Osteoporosis Treatment

1
Osteoporosis Treatment

• Dr. SAEED AHMED

2
osteoporosis

• Bone undergoes a continuous remodeling, process
  involving bone resorption and formation.
• Any process that disrupt this balance by
  increasing resorption relative to formation
  results in osteoporosis

3
Drugs used in osteoporosis

• Calcium
• Vit D
• HRT(estrogen)
• Raloxifene (SERM)
• BISPHOPHONATES
• Calcitonin
• Teriparatide ( PTH, recombinant)

4

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

5

• Causes/ Risk factors
• Long-term use of glucocorticoides/ other drugs
• As a manifestation of endocrine disease
  (thyrotoxicosis/ hyperparathyroidism)
• Malabs syndrome
• Alcohol abuse cigarette smoking
• Age gt 65 yrs
• Idiopathic.
• Occur in elderly in both sexes, \ is most
  pronounced in postmenopausal women.

6
Osteoporosis

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

7
Calcitonin

• Nature A 32-amino acid-polypeptide secreted by
  parafollicular(C-) cells of the thyroid gland
• Calcitonin acts to decrease calcium concentration
  via calcitonin receptors in osteoclasts, GIT,
  kidney brain
• Inhibits Ca2 absorption by the intestines
• Inhibits osteoclast activity in bones
• Inhibits Ca2/phosphate reabsorption by the
  kidney tubules
• Post-menopausal women tend to possess lower
  levels of plasma calcitonin levels
• Pharmaceutical formulations include
• Nasal spray
• Parenteral formulation for IM or S.C. injection

8
Calcitonin

• Pharamcological Actions
• Osteoclasts size motility are decreased leading
  to inhibition of bone resorption
• It inhibits the parathyroid hormone-induced
  acceleration of bone turnover
• GIT gastrin pancreozymin or increased serum
  Ca2 stimulate calcitonin secretion
• It increases renal excretion of Na, K, Ca2,
  Mg2, and phosphate

9
Calcitonin Pharmacokinetics

• Rapid absorption from injection sites (slow with
  addition of gelatin)
• Half-life is short of about 20 minutes
• Weak protein binding
• Renal and hepatic metabolism
• Nasal spray calcitonin has 5-50 availability
  when compared to IM route

10
Calcitonin adverse effects

• Adverse effects are dose-dependent and more
  frequent with parenteral use but rarely observed
  after nasal spray administration
• They include
• Anorexia, nausea, fascial flushing
• Urticaria or anaphylaxis is rare
• Long-term use may lead to formation of antibodies
  that possibly are ineffective
• Uncommon drug-drug interacions except for K
  depletion when calcitonin combined with thiazide
  diuretics

11
Calcium and Vitamin D

• Vitamin DCa2 absorption activation
• PTH up-regulates 25-OH-vitaminD3-1-alpha-hydroxyla
  se in the kidney
• This enzyme activates hyroxylation of
  25-OH-vitamin D, to its active form
  1,25-dihydroxy vitamin D
• This activated form of vitamin D increases the
  absorption of Ca2 ions by the intestine via
  calbindin

12
Calcium and Vitamin D Preparations

• Ca chloride, Ca citrate, Ca lactate, Ca
  gluconate, and Ca carbonate (richest Ca source)
• Insoluble Ca carbonate contains 40 elemental
  Ca2, after conversion to Ca salts in the body
• Vitamin D Used forms 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/week
• 1,25-dihydroxyvitamin-D (calcitriol), the active
  form

13
Calcium and Vitamin D

• 1500 mg of Calcium and 800 IU of vitamin D per
  day are recommended for postmenopausal women
• Vitamin D receptors (VDR) activation in the
  intestine, bone, kidney, parathyroid gland cells
  leads to the maintenance of calcium and
  phosphorus levels in the blood to the
  maintenance of bone content
• Parathyroid hormone and calcitonin play a role

14
Calcium and Vitamin DAdverse Effects

• Oral calcium may cause
• Gastric irritation, nausea constipation
• Excessive Ca? hypercalcemic toxicity especially
  in presence of high vitamin D intake
• Decreased tetracycline absorption
• Vitamin D
• Overdose ? hypercalcemia hyperphosphatemia
• Renal dysfunction (nephro-lithisis -calcinosis)
• Localised/generalised lowered bone density
• GIT complaints

15
Hormone Replacement Therapy (HRT)

• Estrogen deficiency causes bone loss via
  increased bone resorption over bone formation
• 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 CerebroV diseases, gall bladder
  disease, DVT, pulmonary emboli, breast cancer

16
Selective Estrogen Receptor Modulators
(SERMs)Raloxifene

• Non-hormonal agents that bind to estrogen
  receptors with an affinity equivalent to
  estradiol
• They induce estrogen-like effects in some but not
  all tissues
• Raloxifene (60 mg/day) is the only approved
  member for prevention treatment of osteoporosis
• Pharmacokinetics
• It is rapidly absorbed by 60 from oral route
• It has low bioavailability (2) because of
  extensive first-pass metabolism and glucuronide
  conjugation
• It has high plasma protein binding
• Cholestyramine reduces absorption enterohepatic
  cycling

17
RaloxifeneEffects on BMD and Bone Turnover

• Clinical evidence (MORE) of 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

18
RaloxifeneExtra-Skeletal 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 of incidence of the estrogen
  receptor-dependent invasive breast cancer in
  low-risk osteoporotic post-menopausal women
• Adverse Effects It is safe and well-tolerated
• Increased hot flashes leg cramps
• Infrequent venous thromboembolism (VTE), not
  related to leg cramps
• Contraindicated in patients with VTE history

19
Bisphosphonates

• They are used for many bone diseases including
  osteoporosis, Pagets disease, malignacy
  hypercalcemia and bone metastases
• They have a very high affinity for bone tissue,
• 50 of administered dose is excreted unchanged by
  the kidney, the remainder is rapidly taken up by
  the osteoclasts
• Pharmacokinetics
• Poor absorption (2 during fasting)
• Food reduces absorption
• T1/2 1 hour
• Administered 1 hour before meals with water only

20
BisphosphonatesMechanism of Action

• Pyrophosphate-like
• Etidronate
• Metabolised in the cell to forming a
  nonfunctional cytotoxic ATP molecules
• Apoptosis/cell death of osteoclast occurs leading
  to a decrease in the breakdown of bone

• Nitrogen-containing
• Alendronate Risedronate
• 1000-times more potent
• Blocking the enzyme farnesyl diphosphate synthase
  (FPPS) in the HMG-CoA reductase (the mevalonate)
  pathway
• This prevents the formation of two metabolites
  essential for connecting some small proteins to
  the cell membrane (prenylation)
• Proper sub-cellular protein trafficking is
  impaired as well

J Bone Miner Res. 1997, 12(9) 1358-67 Bone 2003
33 (5) 80511
21
BisphosphonatesAdverse Effects

• Oral N-containing bisphosphonates may cause upset
  stomach and inflammation erosions of the
  esophagus, can be prevented by remaining seated
  upright for 30 to 60 minutes after taking the
  medication
• N-containing bisphosphonates contraindicted with
  esophageal pathology
• Intravenous bisphosphonates can give fever and
  flu-like symptoms after the first infusion only
• A slightly increased risk for electrolyte
  disturbances
• In chronic renal failure, the drugs are excreted
  much more slowly, and dose adjustment is required
• At high doses, etidronate may cause osteomalcia

22
Parathyroid Hormone (PTH)Teriparatide
rhPTH(1-34)

• Recombinant hPTH(1-34) showed good efficacy
  against vertebral non-vertebral fractures in
  post-menopausal 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 /or hypercalciuria

23
Parathyroid Hormone (PTH)Reminder of Activity

• PTH acts to increase the concentration of calcium
  in the blood by acting upon PTHR in three organs
• Bone It enhances the release of calcium from the
  large reservoir contained in the bones
• Kidney It enhances active re-absorption of
  calcium and magnesium from distal tubules and the
  thick ascending limb and increases the excretion
  of phosphate
• Intestine It enhances the absorption of calcium
  in the intestine by increasing the production of
  activated vitamin D in the kidney