Bone Growth and Calcium Homeostasis

Bone Growth and Calcium Homeostasis

• Calcium homeostasis is the regulation of calcium ion concentration in extracellular fluid.
• Factors influencing calcium levels are absorption from diet, excretion in urine, and bone remodeling.
• Bones store 99% of body's calcium, acting as a reservoir.
• Calcium levels affect osteoporosis and fractures.

Bone Physiology

• Bone is dynamic and multifunctional tissue, supporting structure, protecting organs, and serving as a mineral reservoir (calcium and phosphorus).
• 99% of calcium and 85% of phosphorus are in bones.
• Calcium: 8.5-10.5 mg/dL; Phosphorus: 2.7-4.6 mg/dL (extracellular measurements).
• Two types of bone:
  • Cortical bone: Dense, strong, stiff (80% bone mass); found in long bones.
  • Trabecular bone: Spongy, metabolically active; found in vertebrae and ends of long bones.
• Bone composition: Collagen (flexibility, absorption) and minerals (stiffness, strength) are both crucial for preventing fractures.
• Peak bone strength is 18-25 years old.
• Modifiable factors affecting strength: calcium/vitamin D, exercise, lifestyle (smoking), hormonal status, diseases, medications.
• Bone mineral density (BMD) predicts fracture risk; 10% bone mass decrease = 1.5-3x fracture risk.
• Bone loss occurs when resorption exceeds formation, beginning in the 30s/40s, increasingly in older adults due to accelerated remodeling and reduced formation.
• Bone strength is a better fracture predictor than BMD.

Bone Remodeling

• Ongoing throughout life, approximately 1-2 million tiny bone sections are remodeling simultaneously.
• Goal: balance resorption and formation to maintain calcium levels and bone strength.
• Triggers for remodeling: micro-damage repair, calcium homeostasis support, impact exercise.
• Goals of remodeling: maintain serum calcium via bone calcium release, replace existing matrix.
• Lower bone mass when resorption exceeds formation.

Bone Remodeling Players

• Hematopoietic stem cell: precursor to osteoclasts
• Mesenchymal stem cell: precursor to osteoblasts
• Osteoclast: resorbs bone
• Osteoblast: forms bone
• Osteocyte: communicates; former osteoblast within matrix; initiates remodeling
• Lining cells: trigger new remodeling
• RANKL: osteoblast/osteocyte cytokine; stimulates osteoclast activity and bone adherence
• OPG: osteoblast cytokine; acts as a decoy to prevent resorption

Steps of Bone Remodeling

• Initiation: Lining cells/osteocytes signal (e.g., microfractures, calcium needs).
• Osteoclast differentiation: Osteoblasts release cytokines; hematopoietic stem cells become mature osteoclasts.
• Resorption: Activated osteoclasts break down bone.
• Osteoblast differentiation: Osteoclasts' cytokines stimulate osteoblast differentiation from mesenchymal stem cells.
• Bone formation: Mature osteoblasts inhibit osteoclasts; build/mineralize bone.
• Quiescence: Formation stops; osteoblasts become lining cells/osteocytes, awaiting signals.

RANK, RANKL, and OPG

• RANK: Receptor on osteoclast surfaces
• RANKL: Protein binding RANK; promotes osteoclast formation/function/survival
• OPG: Decoy; binds RANKL; prevents RANKL-RANK binding; prevents osteoclast formation and bone resorption.

Calcium Homeostasis and Hormones

• Calcium homeostasis regulated by vitamin D, parathyroid hormone (PTH), and calcitonin.
• Calcium absorbed in GI tract (30-35%; 10-15% with low vitamin D).
• Vitamin D: Increases plasma calcium
• PTH: Increases plasma calcium
• Calcitonin: Decreases plasma calcium

Vitamin D

• Sources: UV light, plant/animal intake (Vitamin D2/D3).
• PTH stimulates conversion to active form (1,25-dihydroxyvitamin D3 - Calcitriol).
• Vitamin D levels measured via precursor (25-hydroxy vitamin D - Calcidiol).
• Calcium absorption routes:
  • Paracellular: Passive between cells (high calcium intake)
  • Active: Through cells; influenced by calcitriol; uses calbindin transporter

Kidney's Role in Calcium Homeostasis

• Inadequate calcitriol leads to decreased absorption and hypocalcemia.
• Hypocalcemia increases PTH, called secondary hyperparathyroidism.
• Treatment: vitamin D/calcium supplements, calcimimetic drug (cinacalcet).
• Kidney calcium reabsorption:
  • Proximal convoluted tubule: 60-70%
  • Loop of Henle: 20%
  • Distal tubules/collecting ducts: 15%
  • 98% filtered calcium reabsorbed.

Parathyroid Hormone (PTH)

• Released by low calcium levels;
• Elevates blood calcium:
  • Stimulates bone resorption (calcium release)
  • Decreases urinary calcium loss (renal reabsorption)
  • Stimulates vitamin D activation (indirect calcium absorption)
• Located on thyroid's dorsal side.
• Rapid effects (minutes):
  • Stimulates osteoblasts to release calcium
  • Stimulates bone resorption through osteoclasts
  • Stimulates osteoblasts to produce signaling molecule activating osteoclasts

Calcitonin

• Produced by thyroid gland (high blood calcium);
• Receptors in bones and kidneys
• Lowers calcium/phosphate; inhibits osteoclasts (decreases bone resorption); increases calcium excretion

Disorders of Bone and Calcium Homeostasis

• Hypocalcemia: Low calcium (below 8.5 mg/dL)
• Hypercalcemia: High calcium (above 10.5 mg/dL)
• Osteogenesis imperfecta: Genetic, easy fractures
• Paget's disease: Enlarged, weakened bones
• Hyperparathyroidism (Primary/Secondary): Calcium regulation issues
• Renal osteodystrophy: Kidney disease skeletal manifestations
• Rickets: Bone softening in children (vitamin D deficiency)

Interpretation of Lab Results

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

Osteoporosis

• Compromised bone strength, increasing fracture risk.
• Risk factors: Low BMD, female, age, Asian heritage, fragility fractures, low BMI, premature menopause, chronic steroid use, tobacco, alcohol, low calcium/vitamin D, low physical activity, recent falls, impaired cognition/vision.
• Post-menopausal women: estrogen deficiency increases osteoclast activity.
• Age-related: accelerated turnover, reduced osteoblast formation.
• Types of osteoporosis in men: Primary/Secondary (lifestyle/diseases/medications, e.g., endocrine/hormonal, GI, inflammatory, etc).
• Medications decreasing bone density: diuretics, antiretrovirals, anti-convulsants, aromatase inhibitors, SGLT2 inhibitors, heparin, etc.
• BMD measurement: DXA scan of hip and spine.
• T-score interpretation:

  • -1: Normal

  • -1 to -2.4: Osteopenia
  • < -2.5: Osteoporosis

Pharmacist's Role

• Counseling on risk reduction, Calcium/Vitamin D intake, optimal absorption, Calcium citrate for elderly/PPI/antacid users, exercise guidelines, fall prevention, avoiding tobacco/alcohol.
• Discussing bone health and diet.