Lesson 27 - Calcium Homeostasis PDF

Lesson 27 Calcium Homeostasis 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 INDEX 1.Bone remodelling process 2.Disorders of bone 3.Non-pharmacological treatment 4.Drugs used in bone disorders  1. Bone remodelling The process of remodelling is regula...

Lesson 27 Calcium Homeostasis 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 INDEX 1.Bone remodelling process 2.Disorders of bone 3.Non-pharmacological treatment 4.Drugs used in bone disorders  1. Bone remodelling The process of remodelling is regulated by: Activity of osteoblasts (OB) and osteoclasts (OC) Actions of various cytokines Turnover of bone minerals – particularly calcium and phosphate Actions of several hormones: parathyroid hormone (PTH), vitamin D family, oestrogens, growth hormone, steroids, calcitonin and various cytokines. 1. Bone remodelling The bone matrix The organic matrix of bone is the osteoid, the main component of which is collagen. However, other components such as proteoglycans, osteocalcin and various phosphoproteins also participate, one of which is osteonectin, which binds to both calcium and collagen, linking two of the major constituents of the bone matrix. The deposition of calcium phosphate crystals in the form of hydroxyapatite converts the osteoid into a hard bone matrix. In addition to its structural function in the human body, bone plays an important role in calcium homeostasis.  1. Bone remodelling Osteoblasts Osteoblasts are the cells that form bone and are derived from precursors in the bone marrow and periosteum. They form important components, particularly collagen, of the bone matrix, known as osteoid. They also participate in the activation of osteoclasts. Osteocytes derive from osteoblasts that remained embedded in the bone matrix during bone formation. They influence the response to mechanical stress. They are able to sense this and respond by initiating bone remodelling and they secrete sclerostin, a mediator that reduces bone formation 1. Bone remodelling Osteoclasts Osteoclasts are multinucleated cells with the task of resorbing bone. They are derived from the macrophage- monocyte lineage. Other important cells in bone are macrophage/ monocytes, lymphocytes and vascular endothelium cells, these secrete cytokines and other mediators involved in bone remodelling. 1. Bone remodelling ACTIVITY OF OSTEOBLASTS AND OSTEOCLASTS OC from monocytes OB from MSC 1. Bone remodelling ACTIVITY OF OSTEOBLASTS AND OSTEOCLASTS RANK OPG BONE RESORPTION: Osteoblasts are stimulated to express a surface ligand, the RANKL. It interacts with a receptor on osteoclasts progenitors' surface, RANK, that causes osteoclast progenitors to differentiate and activate and form mature osteoclasts. INHIBITION of BONE RESORPTION: Osteoprotegerin (OPG) is a secreted protein that act as a decoy receptor for RANKL in osteoclasts, inhibiting their differentiation. 1. Bone remodelling REGULATION OF BONE REMODELLING OESTROGENS Act in osteoblasts increasing OPG→reducing bone resorption Inhibits the cytokines that recruit osteoclasts and opposes the bone- resorbing, Ca2+ -mobilising action of PTH Withdrawal of oestrogens (menopause) frequently leads to osteoporosis. PARATOHORMONE PTH stimulates both bone formation and bone resorption Released when [Ca2+] decreased Increases bone resorption to release Ca2+ In kidneys, increases Ca2+ reabsorption and phosphate excretion 1. Bone remodelling REGULATION OF BONE REMODELLING  1. Bone remodelling CALCIUM AND PHOSPHATE METABOLISM CALCIUM METABOLISM The daily turnover: 700 mg of calcium Concentration of ionised Ca2+ in the extracellular fluid and the plasma, needs to be controlled with great precision The plasma Ca2+ concentration is regulated by PTH, calcitriol and calcitonin.  1. Bone remodelling The importance of vitamin D There are two important forms of vitamin D for humans: D2 (ergocalciferol) derived from the diet D3 (cholecalciferol) generated in the skin from 7- dehydrocholesterol through the action of sunlight. In the liver cholecalciferol is converted to calcifediol, which in turn is converted to calcitriol in the kidney. This process is regulated by PTH and is also influenced by plasma phosphate concentration and calcitriol concentration by a negative feedback mechanism.  1. Bone remodelling The importance of vitamin D The main effects of calcitriol include: ✓ stimulation of calcium and phosphate absorption in the intestine ✓ mobilisation of calcium from bone and increased calcium reabsorption in the renal tubules. ✓ Its effect on bone involves the promotion of osteoclast maturation and indirect stimulation of their activity. ✓ Decreased collagen synthesis by osteoblasts Vitamin D deficiency negatively impairs bone mineralisation while vitamin D administration restores bone formation. (calcitriol stimulates the synthesis of osteocalcin, the calcium-binding protein in the bone matrix) 1. Bone remodelling The importance of vitamin D PTH Calcitriol Calcitonin 1. Bone remodelling CALCIUM AND PHOSPHATE METABOLISM PHOSPHATE METABOLISM Phosphates constitute bone, the structure and function of all the cells of the body. They are constituents of nucleic acids, form ATP (energy), and control protein activities. PTH and Calcitriol are involved in phosphate homeostasis.  2. Disorders of the bone OSTEOPOROSIS The reduction of bone mass with distortion of the microarchitecture Commonest causes of osteoporosis are postmenopausal deficiency of oestrogen and age-related deterioration in bone homeostasis OSTEOPENIA Reduction in the mineral content OSTEOMALACIA AND RICKETS Vitamin D deficiency PAGET’S DISEASE Distortion of the processes of bone resorption and remodelling  3. Non-pharmacological treatment Physical activity Healthy habits DIETETIC RECOMMENDATIONS 100-200 mg Ca+proteins Vitamin A, D, P. K and Mg Alkaline diet 4. Drugs used in bone disorders Antiresorptive drugs that decrease bone loss Bisphosphonates Calcitonin Selective [o] e strogen receptor modulators (SERMs) Denosumab Vitamin D, Calcium Calcimimetic compouns Anabolic agents that increase bone formation PTH, teriparatide 4. Drugs used in bone disorders ACTIVITY OF OSTEOBLASTS AND OSTEOCLASTS  4. Drugs used in bone disorders BISPHOSPHONATES Mechanism of action Inhibit bone resorption by an action mainly on the osteoclasts ALENDRONATE IBANDRONATE ZOLEDRONATE (IV, 1/year)  4. Drugs used in bone disorders BISPHOSPHONATES Oral administration: Bisphosphonates should be taken on an empty stomach with a full glass of water, in a seated or standing position, at least 30 minutes before breakfast to reduce the risk of severe esophageal irritation.  4. Drugs used in bone disorders BISPHOSPHONATES ADRs: Gastrointestinal disturbances Atypical femoral fractures Continued use should be reevaluated periodically (e.g. after 5 years). OSTEONECROSIS (IV) Long-term use should be re-evaluated periodically (e.g. after 5 years). Teeth osteonecrosis After zoledronate infusion supplemental calcium and vitamin D are administered for at least 10 days.  4. Drugs used in bone disorders BISPHOSPHONATES CLINICAL USES OSTEOPOROSIS MALIGNANT DISEASE HYPERCALCAEMIA BREAST CANCER METASTATIC TO BONE POSTMENOPAUSAL OSTEOPOROSIS PAGET’S DISEASE  4. Drugs used in bone disorders CALCITONIN Thyroid hormone (opposite action to PTH, increases renal excretion of Ca2+) SALCATONIN (decreases osteocytes activity) Given by SC or IM, or intranasally (less effective) Mechanism of action Inhibits resortive action of OC Induces OC apoptosis Increases renal excretion of Ca2+ Overall effect is to decrease the plasma [Ca2+] 4. Drugs used in bone disorders ADRs: Nausea and vomiting. Facial flushing, as may a tingling sensation in the hands and an unpleasant taste in the mouth Clinical Uses Hypercalcaemia (e.g. associated with neoplasia). Paget’s disease of bone (to relieve pain and reduce neurological complications) – but it is much less convenient than an injected high-potency bisphosphonate. Postmenopausal and corticosteroid-induced osteoporosis (with other agents). Calcitonin can also be used to relieve severe back pain in patients with acute osteoporotic vertebral fractures. 4. Drugs used in bone disorders OESTROGENS AND RELATED COMPOUNDS  4. Drugs used in bone disorders OESTROGENS AND RELATED COMPOUNDS SELECTIVE OESTROGEN RECEPTOR MODULATORS (SERMS): RALOXIFENE Mechanism of action OB activity OC activity Acts as agonist in bones and liver, antagonist in breast and uterus Clinical uses Alternative to a bisphosphonate for secondary prevention in postmenopausal women, who cannot tolerate a bisphosphonate. ADRs: Hot flushes, leg cramps, flulike symptoms and peripheral oedema Less common thrombophlebitis and thromboembolism.  4. Drugs used in bone disorders DENOSUMAB Mechanism of action Recombinant human monoclonal Ab that inhibits RANKL, mimics OPG and inhibiting the differentiation of osteoclasts. Used for the management of osteoporosis in patients at high risk for bone fractures.  4. Drugs used in bone disorders DENOSUMAB Administered sc every 6 months Indications Osteoporsis in post-menopausic women with high risk of fractures Treatment of bone loss associated with hormonal suppression in men with prostate cancer TERATOGENIC  4. Drugs used in bone disorders ROMOSOZUMAB Mechanism of action Monoclonal antibody inhibits sclerostin. Enhances bone formation and bone matrix production by osteoblasts Inhibition of osteoclasts  4. Drugs used in bone disorders VITAMIN D ANALOGUES PREPARATIONS ERGOCALCIFEROL, CALCIFEDIOL, CALCITRIOL Mechanism of action Activation nuclear steroid receptors, favouring maintenance of plasma Ca 2+ by Increasing Ca 2+ absorption in the intestine Mobilising Ca 2+ from bone (by activating OC) Decreasing its renal excretion  4. Drugs used in bone disorders VITAMIN D ANALOGUES PREPARATIONS Clinical Uses Deficiency states: prevention and treatment of rickets , osteomalacia and vitamin D deficiency owing to malabsorption and liver disease ( ergocalciferol ). Hypocalcaemia caused by hypoparathyroidism ( ergocalciferol ). Osteodystrophy of chronic renal failure , which is the consequence of decreased calcitriol generation ( calcitriol or alfacalcidol ). Plasma Ca 2+ levels should be monitored during therapy with vitamin D. ADRs: Excessive intake of vitamin D causes hypercalcaemia-->in the presence of elevated phosphate concentrations: renal failure and kidney stones. calcitriol and PTH have similar actions  4. Drugs used in bone disorders Increased absorption CALCIUM SALTS Vitamin D CALCIUM GLUCONATE Acid pH CALCIUM LACTATE Oestrogens CALCIUM CARBONATE Decreased absorption Fiber Mechanism of action Phosphorus Indirect antagonist of PTH Intolerance ADRs: Oral calcium salts GI disturbance. IV administration in emergency treatment of hyperkalaemia CALCIUM CARBONATE Poorly absorbed from the gut Low-level systemic absorption→potential to cause arterial calcification in patients with renal failure 4. Drugs used in bone disorders CALCIUM SALTS Clinical Uses Dietary deficiency. Hypocalcaemia caused by hypoparathyroidism or malabsorption (iv for acute tetany). Calcium carbonate to treat hyperphosphataemia Prevention and treatment of osteoporosis Cardiac dysrhythmias caused by severe hyperkalaemia (IV). 4. Drugs used in bone disorders CALCIMIMETIC COMPOUNDS CINACALCET Mechanism of action Enhance the sensitivity of the parathyroid Ca2+-sensing receptor to the concentration of blood Ca2+, producing: Decrease in secretion of PTH and reduction in serum Ca2+ concentration Oral preparation used for the treatment of hyperparathyroidism 4. Drugs used in bone disorders PARATHYROID HORMONE  4. Drugs used in bone disorders PARATHYROID HORMONE TERIPARATIDE Recombinant parathyroid hormone used for the treatment of osteoporosis. Mechanism of action At low doses and administered intermittently Reverses osteoporosis by stimulating new bone formation (anabolic function) It increases bone mass, structural integrity and bone strength by increasing the number of osteoblasts and by activating those osteoblasts already in bone. Reduces osteoblast apoptosis 4. Drugs used in bone disorders PARATHYROID HORMONE ADRs: Nausea, dizziness, headache and arthralgias Mild hypercalcaemia, transient orthostatic hypotension and leg cramps have been reported Concerns regarding long-term efficacy and safety, the maximal treatment duration of teriparatide should be limited to 24 months and must not be repeated.