osteoporosis
DESCRIPTION
Pharmacotherapy of Osteoporosis.TRANSCRIPT
PHARMACOTHERAPY OF OSTEOPOROSIS
Dr. JITENDRA AGRAWALSecond Year Resident
OSTEOPOROSIS Reduction in strength of bone
that leads to an increased risk of fracture
Bone mass – reduced, Internal bone architecture –
degradesDecreased bone formation Increased bone resorption
PHARMACOLOGICAL AGENT
ANTIRESORPTIVE BONE ANABOLIC AGENT
BisphosphonatesSERMHRTRANKL antagonistCalcitoninCathepsin K Inhibitor
(Odanacatib ) r Osteoprotegerin
Parathyroid hormoneStrontium Ranelate Endogenous PTH
stimulation – calcium sensing receptor antagonist (calcilytic)
Sclerostin inhibitor
ANTIRESORPTIVE
BISPHOSPHONATES
3rd GenerationRisedronateZoledronate
1st GenerationEtidronateTiludronate
2nd GenerationPamidronateAlendronateIbandronate
BISPHOSPHONATESPyrophosphate 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
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
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.
AlendronateApproved for:
◦Treatment and prevention of osteoporosis in post – menopausal women
◦Treatment of osteoporosis in men◦Treatment of steroid induced
osteoporosisDose : 10mg /d or 70 mg/ weekRoute : oral
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
RisedronateControlled 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%.
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 Glucocorticoid-
Induced Osteoporosis◦ 5 mg daily
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
◦ 3 mg every 3 months IV
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 hip fractures by 40%
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
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
BISPHOSPHONATES – ADVERSE EFFECTS
Oral bisphosphonates can cause heartburn, esophageal irritation, or esophagitis.
Other GI side effects include abdominal pain and diarrhea
Osteonecrosis of the jawHypocalcemiaMusculo-skeletal pain
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
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
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
LASOFOXIFENE
Investigational SERM
Not approved by FDA, US.
Approved by the European Commission
for the treatment of osteoporosis
fractures in post-menopausal women.
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.
OTHER SERMs under Clinical Trials:
Bazedoxifene Ospemifene Arzoxifene
Hormone Replacement TherapyHRT restores the Ca 2+ balanceBone loss is preventedAdministered orally or
transdermallyDoses: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.
Hormone Replacement TherapyWHI (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.
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.
DenosumabDose : 60 mg every 6 monthRoute : 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
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.
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.
ODANACATIB
Cathepsin K- plays a key role in
degradation of the matrix
Cathepsin K Inhibitor
Investigational Drug
Under Clinical Trial
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.
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.
BONE ANABOLIC
AGENT
PARATHYROID HORMONE - TERIPARATIDE
Exogenous PTH analogueRecombinant 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
TERIPARATIDEReduced 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.
TERIPARATIDEApproved for :
◦Osteoporosis in postmenopausal women
◦ Idiopathic and hypogonadal osteoporosis in
men◦Glucocorticoid induced osteoprorosis
DOSE : 20 mcg / day ROUTE : SCSide effects :
◦ muscle pain, weakness, dizziness, headache, and nausea
In Rodents – caused osteogenic sarcoma
STRONTIUM RANELATEA 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 pre-osteoblast 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.
STRONTIUM RANELATE
Not approved by US FDA
Approved in European Country
Indicated for post- menopausal
osteoporosis
Dose : 2 g / day
Route : oral
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 calcium-sensing receptor (calcilytics) stimulate PTH secretion
Investigational drug
SCLEROSTIN INHIBITOR
Sclerostin is a potent inhibitor of
osteoblastogenesis is a
glycoprotein secreted by
osteocytes
Monoclonal antibody
can be administered
subcutaneously
Investigational Drug
References:
1. 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.
2. 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.
3. Robert M. Neer, Ehrin J. Armstrong, Armen H. Tashjian, Jr. Pharmacology of Bone Mineral Homeostasis. In: David Golan, editor. Principles of Pharmacology, The Pathophysiological Basis of Drug Therapy, 3rd ed. Philadelphia: Lippincott Williams and Wilkins Publications; 2012.p.541-61.
4. 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.
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.
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