Calcium Homeostasis Lesson 27

Calcium Homeostasis

• Lesson 27, 3rd Medicine, Academic year 2024/25
• Professor: Vittoria Carrabs PhD

Index

• Bone remodelling process
• Disorders of bone
• Non-pharmacological treatment
• Drugs used in bone disorders

Bone Remodelling

• Regulated by osteoblast (OB) and osteoclast (OC) activity
• Influenced by various cytokines
• Bone mineral turnover (calcium, phosphate) is key
• Actions of several hormones: parathyroid hormone (PTH), Vitamin D, oestrogens, growth hormone, steroids, calcitonin, and various cytokines

Bone Matrix

• Organic matrix is osteoid, primarily collagen
• Other components: proteoglycans, osteocalcin, phosphoproteins (e.g., osteonectin)
• Calcium phosphate crystals (hydroxyapatite) convert osteoid to hard bone matrix
• Plays crucial role in calcium homeostasis

Osteoblasts

• Cells that form bone tissue
• Derived from precursors in bone marrow and periosteum
• Form important components of bone matrix (osteoid), particularly collagen
• Involved in activating osteoclasts

Osteocytes

• Derived from osteoblasts embedded in bone matrix
• Influence response to mechanical stress
• Initiate bone remodelling
• Secrete sclerostin (reduces bone formation)

Osteoclasts

• Multinucleated cells that resorb bone
• Derived from macrophage-monocyte lineage
• Other important cells in bone: macrophages, monocytes, lymphocytes, vascular endothelium cells - they secrete cytokines and other mediators involved in bone remodelling

Activity of Osteoblasts and Osteoclasts

• The bone remodelling cycle:
• Bone resorption: precursor cells differentiate into osteoclasts (OCs) or osteoblasts (OBs); OCs digest bone
• Bone formation: OBs secrete osteoid (bone matrix); mineralization of osteoid occurs (hydroxyapatite deposition)

Bone Resorption

• Osteoblasts express RANKL
• RANKL interacts with RANK on osteoclast progenitors' surface
• This initiates osteoclast activation and differentiation
• Osteoprotegerin (OPG) acts as decoy receptor for RANKL, inhibiting osteoclast differentiation

Regulation of Bone Remodelling - Oestrogens

• Act on osteoblasts, increasing OPG, reducing bone resorption.
• Inhibit cytokines that recruit osteoclasts.
• Opposes PTH's bone-resorbing, calcium-mobilising action
• Menopause frequently leads to osteoporosis.

Regulation of Bone Remodelling - Parathyroid Hormone (PTH)

• Stimulates both bone formation and bone resorption
• Released when calcium levels are low
• Increases bone resorption to release calcium
• In kidneys, increases calcium reabsorption and phosphate excretion

Calcium and Phosphate Metabolism

• Daily calcium turnover: 700 mg
• Plasma calcium concentration must be precisely controlled by:
  • PTH
  • Calcitriol
  • Calcitonin

Importance of Vitamin D

• Two forms: ergocalciferol (diet), cholecalciferol (sunlight)
• Liver converts cholecalciferol to calcifediol
• Kidney converts calcifediol to calcitriol
• Regulated by PTH and plasma phosphate concentration

Vitamin D - Main effects of calcitriol

• Stimulation of calcium and phosphate absorption in the intestine
• Mobilisation of calcium from bone and increased calcium reabsorption in renal tubules
• Promotion of osteoclast maturation and indirect stimulation of osteoclast activity
• Decreased collagen synthesis by osteoblasts

Disorders of the Bone

• Osteoporosis: Reduction of bone mass, distortion of microarchitecture; commonly due to postmenopausal estrogen deficiency or age-related deterioration
• Osteopenia: Reduction in mineral content
• Osteomalacia and Rickets: Vitamin D deficiency
• Paget's Disease: Distortion of bone processes of resorption and remodelling

Non-Pharmacological Treatment

• Physical activity
• Healthy habits
• Dietary recommendations:
  • 100-200 mg calcium+proteins
  • Vitamins A, D, P, K, Mg
  • Alkaline diet

Drugs used in Bone Disorders

• Antiresorptive drugs: Decrease bone loss.
  • Bisphosphonates
  • Calcitonin
  • Selective estrogen receptor modulators (SERMs)
  • Denosumab
  • Vitamin D, Calcium
  • Calcimimetic compounds
• Anabolic agents: Increase bone formation.
  • PTH, teriparatide

Bisphosphonates

• Inhibit bone resorption—mainly on osteoclasts
• Oral administration, empty stomach, with water; seated/standing at least 30 minutes before breakfast
• ADRs: gastrointestinal disturbances, atypical femoral fractures, osteonecrosis (IV)
• Long-term use requires periodic reevaluation

Calcitonin

• Thyroid hormone, opposite action to PTH
• Increases renal excretion of calcium
• Reduced osteocyte activity
• Mechanism of action:
• Falls in plasma calcium leads to parathyroid hormone secretion, leading to calcitriol conversion, and increased calcium absorption in the intestine - Overall decrease in plasma calcium
• ADRs: Nausea, vomiting, facial flushing

Estrogens and Related Compounds

• Important for bone integrity in females.
• Deficiency at menopause leads to osteoporosis.
• Large doses of glucocorticoids can lead to osteoporosis.
• Vitamin D is used to treat bone diseases.
• HRT, raloxifene

Selective Estrogen Receptor Modulators (SERMs): Raloxifene

• Acts as agonist in bones and liver and antagonist in breast and uterus
• Alternative to bisphosphonates for postmenopausal osteoporosis prevention (in women not tolerating bisphosphonates)
• ADRs: Hot flushes, leg cramps, flu-like symptoms, peripheral oedema, less common thrombophlebitis, and thromboembolism

Denosumab

• Recombinant human monoclonal antibody that inhibits RANKL (mimics OPG), inhibits osteoclast differentiation
• Administered sc every 6 months
• Used for osteoporosis in high-risk fracture patients

Romosozumab

• Monoclonal antibody that inhibits sclerostin, enabling bone formation and osteoblast matrix production

Vitamin D Analogues Preparations: Ergocalciferol, Calcifediol, Calcitriol

• Activate nuclear steroid receptors that increase calcium absorption in the intestine, mobilise calcium from bone by activating osteoclasts, and decrease renal excretion
• Used for deficiency states, hypocalcaemia

Calcium Salts

• Increased absorption by increased vitamin D, acid pH, oestrogens
• Decreased absorption with fiber, phosphorus, and intolerance
• Orally, calcium salts can lead to GI disturbances
• IV administration used for emergency treatment of hyperkalaemia.
• Calcium carbonate is poorly absorbed in the gut and could lead to arterial calcification in patients with renal failure

Calcicimimetic Compounds: Cinacalcet

• Enhances the sensitivity of parathyroid Ca2+-sensing receptor to blood calcium concentration.
• Decrease in parathyroid hormone secretion and reduction in serum calcium concentration

Parathyroid Hormone: Teriparatide

• Recombinant parathyroid hormone for osteoporosis treatment
• Administered at low doses intermittently
• Reverses osteoporosis by stimulating new bone formation (anabolic function)
• Increases osteoblast numbers and stimulates osteoblast activity
• Reduces osteoblast apoptosis
• ADRs: Nausea, dizziness, headache, arthralgias, mild hypercalcemia, transient orthostatic hypotension, leg cramps - limited to 24 months (not repetetive)

Explore the intricacies of calcium homeostasis in the context of bone remodeling in this detailed quiz from 3rd Medicine. Understand the roles of osteoblasts, osteoclasts, and various hormones regulating bone health. Dive into disorders of bone and treatments available, both pharmacological and non-pharmacological.