Osteoporosis Treatment

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Osteoporosis Treatment

• Dr. SAEED AHMED

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osteoporosis

• Bone undergoes a continuous remodeling process
  involving bone resorption and formation.
• Increase resorption more than formation ?
  osteoporosis

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Characteristics

• Abnormal loss of bone skeletal fragility
  predisposing to fractures.
• In osteoporosisbone mineral density(BMD) is
  reduced bone microarchitecture is disrupted.

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Causes and risk factors

• Age gt 65 years
• Occurs in elderly, most pronounced in
  postmenopausal women
• Malabsorption syndrome
• As a manifestation of endocrine disease
  (thyrotoxicosis or hyperparathyroidism)
• Alcohol abuse cigarette smoking
• Long-term use of glucocorticoids or other drugs
• Idiopathic

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• Long-term use of Glucocorticoidsmight induce
  osteoporosis by the following mechanisms
• 1- Decreasing Calcium intestinal absorption
• 2- Increasing Calcium renal excretion
• 3- Decreasing bone formation

Antagonizing vit.D
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Osteoporosis

• In osteoporosis there is decreased bone mineral
  density (BMD) disrupted bone architecture
• This would increase fractures liability (common
  in hip bone and vertebrae)
• Three hormones are responsible for Calcium
  homeostasis
• Calcitonin
• Parathyroid hormone
• 1,25-OH-D3 production

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Drugs used in osteoporosis

• Hormones
• Calcium
• Vit D
• Hormone replacement therapy (estrogen)
• Raloxifene (Selective Estorgen Receptor
  Modulator)
• Calcitonin
• Teriparatide ( r-PTH)
• Nonhormones
• bisphosphonates

All drugs inhibit bone resorption except
teriparatide
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Calcitonin

• A 32-amino-acid peptide secreted by
  parafollicular C cells of the thyroid
  gland
• Calcitonin acts to decrease calcium concentration
  via calcitonin receptors in osteoclasts, GIT,
  kidney brain
• Inhibits osteoclastic activity in bones
• Inhibits Ca2/phosphate reabsorption by the renal
  tubules
• Inhibits Ca2 absorption by the intestine
• Postmenopausal women tend to possess lower levels
  of plasma calcitonin levels

Gastrin, pancreozymin (CCK), and increased serum
Ca? ?secretion of calcitonin
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Calcitonin

• Pharamcological Actions
• Osteoclasts size motility are decreased leading
  to inhibition of bone resorption
• It inhibits the parathyroid hormone-induced
  acceleration of bone-turnover
• It increases renal excretion of Na, K, Ca2,
  Mg2, and phosphate

• Pharmaceutical formulations include
• Nasal spray
• Parenteral formulation for IM or S.C. injection

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Calcitonin Pharmacokinetics

• Rapid absorption from injection sites (slow with
  the addition of gelatin)
• T1/2 20 minutes
• Weak protein binding
• Hepatic (mainly) and renal metabolism
• Nasal spray calcitonin has 5-50 bioavailability
  when compared to IM route

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Calcitonins adverse effects

• Dose dependent.
• Increased with parenteral route.
• They include
• Anorexia, nausea, and facial flushing
• Urticaria or anaphylaxis are rare
• Long-term use may lead to the formation of
  antibodies that are possibly ineffective
• Drug-drug interaction calcitonin thiazide K
  depletion

Long term use ? ?Ca and phosphate ? impaired bone
formation
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Vitamin D

• Vitamin DCa2 absorption activation
• PTH stimulates 25-OH-vitaminD3 1-a-hydroxylase in
  the kidney
• This enzyme catalyzes hyroxylation of
  25-OH-vitamin D3, to its active form
  1,25-dihydroxy vitamin D3 (calcitriol)
• This activated form of vitamin D increases the
  absorption of Ca2 by the intestine via
  calbindin(calcium binding protein)

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Preperations of Vit.D

• include
• Vitamin D2 (ergocalciferol)
• Vitamin D3 (adequate amounts of vitamin D3 can
  be made in the skin after 10-15 min of sun
  exposure 2 times per week)
• 1,25-dihydroxyvitamin-D (calcitriol), the active
  form

Usually D2 or D3 are given with Ca If there was
impaired activation of vit.D you can give
calcitriol as a supplement
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uses

• Can be used in hypo and hyperparathyroidism

Recommendation

• 800 IU per day is recommended for postmenopausal
  women

Vitamin D receptors (VDR) activation in the
intestine, bone, kidney, parathyroid gland cells
leads to the maintenance of calcium and phosphate
levels in the blood for the maintenance of bone
content
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Low levels of vit.D? ?mineralization of bone High
levels ? potentiates the action of PTH
In toxicity only
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Calcium
Pharmaceutical forms

• Ca2 chloride, Ca2 citrate, Ca2lactate,
  Ca2gluconate(IV because has least vascular
  irritation), and Ca2carbonate (taken orally)
• Ca2 carbonate converts to Ca2 in the body which
  contains 40 elemental Ca

Recommendation
1500 mg per day for post menopausal women
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Calcium Adverse Effects

• Oral calcium may cause
• Gastric irritation, nausea constipation
• Excessive Ca2? hypercalcemic toxicity especially
  in the presence of high vitamin D intake
• Decrease tetracycline absorption

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Hormone Replacement Therapy (HRT)

• Estrogen deficiency causes bone loss via
  increased bone resorption.
• Loss of estrogen? ?IL-1, IL-6 TNF-a? enhance
  osteoclast replication differentiation
• HRT Beneficial Effects
• HRT increases BMD ? beneficial in vertebral
  non-vertebral fractures
• Control of menopausal urogenital symptoms
• Reduced risk of colon cancer
• HRT Risk
• ?CV Cerebrovasculardiseases, gallbladder
  disease, DVT, pulmonary thromboembolism,breast
  cancer

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Selective Estrogen Receptor Modulators
(SERMs)Raloxifene

• A non-hormonal agent that binds to estrogen
  receptors
• They induce estrogen-like effects in some but not
  all tissues (specific)
• Raloxifene(60 mg/day) is the only approved member
  for prevention treatment of osteoporosis
• Pharmacokinetics
• 60 absorption from oral route
• Bioavailability 2 because of 1st pass
  metabolism and conjugation
• high plasma protein binding.
• Cholestyramine reduces absorption enterohepatic
  cycling.

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RaloxifeneEffects on BMD and Bone Turnover

• 30-50 reduction of vertebral fractures
• Non-vertebral fractures are either
  non-significantly affected or reduced in women
  with severe vertebral factures
• Significant increase of BMD in the lumbar spine
  and femoral neck
• Reduction of bone turnover markers

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RaloxifeneExtra-Skeletal Benefits and Adverse
Effects

• Reduction of total lipids and LDL-cholesterol
• Reduction of CVD risk only in women at high risk
  or with established CVD
• Reduction in the incidences of estrogen
  receptor-dependent invasive breast cancer in
  low-risk osteoporotic postmenopausal women
• Adverse Effects Are safe and well-tolerated
• Hot flashes leg cramps
• Infrequent venous thromboembolism (VTE),
  unrelated to leg cramps
• Contraindicated in patients with VTE history

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Bisphosphonates

• Used for osteoporosis, Pagets disease,
  malignacyhypercalcemia and bone metastases
• They have high affinity for bone tissue.
• 50 is excreted by the kidney. The rest taken up
  by osteoclast
• Pharmacokinetics
• 2 absorption during fasting
• Food reduces absorption
• T1/2 1 hour
• Administered 1 hour before meals with water only.
  The patient is advised to take it in an upright
  position and remain so for 30 to 60 minutes in
  order to prevent esophagitis and esophageal
  ulcers.

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BisphosphonatesMechanism of Action

• Pyrophosphate-like
• Etidronate
• Mechanism
• Metabolized in cells forming non-functional
  cytotoxic ATP molecules
• Cell death of osteoclast? ?bone resorption

• Nitrogen-containing
• AlendronateRisedronate
• Mechanism
• 1000-times more potent
• Blocking the enzyme farnesyldiphosphatesynthase
  (FPPS) in the HMG-CoAreductase (the mevalonic
  acid) pathway
• This prevents the formation of two metabolites
  essential for connecting small proteins to the
  cell membrane of osteoclast (prenylation)
• Proper sub-cellular protein trafficking is
  impaired

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BisphosphonatesAdverse Effects

• N-containing bisphosphonates are contraindicted
  with esophageal pathology. (they may cause
  gastroesophageal reflux)
• IV ? fever and flu like symptoms (after 1st
  infusion)
• ?risk for electrolyte disturbances
• In chronic renal failure, the drugs are excreted
  much more slowly, thus dose adjustment is
  required.
• At high doses, etidronate may cause osteomalacia.

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Parathyroid Hormone (PTH)

• PTH acts to increase the concentration of calcium
  in the blood by acting upon PTH receptors in
  three organs
• Bone Release of calcium from the large
  reservoir contained in the bones
• KidneyReabsorption of calcium and magnesium from
  distal tubules and the thick ascending limb and
  increases the excretion of phosphate
• Intestine Absorption of calcium in the intestine
  indirectly by increasing the production of
  activated vitamin D in the kidney.

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Bone physiologic effects of PTH

• In high amounts of PTH (physiologic PTH) ?
  induction of bone resorption(stimulate
  osteoclasts)
• In small quantity or intermittent amounts of PTH?
  bone formation (stimulates osteoblasts)

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Parathyroid Hormone (PTH)Teriparatide
rh-PTH(1-34)

• Recombinant hPTH(1-34) shows good efficacy
  against vertebral non-vertebral fractures in
  postmenopausal women.
• It increases BMD at skeleton sites except radius
• It increases BMD at the spine in severe
  osteoporotic men glucocorticoid-induced
  osteoporosis postmenopausal women.
• Adverse effects
• Nausea, headache, dizziness
• Infrequently leg cramps
• Occasional hypercalcemia and/or hypercalciuria

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• A 58-year old postmenopausal woman waas sent for
  dual-energy x-ray absorptiometry to evaluate her
  BMD of her lumbar spine, femoral neck and total
  hip. The test results revealed significantly low
  BMD in all sites.

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• Chronic use of which of the following drugs is
  MOST likely to have contributed to this woman's
  osteoporosis?
• Lovastatin
• Metformin
• Prednisone
• Propranalol
• Thiazide diuretic

prednisone
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• If this patient began oral therapy with
  alendronate, she would be advised to drink large
  quantities of water with the tablets and remain
  in the upright position for at least 30 min and
  until eating the first meal of the day. These
  instructions would be given to decrease the risk
  of
• Cholelithiasis
• Diarrhea
• Constipation
• Erosive esophagitis
• Pernicious anemia

Erosive esophagitis
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• The patients condition was not sufficiently
  controlled with alendronate, so she began therapy
  with a nasal spray containing a protein that
  inhibit bone resorption. The drug contained in
  the nasal spray was
• Calcitonin
• Calcitriol
• Cinacalcet
• Cortisol
• Teriparatide

Calcitonin