TERIPARATIDE

Teriparatide [rDNA origin]

ACTION: Works through a normal physiologic pathway via PTH receptors on bone

EFFECT: Increases bone remodeling

RESULT: Bone formation significantly exceeds bone resorption

OUTCOME: Increase in skeletal mass and bone strength

Teriparatide is an anabolic agent with a unique mechanism of action compared to that of currently available antiresorptive therapies.

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Ser Val Ser Glu Ile Gln Leu Met His AsnLeu

GlyLysHisLeuAsnSerMetGluArgValGlu

Trp

LeuArg Lys Lys Leu Gln Asp Val His Asn Phe

50

40

6070

80

-COOH

H2N-

Sequence is identical to that of 34 N-terminal amino acids of the endogenous 84-aminoacids

Intact PTH is hPTH (1-84)

Teriparatide is hPTH (1-34)- synthetic- recombinant

Human Parathyroid Hormone 1-34 and 1-841

acid human PTH

Busy slide

Teriparatide It is recombinant parathyroid

hormone that is approved for postmenopausal women and men with osteoporosis who are at high-risk for having a fracture or who have failed or been intolerant of previous osteoporosis therapy & in Steroid induced Osteoporosis.

Actions: Increases bone density and causesthickening of the outer shell of bones

Teriparatide [rDNA origin]

Teriparatide increases the number and action of osteoblasts to stimulate new bone formation on both trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity

It rapidly (in as little as 3 months) increase BMD in postmenopausal women with osteoporosis

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Preferentially osteoblastic bone formation over osteoclastic bone resorption

Skeletal mass and bone strength Lumbar spine and femoral neck BMD

Vertebral and non vertebral fractures

Back pain

Teriparatide – Pharmacological Action

Teriparatide is produced in a strain of E.coli employing recombinant DNA technology. It is a water soluble protein with a molecular weight of 4117.8 Daltons.

Significantly increases• whole BMD• lumbar BMD• femoral BMD

Significantly reduces • new vertebral fractures (RR - 0.35)• new non-vertebral fractures (RR - 0.54)

Administration and dose determine PTH effects on bone

Mode Effect

Daily(Low Dose) Anabolic

Continuous(High Dose) Catabolic

PTHonce-daily continuous

RANKL OPG

osteoclast

bone resorption

serum Ca++

osteoblast apoptosis

boneliningcells

cbfa1 (pre-OB)

osteoblast number/function

bone formation

bone mass/strength

Mode of Delivery Determines Skeletal Response to PTH

Parathyroid hormone (PTH) – Mechanism of action

PTH binds to cell surface G protein-coupled receptor

Decreased apoptosis of osteoblasts

Stimulates differentiation of bone lining cells and

preosteoblasts to osteoblast

Net increase in number and action of bone forming osteoblasts

Effects on Bone Remodeling

Effects of Antiresorptives

Effects of teriparatide [rDNA origin] injection

Normal Bone Remodeling Process

Resorption Cavities

Bone

Osteoclasts

Lining Cells

Lining Cells

Mineralized Bone

Osteoblasts

Osteoid

High Bone Turnover Leads to Development of Stress Risers and Perforations

Stress RisersPerforations

Bone

Osteoclasts

Biochemical Markers of Bone Turnover

Components of bone matrix that are released during the process of bone remodeling (resorption and formation)

Reflect, but do not regulate bone remodeling dynamics

Serum Markers of Bone Turnover

Formation

Bone alkaline phosphatase Bone ALP

Osteocalcin OC

Procollagen type I C propeptide PICP

Procollagen type I N propeptide PINP

Resorption

N-terminal cross-linking telopeptide of type I collagen NTX

C-terminal cross-linking telopeptide of type I collagen CTX

Tartrate-resistant acid phosphatase TRAP

Delmas P. J Bone Miner Res. 2001;16:2370.

Urine Markers of Bone Turnover

Resorption

Hydroxyproline HypPyridinoline PYDDeoxypyridinoline

DPDN-terminal cross-linking telopeptide

of type I collagen NTXC-terminal cross-linking telopeptide

of type I collagen CTX

Delmas P. J Bone Miner Res. 2001;16:2370.

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- 68

Months0 1 3 6 12

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-50

0

50

100

150

200

250Teriparatide

Months0 1 3 6 12

-100

-50

0

50

100

150

200

250Alendronate

NTxPINP

Mea

n %

Ch

ang

e w

ith

SE

197

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Biochemical Markers of Bone Turnover Contrasted Data on Mechanism of Action1

1. J Bone Miner Res . 2003;18:1932-1941.

After 21 monthsBaseline

These microCT images of iliac crest bone biopsies were obtained from a 65-year-old woman who had a BMD response that is representative of the treatment group.1 FORTEO forms normal-quality bone (as shown by lack of woven bone and marrow fibrosis).

Teriparatide [rDNA origin] Stimulates New Bone Formation

Thus is indicated for:

Treatment of postmenopausal women with osteoporosis at high risk for fracture

Primary or hypogonadal osteoporosis with high risk for fractures.

Treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy at high risk for fracture.

Indications

Teriparatide in Glucocorticoid-induced

Osteoporosis

Kenneth G. Saag1, Elizabeth Shane2, Steven Boonen3,Fernando Marin4, David W Donley4, Kathleen A. Taylor4,

Gail P. Dalsky4, Robert Marcus4

1University of Alabama at Birmingham, Birmingham, AL2Columbia University, New York, NY

3Katholieke Universiteit-Leuven, Leuven, Belgium4Lilly Research Laboratories, Indianapolis IN

Dosage and Administration

Recommended dose: 20 µg administered once daily

Route: To be injected subcutaneously in thigh or abdomen.

Concurrently the patients should receive calcium and vitamin D supplements if dietary intake is inadequate.

It should be administered initially while the patient is in a supine or sitting position as orthostatic hypotension may occur.The safety and efficacy of Teriparatide have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 18 months is not recommended.

Effects on Serum and Urine Biochemical Tests

Hypercalcemia was absent or mild and transient (normally 24 hours after dose)

Mean serum uric acid concentrations increased 13-20% (no sequelae)

No clinical adverse events were associated with increases in serum or urine calcium

Changes reversed after Teriparatide withdrawal

Studies in rats indicate an increased risk of osteosarcoma at systemic exposures ranging from 3-60 times the exposure in humans given 20 µg dose. However, incidence of osteosarcoma is very rare in humans.

Since the paediatric patients and young adults with open epiphyses have an increased baseline risk of osteosarcoma, teriparatide should not be used.

Paget’s disease of bone, HyperParathyroidism.

Prior Radiotherapy given for Primary/Secondary Bone Tumors or in bony metastasis.

Warnings

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Body as a whole: Pain, Headache, Asthenia, Neck pain

Cardiovascular: Hypertension, Angina pectoris, Syncope

Digestive System: Nausea, Constipation, Diarrhea, Dyspepsia, Gastrointestinal disorder, Vomiting, Tooth disorder

Musculoskeletal: Arthralgia, Leg cramps

Published Adverse Events

Nervous System:

Dizziness, Depression, Insomnia, Vertigo

Respiratory System: Rhinitis ,Increased cough, Pharyngitis, Dyspnea, Pneumonia

Skin and Appendages:

Rash, Sweating

Published Adverse Events

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Adverse Events

Adverse events usually were mild and generally did not require discontinuation of therapy

Reported adverse events that appeared to be increased by Teriparatide treatment were dizziness and leg cramps

Transient episodes of symptomatic orthostatic hypotension were observed frequently .

Limited information is available to evaluate safety in patients with hepatic, renal, and cardiac disease.

Teripartide should be used with caution in patients with active or recent urolithiasis. It should be used with caution in patients taking digitalis. Caution should be taken in patients with moderate renal impairment .

NT: Dosage adjustment based on age is not required in Geriatric Population

Precautions

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Should not be used in Pregnancy & Lactation.

It is not known whether rhPTH is excreted into milk.

Teriparaitide should be used by breast-feeding women depending on the importance of the drug to the mother.

Contraindications Teriparatide is not given in following patients:

Pre-existing hypercalcemia

Moderate to Severe renal impairment

Metabolic bone diseases other than primary osteoporosis (including hyperparathyroidism and Paget's disease of the bone).

Unexplained elevations of alkaline phosphatase. In cases where Radiotherapy for Bony Tumors being given.

Patients with skeletal malignancies or bone metastases

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Teriparatide (rhPTH (1-34))

TWO: Published Studies onrhPTH vs. Antiresorptives

* P<0.001 Ref: Cosman et al. 2011, J Bone Miner Res.

Teriparatide Vs. Zoledronic acid

Effects of Intravenous Zoledronic acid Plus Subcutaneous Teriparatide rhPTH(1–34)] in Postmenopausal Osteoporosis.

Journal of Bone and Mineral Research, Vol. 26, No. 3, March 2011, pp 503–511

%BMD rise in Combination v/s single agent

Combination therapy provides the largest, most rapid increments when both spine and hip sites are

considered.

Outcomes

TAKE HOME MESSAGE

Teriparatide remain the workhorse of Refractory osteoporosis

& Glucorticoid induced Osteoporosis.