Pharmacotherapy of Osteoporosis.

1. PHARMACOTHERAPY OF
OSTEOPOROSIS
Dr. JITENDRA AGRAWAL
Second Year Resident

2. OSTEOPOROSIS
Reduction in strength of bone that
leads to an increased risk of fracture
 Bone mass – reduced,
 Internal bone architecture – degrades
 Decreased bone formation
 Increased bone resorption


3. ANTIRESORPTIVE
BONE ANABOLIC AGENT
Bisphosphonates
 SERM
 HRT
 RANKL antagonist
 Calcitonin
 Cathepsin K Inhibitor
(Odanacatib )
 r Osteoprotegerin


Parathyroid hormone
 Strontium Ranelate
 Endogenous PTH
stimulation – calcium
sensing receptor
antagonist (calcilytic)
 Sclerostin inhibitor
PHARMACOLOGICAL AGENT

5. BISPHOSPHONATES
1st Generation
Etidronate
Tiludronate
2nd Generation
Pamidronate
Alendronate
Ibandronate
3rd Generation
Risedronate
Zoledronate

6. BISPHOSPHONATES
Pyrophosphate analouge : carbon
atom replacing oxygen in the P-O-P
skeleton
 The most effective antiresorptive drug
 1st generetion compound have simple
side chain
 2nd & 3rd generation have an amino or
nitrogenous ring substitution in the
side chain


7. Mechanism of Action
Strong affinity for calcium phosphate
↓
Concentrate in mineralized tissue
↓
Remain unmetabolized and biologically active
↓
Acids secreted by osteoclast dissociates it from
mineral
↓
Within osteoclast blocks mevalonate pathway
↓
Osteoclast apoptosis

8. Alendronate
Alendronate treatment (5 mg/d for 2 years and
10 mg/d for 9 months afterwards) reduces
vertebral fracture risk by about 50%, multiple
vertebral fractures by up to 90%, and hip
fractures by up to 50%.
 Trials comparing once-weekly alendronate, 70
mg, with daily 10-mg dosing have shown
equivalence with regard to bone mass and bone
turnover responses.
 once-weekly therapy generally is preferred
because of the low incidence of gastrointestinal
side effects and ease of administration.


9. Alendronate

Approved for:
◦ Treatment and prevention of osteoporosis
in post – menopausal women
◦ Treatment of osteoporosis in men
◦ Treatment of steroid induced osteoporosis
Dose : 10mg /d or 70 mg/ week
 Route : oral


10. Alendronate

Empty stomach, full glass of water,
before breakfast

Remain upright for at least 30 min after
taking the medication

To
prevent
esophageal
irritation,
oesophagitis

Contraindicated in patients who have
stricture or inadequate emptying of the
esophagus

11. Risedronate

Controlled clinical trials have demonstrated
40–50% reduction in vertebral fracture risk
over 3 years, accompanied by a 40%
reduction in clinical nonspine fractures.

The only clinical trial specifically designed
to evaluate hip fracture outcome (HIP)
indicated that risedronate reduced hip
fracture risk in women in their seventies
with confirmed osteoporosis by 40%.

12. Risedronate

Osteoporosis in Postmenopausal Women:
◦
◦
◦
◦

5 mg daily
35 mg once a week
75 mg taken on two consecutive days each month
150 mg once a month
Prevention of Osteoporosis in Postmenopausal
Women:
◦ 5 mg daily, 35 mg once a week

Men with Osteoporosis:
◦ 35 mg once a week

Treatment and Prevention of GlucocorticoidInduced Osteoporosis
◦ 5 mg daily

13. Ibandronate

Reduce vertebral fracture risk by 40% but
with
no
overall
effect
on
nonvertebral
fractures

Approved for
◦ Treatment and prevention of postmenopausal
osteoporosis

Dose:
◦ One 150 mg tablet taken once monthly
◦ one 2.5 mg tablet taken once daily

14. Zoledronate

Highly
effective
in
fracture
risk
reduction

Zoledronic acid (5 mg as a single IV
infusion annually) reduced the risk of
vertebral
fractures
by
70%,
nonvertebral fractures by 25%, and

15. Zoledronate

Approved For:
◦ Treatment of osteoporosis in
postmenopausal women
◦ Treatment to increase bone mass in men
with osteoporosis
◦ Treatment and prevention of
glucocorticoid-induced osteoporosis in
patients expected to be on glucocorticoids
for at least 12 months

16. Zoledronate

Dose
◦a
5
mg
infusion
once
a
year
given
intravenously over no less than 15 minutes

Administer through a separate vented
infusion line and do not allow to come in
contact with any calcium or divalent
cation-containing solutions

17. BISPHOSPHONATES –
ADVERSE EFFECTS
Oral bisphosphonates can cause
heartburn, esophageal irritation, or
esophagitis.
 Other GI side effects include
abdominal pain and diarrhea
 Osteonecrosis of the jaw
 Hypocalcemia
 Musculo-skeletal pain


18. SERMs

Group of compound – binds to estrogen
receptor (ER)

Tissue selective effects on target organ

Estrogen agonist or antagonist

Retain the beneficial effects on estrogen
in one or more tissues

Eliminates the undesirable effects of
estrogen in other tissue

19. RALOXIFENE

Estrogen agonist in bone , antagonist in
breast and endometrium

Approved
for
the
treatment
and
prevention of osteoporosis in post –
menopausal women

Dose: 60 mg/d, orally

Increases bone mass density

Reduce the risk of breast cancer

No risk of endometrial carcinoma

20. RALOXIFENE

Reduces
serum
total
and
low-density
lipoprotein cholesterol, lipoprotein(a), and
fibrinogen. Reduce vertebral fracture

No effect on incidence of heart disease

Increase risk of venous thromboses and
pulmonary embolism

Increases the occurrence of hot flashes

21. LASOFOXIFENE

Investigational SERM

Not approved by FDA, US.

Approved by the European Commission
for
the
treatment
of
osteoporosis
fractures in post-menopausal women.

22. LASOFOXIFENE

Phase II or phase III clinical trials
demonstrated efficacy and safety in the
suppression of bone loss and the prevention
of vertebral and nonvertebral fractures.

Reduce breast cancer risk and the
occurrence of vaginal atrophy.

23. OTHER SERMs under Clinical
Trials:
Bazedoxifene
 Ospemifene
 Arzoxifene


24. Hormone Replacement
Therapy






HRT restores the Ca 2+ balance
Bone loss is prevented
Administered orally or transdermally
Doses:
oral estrogens
esterified estrogens - 0.3 mg/d
 conjugated equine estrogens - 0.625
mg/d
 ethinyl estradiol – 5 mcg/d .
Transdermal estrogen,
◦ 50 mcg estradiol per day.

25. Hormone Replacement
Therapy

WHI (Womens Health Initiative) data:

Hip and vertebral fractures reduced by 34%

All osteoporotic fractures reduced by 24%

Increased risk of fatal and nonfatal myocardial
infarction by 29%


Risk of invasive breast cancer increased by 25%
The FDA now recommends that estrogen be
reserved for women at significant risk of
osteoporosis who cannot take other
medications.

26. RANKL antagonist - Denosumab

Human monoclonal antibody

Target - RANKL (RANK ligand)

Approved by the FDA in 2010
◦ Treatment of postmenopausal women who
have a high risk for osteoporotic fractures,
including those with a history of fracture or
multiple risk factors for fracture
◦ Who have failed or are intolerant to other
osteoporosis therapy.

27. Denosumab
Dose : 60 mg every 6 month
 Route : S.C.
 Increase BMD in the spine, hip, and
forearm and reduce vertebral, hip, and
nonvertebral fractures
 Adverse reactions

◦ hypocalcemia, infections, and
dermatologic reactions such as dermatitis,
rashes, and eczema
◦ Osteonecrosis of jow

28. CALCITONIN

Polypeptide hormone produced by the
thyroid gland

Suppresses osteoclast activity by
direct action on the osteoclast
calcitonin receptor

Approved by the FDA for osteoporosis
in women >5 years past menopause.

29. CALCITONIN

Preparation :
◦ Nasal spray : 200 IU/d
◦ Parentral : S.C. or I.M. 50 to 100
IU/alternative day

Difficulty of administration and
frequent reactions, including nausea
and facial flushing, make general use
limited.

30. ODANACATIB

Cathepsin K- plays a key role in
degradation of the matrix

Cathepsin K Inhibitor

Investigational Drug

Under Clinical Trial

31. Gene therapy ( r Osteoprotegerin

Osteoprotegerin (OPG) is a naturally
occuring protein that prevents bone
resorption by inhibiting osteoclast formation,
function and survival

Binds to RANKL and prevents its binding to
RANK on Osteoclast precursor and
osteolclast

Gene therapy has the potential to deliver
protein-based antiresorptive agents without
the need for repeated administration.

32. Gene therapy ( r
Osteoprotegerin)

Adeno-associated virus (AAV) could
deliver OPG at levels that are sufficient
to reverse established osteopenia in
ovariectomized (OVX) mice without
causing liver toxicity

AAV delivery appears to be a safe and
effective method for producing sustained
systemic exposure to OPG.

34. PARATHYROID HORMONE TERIPARATIDE




Exogenous PTH analogue
Recombinant human parathyroid
hormone (1-34), [rhPTH(1-34)]
Direct actions on osteoblast activity
Stimulates IGF-I and collagen
production and appears to increase
osteoblast number by stimulating
replication, enhancing osteoblast
recruitment, and inhibiting apoptosis

35. TERIPARATIDE




Reduced vertebral fractures by 65% and
nonvertebral fractures by 45%
Increases in bone mass and mediates
architectural improvements in skeletal
structure.
These effects are lower when patients
have been exposed previously to
bisphosphonates
When 1–34hPTH is being considered
for treatment-naive patients, it is best
administered as monotherapy and
followed by an antiresorptive agent such
as a bisphosphonate.

36. TERIPARATIDE

Approved for :
◦ Osteoporosis in postmenopausal women
◦ Idiopathic and hypogonadal osteoporosis in
men
◦ Glucocorticoid induced osteoprorosis



DOSE : 20 mcg / day
ROUTE : SC
Side effects :
◦ muscle pain, weakness, dizziness,
headache, and nausea

In Rodents – caused osteogenic

37. STRONTIUM RANELATE



A new antiosteoporotic treatment with a
dual mode of action, both increasing
bone formation and decreasing bone
resorption
Stimulates the calcium sensing receptors
and leads to the differentiation of preosteoblast to osteoblast which increases
the bone formation.
Stimulates osteoblasts to secrete
osteoprotegerin in inhibiting osteoclasts
formed from pre-osteoclasts in relation to
the RANKL system, which leads to the
decrease of bone resorption.

38. STRONTIUM RANELATE

Not approved by US FDA

Approved in European Country

Indicated for post- menopausal
osteoporosis

Dose : 2 g / day

Route : oral

39. CALCIUM SENSING
RECEPTOR ANTAGONIST
(CALCILYTIC)
Calcium-sensing receptor (CaSR) is a
G protein-coupled receptor which was
identified as a molecule that
medicates
the
suppression
of
parathyroid hormone (PTH) secretion
by extracellular Ca.
 Oral antagonists of the calciumsensing receptor (calcilytics) stimulate
PTH secretion
 Investigational drug


40. SCLEROSTIN INHIBITOR

Sclerostin
is a potent inhibitor of
osteoblastogenesis is a glycoprotein
secreted by osteocytes

Monoclonal antibody

can be administered subcutaneously

Investigational Drug

41. References:
1.
2.
3.
4.
Robert Lindsay, Felicia Cosman. Osteoporosis. In: Fauci S,
editor : Harrison’s Principles of Internal Medicine, 18th ed. .
New York: Mcgraw Hill; 2012.p.3120- 35.
Peter A Friedman.Agents Affecting Mineral Ion Homeostasis
and Bone Turnover In: Brunton L, editor.Goodman &
Gillman’s The Pharmacological Basis of Therapeutics, 12th
ed. New York: Mcgraw Hill; 2011.p.1275- 1306.
Robert M. Neer, Ehrin J. Armstrong, Armen H. Tashjian, Jr.
Pharmacology of Bone Mineral Homeostasis. In: David
Golan,
editor.
Principles
of
Pharmacology,
The
rd
Pathophysiological Basis of Drug Therapy, 3
ed.
Philadelphia: Lippincott Williams and Wilkins Publications;
2012.p.541-61.
Lewiecki EM. Odanacatib, a cathepsin K inhibitor for the
treatment of osteoporosis and other skeletal disorders
associated with excessive bone remodeling. IDrugs. 2009
Dec;12(12):799-809.

42. References:


John MR et al. ATF936, a novel oral calcilytic, increases bone
mineral density in rats and transiently releases parathyroid
hormone in humans. Bone. Aug 2011;49(2):233-41. Epub
2011 Apr 14.
Luigi Gennari, Daniela Merlotti, Vincenzo De Paola, and
Ranuccio Nuti. Lasofoxifene: Evidence of its therapeutic
value in osteoporosis. Core Evid. 2009; 4: 113–129.