drug treatment of metabolic bone diseases
DESCRIPTION
Drug treatment of metabolic bone diseases. Bone remodeling. Bone is in a dynamic state of loss (resorption) followed by formation. These two opposing processes are called bone remodeling and are usually coupled in bone-remodeling units (BRUs). Bone Remodeling Cycle in Normal Bone. - PowerPoint PPT PresentationTRANSCRIPT
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DRUG TREATMENT OF METABOLIC BONE DISEASES
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Bone remodeling
Bone is in a dynamic state of loss (resorption) followed by formation. These two opposing processes are called bone remodeling and are usually coupled in bone-remodeling units (BRUs).
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Bone Remodeling Cycle in Normal Bone
Osteocytes
Resting
Bone
ResorptionOsteoclasts digest bone within a sealed resorption vacuole
Bone
Reversal
Apoptotic osteoclasts
Preosteoblasts
Bone
Mature osteoblasts building osteoid tissue
MineralizationFormation
Bone
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Bone remodeling
Steps of bone remodeling:1- Stimulation of osteoclasts. osteoclasts. Osteoclasts
secrete collagenases and proteinases that solubilize bone matrix, releasing calcium into circulation for physiological functions.
2- Once osteoclasts die, osteoblasts osteoblasts differentiate and lay down new bone matrix (osteoid) at the sites of previous resorption.
3- Once bone formation is complete, osteoblasts are inactivated and differentiate into osteocytesosteocytes on the surface of the new bone.
4- The new bone is then mineralized with hydroxyapatite. The complete mineralization and hardening process takes several months.
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Metabolic bone diseases
1- Osteoporosis: A skeletal disorder characterized by compromized bone strength with an increased risk of fracture.
2- Osteomalacia and rickets: abnormal bone formation due to inadequate mineralization
3- Paget’s disease: Localized bone disease characterized by uncontrolled bone resorption with secondary increase of bone formation. The new bone is poorly organized.
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Osteoporosis
Normal bone Osteoporosis
No
Mechanism of osteoporosis:Imbalance between rate of resorption and formation
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Osteoporosis
Types of osteoporosis Primary
Type 1- post menopausal Type 2- senile
Secondary Medications Steroid induced Medical conditions
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Osteoporosis - types
I- Postmenopausal osteoporosis (type I)I- Postmenopausal osteoporosis (type I)Mechanism:
˗ Estrogen deficiencydeficiency causes:
1. increases proliferation and activation of osteoclasts
2. prolongs survival of osteoclasts
II- Senile osteoporosis (type II)II- Senile osteoporosis (type II) Bone loss due to increased bone turnover Malabsorption Mineral and vitamin deficiency
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Secondary osteoporosis9
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Drugs causing osteoporosis
1- Long-term glucocorticoids2- Anticoagulants3- Gonadotropin-releasing hormone
agonists4- Antiepileptic drugs5- Furosemide
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Drugs causing osteoporosis
Drug-induced osteoporosis:1- Long-term glucocorticoids Proposed mechanisms of osteoporosis:a) alteration in calcium absorption and elimination
leading to secondary hyperparathyroidismb) inhibitory effect on sex hormone productionc) direct inhibition of osteoblast function.
Inhaled corticosteroids do not decrease bone density at low to moderate dosages, but may have some effect at higher dosages.
Some bone mass restoration may occur on withdrawal of glucocorticoid therapy.
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Drugs causing osteoporosis
• Prevention of glucocorticoid-induced osteoporosis in patients who will take glucocorticoids for > 6 months
1. Consider thiazide diuretic if otherwise indicated (e.g., patient is hypertensive)
2. Correct hypogonadal state if presentA) Premenopausal women: oral contraceptionB) Postmenopausal women: estrogen ± progesteroneC) Men: testosterone
3. Consider alternative or additional therapy A) Bisphosphonates (alendronate, risedronate, etidronate) B) Calcitonin for patients who cannot take bis- phosphonates
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Drugs causing osteoporosis
2- Anticoagulants:1. Long-term use of high dose heparin therapy
(>15,000 U/day for >3 months) can cause reversible osteoporosis.
Potential mechanisms include: A) increased osteoclast activity B) decreased osteoblast activity D) heparin-induced increase in collagenase activityE) decrease in the production of 1,25-hydroxyvitamin D
[1,25-(OH)2-D] caused by decreased renal conversion enzyme activity.
2. Long-term oral anticoagulants may increase the risk of osteoporosis by their antagonistic effect on vitamin K, a key factor in the synthesis of bone matrix proteins.
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Drugs causing osteoporosis
3- Gonadotropin-releasing hormone agonistsThe gonadotropin-releasing hormone (GnRH)
agonists, leuprolide, goserelin, and nafarelin.Prevention: use of these agents must be limited to 6 monthsIf more than 6 months are required, a bone-
protective agent is used concurrently as low-dose estrogen and progesterone or progesterone alone or bisphosphonates.
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Drugs causing osteoporosis
4- Antiepileptic drugs (e.g. phenytoin)
Mechanism: induction of cytochrome P450 which converts vitamin D into inactive metabolites.
5- Other substances• Furosemide and other loop diuretics
decrease serum calcium.
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Osteoporosis
Prevention and treatment of primary osteoporosis
A. Non-pharmacological Life style modification: Stop alcohol and smoking
and increase Ca in diet. Regular exercise Avoid drugs that induce osteoporosis
B. Pharmacological therapy:1) Bisphosphonates2) Calcium3) Vitamin D4) Estrogen5) Estrogen receptor modulators (SERM)
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Osteoporosis
I- Antiresorptive therapy:1) Bisphosphonates (first line)2) Calcium3) Vitamin D4) Estrogen5) Estrogen receptor
modulators (SERM)6) CalcitoninII- Anabolic therapy:1) Teriparatide
Treatment of osteoporosis
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Mechanism of action of bisphosphonates
1.1. BISPHOSPHONATES bind to bone BISPHOSPHONATES bind to bone mineral surfacemineral surface
2.2. BISPHOSPHONATES are taken up by the BISPHOSPHONATES are taken up by the osteoclastosteoclast
3.3. BISPHOSPHONATES induce apoptosis of BISPHOSPHONATES induce apoptosis of osteoclasts osteoclasts
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Available Bisphosphonates for Osteoporosis
Oral Alendronate (daily, weekly) Risedronate (daily, weekly, monthly) Ibandronate (daily, monthly)
Intravenous Ibandronate (quarterly) Zoledronic acid (annual)
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Bisphosphonates
Absorption, Fate, and Excretion. very poorly absorbed from the intestine and have
bioavailability <1% to 6%]. Bisphosphonates are excreted primarily by the kidneys.
Bisphosphonates are not recommended for patients with impaired renal function
Adverse Effects Alendronate may cause esophagitis, gastritis or peptic
ulcer
Mild fever and aches may attend the first parenteral infusion of pamidronate, likely owing to cytokine release. These symptoms are short-lived and generally do not recur with subsequent administration.
Zoledronate has been associated with renal toxicity, deterioration of renal function, and potential renal failure.
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Bisphosphonates
Alendronate and RisedronateIndications:1. Prevention of osteoporosis in
postmenopausal women2. Treatment of osteoporosis in men,
postmenopausal women, and those with corticosteroid-induced osteoporosis.
3. Treatment of hypercalcemia associated with malignancy
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Inability to sit down or stand
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Calcium
Action:Calcium alone is inadequate to completely inhibit the
rapid bone loss that occurs at menopause but is necessary to optimize response to antiresorptive agents.
Administration:Orally as calcium carbonate, phosphate, citrate, …Adverse effects:Mainly GIT as:1. Nausea 2. Constipation (treated by increased water intake,
dietary fibers and excercise)3. Abdominal distension (with calcium carbonate.
Treated by using calcium citrate instead)
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Calcium
Drug interactions:
1. Fibers and iron therapy impair absorption
2. Patients should take tetracycline compounds and calcium at least 2 hours apart to avoid intestinal chelation.
Dose for elderly men and women: • A total daily calcium intake of 1500 mg is
recommended for elderly men and women = about 1000 mg/day as a drug + 400 to 500 mg of dietary calcium found in the diet of elderly men and women
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Vitamin D
Specific Forms of Vitamin D. Calcitriol (1,25-dihydroxycholecalciferol) is
available for oral administration or injection. 1a-hydroxyvitaminD3 is a synthetic vitamin D3
derivative. It is rapidly hydroxylated in the liver to form 1,25-(OH)2D3. It is used to treat renal rickets
1a-hydroxyvitamin D2: activated by hepatic 25-hydroxylation to generate the biologically active compound, 1a,25-(OH)2D2
Vitamin D2: It is available for oral, intramuscular, or intravenous administration.
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Vitamin D
Action: 1,25-(OH)2-D enhances GI absorption of calcium. Forms of vitamin D for use in osteoporosis:1) Vitamin D2 and D3 (dose for either=800 IU/2) 1,25-(OH)2-D (calcitriol, dose=0.5 μg/d). Distribution: 1) Distributed bound to vitamin D-binding protein
(α-globulin)2) Vitamin D is hydroxylated in the liver and
kidney to produce the physiologically active compound 1,25-(OH)2-D (calcitriol).
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Vitamin D
Indications:Patients at risk for vitamin D deficiency, such
as older adults or patients on low-dose corticosteroids or anticonvulsant therapy.
Adverse effects:Hypercalcemia (symptoms: anorexia, nausea
and weakness)Drug interactions: Concomitant use of thiazide diuretics and
calcitriol may increase the risk of hypercalcemia.
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Estrogen
Mechanism of action in osteoporosis: Estrogen suppresses bone resorption by inhibiting
osteoclastsAdverse effects:1. increase the incidence of breast and endometrial cancers 2. increase in risks for deep venous thrombosis and gall
bladder disease. Prescription: Long-term use of estrogen (>5y) carries the risk of breast
and endometrial cancer. Therefore, estrogen is not prescribed for prevention or treatment of osteoporosis.
Women who are using estrogen for management of menopausal symptoms will experience a delay in postmenopausal bone loss and may be able to postpone initiation of antiosteoporotic therapy until they discontinue HT
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↓Total cholesterol
↓LDL No effect on HDL, TG
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Selective estrogen receptor modulators (SERMs)Uses:1. Postmenopausal women at risk for
osteoporosis who cannot take bisphosphonates
2. Postmenopausal women at increased risk for breast cancer
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Calcitonin (Salmon calcitonin) Mechanism of action:
1)Inhibits bone resorption by inhibiting osteoclast activity (with time both formation and resorption are reduced)
2)Has an analgesic effect on acute pain from VF that is independent of its effects on bone metabolism.
Administration:
Given by injection (subcutaneous or intramuscular) and intranasaly. Patients should ingest adequate calcium and vitamin D during calcitonin treatment (why?).
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Calcitonin (Salmon calcitonin) Side effects of injectable calcitonin (minimized by S.c., not i.m., injection. 1) Nausea and GI discomfort2) Initial facial flushing and dermatitis3) Pruritus at the injection site. Side effects of nasal calcitonin :1)Rhinitis Indications:1) 2nd line treatment for patients with osteoporosis who cannot tolerate other antiosteoporotic agents.
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Teriparatide(recombinant PTH)
Indications:Treatment of osteoporosis in men and
postmenopausal women who have failed antiresorptive therapy.
Administration:Injected daily s.c. Use of this agent is limited to 2-years
duration due to lack of long-term safety data.
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OsteomalaciaCauses of osteomalacia:1. Most common cause: severe, prolonged vitamin D deficiency. 2.Drugs that can cause osteomalacia: Longterm anticonvulsant therapy (mechanism: phenytoin, phenobarbital, and carbamazepine induce cytochrome P450 system →↑vitamin D conversion to inactive metabolites). Prevention: oral vitamin D3 from 1,000 to 4,000 units per day.
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Osteomalacia
Pathophysiology In osteomalacia: normal bone resorption
and formation Osteomalacia is characterized by the
body's inability to fully mineralize the newly formed osteoid tissue, resulting in decreased bone strength
Treatment of osteomalacia: High-doses of vitamin D
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Rickets
Nutritional Deficiency of vitamin D
1. Diet 2. Vitamin D
Vitamin D resistant rickets
X linked Large doses of vitamin D
Vitamin D dependent rickets type I
Autosomal recessive
Mutations in 1a-hydroxylase leading to decreased formation of 1,25(OH)₂-vitamin D
Physiological doses of vitamin D3
Vitamin D dependent rickets type II
Autosomal recessive
Mutations of the vitamin D receptor with increased formation of 1,25(OH)₂-vitamin D
Refractory to vitamin D – treated with i.v. Ca
Renal osteodystrophy
Renal failure decreased formation of 1,25(OH)₂-vitamin D
1a-hydroxyvitaminD3 (alfacalcidol) or calcitriol
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Paget’s disease
Paget’s disease is a disorder of bone remodeling in discrete sections of bone. The main areas affected are the skull, spine, pelvis, femur, and tibia. Pathogenesis:It is characterized by increased bone resorption and formation. The accelerated bone formation does not allow for proper layering of collagen leading to disorganized or woven collagen. Treatment:1. Bisphosphonates are the drug of choice for managing Paget’s disease because they work directly on osteoclasts to slow down bone turnover, allowing more time for proper bone formation. Therapy can be repeated if symptoms return or serum alkaline phosphatase increases by 25% or more. 2. Subcutaneous or intramuscular salmon calcitonin can be used if bisphosphonates therapy is contraindicated.
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