Teriparatide

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[6] used in the treatment of some forms of osteoporosis.[7] It is also occasionally used off-label to speed fracture healing. Teriparatide is identical to a portion of human parathyroid hormone and intermittent use activates osteoblasts more than osteoclasts, which leads to an overall increase in bone.

Teriparatide
Clinical data
Trade namesForteo/Forsteo
BiosimilarsBonsity,[1] Livogiva, Osnuvo,[2] Qutavina, Teribone,[3]
AHFS/Drugs.comMonograph
MedlinePlusa603018
License data
Pregnancy
category
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: Rx-only / Schedule D
  • US: ℞-only
  • EU: Rx only [5]
Pharmacokinetic data
Bioavailability95%
MetabolismLiver (nonspecific proteolysis)
Elimination half-lifeSubcutaneous: 1 hour
ExcretionKidney (metabolites)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard100.168.733
Chemical and physical data
FormulaC181H291N55O51S2
Molar mass4117.77 g·mol−1
3D model (JSmol)
SMILES
  • [H]/N=C(\N)/NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1c[nH]c2c1cccc2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN/C(=N/[H])/N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cnc[nH]3)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](Cc4ccccc4)C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc5cnc[nH]5)NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](Cc6cnc[nH]6)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CO)N
InChI
  • InChI=1S/C181H291N55O51S2/c1-21-96(18)146(236-160(267)114(48-53-141(250)251)212-174(281)132(84-239)232-177(284)143(93(12)13)233-147(254)103(185)82-237)178(285)216-111(45-50-134(187)241)155(262)219-119(65-90(6)7)163(270)213-116(55-62-289-20)158(265)224-124(71-100-79-196-86-203-100)167(274)226-126(73-135(188)242)169(276)217-117(63-88(2)3)148(255)201-81-138(245)205-105(39-27-30-56-182)149(256)223-123(70-99-78-195-85-202-99)166(273)221-121(67-92(10)11)164(271)225-128(75-137(190)244)171(278)231-131(83-238)173(280)214-115(54-61-288-19)157(264)210-112(46-51-139(246)247)153(260)208-109(43-34-60-199-181(193)194)159(266)234-144(94(14)15)175(282)215-113(47-52-140(248)249)156(263)222-122(69-98-77-200-104-38-26-25-37-102(98)104)165(272)220-120(66-91(8)9)161(268)209-108(42-33-59-198-180(191)192)151(258)206-106(40-28-31-57-183)150(257)207-107(41-29-32-58-184)152(259)218-118(64-89(4)5)162(269)211-110(44-49-133(186)240)154(261)228-129(76-142(252)253)172(279)235-145(95(16)17)176(283)229-125(72-101-80-197-87-204-101)168(275)227-127(74-136(189)243)170(277)230-130(179(286)287)68-97-35-23-22-24-36-97/h22-26,35-38,77-80,85-96,103,105-132,143-146,200,237-239H,21,27-34,39-76,81-84,182-185H2,1-20H3,(H2,186,240)(H2,187,241)(H2,188,242)(H2,189,243)(H2,190,244)(H,195,202)(H,196,203)(H,197,204)(H,201,255)(H,205,245)(H,206,258)(H,207,257)(H,208,260)(H,209,268)(H,210,264)(H,211,269)(H,212,281)(H,213,270)(H,214,280)(H,215,282)(H,216,285)(H,217,276)(H,218,259)(H,219,262)(H,220,272)(H,221,273)(H,222,263)(H,223,256)(H,224,265)(H,225,271)(H,226,274)(H,227,275)(H,228,261)(H,229,283)(H,230,277)(H,231,278)(H,232,284)(H,233,254)(H,234,266)(H,235,279)(H,236,267)(H,246,247)(H,248,249)(H,250,251)(H,252,253)(H,286,287)(H4,191,192,198)(H4,193,194,199)/t96-,103-,105-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,130-,131-,132-,143-,144-,145-,146-/m0/s1 N
  • Key:OGBMKVWORPGQRR-UMXFMPSGSA-N N
 NY (what is this?)  (verify)

Medical uses

It is effective in growing bone (e.g., 8% increase in bone density in the spine after one year)[8] and reducing the risk of fragility fractures.[9][10] When studied, teriparatide only showed bone mineral density (BMD) improvement during the first 18 months of use. Teriparatide should only be used for a period of 2 years maximum. After 2 years, another agent such a bisphosphonate or denosumab should be used in cases of osteoporosis[11] although repeat administration has been used in hypophosphatasia, where bisphosphonates are contraindicated.[12][13]

Teriparatide cuts the risk of hip fracture by more than half but does not reduce the risk of arm or wrist fracture.[14]

Contraindications

Teriparatide should not be prescribed for people who are at increased risks for osteosarcoma. This includes those with Paget's Disease of bone or unexplained elevations of serum alkaline phosphate, open epiphysis, or prior 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 2 years of use.[15]

In 2021, the United States Food and Drug Administration removed the time limit for treatment with teriparatide, if a patient remains at or has returned to having a high risk for fracture.[16]

Patients should not start teriparatide until any vitamin D deficiency is corrected.[17]

Adverse effects

Adverse effects of teriparatide include headache, nausea, dizziness, and limb pain.[9] Teriparatide has a theoretical risk of osteosarcoma, which was found in rat studies but not confirmed in humans.[6] This may be because, unlike humans, rat bones grow for their entire life.[6] The tumors found in the rat studies were located on the end of the bones which grew after the injections began.[17] After nine years on the market, there were only two cases of osteosarcoma reported.[8] This risk was considered by the FDA as "extremely rare" (1 in 100,000 people)[9] and is only slightly more than the incidence in the population over 60 years old (0.4 in 100,000).[9]

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.[18][19][20]

Teriparatide is the first FDA approved agent for the treatment of osteoporosis that stimulates new bone formation.[21]

Society and culture

Teriparatide was approved by the US Food and Drug Administration (FDA) on 26 November 2002, for the treatment of osteoporosis in men and postmenopausal women who are at high risk for having a fracture.[22] The drug is also approved to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture. In October 2019, the US FDA approved a recombinant teriparatide product, Teriparatide Injection (previously referred to as PF708 and Bonsity) from Pfenex Inc. Teriparatide Injection is the first FDA approved proposed therapeutic equivalent candidate to Forteo.

Biosimilars

Recombinant teriparatide is sold by Eli Lilly and Company under the brand name Forteo/Forsteo. On 11 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.[1] 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.[23]

Teriparatide was approved for medical use in the European Union in June 2003.[5] A synthetic teriparatide from Teva Generics has been authorized for marketing in the European Union.[24] Biosimilar product from Gedeon Richter plc has been authorized in the European Union.[25] In October 2019, the US FDA approved a recombinant teriparatide product.[1]

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.[26][27] Qutavina and Livogiva were approved for medical use in the European Union in August 2020.[28][29]

Osnuvo was approved for medical use in Canada in January 2020.[2]

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.[30][31]

Society and culture

Teriparatide can be used off-label to speed fracture repair and treat fracture nonunions.[32] It has been reported to have been successfully used to heal fracture nonunions.[33] Generally, due to HIPAA regulations, it is not publicized when American athletes receive this treatment to improve fracture recovery.[32] But an Italian football player, Francesco Totti, was given teriparatide after a tibia/fibula fracture, and he unexpectedly recovered in time for the 2006 World Cup.[32] It has been reportedly used by Mark Mulder of the Oakland A's to recover from a hip fracture before the 2003 MLB playoffs[34] and Terrell Owens to recover from an ankle fracture before the 2005 Super Bowl.[34] Teriparatide is currently being trialled with Zoledronic acid as a treatment for Osteogenesis Imperfecta to reduce the risk of broken bones. The trial is due to end in 2023.[35]

References
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  2. "Summary Basis of Decision (SBD) for Osnuvo". Health Canada. Retrieved 29 May 2022.
  3. Lisbeth Tristan de Brea (18 September 2018). "Nota de Seguridad de Medicamentos" (PDF). Panama: Directora Nacional de Farmacia y Drogas.
  4. "Teriparatide Use During Pregnancy". Drugs.com. 25 November 2019. Retrieved 14 September 2020.
  5. "Forsteo EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 26 June 2020.
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  7. Saag KG, Shane E, Boonen S, Marín F, Donley DW, Taylor KA, et al. (November 2007). "Teriparatide or alendronate in glucocorticoid-induced osteoporosis". The New England Journal of Medicine. 357 (20): 2028–39. doi:10.1056/NEJMoa071408. PMID 18003959.
  8. Kawai M, Mödder UI, Khosla S, Rosen CJ (February 2011). "Emerging therapeutic opportunities for skeletal restoration". Nature Reviews. Drug Discovery. 10 (2): 141–56. doi:10.1038/nrd3299. PMC 3135105. PMID 21283108.
  9. Rizzoli R, Reginster JY, Boonen S, Bréart G, Diez-Perez A, Felsenberg D, et al. (August 2011). "Adverse reactions and drug-drug interactions in the management of women with postmenopausal osteoporosis". Calcified Tissue International. 89 (2): 91–104. doi:10.1007/s00223-011-9499-8. PMC 3135835. PMID 21637997.
  10. Murad MH, Drake MT, Mullan RJ, Mauck KF, Stuart LM, Lane MA, et al. (June 2012). "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. doi:10.1210/jc.2011-3060. PMID 22466336.
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  12. Camacho, Pauline M.; Mazhari, Alaleh M.; Wilczynski, Cory; Kadanoff, Ruth; Mumm, Steven; Whyte, Michael P. (August 2016). "Adult Hypophosphatasia Treated with Teriparatide: Report of 2 Patients and Review of the Literature". Endocrine Practice. 22 (8): 941–950. doi:10.4158/EP15890.OR. ISSN 1530-891X. PMID 27042741.
  13. Bishop, Nick (2015). "Clinical management of hypophosphatasia". Clinical Cases in Mineral and Bone Metabolism. 12 (2): 170–173. doi:10.11138/ccmbm/2015.12.2.170. ISSN 1724-8914. PMC 4625775. PMID 26604944.
  14. Díez-Pérez A, Marin F, Eriksen EF, Kendler DL, Krege JH, Delgado-Rodríguez M (March 2019). "Effects of teriparatide on hip and upper limb fractures in patients with osteoporosis: A systematic review and meta-analysis". Bone. 120: 1–8. doi:10.1016/j.bone.2018.09.020. PMID 30268814.
  15. Harper KD, Krege JH, Marcus R, Mitlak BH (February 2007). "Osteosarcoma and teriparatide?". Journal of Bone and Mineral Research. 22 (2): 334. doi:10.1359/jbmr.061111. PMID 17129179. S2CID 36420876.
  16. Miller, Paul D.; Lewiecki, E. Michael; Krohn, Kelly; Schwartz, Elliott (2021). "Teriparatide: Label changes and identifying patients for long-term use". Cleveland Clinic Journal of Medicine. 88 (9): 489–493. doi:10.3949/ccjm.88a.21011. PMID 34470753. S2CID 237375776.
  17. "Forteo". drugs.com.
  18. Bauer W, Aub JC, Albright F (January 1929). "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. doi:10.1084/jem.49.1.145. PMC 2131520. PMID 19869533.
  19. Selye H (1932). "On the stimulation of new bone formation with parathyroid extract and irradiated ergosterol". Endocrinology. 16 (5): 547–558. doi:10.1210/endo-16-5-547.
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  21. "Fortéo: teriparatide (rDNA origin) injection". Archived from the original on 27 December 2009.
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  24. BfArM (8 May 2017). "PUBLIC ASSESSMENT REPORT - Decentralised Procedure - Teriparatid-ratiopharm 20 µg / 80ml, Solution for injection" (PDF).
  25. "Summary of the European public assessment report (EPAR) for Terrosa". Retrieved 14 August 2019.
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  28. "Qutavina EPAR". European Medicines Agency (EMA). Retrieved 25 January 2021.
  29. "Livogiva EPAR". European Medicines Agency (EMA). Retrieved 25 January 2021.
  30. Leder, Benjamin Z.; Tsai, Joy N.; Uihlein, Alexander V.; Burnett-Bowie, Sherri-Ann M.; Zhu, Yuli; Foley, Katelyn; Lee, Hang; Neer, Robert M. (1 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 & Metabolism. 99 (5): 1694–1700. doi:10.1210/jc.2013-4440. ISSN 0021-972X. PMC 4010689. PMID 24517156.
  31. Tsai, Joy N; Uihlein, Alexander V; Lee, Hang; Kumbhani, Ruchit; Siwila-Sackman, Erica; McKay, Elizabeth A; Burnett-Bowie, Sherri-Ann M; Neer, Robert M; Leder, Benjamin Z (July 2013). "Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial". The Lancet. 382 (9886): 50–56. doi:10.1016/s0140-6736(13)60856-9. ISSN 0140-6736. PMC 4083737. PMID 23683600.
  32. Jancin B (12 December 2011). "Accelerating Fracture Healing With Teriparatide". Internal Medicine News Digital Network. Retrieved 20 September 2013.
  33. Giannotti S, Bottai V, Dell'osso G, Pini E, De Paola G, Bugelli G, Guido G (May 2013). "Current medical treatment strategies concerning fracture healing". Clinical Cases in Mineral and Bone Metabolism. 10 (2): 116–20. PMC 3796998. PMID 24133528.
  34. William L. Carroll (2005). "Chapter 1: Defining the Issue". The Juice: The Real Story of Baseball's Drug Problems. ISBN 1-56663-668-X.
  35. "New trial for people with brittle bone disease". BBC News. 16 January 2017. Retrieved 31 August 2021.
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