Osteoporosis is a disease characterized by low bone mass and deterioration of bone structure. It increases bone fragility and risk of fractures. Primary types include postmenopausal osteoporosis in women over 50 and senile osteoporosis in those over 70. Treatment focuses on preventing bone loss and increasing bone mass. First line drugs are bisphosphonates like alendronate and risedronate. Second line includes selective estrogen receptor modulators like raloxifene. Non-pharmacological prevention focuses on calcium, vitamin D, and weight-bearing exercise.

1. PHARMACOTHERAPY
OF OSTEOPOROSIS
1
Dr. Rupesh Dalavi
JR - I
Dept. of Pharmacology

2. OSTEOPOROSIS
2
 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

3. TYPES OF OSTEOPOROSIS
3
 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.  SECONDARY
 Due to systemic illness or medication (glucocorticoid)
 Most successful approach: prompt resolution of
underlying cause or drug discontinuation
4

5. RISKS FOR OSTEOPOROSIS
5
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

6. 6

7. DIAGNOSIS
7
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

8. 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.
8

9. LABORATORY TESTS
9
 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.

10. CURRENT TREATMENT OPTIONS
FOR OSTEOPOROSIS
Treatment
10
Dosage Form
Hormone replacement therapy (HRT)
Calcitonin
Oral, transdermal
Nasal spray (daily)
Selective estrogen receptor modulators Oral (daily)
Bisphosphonate: Alendronate
Teriparatide Parathyroid Hormone
Oral (daily, weekly)
S.C

11. INTEGRATED APPROACH TO
PREVENT AND TREAT
OSTEOPOROSIS
11

12. 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).
12

13. TREATMENT OF OSTEOPOROSIS
13
 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)

14. ANTIRESORPTIVE DRUGS
SELECTIVE ESTROGEN RECEPTOR
MODULATORS
BISPHOSPHONATES
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15. BISPHOSPHONATES
15

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

17. CELLULAR MECHANISM OF ACTION
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
17

18. PRECAUTIONS
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 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

19. 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
19

20. ALENDRONATE
20
 II generation nitrogen containing bisphosphonate.
for prevention and
treatment of steroid
 FDA approved on 7 April 2005
treatment of postmenopausal and
induced osteoporosis.
 Decreases risk of vertebral & hip fractures.

21.  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.
21

22. PAMIDRONATE
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 II generation bisphosphonate.
 Available only as IV preparation because 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.

23. IBANDRONATE
23
 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.

24. ZOLENDRONATE
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 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.

25. RISEDRONATE
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 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

26. 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

27. SELECTIVE ESTROGEN
RECEPTOR MODULATORs
(SERMs)
27

28.  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.
28

29. The “Ideal” SERM Would be
Strengthen bones
Lower LDL cholesterol and raise HDL cholesterol
Relieve hot flushes
Reduce breast cancer risk
Reduce uterine cancer risk
29

30. RALOXIFENE
30
 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.

31. 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
31

32. CALCITONIN
32
 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.

33. VIT-D
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 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.

34. TERIPARATIDE
34
 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.

35.  Significantly increases bone mineral density, especially in
the spine.
 Faster acting than bisphosphonate & SERMs
 Effective in glucocorticoid induced osteoporosis.
 Dose is 20 μ
gper day SC.
 Side effects: leg cramps and dizziness.
35

36. RECENT ADVANCES
36

37. NERIDRONATE
37
 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.

38. DENOSUMAB
38
 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.

39.  Significantly reduced the incidence of new vertebral
fractures.
 Dose: 120 mg subcutaneously every 4 weeks.
 S/E: arthralgia and back pain due to hypocalcaemia.
39

40. ROMOSOZUMAB
40
 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.

41. CATHEPSIN K INHIBITORS
41
 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.

42. ODANACATIB
42
 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.

43. SRC KINASE INHIBITORS
43
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

44. TEDUGLUTIDE
44
 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.

45. ABALOPARATIDE
45
 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.

46. LASOFOXIFENE
46
 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

47. BAZEDOXIFENE
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 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

48. PREVENTION OF OSTEOPOROSIS
48

49. CONCLUSION
49
 Osteoporosis is a significant health risk – particularly in
postmenopausal women and men over 65.
 First line drugs for treatment of osteoporosis
are bisphosphonates, second line drug are
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.

50. REFERENCES
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 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

51. THANK YOU
51