Drugs affecting calcium and bone metabolism

Transcription

1 Drugs affecting calcium and bone metabolism Factors which influence bone remodelling Continuous remodelling process (0.5-1% bone loss per year, after the menopause 1-3% per year) - Cells: osteoblasts secrete, osteoclasts break down bone matrix-recruited and activated by cytokines and hormones - Minerals: calcium and phosphate - Cytokines: insulin-like growth factor (IGF); transforming growth factor (TGF-b); bone morphogenic protein (BMP); interleukins; TNF- embedded in the bone matrix (osteoid) - Hormones: parathyreoid hormone (PTH); the vitamin D family; oestrogens; growth hormone (GH); steroids and calcitonin - Diet - Drugs - Physical factors (exercise, loading) Bone remodelling cycle Recruitment of OC precursors by OBderived mediators Differentiation to mat. multinoculated OCs by cytokines Adherence to the trabecular bone, moving along and secreting H+ and proteolytic enzymes Liberation of cytokines embedded in the osteoid Consequent recruitment and activation of OBs Osteoid and cytokine secretion Osteocyte form. after being embedded in the osteoid 1

2 Disorders of the bone 1. Disorders of the bone structure: - Osteoporosis: structural (microarchitectural) deterioriation and decreased bone mass Frequent fractures Causes: postmenopausal oestrogen defficiency, age-related deterioration, excessive thyroid hormone or glucocorticoid production/intake, rheumatoid arthritis - Osteopenia: reduction of the mineral content of the bone - Osteomalacia and rickets (juvenile form): defects of bone mineralization due to vitamin D deficiency - Paget s disease: distortion of bone resorption and remodelling processes 2. Disorders of bone mineral metabolism: - Hypocalcaemia: hypoparathyroidism, vit. D deficiency, congenital rickets, kidney diseases - Hypercalcaemia: hyperparathyroidism, sarcoidosis, malignancies - Hypophosphataemia: nutritional deficiencies - Hyperphosphataemia: renal failure Role of osteoblasts and cytokines in octeoclast activation Mechanism of antiresorptive drugs RANK: receptor activation og nuclear factor kappa B (NF-kB) osteoclast differentiation and activation receptor = OPG: osteoprotegerin (OPG) released by Obs and stromal cells; ropg: recombinant OPG (clin. trials) 2

3 Turnover of bone minerals I. Calcium metabolism: - The human body contains mg calcium (98% hidroxyapatite in the bones); 700 mg per day turnover - Plasma Ca 2+ : 2.5 mmol/l - Regulation of plasma Ca 2+ : PTH, vitamin D family; calcitonin - GI absorption via Ca 2+ -binding protein whose synthesis is regulated by calcitriol - Urinary Ca 2+ excretion is constant PTH and calcitriol enhance resorption in the tubules), therefore reduce excretion II. Phosphate metabolism: mg phosphate (85% in the bones) - GI absorption is an energy-requiring process regulated by calcitriol - Deposition in the bone as hydroxyapatite is regulated by PTH and calcitriol (mobilise calcium and phosphate from the bone matrix) - Excretion through the kidney PTH inhibits reabsorption Main factors which influence Ca 2+ concentration of the plasma 3

4 I. Hormones regulating bone metabolism 1. Parathormone (PTH, parathyreoid hormone): - 84 aminoacid-containing polypeptide synthesized in parathyreoid cells and stored in vesicles - secretion is controlled by plasma Ca 2+ (low Ca 2+ stimulates secretion, high Ca 2+ inhibits it by Ca 2+ sensing Gi protein-coupled surface receptors) - mobilises Ca 2+ from bone ( OC recruitment and activation; BUT! exogenous administration of low, intermittent doses or fragments OB activity) - enhances tubular resorption of Ca 2+ and excretion of phosphate - stimulates calcitriol synthesis increases GI Ca 2+ absorption and mobilises Ca 2+ from bone Increases plasma Ca 2+ and lower plasma phosphate Teriparatide: fragment of recombinant PTH - anabolic on the bone increases bone mass, structural integrity and strength, number and activity of Obs, decreases OB apoptosis - acts via G-protein-coupled PTH-1 receptors (AC and PL activation) - well-tolerated, nausea, dizziness, headache, joint pain, mild hypercalcaemia, orthostatic hypotension, headache might occur - s.c. injection once a day - Clinical use: osteoporosis; prevention and treatment of pathological fractures (1-84-PTH is also effective, but results are less prominent) 4

5 2. Vitamin D family: - preprohormone converted to active hormones plant ergosterol D 2 (ergocalciferol) cholesterol 7- dehydrocholesterol (intestinal wall) D 3 (cholecalciferol;skin by UV irradiation) 25- hydroxy-cholecalciferol (calcifediol; liver) 1,25-dihydroxycholecalciferol (calcitriol) 7-dehydrocholesterol kidney liver - increase Ca 2+ absorption from the GI tract - decrease renal excretion of Ca 2+ mobilize Ca 2+ from the bone - activates OBs and promotes cell differentiation 5

6 Medical preparations: ergocalciferol, alfacalcidol, calcitriol, 19-nor-paracalcitol, doxercalciferol (less potent to cause hypercalcaemia) - fat-soluble vitamins, given orally, bind to specific a- globulins, accumulated in the fat, eliminated by the faeces - Side effects: hypercalcaemia constipation, depression, weakness, fatigue, kidney stones, renal failure - Clinical uses: Vitamin D deficiencies (malabsorption, liver disease) to prevent osteomalacia Osteodystrophy associated with renal failure (due to decreased calcitriol) Hypoparathyroidism, hypocalcaemia Plasma Ca 2+ levels should be monitored during therapy! 3. Calcitonin: - secreted by specialized C cells of the thyroid follicles determined by the plasma Ca 2+ concentration - inhibits of bone resorption by receptors on the OCs - decreases calcium and phosphate resorption in the proximal tubules of the kidney Decreases plasma Ca 2+ Salcatonin: synthetic salmon salmon calcitonin Synthetic (recombinant) human calcitonin - s.c. or i.m. inj. or intranasal (200 IU/day) administration - plasma t 1/2 : 4-12 min, but action lasts for hours - Side effects: local inflammation at injection site, nausea, vomiting, flush, unpleasant taste, tingling of the hands - Clinical uses: hypercalcaemia, osteoporosis (vertebral compressions) - 6

7 4. Oestrogens: Maintaining bone integrity (during repr. cycle in women) - inhibit cytokines that recruit Ocs - diminish bone-resorbing action of PTH 5. Glucocorticoids: - physiological concentrations are required for OB differentiation - excessive concentrations (pharmacological or pathological) inhibit OB differentiation and activity + stimulate OC action osteoporosis 6. Thyroid hormones: - Osteoid formation - OB activity II. Hormone-like synthetic compounds 1. Tibolone: - synthetic compound, which breaks down to an oestrogen-like, a gestagen-like and an androgen-like molecule - Oestogen-like effects are predominant in the bones (diminish bone loss) and diminishes postmenopausal symptoms, but does not stimulate the mammaries and the uterus 2. Raloxifen (selective oestrogen receptor modulator: SERM): - advantage over HRT: induce agonistic actions on some systems (bone and CV system) and antagonistic on others (mammary glands and uterus) - D-dependent increase in OB activity (IGF-I ) and reduction in OC action (IL-6, IL-1, TNF ) - Increasing bone density (2-3% per year) and decreasing pathological risks (45-50%) - good GI absorption, extensive first-pass metabolism (BA: 2%), wide distribution, fecal excretion, plasma t 1/2 : 32 h - Side effects: hot flushes, leg cramps, venous thrombembolism (?) 7

8 III. Non-hormonal agents influencing bone metabolism 1. Bisphosphonates: aledronate, risedronate, etidronate, clodronate, ibandronate, pamidronate, tiludronate, zoledronate (one i.v. infusion in malignancies, Paget s disease and osteoporosis) - enzyme-resistant analogues of pyrophosphate that inhibit OCs diminish bone resorption - they are bound to the matrix, released slowly and ingested by OCs when they resorb bone - Mechanism of action: Amin-bisphosphonates Simple structures Simple structures (etidronate, clodronate): Incorporate into ATP analogues (cytotoxic ATP analogues) that are accumulate in the OCs and induce apoptosis N-containing compounds (amin-bisphosphonates: aledronate, risedronate): interfere with the with the formation of the ruffled border at the cell-site attachment preventing bone resorption. They inhibit farnesyl-diphosphate synthase (an enzyme in the mevalonate pathway) prevention of the synthesis of certain lipids involved in the activity of small GTP-ase signalling proteins necessary in the formation of the ruffled border 8

9 - Kinetics: Given orally, but poorly absorbed i.v. injection in malignancies 50% accumulates in the bone at the site of mineralization and remains there for months Excreted unchanged in the urine - Side effects: GI disorders (peptic ulcers, aldronate: oesophagitis) Bone pain (etidronate: increased risk of fractures) - Clinical uses: Prevention/treatment of postmenopausal osteoporosis (with or without oestrogens) and glucocorticoid-induced osteoporosis Hypercalcaemia caused by malignanies Cancer metastases in bone Paget s disease 2. Stroncium ranelate: - two stroncium atoms combined with organic ralenic acid carrier - inhibits bone resorption and stimulates bone formation - Mechanism (?): stroncium is similar to calcium, absorbed on the hydroxyapatite crystals, exchanged to calcium in the bone minerals and remain in the bone for many years - Well tolerated, diarrhea and nausea might be side-effects - effectively inhibits fractures in elderly women Rarely used drugs: 3. Thiazide diuretics: - decrease calcium and oxalate excretion 4. Fluoride: last choice - Incorporated into fluoroapatite inhibit OCs and enhance the mitosis and activity of OBs increase trabecular bone mass - Problem: very narrow therapeutic width - Side effects: GI irritation and bleeding, 5. Anabolic steroids: norandosttenolon deconat (depot inj.) 9

10 6. Calcium salts: - gluconate and lactate- p.o. or i.v. (i.m. injection causes necrosis) - carbonate: antacid, poorly absorbed, causes calcification 7. Calcimimetic compounds: - Enhance the sensitivits of parathyreoid Ca2+-sensing receptors - Decrease PTH secretion and reduce serum Ca2+ Type I. calcimimetics: agonists, polycations Type II. : allosteric activators cinacalcet (hyperparathyroidism) 10