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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