Main Point: FORTEO® (teriparatide [rDNA origin] injection) works differently than available antiresorptive therapies. The mechanisms of action by which antiresorptive drugs confer protection against fractures differ fundamentally from the mechanism of fracture protection of FORTEO® (teriparatide [rDNA origin] injection). Antiresorptive drugs suppress bone remodeling, thereby reducing the number of active remodeling sites at any time. Because the prevalence of remodeling activity on bone surfaces is lower, there are fewer cavities to concentrate the effect of mechanical loads (stress risers). In addition, by slowing the rate at which new bone remodeling units are formed, antiresorptive drugs prolong the phase of secondary mineralization (deposition of mineral) until a new remodeling unit initiates a new wave of resorption. Thus, the bone substance contains more mineral per unit matrix than before therapy.1,2 Once-daily administration of FORTEO directly stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. New bone is formed on surfaces that have not undergone a prior phase of bone resorption as well as at sites where remodeling is taking place.The bone-forming effects of teriparatide are manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. References: Osteoporosis. 2nd ed. San Diego, CA: Academic Press; 2001; 1:455. Primer on Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. Washington, DC: American Society for Bone and Mineral Research; 2003: 62.
Main Point: This slide contrasts naturally occurring PTH (1-84) with FORTEO® (teriparatide [rDNA origin] injection) recombinant human parathyroid hormone (1-34). Human parathyroid hormone is a single chain polypeptide with 84 amino acids and a molecular weight of 9425 daltons. Endogenous 84-amino-acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Physiological actions of PTH include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. The N-terminal region, 1-34, shown here in yellow, is biologically active and sufficient for regulation of mineral ion homeostasis. FORTEO contains recombinant human parathyroid hormone (1-34), [rhPTH (1-34)], which has an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone. Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown above. Teriparatide is manufactured by Eli Lilly and Company using a strain of Escherichia coli modified by recombinant DNA technology. The biological actions of PTH and teriparatide are mediated through binding to specific high-affinity cell-surface receptors. Teriparatide and the 34 N-terminal amino acids of PTH bind to these receptors with the same affinity and have the same physiological actions on bone and kidney. Teriparatide is not expected to accumulate in bone and other tissues. Human PTH (1-84) refers to intact human PTH and teriparatide refers to human PTH (1-34). FORTEO refers to recombinant teriparatide 20mg.
Main Point: FORETO® (teriparatide [rDNA origin] injection) rapidly stimulates bone formation to achieve substantial gains in BMD in early as 3 months and significantly reduces both vertebral and nonvertebral fractures within 2 years. FORTEO 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. FORTEO rapidly (in as little as 3 months) achieves substantial gains in BMD in postmenopausal women with osteoporosis. Treatment of postmenopausal women with FORTEO once daily for a median duration of 19 months: Increased spinal BMD by 11.8 % in women given FORTEO for at least 18 months and for whom data were available at all time points Increased femoral neck BMD by 2.8% Increased total hip BMD by 2.6% FORTEO forms bone of normal quality (as evidenced by the absence of woven bone and marrow fibrosis) and increases bone strength. FORTEO reduces the risk of both vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. Treatment of postmenopausal women with FORTEO once daily for a median duration of 19 months: Reduced risk of new vertebral fractures by 65%, with an absolute risk reduction of 9.3% Reduced risk of nonvertebral fragility factures by 53%, with an absolute risk reduction of 2.9%
The dual actions of PTH as a function of dosing and amount were teased apart, which led to the idea that continuous high-dose PTH is catabolic primarily for cortical bone, whereas the daily low dose was associated with anabolic effects. Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997;138:4607-12.
Main Point: The skeletal effects of PTH depend upon the pattern of systemic exposure. Once-daily administration of teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. In monkey studies, teriparatide improved trabecular microarchitecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone. In humans, the anabolic effects of teriparatide are manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. This effect of PTH leads to a rapid increase in skeletal mass and an increase in bone turnover markers. By contrast, continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation. The continuous infusion of PTH (1-38) in rats resulted in increased expression of osteoclast differentiation factor, or RANKL, and decreased expression of both osteoprotegerin (OPG) and bone-formation-associated genes such as osteoblast specific transcription factor, osteocalcin, bone sialoprotein, and type I collagen.1 Reference: 1. Endocrinology. 2001; 142:4047-4054
Cells involved in bone remodeling Osteoblast cells function to form new bone (bone formation). Osteoclast cells function to resorb or remove old bone (bone resorption). Bone lining cells are found on the surfaces of bone.…
Effects of FORTEO FORTEO® (teriparatide [rDNA origin] injection) increases the number and action of osteoblasts, stimulating new bone formation. As a result, normal-quality bone refills resorption cavities and creates an additional layer over the existing bone. This process results in increased bone mass, bone strength, and reduced fracture risk. Effects of antiresorptives Antiresorptive agents reduce the number and action of osteoclasts, decreasing the number and depth of resorption cavities. This allows the osteoblasts to fill in the resorption cavities. This can increase bone mineral density and stabilize bone mass, resulting in reduced fracture risk. However, the bone reaches a new steady state with reduction in both bone formation and bone resorption. The differences in the mechanisms of action and effects on bone of antiresorptives and FORTEO® are illustrated by comparing the formation and highlighted resting stages.
Main Point: Bone remodeling is a continuous process that with age becomes inadequate for preserving bone. Bone remodeling is a continuous process throughout life, by which bone is renewed. However, in adults, this process is not completely efficient, so each cycle leaves a small deficit in bone. This slide shows the sequence of events that comprise a single cycle. The bone remodeling process begins when the cells lining the bone surface are activated to form osteoclasts. Osteoclasts secrete acid, which dissolves the bone mineral, to form resorption cavities (pits). Osteoblasts are recruited to the resorbed bone and secrete osteoid matrix, which is comprised mainly of collagen. Over time, the osteoid matrix becomes mineralized to form bone.
Main Point: Osteoporosis increases the rate of bone turnover and leads to weak areas in bone, which then is susceptible to fracture. Note that stress risers are NOT microfractures or microcracks. Stress risers are only points of critical mechanical compromise in the bone structure, at which the application of a significant mechanical stress (strain, torsion, etc.) makes this area as very susceptible to fracture. Application of force to this bone gives a series of parallel force vectors, representing how force is transmitted across the bone. The lower bone has 3 surface irregularities, representing sites of remodeling activity. Application of the same force yields non-parallel transmission vectors that converge on and overload the surface defects (called “stress risers” or “concentrators”), leading to fracture. In other words, damage to the bone surface results in weak areas where, if failure is going to occur, it will occur at these points.
Main Point: This graph highlights the difference in mechanisms of action of alendronate and teriparatide by showing effects of biochemical markers of bone turnover. The objective of this study was to contrast the effects of teriparatide and those of a potent aminobisphosphonate, alendronate, on bone mineral density and biochemical markers of bone turnover. This was a randomized, double-blind, active comparator study. Postmenopausal women with osteoporosis (N = 203) were randomized to receive either daily TPTD 20mcg and oral placebo (N = 102) or daily alendronate 10mg and injectable placebo (N=101) for 18 months. All participants received calcium (1000/mg) and vitamin D (400-800/IU) supplementation. Study endpoints were % change from baseline in overall and volumetric bone mineral density and biochemical markers of bone turnover. In the graph above, alendronate significantly decreased NTx, a marker of resorption, after 1 month and PINP, a marker of formation, after 3 months. Teriparatide significantly increased both markers of bone remodeling. Concentrations of PINP increased 105% above baseline at 1 month and peaked at 6 months (218%). The increases in NTx (58% at peak) reach significance only after 3 months of treatment. The different effects of the 2 drugs on bone remodeling were evident after 1 month of treatment, with significant differences between the groups for each marker at 1, 3, 6, and 12 months ( p&lt; 0.001). According to the article (direct quote): &quot;The significant increases in trabecular BMD observed with teriparatide are accompanied by activating bone formation and increasing trabecular bone volume, while the smaller increases in BMD seen with alendronate are the result of the inhibition of bone turnover, resulting in the filling of remodeling spaces and increased mineralization of bone matrix.” Biochemical markers of bone turnover reflect the different mechanisms of action of teriparatide and alendronate. Information regarding mechanisms of action does not provide evidence of comparative fracture protection. Reference: 1. Arch Intern Med. 2005;165:1762-1768 (McClung MR, et al)
Main Point: These images show the same patient at baseline and completion of course of therapy of FORTEO® (teriparatide [rDNA origin] injection). These are microCT images of iliac crest bone biopsies, obtained at baseline and after 21 months of treatment with FORTEO, from a 65-year-old postmenopausal woman who had a BMD response that is representative of the treatment group.1 The lumbar spine BMD increased by 7.4%1 (group mean was 9.7 7.4%2) and total hip BMD increased 5.2%1 (group mean was 2.6 4.9%2). Reference: J Bone Miner Res. 2003;18:1932-1941. (Jiang Y, et al) N Engl J Med. 2001;344:1434-1441.(Neer RM, et al)
Saag KG, Shane E, Boonen S, Marín F, Donley DW, Taylor KA, Dalsky GP, Marcus R. Teriparatide or Alendronate in Glucocorticoid-Induced Osteoporosis. N Engl J Med. 2007;357:14-25. *page numbes may change; publication date is November 15, 2007
Main Point: This slide shows the effects of FORTEO® (teriparatide [rDNA origin] injection) on serum and urine biochemical tests measured in the Fracture Prevention Trial. FORTEO transiently increased serum calcium, with the maximal effect observed at approximately 4 to 6 hours post-dose. Serum calcium measured at least 16 hours post-dose was not different from pre-treatment levels. In clinical trials, the frequency of at least 1 episode of transient hypercalcemia in the 4 to 6 hours after FORTEO administration was increased from 1.5% of women treated with placebo to 11.1% of women treated with FORTEO. The number of patients treated with FORTEO whose transient hypercalcemia was verified on consecutive measurements was 3.0% of women and 1.3% of men. FORTEO increased urinary calcium excretion but the frequency of hypercalciuria (&gt;7.5 mmol Ca/day or 300 mg/day) in clinical trials was similar for subjects with FORTEO and placebo. The median urinary excretion of calcium was 4.8 mmol/day (190 mg/day) at 6 months and 4.2 mmol/day (170 mg/day) at 12 months. These levels were 0.76 mmol/day (30 mg/day) and 0.30 mmol/day (12 mg/day) higher, respectively, than in placebo subjects. The incidence of hypercalciuria (&gt;7.5 mmol Ca/day or 300 mg/day) was similar to that in placebo-treated subjects. FORTEO increased serum uric acid concentrations. In clinical trials, 2.8% of FORTEO subjects had serum uric acid concentrations above the upper limit of normal compared to 0.7% of placebo subjects. However, the hyperuricemia did not result in an increase in gout, arthralgia, or urolithiasis. The changes in serum and urine biochemical tests returned to pretreatment values after cessation of treatment.
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.
Ser Val Ser Glu Ile Gln Leu Met His Asn
Arg Lys Lys Leu Gln Asp Val His Asn Phe
Sequence is identical to that of 34 N-terminal amino acids
of the endogenous 84-aminoacids
Intact PTH is
Human Parathyroid Hormone 1-34 and 1-841
acid human PTH
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
Increases bone density and causes
thickening 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
It rapidly (in as little as 3 months) increase BMD in postmenopausal
women with osteoporosis
Preferentially osteoblastic bone formation over osteoclastic bone
Skeletal mass and bone strength
Lumbar spine and femoral neck BMD
Vertebral and non vertebral fractures
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
• whole BMD
• lumbar BMD
• femoral BMD
• new vertebral fractures (RR - 0.35)
• new non-vertebral fractures (RR - 0.54)
Administration and dose determine
PTH effects on bone
(Low Dose) Anabolic
(High Dose) Catabolic
Mode of Delivery Determines Skeletal
Response to PTH
Parathyroid hormone (PTH) –
Mechanism of action
PTH binds to cell surface G protein-coupled receptor
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
High Bone Turnover Leads to Development
of Stress Risers and Perforations
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
Bone alkaline phosphatase Bone ALP
Procollagen type I C propeptide PICP
Procollagen type I N propeptide PINP
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
N-terminal cross-linking telopeptide
of type I collagen NTX
C-terminal cross-linking telopeptide
of type I collagen CTX
Delmas P. J Bone Miner Res. 2001;16:2370.
0 1 3 6 12
0 1 3 6 12
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
forms normal-quality bone (as shown by lack of woven bone and marrow fibrosis).
Teriparatide [rDNA origin] Stimulates New
Thus is indicated for:
Treatment of postmenopausal women with osteoporosis at
high risk for fracture
Primary or hypogonadal osteoporosis with high risk for
Treatment of men and women with osteoporosis associated
with sustained systemic glucocorticoid therapy at high risk for
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, AL
2Columbia University, New York, NY
3Katholieke Universiteit-Leuven, Leuven, Belgium
4Lilly Research Laboratories, Indianapolis IN
Dosage and Administration
Recommended dose: 20 µg administered once daily
Route: To be injected subcutaneously in thigh or
Concurrently the patients should receive calcium
and vitamin D supplements if dietary intake is
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
Hypercalcemia was absent or mild and transient (normally 24 hours
Mean serum uric acid concentrations increased 13-20% (no sequelae)
No clinical adverse events were associated with increases in serum or
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
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.
Body as a whole:
Pain, Headache, Asthenia, Neck pain
Hypertension, Angina pectoris, Syncope
Nausea, Constipation, Diarrhea, Dyspepsia, Gastrointestinal
disorder, Vomiting, Tooth disorder
Arthralgia, Leg cramps
Published 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
Caution should be taken in patients with
moderate renal impairment .
NT: Dosage adjustment based on age is not
required in Geriatric Population
Should not be used in Pregnancy
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
Teriparatide is not given in following patients:
Moderate to Severe renal impairment
Metabolic bone diseases other than primary osteoporosis
(including hyperparathyroidism and Paget's disease of the
Unexplained elevations of alkaline phosphatase.
In cases where Radiotherapy for Bony Tumors being
Patients with skeletal malignancies or bone metastases
Teriparatide (rhPTH (1-34))
TWO: Published Studies on
rhPTH vs. Antiresorptives
Ref: Cosman et al. 2011, J Bone Miner Res.
Teriparatide Vs. Zoledronic
Effects of Intravenous Zoledronic acid Plus
Subcutaneous Teriparatide rhPTH(1–34)] in
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
TAKE HOME MESSAGE
Teriparatide remain the workhorse of
Glucorticoid induced Osteoporosis.
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