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
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
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
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
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.
33.
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.