by: Dr. Vishal Pawar, MD Pharmacology all u need to know regarding the treatment of osteoporosis

1. PHARMACOTHERAPY
OF OSTEOPOROSIS
Dr. Vishal Pawar
JR II
Dept. of Pharmacology
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2. OSTEOPOROSIS
 World Health Organization
“A bone mineral density < 2.5 standard deviation below the
young normal mean.”
 A systematic skeletal disease characterized by low bone
mass and micro architectural deterioration of bone tissue.
 Consequent increase in bone fragility and susceptibility to
fractures with minimal trauma
2

3. PROBLEM STATEMENT
 Osteoporosis is a disease that usually affects elderly,
where the bones become thin and weaken from calcium
depletion.
 The condition remains silent and undetected in many
cases until a fracture occurs.
 Most serious consequence of menopause.
 Osteoporosis is the most common cause of fractures in
older people.
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4. TYPES OF OSTEOPOROSIS
 PRIMARY
Type I (postmenopausal osteoporosis)
 Women > men, typically develops between 50 and 70yrs.
 Results in decrease in the amount of trabecular bone
(the spongy bone inside of hard cortical bone).
Type II osteoporosis (senile osteoporosis)
 Typically happens after 70yrs and affects women twice as
frequently as men.
 Thinning of both trabecular bone and hard cortical bone.
4

5.  SECONDARY
 Due to systemic illness or medication (glucocorticoid)
 Most successful approach: prompt resolution of
underlying cause or drug discontinuation
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6. RISKS FOR OSTEOPOROSIS
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In young women
Low calcium intake
Low body weight
Hypoestrogenism
In others
Menopausal/postmenopausal
status without HRT
Cigarette smoking
Alcohol consumption
Low-trauma fractures
Hyperparathyroidism
Chronic corticosteroid use

7. 7

8. DIAGNOSIS
A medical evaluation to diagnose osteoporosis and
estimate risk of breaking a bone may involve one or
more of the following steps:
 Medical history
 Physical examination
 Bone density test
 Laboratory tests
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9. DENSITOMETRIC EVALUATION BY
DUAL ENERGY X RAY
 Only test that can diagnose osteoporosis before a broken
bone occurs.
 Helps to estimate the density of bones and chance of
breaking a bone.
 At present, DEXA scanning focuses on two main areas hip
and spine.
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10. LABORATORY TESTS
 Blood calcium levels
 24-hour urine calcium measurement
 Parathyroid hormone levels
 Testosterone levels in men
 25-hydroxyvitamin D test to determine whether the body
has enough vitamin D.
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11. CURRENT TREATMENT OPTIONS
FOR OSTEOPOROSIS
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Treatment Dosage Form
Hormone replacement therapy (HRT) Oral, transdermal
Calcitonin Nasal spray (daily)
Selective estrogen receptor modulators Oral (daily)
Bisphosphonate: Alendronate Oral (daily, weekly)
Teriparatide Parathyroid Hormone S.C

12. INTEGRATED APPROACH TO
PREVENT AND TREAT
OSTEOPOROSIS
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13. NON-PHARMACOLOGICAL
TREATMENT
 Nutrition:
 Calcium supplementation as needed
most common: Calcium Carbonate (1200 mg total)
 Vitamin D as needed (400 IU to 800 IU daily)
 Exercise: weight bearing and strength training exercises.
 Multiple health benefits
 Fall prevention and/or hip protectors in the frail elderly
 Avoiding alcohol and tobacco abuse ( osteoblastic activity).
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14. TREATMENT OF OSTEOPOROSIS
 Bone loss in osteoporosis results from an imbalance
between the two components of the bone renewal
process: Bone Resorption And Bone Formation.
 The goal of treatment is to prevent bone fractures by:
 Stopping bone loss (Antiresorptive)
 Increasing bone mass and strength (Anabolic)
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15. 15
ANTIRESORPTIVE DRUGS
SELECTIVE ESTROGEN RECEPTOR
MODULATORS
BISPHOSPHONATES

16. BISPHOSPHONATES
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17. CLASSIFICATION
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I
Etidronate
Medronate
Clodronate
Tiludronate
II
Alendronate
Pamidronate
Ibandronate
III
Risedronate
Zoledronate
Neridronate
LEAST POTENT MOST POTENT

18. CELLULAR MECHANISM OF ACTION
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1. Osteoclast actively reabsorbs bone matrix
2. Bisphosphonate ( ) binds to bone
mineral surface
3. Bisphosphonate is taken up by
the osteoclast
4. Osteoclast is inactivated
5. Osteoclast becomes apoptotic and dies

19. PRECAUTIONS
 Administered with a full glass of water following an
overnight fast and at least 30 minutes before breakfast
and should remain upright
 Patients with active upper GI disease, decreased renal
function should not be given oral bisphosphonates
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20. 20
Bisphosph-
onates
Osteoporosis
Hypercal-
cemia due to
Bone
metastasis
Osteolytic
lesions of
Bone
metastasis
DEXA scan for
Bone Mineral
Density values
Paget’s
Disease of
bone

21. ALENDRONATE
 II generation nitrogen containing bisphosphonate.
 FDA approved on 7 April 2005 for prevention and
treatment of postmenopausal and treatment of steroid
induced osteoporosis.
 Decreases risk of vertebral & hip fractures.
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22.  5-10 mg daily dose/ 30-35mg weekly, orally.
 Taken on empty stomach with glass of water, should not
lie down for half hour.
 Maximum duration of therapy is for 7 yrs.
 Side effects - esophagitis, myalgias, less compliance.
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23. PAMIDRONATE
 II generation bisphosphonate.
 Available only as IV preparation b/c of poor GI absorption
and high frequency of GI symptoms.
 I.V. Pamidronate: approved for Hypercalcemia of
malignancy & other skeletal disorders, Paget’s disease.
 Adverse effects: bone pain, thrombophelebitis of vein, fever,
leucopenia.
 Acute and delayed hypersensitivity reaction can occur with
i.v pamidronate.
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24. IBANDRONATE
 II generation bisphosphonate
 Administered every 3 months as single intravenous injection
over a period of 15 to 30 seconds.
 Approved for prevention and treatment of Osteoporosis
related vertebral fracture in 6 January 2006.
 Compliance with monthly dose is good.
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25. ZOLENDRONATE
 III generation bisphosphonate
 Approved: treatment of malignant hypercalcemia, multiple
myeloma and skeletal metastasis on 20 August 2001.
 Inhibition of proliferation of bony metastasis of prostate /
breast cancer.
 Only available in IV preparation. 4mg/day for one year.
 Dose Reduction in bone turnover and increased bone mineral
density.
 Osteonecrosis of jaw is adverse effect with long term use.
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26. RISEDRONATE
 Third generation nitrogen containing bisphosphonate.
 FDA approved in 27 march 1998 for prevention and
treatment of postmenopausal and steroid induced
osteoporosis.
 Reduced incident of vertebral and hip fracture.
 Dose is 5 mg daily or 30-35 mg weekly, orally
 S/E esophagitis, myalgias, less compliance
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27. BISPHOSPHONATE SIDE EFFECTS
 GIT upset: Inflammation/erosions of esophagus.
 Nausea, dyspepsia.
 Fever/flu-like symptoms- myalgias, arthalgias.
 Increased risk of Atrial fibrillation.
 Transient hypocalcaemia with secondary hyperparathyroidism.
 Ocular inflammation.
 Bisphosphonate related ostionecrosis of jaw. 27

28. SELECTIVE ESTROGEN
RECEPTOR MODULATORs
(SERMs)
28

29.  SERMs are ER ligands that act like estrogens (agonist) in
bone, liver & estrogen antagonist in breast tissue.
 Classification:
 Tamoxifen and analogues:
Tamoxifen, Toremifene, Droloxifene, Idoxifene
 Fixed ring compound
Raloxifene, Lasofoxifene, Arzoxifen, Miproxifene,
Ormeloxifene, Levormeloxifene.
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30. 30
The “Ideal” SERM Would be
Strengthen bones
Lower LDL cholesterol and raise HDL cholesterol
Relieve hot flashes
Reduce breast cancer risk
Reduce uterine cancer risk

31. RALOXIFENE
 It non-specifically acts on both the estrogen receptors ERα
and ERβ.
 It act as partial agonist in bone & cardiovascular system,
antagonist endometrium & breast.
 It prevent bone loss, increases bone mineral density, agonist
activity in lipid metabolism and coagulation profile.
 Increases Bone Mineral Density (BMD) by 0.9-3.4 % and
reduces the risk of vertebral fractures.
 Less effective than bisphosphonate.
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32. Pharmacokinetics:
 Well absorbed orally
 Dose 60 mg once a day
Use:
 Prevention and treatment of postmenopausal osteoporosis
in women.
 Prevention of breast cancer in women having risk factor.
Adverse Effect:
 Hot flushes, leg cramps, vaginal bleeding.
 Increased risk of venous thromboembolism
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33. CALCITONIN
Inhibits bone resorption by action on osteoclast by reducing
contact of osteoclast with respective pit.
Reduces the remodeling space.
Significantly reduces vertebral fracture than non-vertebral
fracture in postmenopausal women.
Calcitonin: 200 units daily by nasal spray
Approved for treatment (not prevention)
Adverse effects: nausea, flushing, epistaxis, nasal
stuffiness.
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34. VIT-D
 Increases recruitment & differentiation of osteoclast
precursor.
 Reduces bone remodeling.
 Acts on osteoblast cell to increase bone mineralization
indirectly by maintaining plasma calcium concentration.
 Osteoporosis due to hyperparathyroididsm
 Dose: 100-200,000 IU of vitamin D2 or D3, orally daily or
every two months for six months.
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35. TERIPARATIDE
 It is recombinant human parathyroid hormone analogue.
 FDA has approved in 2002 for severe osteoporosis.
 Only agent that increases new bone formation (Anabolic)
 Increases the axial bone mineralization but has no effect
on cortical bone.
 Also for treatment of osteoporosis in men and women who
are at high risk of breaking a bone as a result of taking
steroid medicines for a long time.
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36.  Significantly increases bone mineral density, especially in
the spine.
 Faster acting than bisphosphonate & SERMs
 Effective in glucocorticoid induced osteoporosis.
 Dose is 20 μg per day SC.
 Side effects: leg cramps and dizziness.
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37. RECENT ADVANCES
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38. NERIDRONATE
 It’s an amino bisphosphonate, licensed in Italy for the
treatment of osteogenesis imperfecta (OI) and Paget’s
disease of bone (PDB).
 Completed phase 3 .
 Neridronate may be administered both intravenously and
intramuscularly.
 More potent than first generation bisphosphonate.
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39. DENOSUMAB
 FDA approved for osteoporosis in 2011.
 It’s a monoclonal antibody
 Binds to RANKL, a protein involved in the formation,
function, and survival of osteoclasts, the cells responsible
for bone resorption.
 Denosumab resulted in a statistically significant effect on
BMD as compared to placebo in patients with non
metastatic prostate or breast cancer.
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40.  Significantly reduced the incidence of new vertebral
fractures.
 Dose: 120 mg subcutaneously every 4 weeks.
 S/E: arthralgia and back pain due to hypocalcaemia.
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41. ROMOSOZUMAB
 Humanized monoclonal antibody that targets sclerostin for
the treatment of osteoporosis.
 Sclerostin is expressed in osteocytes and some
chondrocytes and it inhibits bone formation by osteoblasts.
 Phase 3 of clinical trial.
 Increased bone density in the hip and spine in healthy men
and postmenopausal women.
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42. CATHEPSIN K INHIBITORS
 Cathepsin K is a protease which has high specificity
for kinins, that is involved in bone resorption.
 The enzyme's ability to catabolize elastin, collagen,
and gelatin allows it to break down bone and cartilage.
 Inhibition of Cathepsin K enzyme decreases the bone
resorption.
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43. ODANACATIB
 Phase 3 of clinical trial.
 It significantly reduced the risk of osteoporotic fractures
compared to placebo .
 Once weekly 50 mg injection is given.
 Adverse Effect: atrial fibrillation, skin rashes, stroke,
cereberovascular event.
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44. SRC KINASE INHIBITORS
SARACATINIB
 Src is a non receptor tyrosine kinase thought to be essential
for osteoclast function and bone resorption.
 Inhibits bone resorption by inhibiting osteoclast function.
 Phase 2 of clinical trial.
 S/E: anemia, nausea, anorexia, asthenia, pyrexia, vomiting,
diarrhea
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45. TEDUGLUTIDE
 Glucagon-like peptide 2 (GLP-2) analog.
 Most bone loss takes place at night and may be linked to
food intake.
 Bone resorption marker fall after feeding & GLP-2 level
rises after feeding.
 GLP-2 at bedtime significantly reduces overnight bone loss.
 Phase 2 of clinical trial for osteoporosis.
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46. ABALOPARATIDE
 It’s a new synthetic peptide analog of hPTHrP (human
parathyroid hormone-related protein).
 Phase 2 clinical trials.
 Reduction of fractures in postmenopausal osteoporosis.
 Statistically significant increases in BMD at the lumbar
spine, total hip, and femoral neck.
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47. LASOFOXIFENE
 Phase 3 of clinical trial.
 Third generation SERM.
 Good oral bioavailability
 Proapoptotic effect on osteoclast precursors.
 Adverse Effect: hot flashes, leg cramps, 2-fold increased
risk of venous thromboembolism
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48. BAZEDOXIFENE
 Phase 3 of clinical trial postmenopausal osteoporosis.
 Approved in the European Union (marketed in Italy, Spain).
 Significant decrease in metabolic bone markers was seen
with bazedoxifene treatment compared to placebo.
 Decreases the vertebral fracture than non-vertebral.
 S/E: hot flushes, leg cramps
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49. PREVENTION OF OSTEOPOROSIS
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50. CONCLUSION
 Osteoporosis is a significant health risk – particularly in
postmenopausal women and men over 65.
 First line drugs for treatment of osteoporosis is
bisphosphonate, second line drug is SERM.
 Eat a well-balanced diet rich in calcium and vitamin D.
 Engage in regular physical activity or exercise.
 Weight-bearing activities, such as walking, jogging,
dancing, and lifting weights, are the best for strong bones.
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51. REFERENCES
 Goodman and Gilman’s, Agents affecting Mineral ion homeostasis
and bone turnover, chapter 44, the pharmacological basis of
therapeutics, 12th edition,1275
 Bertram G. Katzung, Agents affecting Mineral ion homeostasis
and bone turnover, chapter 42, Basic and Clinical Pharmacology,
13th edition, 1008
 H. Sharma, estrogens, drugs affecting calcium balance, chapter
43,46; principles of pharmacology, 3rd edition, 584,624
 https://www.fda.gov/downloads/drugs/newsevents/ucm470574.pdf
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426100
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52. THANK YOU
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