Teriparatide Explained

Teriparatide, sold under the brand name Forteo, is a form of parathyroid hormone (PTH) consisting of the first (N-terminus) 34 amino acids, which is the bioactive portion of the hormone. It is an effective anabolic (promoting bone formation) agent[1] used in the treatment of some forms of osteoporosis.[2] Teriparatide is a recombinant human parathyroid hormone analog (PTH 1-34). It has an identical sequence to the 34 N-terminal amino acids of the 84-amino acid human parathyroid hormone.

Medical uses

Teriparatide is indicated for the treatment of postmenopausal women with osteoporosis; for the increase of bone mass in men with primary or hypogonadal osteoporosis; and treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy.

It is effective in growing bone (e.g., 8% increase in bone density in the spine after one year)[3] and reducing the risk of fragility fractures.[4] [5]

Teriparatide cuts the risk of hip fracture by more than half but does not reduce the risk of arm or wrist fracture.[6]

Contraindications

Teriparatide is contraindicated for those with open epiphyses, metabolic bone diseases, Paget's Disease of bone, bone metastases, history of skeletal malignancies, or prior external beam or implant radiation therapy involving the skeleton. In the animal studies and in one human case report, it was found to potentially be associated with developing osteosarcoma in test subjects after over two years of use.[7]

Adverse effects

Adverse effects of teriparatide include headache, nausea, dizziness, and limb pain.[4] Teriparatide has a theoretical risk of osteosarcoma, which was found in rat studies but not confirmed in humans.[1] This may be because, unlike humans, rat bones grow for their entire life.[1] The tumors found in the rat studies were located on the end of the bones which grew after the injections began.[8] After nine years on the market, there were only two cases of osteosarcoma reported.[3] This risk was considered by the FDA as "extremely rare" (1 in 100,000 people)[4] and is only slightly more than the incidence in the population over 60 years old (0.4 in 100,000).[4]

Mechanism of action

Teriparatide is a portion of human parathyroid hormone (PTH), amino acid sequence 1 through 34, of the complete molecule (containing 84 amino acids). Endogenous PTH is the primary regulator of calcium and phosphate metabolism in bone and kidney. PTH increases serum calcium, partially accomplishing this by increasing bone resorption. Thus, chronically elevated PTH will deplete bone stores. However, intermittent exposure to PTH will activate osteoblasts more than osteoclasts. Thus, once-daily injections of teriparatide have a net effect of stimulating new bone formation leading to increased bone mineral density.[9] [10] [11]

Society and culture

Legal status

Teriparatide was approved for medical use in the United States in 1987.[12] Teriparatide (Forteo) was approved by the FDA in November 2002, for the treatment of osteoporosis in men and postmenopausal women who are at high risk for having a fracture.[13] In October 2019, the US FDA approved the recombinant teriparatide product with brand name Bonsity.

Biosimilars

Recombinant teriparatide is sold by Eli Lilly and Company under the brand names Forteo and Forsteo. In June 2020, Alvogen, Inc, Pfenex Inc.'s commercialization partner, launched teriparatide injection (Bonsity) in the United States. Teriparatide injection was developed by Pfenex Inc and approved by the US Food and Drug Administration (FDA) in October 2019.[14] Teriparatide injection is pharmaceutically equivalent to Forteo (that is, has the same active ingredient in the same strength, dosage form and route of administration) and has been shown to have comparable bioavailability. These characteristics allowed the product to be approved under a 505(b)(2) NDA for which Forteo was the reference drug. It may provide a lower-cost teriparatide option for increasing bone density in patients at high risk for fracture, and is FDA-approved for the same indications as Forteo, which means it can be used for the same patients as Forteo, including new patients and those currently responding to treatment.[15]

Teriparatide was approved for medical use in the European Union in June 2003.[16] A synthetic teriparatide from Teva Generics has been authorized for marketing in the European Union.[17] Biosimilar product from Gedeon Richter plc has been authorized in the European Union.[18] In October 2019, the US FDA approved a recombinant teriparatide product.

In June 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of the biosimilar products Qutavina and Livogiva. Qutavina and Livogiva were approved for medical use in the European Union in August 2020.[19] [20]

Osnuvo was approved for medical use in Canada in January 2020.[21]

Sondelbay was approved for medical use in the European Union in March 2022.[22] [23]

On 10 November 2022, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kauliv, intended for the treatment of osteoporosis. The applicant for this medicinal product is Strides Pharma Cyprus.[24] Kauliv was approved for medical use in the European Union in February 2023.[25] [26]

Research

Teriparatide is undergoing a clinical trial with zoledronic acid as a treatment for osteogenesis imperfecta to reduce the risk of broken bones.[27]

Combined teriparatide and denosumab

Combined teriparatide and denosumab increased BMD more than either agent alone and more than has been reported with approved therapies. Combination treatment might, therefore, be useful to treat patients at high risk of fracture by increasing BMD. However, there is no evidence of fracture rate reduction in patients taking a teriparatide and denosumab combination. The first such trial was published by Leder et al. in Lancet in 2013 with further data subsequently published in JCEM in a trial of post menopausal osteoporotic women demonstrating larger bone mineral density increases in the spine and hip with combination therapy compared to either drug alone.[28] [29]

Notes and References

  1. Riek AE, Towler DA . The pharmacological management of osteoporosis . Missouri Medicine . 108 . 2 . 118–23 . 2011 . 21568234 . 3597219 .
  2. Saag KG, Shane E, Boonen S, Marín F, Donley DW, Taylor KA, Dalsky GP, Marcus R . Teriparatide or alendronate in glucocorticoid-induced osteoporosis . The New England Journal of Medicine . 357 . 20 . 2028–39 . November 2007 . 18003959 . 10.1056/NEJMoa071408 . free .
  3. Kawai M, Mödder UI, Khosla S, Rosen CJ . Emerging therapeutic opportunities for skeletal restoration . Nature Reviews. Drug Discovery . 10 . 2 . 141–56 . February 2011 . 21283108 . 3135105 . 10.1038/nrd3299 .
  4. Rizzoli R, Reginster JY, Boonen S, Bréart G, Diez-Perez A, Felsenberg D, Kaufman JM, Kanis JA, Cooper C . Adverse reactions and drug-drug interactions in the management of women with postmenopausal osteoporosis . Calcified Tissue International . 89 . 2 . 91–104 . August 2011 . 21637997 . 3135835 . 10.1007/s00223-011-9499-8 .
  5. Murad MH, Drake MT, Mullan RJ, Mauck KF, Stuart LM, Lane MA, Abu Elnour NO, Erwin PJ, Hazem A, Puhan MA, Li T, Montori VM . Clinical review. Comparative effectiveness of drug treatments to prevent fragility fractures: a systematic review and network meta-analysis . The Journal of Clinical Endocrinology and Metabolism . 97 . 6 . 1871–80 . June 2012 . 22466336 . 10.1210/jc.2011-3060 . free . doi .
  6. Díez-Pérez A, Marin F, Eriksen EF, Kendler DL, Krege JH, Delgado-Rodríguez M . Effects of teriparatide on hip and upper limb fractures in patients with osteoporosis: A systematic review and meta-analysis . Bone . 120 . 1–8 . March 2019 . 30268814 . 10.1016/j.bone.2018.09.020 . free . doi . 10230/36878 . free .
  7. Harper KD, Krege JH, Marcus R, Mitlak BH . Osteosarcoma and teriparatide? . Journal of Bone and Mineral Research . 22 . 2 . 334 . February 2007 . 17129179 . 10.1359/jbmr.061111 . 36420876 . free .
  8. Web site: Forteo . drugs.com . 23 January 2018 . 15 June 2018 . https://web.archive.org/web/20180615135231/https://www.drugs.com/pro/forteo.html . live .
  9. Bauer W, Aub JC, Albright F . Studies of calcium and phosphorus metabolism: V. Study of the bone trabeculae as a readily available reserve supply of calcium . The Journal of Experimental Medicine . 49 . 1 . 145–62 . January 1929 . 19869533 . 2131520 . 10.1084/jem.49.1.145 .
  10. Selye H . 1932 . On the stimulation of new bone formation with parathyroid extract and irradiated ergosterol . Endocrinology . 16 . 5. 547–558 . 10.1210/endo-16-5-547. free . doi .
  11. Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R . Anabolic actions of parathyroid hormone on bone . Endocrine Reviews . 14 . 6 . 690–709 . December 1993 . 8119233 . 10.1210/edrv-14-6-690 . Felicia Cosman .
  12. Web site: Teriparatide injection, solution . DailyMed . 1 November 2019 . 8 March 2023 . 25 May 2022 . https://web.archive.org/web/20220525190844/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1b007339-dd0d-f019-5e0a-9b1b0f75011c . live .
  13. Web site: Drug Approval Package: Forteo [teriparatide (rDNA origin)] Injection; NDA #021318 ]. U.S. Food and Drug Administration (FDA) . 14 September 2020 . 31 March 2021 . https://web.archive.org/web/20210331171441/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-318_Forteo.cfm . live .
  14. Web site: Drug Approval Package: Bonsity . U.S. Food and Drug Administration (FDA) . 26 February 2020 . 14 September 2020 . 2 April 2021 . https://web.archive.org/web/20210402095857/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211939Orig1s000TOC.cfm . live .
  15. Pfenex Inc . Pfenex Announces U.S. Commercial Launch of Teriparatide Injection . GlobeNewswire . 12 June 2020 . 13 October 2020 . 7 April 2021 . https://web.archive.org/web/20210407124159/http://www.globenewswire.com/news-release/2020/06/12/2047405/0/en/Pfenex-Announces-U-S-Commercial-Launch-of-Teriparatide-Injection.html . live .
  16. Web site: Forsteo EPAR . European Medicines Agency (EMA) . 17 September 2018 . 26 June 2020 . 27 June 2020 . https://web.archive.org/web/20200627011444/https://www.ema.europa.eu/en/medicines/human/EPAR/forsteo . live .
  17. Web site: PUBLIC ASSESSMENT REPORT - Decentralised Procedure - Teriparatid-ratiopharm 20 µg / 80ml, Solution for injection. BfArM. 8 May 2017. 24 June 2019. 24 June 2021. https://web.archive.org/web/20210624203342/https://mri.cts-mrp.eu/Human/Downloads/DE_H_4292_001_PAR.pdf. live.
  18. Web site: Summary of the European public assessment report (EPAR) for Terrosa.. 17 September 2018 . 14 August 2019. 14 August 2019. https://web.archive.org/web/20190814064635/https://www.ema.europa.eu/en/medicines/human/EPAR/terrosa. live.
  19. Web site: Qutavina EPAR . European Medicines Agency (EMA) . 26 May 2020 . 25 January 2021 . 30 January 2021 . https://web.archive.org/web/20210130154226/https://www.ema.europa.eu/en/medicines/human/EPAR/qutavina . live .
  20. Web site: Livogiva EPAR . European Medicines Agency (EMA) . 26 May 2020 . 25 January 2021 . 30 January 2021 . https://web.archive.org/web/20210130154226/https://www.ema.europa.eu/en/medicines/human/EPAR/qutavina . live .
  21. Web site: Summary Basis of Decision (SBD) for Osnuvo . . 23 October 2014 . 29 May 2022 . 30 May 2022 . https://web.archive.org/web/20220530223828/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00470&lang=en . live .
  22. Web site: Sondelbay EPAR . European Medicines Agency . 24 January 2022 . 3 March 2023 . 4 March 2023 . https://web.archive.org/web/20230304090507/https://www.ema.europa.eu/en/medicines/human/EPAR/sondelbay-0 . live .
  23. Web site: Sondelbay Product information . Union Register of medicinal products . 3 March 2023 . 4 March 2023 . https://web.archive.org/web/20230304090507/https://ec.europa.eu/health/documents/community-register/html/h1628.htm . live .
  24. Web site: Kauliv: Pending EC decision . European Medicines Agency . 11 November 2022 . 3 March 2023 . 31 December 2022 . https://web.archive.org/web/20221231003109/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/kauliv . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  25. Web site: Kauliv Product information . Union Register of medicinal products . 3 March 2023 . 27 January 2023 . https://web.archive.org/web/20230127225411/https://ec.europa.eu/health/documents/community-register/html/h1710.htm . live .
  26. Web site: Kauliv EPAR . European Medicines Agency (EMA) . 18 July 2022 . 8 March 2023 . 9 March 2023 . https://web.archive.org/web/20230309063241/https://www.ema.europa.eu/en/medicines/human/EPAR/kauliv . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  27. News: 16 January 2017. New trial for people with brittle bone disease. BBC News. 31 August 2021. 31 August 2021. https://web.archive.org/web/20210831184959/https://www.bbc.com/news/uk-scotland-edinburgh-east-fife-38636309. live.
  28. Leder BZ, Tsai JN, Uihlein AV, Burnett-Bowie SA, Zhu Y, Foley K, Lee H, Neer RM . May 2014 . Two Years of Denosumab and Teriparatide Administration in Postmenopausal Women With Osteoporosis (The DATA Extension Study): A Randomized Controlled Trial. The Journal of Clinical Endocrinology and Metabolism . 99. 5. 1694–1700. 10.1210/jc.2013-4440. 24517156. 4010689.
  29. Tsai JN, Uihlein AV, Lee H, Kumbhani R, Siwila-Sackman E, McKay EA, Burnett-Bowie SA, Neer RM, Leder BZ . July 2013. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. The Lancet. 382. 9886. 50–56. 10.1016/s0140-6736(13)60856-9. 23683600. 4083737 .

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