly or those taking antacids/PPIs.
• Provide guidelines for weight-bearing and muscle strength exercises.
• Offer strategies for fall prevention and balance training.
• Counsel on avoiding tobacco, smoking and excessive alcohol intake.
• Discuss bone health and a healthy diet.

Questions cover bone's energy absorption, calcium balance mechanisms, and the impact of metabolic changes on bone. Focus on bone remodeling, fracture risk factors, and kidney disease-related hypocalcemia. Biomarkers for bone resorption assessment are covered.