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Forteo ® (teriparatide injection)
20-mcg daily dose in a 2.4-mL prefilled delivery device
This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling. See Prescribing Information above, if applicable.
What is the mechanism of action of FORTEO® (teriparatide injection)?
Once-daily administration of teriparatide preferentially stimulates osteoblastic activity over osteoclastic activity, resulting in new bone formation.
Overview
Teriparatide binds with similar affinity as endogenous parathyroid hormone (PTH) to a specific G-protein coupled cell-surface receptor, the parathyroid hormone/parathyroid hormone related protein (PTH/PTHrP) receptor, expressed in bone and kidney.1 Teriparatide rapidly (within minutes) activates the
- adenylyl cyclase/cyclic adenosine monophosphate (AC/cAMP) system, and
- phosphoinositol/phospholipase C pathway.1
Once-daily administration of teriparatide preferentially stimulates osteoblastic activity over osteoclastic activity, resulting in new bone formation on trabecular, periosteal, and/or endosteal cortical bone surfaces.2-6
Remodeling in Bone Tissue
Bone histomorphometry performed on transiliac bone biopsies is the primary method by which the mechanisms of action of bone-active drugs are assessed.7
The Forteo Alendronate Comparator Trial (FACT) was a randomized, double-blind, active comparator-controlled study of 18 months duration that compared the effects of teriparatide 20 mcg/daily to alendronate 10 mg/daily in 203 postmenopausal women (PMW) with osteoporosis.8
A subset of patients participated in a cross-sectional study in which evaluable transiliac crest bone biopsies were obtained after tetracycline double labeling from
- 17 patients (teriparatide, n=8; alendronate, n=9) at 6 months, and
- 15 patients (teriparatide, n=8; alendronate, n=7) at 18 months.9
Teriparatide stimulated significantly higher values for the index of bone formation, mineralizing surface/bone surface (MS/BS), than alendronate at both 6 months (8.10% vs 0.22%, p<.001) and 18 months (4.40% vs 0.38%, p<.01).9
The Skeletal Histomorphometry in Subjects on Teriparatide or Zoledronic Acid Therapy (SHOTZ) study was a 2-year trial that compared the biological effects of teriparatide 20 mcg/day with those of zoledronic acid 5 mg/year in PMW with osteoporosis. Histomorphometric analyses of transiliac crest biopsies obtained at 6 and 24 months showed that treatment with teriparatide resulted in higher bone formation indices than zoledronic acid in all 4 bone envelopes (cancellous, endocortical, intracortical, and periosteal). Moreover, the difference persisted for at least 2 years.10
Similar results were obtained in the AVA Osteoporosis study, wherein PMW with osteoporosis were randomized to receive teriparatide 20 mcg/day for 6 months or denosumab 60 mg once. Histomorphometric analysis of transiliac bone biopsies obtained at 3 months showed that teriparatide increased bone formation indices, whereas denosumab decreased them.11
Radionuclide bone scan imaging has demonstrated a direct metabolic effect of teriparatide on the whole skeleton and various subskeletal sites.12
A randomized, double-blind, placebo-controlled trial showed that the predominant early effect (average treatment duration, 6.1 weeks) of teriparatide 20 mcg/day was to stimulate remodeling-based bone formation (RBF) and overflow RBF (oRBF) in the cancellous and endocortical envelopes of the femoral neck in patients about to undergo a total hip replacement for osteoarthritis. There was also a nonsignificant increase in modeling-based bone formation in both envelopes.13
Surrogate Markers of Bone Remodeling
In the FACT, in PMW treated with teriparatide and alendronate for 18 months, teriparatide significantly increased markers of bone turnover that peaked at 6 months (procollagen type I N-terminal propeptide [PINP], 218%; N‑terminal telopeptide [NTX], 58%; p<.001).8
Alendronate decreased bone turnover markers at 6 months (PINP, -67%; NTX, -72%; p<.001).8
Effects on Bone Microarchitecture
The largest clinical study with teriparatide was the Fracture Prevention Trial (FPT). This trial was a double-blind, randomized, placebo-controlled, multinational trial in 1637 PMW with osteoporosis and prior vertebral fractures.14
For a median duration of 19 months (maximum 24 months), subjects received calcium (1000 mg/day) and vitamin D (400 to 1200 IU/day) in addition to a once-daily subcutaneous injection of either
- teriparatide 20 mcg
- teriparatide 40 mcg, or
- placebo.14
Histomorphometry was conducted on iliac crest biopsies from a subset of patients.7
Structural trabecular and cortical bone analysis demonstrated that teriparatide significantly
- improved trabecular bone volume
- improved structure model index
- increased trabecular connectivity, and
- increased cortical thickness.7
The bone formed with teriparatide 20 mcg or teriparatide 40 mcg was of normal quality without evidence of woven bone or marrow fibrosis.7
In the TERABIT study, a multicenter, open-label, randomized controlled trial, 131 PMW with osteoporosis and a history of fragility fractures were randomized to receive
- teriparatide 20 mcg/day (n=46)
- teriparatide 56.5 mcg/week (n=45), or
- oral bisphosphonates (alendronate 35 mg/week or risedronate 17.5 mg/week; n=40).15
Only the results for the daily teriparatide and bisphosphonate groups are discussed herein.15
Treatment with either daily teriparatide or weekly bisphosphonate for 18 months significantly increased (p<.05 vs baseline)
- cortical thickness at the distal radius and distal tibia
- trabecular volumetric bone mineral density (vBMD) at the distal radius, and
- failure load at the distal radius and distal tibia.15
Daily teriparatide, but not bisphosphonates, increased trabecular vBMD significantly at the distal tibia (p<.05 vs baseline; group difference, p<.05). Both treatments decreased cortical volumetric tissue mineral density (vTMD) significantly at the distal radius (p<.05 vs baseline), but the decrease was greater with daily teriparatide (group difference, p<.05).15
Other studies have also shown favorable effects of teriparatide on primate and human bone microarchitecture.16-21
Effects on Mineralization
Bone strength depends on both bone quantity and bone quality. Bone architecture and material properties are two important components of bone quality. Key determinants of material properties include
- mineral to matrix ratio
- mineral maturity/crystallinity, and
- collagen cross-links.22
In addition, bone mineralization density distribution (BMDD) describes the local mineral content of the bone matrix throughout a sample as characterized by local calcium concentrations.22
The FPT utilized a Fourier Transform Infrared Imaging analysis of paired transiliac crest bone biopsies at 12 months or study endpoint (N=26) among patients treated. Those treated with teriparatide 20 mcg or 40 mcg, compared to those given placebo, showed significantly lower
- collagen cross-link ratio
- matrix mineralization, and
- mineral crystallinity.22
In the SHOTZ study wherein PMW with osteoporosis were treated with either teriparatide or zoledronic acid, quantitative backscattered electron imaging of transiliac crest biopsies obtained at 6 and 24 months showed that teriparatide stimulated new bone formation, and the mineralized bone matrix that was produced remained relatively heterogenous with a stable mean mineral content with continuation of therapy.23
In contrast, zoledronic acid slowed bone turnover and prolonged secondary mineralization. This resulted in a progressively more homogeneous and highly mineralized bone matrix.23
In another analysis of the SHOTZ study, vibrational spectroscopic analyses were conducted on tetracycline-labeled transiliac biopsies obtained from both groups at month 6. It was found that compared with zoledronic acid, teriparatide treatment for 6 months resulted in
- lower mineral and higher organic matrix content
- increased tissue water content, and
- lower mineral to matrix ratio, mineral maturity/crystallinity, glycosaminoglycan content, and pyridinoline/divalent enzymatic collagen cross-link ratio.24
In an observational cross-sectional study, Raman microspectroscopic analysis was used to assess bone quality indices at actively forming trabecular surfaces in iliac crest biopsies from PMW with osteoporosis who received teriparatide 20 mcg/day. The results were compared with biopsy data from healthy adult premenopausal women (HC group) and PMW with osteoporosis who received placebo (PMOP-PLC group).25
PMW with osteoporosis who were treated with teriparatide for 24 months had
- a higher mineral to matrix ratio than the HC and PMOP-PLC groups
- lower glycosaminoglycan content than the HC group, and
- mineral maturity/crystallinity, tissue water content, and pyridinoline content similar to the HC group but lower than the PMOP-PLC group.25
Thus, treatment with teriparatide for 24 months restored bone mineral and organic matrix quality indices to levels found in healthy premenopausal women.25
A study analyzed iliac crest biopsies from 16 women with osteoporosis from the Open-Label Study to Determine How Prior Therapy With Alendronate or Risedronate in Postmenopausal Women With Osteoporosis Influences the Clinical Effectiveness of Teriparatide (OPTAMISE) to evaluate the effects of sequential antiresorptive and anabolic treatment on BMDD. Following at least 2 years treatment with bisphosphonates, the patient biopsies were collected before and after 1 year of teriparatide.26
Analysis of the influence of prior bisphosphonate treatment showed that BMDD response to 1 year of teriparatide treatment did not depend on the type of prior bisphosphonate. In a pooled analysis, teriparatide significantly increased cancellous and cortical BMDD.26
A separate analysis of the OPTAMISE study also evaluated paired iliac crest biopsies collected from 16 women with osteoporosis. The aim of the analysis was to investigate the effects of teriparatide as a function of prior bisphosphonate therapy, independent of bone turnover, on
- mineral to matrix ratio
- mineral crystallite maturity/crystallinity
- relative proteoglycan content, and
- ratio of pyridinoline to divalent collagen cross-links.27
Utilizing the Raman and Fourier Transform Infrared Imaging microspectroscopic analysis, after at least 2 years treatment with bisphosphonates, biopsies were collected and evaluated before and after 1 year of teriparatide treatment.27
Teriparatide increased the new bone (within the double labels) mineral/matrix ratio in patients with prior bisphosphonate therapy (p<.0001).27
At baseline, the pyridinoline/divalent collagen cross-link ratio was significantly lower in the risedronate group than in the alendronate group (p<.0001).27
Following treatment with teriparatide, the alendronate group, but not the risedronate group, had a significant baseline-to-endpoint reduction in the cross-link ratio (p=.0011).27
At endpoint, the pyridinoline/divalent collagen cross-link ratio was significantly lower in the prior risedronate group compared to prior alendronate group (p=.0021).27
Relationship Between Changes in Bone Mineral Density vs Bone Turnover Markers or Microarchitectural Parameters
In the FPT, the percent change from baseline to endpoint in lumber spine bone mineral density (BMD) was 1.1% in the placebo group compared with 9.7% in the teriparatide 20 mcg group (p<.001).14,28
In addition, treatment with teriparatide 20 mcg/day significantly reduced the relative risk of vertebral fractures by 65% (absolute risk reduction [ARR]=9.3%) and nonvertebral fragility fractures by 53% (ARR=2.9%).14,28
The relationship between actual changes in lumbar spine and femoral neck BMD and in microarchitectural parameters (measured by 2-D and 3-D microcomputed tomography of transiliac bone biopsies from subset of patients in FPT) were assessed using Pearson’s correlation among patients treated with teriparatide for 12 months (n=21) and 22 months (n=36).29
Increases in both lumbar spine BMD and femoral neck BMD were associated with improvements in indices of trabecular microarchitecture. These data suggest that improvements in trabecular bone microarchitecture during teriparatide treatment may help to explain how increases in BMD improve bone strength.29
In a prospective study involving 248 PMW with severe osteoporosis, treatment with teriparatide 20 mcg/day for 12 months significantly increased PINP levels (p<.001), lumbar spine and hip BMD, as well as lumbar spine trabecular bone score (TBS, an indicator of bone microarchitecture).30
Only percentage change and absolute change (>10 mcg/L) in PINP from baseline to 3 months were correlated with percentage change in lumbar spine BMD at 12 months (p=.022 and p=.048, respectively). No correlation was observed between changes in TBS and changes in axial BMD.30
In the FACT, BMD was increased in the spine and hip in both the teriparatide and alendronate treated groups. The increases in lumbar spine were similar up to month 3 and were significantly higher for the teriparatide group beginning at month 6 (p<.05). The increases in lumbar spine continued until 18 months, teriparatide by 10.3% and alendronate by 5.5% (p<.001).8
There was a significant positive correlation between the PINP area under the curve (AUC) at 6 months and areal BMD (aBMD) of the lumbar spine at 18 months in the teriparatide group, and there was a negative correlation between the PINP AUC and aBMD of the lumbar spine in the alendronate group.8
Other studies examining changes in BMD and bone turnover markers in PMW treated with teriparatide or antiresorptives show similar effects.31,32
The results from these studies illustrate the marked differences in mechanism of action between antiresorptive agents, such as alendronate and risedronate, and a bone-forming agent, such as teriparatide. Both classes of drugs increase BMD, but do so by different and opposite mechanisms of action.
The increase in BMD obtained with antiresorptive therapies is not the result of new bone being formed, but rather results from
- the preservation of existing bony structures
- a closing down of the remodeling space, and
- increased mineralization of these structures over time.
This is reflected by the pronounced reduction in bone turnover with alendronate and risedronate treatment.
In contrast, teriparatide causes the opposite changes in bone remodeling with an increase in bone formation rates and increased turnover, and stimulation of a large number of active bone remodeling units laying down new bone.
The increase in BMD obtained with teriparatide treatment is the result of new bone formation and subsequent mineralization of this new bone over time.
Enclosed Prescribing Information
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Gardella TJ, Nissenson RA, and Juppner H. Parathyroid Hormine. In: Bilezikian JP, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 9th ed. Hoboken, NJ: Wiley & Sons Inc. 2019:205-211.Chapter 27 http://dx.doi.org/10.1002/9781119266594
2Riggs BL, Parfitt AM. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res. 2005;20(2):177-184. http://dx.doi.org/10.1359/JBMR.041114
3Lindsay R, Cosman F, Zhou H, et al. A novel tetracycline labeling schedule for longitudinal evaluation of the short-term effects of anabolic therapy with a single iliac crest bone biopsy: early actions of teriparatide. J Bone Miner Res. 2006;21(3):366-373. https://doi.org/10.1359/jbmr.051109
4Ma YL, Zeng Q, Donley DW, et al. Teriparatide increases bone formation in modeling and remodeling osteons and enhances IGF-II immunoreactivity in postmenopausal women with osteoporosis. J Bone Miner Res. 2006;21(6):855-864. https://doi.org/10.1359/jbmr.060314
5Lindsay R, Zhou H, Cosman F, et al. Effects of a one-month treatment with PTH(1-34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human ilium. J Bone Miner Res. 2007;22(4):495-502. http://dx.doi.org/10.1359/JBMR.070104
6Adachi JD, Hanley DA, Lorraine JK, Yu M. Assessing compliance, acceptance, and tolerability of teriparatide in patients with osteoporosis who fractured while on antiresorptive treatment or were intolerant to previous antiresorptive treatment: an 18-month, multicenter, open-label, prospective study. Clin Ther. 2007;29(9):2055-2067. https://doi.org/10.1016/j.clinthera.2007.09.024
7Jiang Y, Zhao JJ, Mitlak BH, et al. Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res. 2003;18(11):1932-1941. https://doi.org/10.1359/jbmr.2003.18.11.1932
8McClung MR, San Martin J, Miller PD, et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med. 2005;165(15):1762-1768. http://dx.doi.org/10.1001/archinte.165.15.1762
9Arlot M, Meunier PJ, Boivin G, et al. Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters. J Bone Miner Res. 2005;20(7):1244-1253. http://dx.doi.org/10.1359/JBMR.050309
10Dempster DW, Zhou H, Recker RR, et al. A longitudinal study of skeletal histomorphometry at 6 and 24 months across four bone envelopes in postmenopausal women with osteoporosis receiving teriparatide or zoledronic acid in the SHOTZ trial. J Bone Miner Res. 2016;31(7):1429-1439. http://dx.doi.org/10.1002/jbmr.2804
11Dempster DW, Zhou H, Recker RR, et al. Differential effects of teriparatide and denosumab on intact PTH and bone formation indices: AVA osteoporosis study. J Clin Endocrinol Metab. 2016;101(4):1353-1363. http://dx.doi.org/10.1210/jc.2015-4181
12Moore AE, Blake GM, Taylor KA, et al. Changes observed in radionuclide bone scans during and after teriparatide treatment for osteoporosis. Eur J Nucl Med Mol Imaging. 2012;39(2):326-336 http://dx.doi.org/10.1007/s00259-011-1974-y
13Rooney AM, Dempster DW, Nieves JW, et al. Effects of teriparatide and loading modality on modeling-based and remodeling-based bone formation in the human femoral neck. Bone. 2022;157:116342. https://doi.org/10.1016/j.bone.2022.116342
14Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434-1441. http://dx.doi.org/10.1056/nejm200105103441904
15Chiba K, Okazaki N, Kurogi A, et al. Randomized controlled trial of daily teriparatide, weekly high-dose teriparatide, or bisphosphonate in patients with postmenopausal osteoporosis: The TERABIT study. Bone. 2022;160:116416. https://doi.org/10.1016/j.bone.2022.116416
16Brommage R, Hotchkiss CE, Lees CJ, et al. Daily treatment with human recombinant parathyroid hormone-(1-34), LY333334, for 1 year increases bone mass in ovariectomized monkeys. J Clin Endocrinol Metab. 1999:84(10):3757-3763. http://www.ncbi.nlm.nih.gov/pubmed/10523026
17Hodsman AB, Kisiel M, Adachi JD, et al. Histomorphometric evidence for increased bone turnover without change in cortical thickness of porosity after 2 years of cyclical hPTH(1-34) therapy in women with severe osteoporosis. Bone. 2000;27(2):311-318. http://www.ncbi.nlm.nih.gov/pubmed/10913928
18Sato M, Westmore M, Clendenon J, et al. Three-dimensional modeling of the effects of parathyroid hormone on bone distribution in lumbar vertebrae of ovariectomized cynomolgus macaques. Osteoporos Int. 2000;11(10):871-880. http://dx.doi.org/10.1007/s001980070047
19Burr DB, Hirano T, Turner CH, et al. Intermittently administered human parathyroid hormone(1-34) treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys. J Bone Miner Res. 2001;16(1):157-165. http://dx.doi.org/10.1359/jbmr.2001.16.1.157
20Dempster DW, Cosman F, Kurland ES, et al. Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner Res. 2001;16(10):1846-1853. http://dx.doi.org/10.1359/jbmr.2001.16.10.1846
21Jerome CP, Burr DB, Van Bibber T, et al. Treatment with human parathyroid hormone (1-34) for 18 months increases cancellous bone volume and improves trabecular architecture in ovariectomized cynomolgus monkeys (Macaca fascicularis). Bone. 2001;28(2):150-159. http://dx.doi.org/10.1016/S8756-3282(00)00430-0
22Paschalis EP, Glass EV, Donley DW, Eriksen EF. Bone mineral and collagen quality in iliac crest biopsies of patients given teriparatide: new results from the fracture prevention trial. J Clin Endocrinol Metab. 2005;90(8):4644-4649. http://dx.doi.org/10.1210/jc.2004-2489
23Dempster DW, Roschger P, Misof BM, et al. Differential effects of teriparatide and zoledronic acid on bone mineralization density distribution at 6 and 24 months in the SHOTZ study. J Bone Miner Res. 2016;31(8):1527-1535. http://dx.doi.org/10.1002/jbmr.2825
24Paschalis EP, Dempster DW, Gamsjaeger S, et al. Mineral and organic matrix composition at bone forming surfaces in postmenopausal women with osteoporosis treated with either teriparatide or zoledronic acid. Bone. 2021;145:115848. https://doi.org/10.1016/j.bone.2021.115848
25Paschalis EP, Gamsjaeger S, Klaushofer K, et al. Treatment of postmenopausal osteoporosis patients with teriparatide for 24 months reverts forming bone quality indices to premenopausal healthy control values. Bone. 2022;162:116478. https://doi.org/10.1016/j.bone.2022.116478
26Misof BM, Paschalis EP, Blouin S, et al. Effects of 1 year of daily teriparatide treatment on iliacal bone mineralization density distribution (BMDD) in postmenopausal osteoporotic women previously treated with alendronate or risedronate. J Bone Miner Res. 2010;25(11):2297-2303. http://dx.doi.org/10.1002/jbmr.198
27Gamsjaeger S, Buchinger B, Zoehrer R, et al. Effects of one year daily teriparatide treatment on trabecular bone material properties in postmenopausal osteoporotic women previously treated with alendronate or risedronate. Bone. 2011;49(6):1160-1165. http://dx.doi.org/10.1016/j.bone.2011.08.015
28Forteo [package insert]. Indianapolis, IN: Eli Lilly and Company; 2021.
29Chen P, Miller PD, Recker R, et al. Increases in BMD correlate with improvements in bone microarchitecture with teriparatide treatment in postmenopausal women with osteoporosis. J Bone Miner Res. 2007;22(8):1173-1180. http://dx.doi.org/10.1359/jbmr.070413
30Chen FP, Fu TS, Lin YC, et al. Association between P1NP and bone strength in postmenopausal women treated with teriparatide. Taiwan J Obstet Gynecol. 2022;61(1):91-95. https://doi.org/10.1016/j.tjog.2021.11.017
31Anastasilakis AD, Goulis DG, Polyzos SA, et al. Head-to-head comparison of risedronate vs. teriparatide on bone turnover markers in women with postmenopausal osteoporosis: a randomised trial. Int J Clin Pract. 2008;62(6):919-924. http://dx.doi.org/10.1111/j.1742-1241.2008.01768.x
32Panico A, Lupoli GA, Marciello F, et al. Teriparatide vs. alendronate as a treatment for osteoporosis: changes in biochemical markers of bone turnover, BMD and quality of life. Med Sci Monit. 2011;17(8):CR442-CR448. https://doi.org/10.12659/msm.881905
Date of Last Review: December 07, 2022