Drugs affecting calcium and bone metabolism
Factors which influence bone remodellingContinuous 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 OB-derived 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 cytokinesecretion
• Osteocyte form. after being embedded in the osteoid
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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)
Turnover of bone minerals
I. Calcium metabolism:
- The human body contains 1000-2000 mg calcium (98% hidroxyapatite in the bones); 700 mg per day turnover - Plasma Ca 2+: 2.5 mmol/l
- Regulation of plasma Ca2+: PTH, vitamin D family; calcitonin
- GI absorption via Ca2+-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:
- 1000 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
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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 Ca2+ (low Ca2+
stimulates secretion, high Ca2+inhibits it by Ca2+–sensing
Gi protein-coupled surface receptors)
- mobilises Ca2+ from bone (OC recruitment and
activation; BUT! exogenous administration of low, intermittent doses or fragments OB activity)
- enhances tubular resorption of Ca2+ and excretion of
phosphate
- stimulates calcitriol synthesis increases GI Ca2+
absorption and mobilises Ca2+ from bone
Increases plasma Ca2+ and lower plasma phosphate
Teriparatide:
- 1-34 fragment of recombinant PTH
- anabolic on the boneincreases 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
2. Vitamin D family: - preprohormone converted to active hormones • plant ergosterolD2 (ergocalciferol) • cholesterol 7-dehydrocholesterol (intestinal wall)D3 (cholecalciferol;skin by UV irradiation) 25-hydroxy-cholecalciferol (calcifediol; liver) 1,25-dihydroxy-cholecalciferol (calcitriol) 7-dehydrocholesterol kidney liver - increase Ca2+
absorption from the GI tract
- decrease renal excretion of Ca2+
mobilize Ca2+from the
bone
- activates OBs and promotes cell
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: hypercalcaemiaconstipation, 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 Ca2+levels should be monitored during therapy!
3. Calcitonin:
- secreted by specialized „C” cells of the thyroid follicles determined by the plasma Ca2+concentration
- inhibits of bone resorption by receptors on the OCs - decreases calcium and phosphate resorption in the
proximal tubules of the kidney
Decreases plasma Ca2+
Salcatonin: synthetic salmon salmon calcitonin Synthetic (recombinant) human calcitonin
- s.c. or i.m. inj. or intranasal (200 IU/day) administration - plasma t1/2: 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)
-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 actionosteoporosis
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 t1/2: 32 h - Side effects: hot flushes, leg cramps, venous
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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:
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
- 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 OBsincrease trabecular bone mass - Problem: very narrow therapeutic width
- Side effects: GI irritation and bleeding,
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)