Teriparatide

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Teriparatide
Teriparatide structure.svg
Names
Trade namesForteo, Forsteo, Teribone, Bonsity
Clinical data
Drug classParathyroid hormone (PTH)
Main usesOsteoporosis[1]
Side effectsPain, nausea, rash, depression, problems with teeth[1]
Pregnancy
category
  • AU: B3[2]
  • US: C (Risk not ruled out)[2]
Routes of
use
Subcutaneous
Defined daily dose20 ug OD[3]
External links
AHFS/Drugs.comMonograph
US NLMTeriparatide
MedlinePlusa603018
Legal
License data
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx only
Pharmacokinetics
Bioavailability95%
MetabolismLiver (nonspecific proteolysis)
Elimination half-lifeSubcutaneous: 1 hour
ExcretionKidney (metabolites)
Chemical and physical data
FormulaC181H291N55O51S2
Molar mass4117.77 g·mol−1
3D model (JSmol)
  • [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=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
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Teriparatide, sold under the brand name Forteo among others, is a form of parathyroid hormone (PTH) used to treat osteoporosis.[1] It may be used in those in who bisphosphonates do not work or those at very high risk.[1] It is given by injection under the skin.[1] It may be used for up to two years.[3]

Common side effects include pain, nausea, rash, depression, and problems with the teeth.[1] Other side effect may include an increased risk of osteosarcoma, anaphylaxis, low blood pressure with standing.[1] It consists of the active portion of PTH and works by promoting bone formation.[1][4]

Teriparatide was approved for medical use in the United States in 2002 and Europe in 2003.[1][4] In the United Kingdom a month supply costs the NHS about £240 as of 2021.[3] This amount in the United States costs about 3,900 USD.[5]

Medical uses

Osteoporosis

It is effective in growing bone (e.g., 8% increase in bone density in the spine after one year)[6] and reducing the risk of fragility fractures.[7][8] 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[9] although repeat administration has been used in hypophosphatasia, where biphosphonates are contraindicated.[10][11]

Teriparatide cuts the risk of hip fracture by more than half but does not reduce the risk of arm or wrist fracture.[12]

Other

There is tentative evidence that it may help heal fracture nonunions.[13]

Dosage

It is used at a dose of 20 ug per day for up to 2 years.[3]

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.[14]

People should not start teriparatide until any vitamin D deficiency is corrected.[15]

Side effects

Side effects of teriparatide include headache, nausea, dizziness, and limb pain.[7] Teriparatide has a theoretical risk of osteosarcoma, which was found in rat studies but not confirmed in humans.[16] This may be because, unlike humans, rat bones grow for their entire life.[16] The tumors found in the rat studies were located on the end of the bones which grew after the injections began.[15] After nine years on the market, there were only two cases of osteosarcoma reported.[6] This risk was considered by the FDA as "extremely rare" (1 in 100,000 people)[7] and is only slightly more than the incidence in the population over 60 years old (0.4 in 100,000).[7]

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.[17][18][19]

Teriparatide is the first FDA approved agent for the treatment of osteoporosis that stimulates new bone formation.[20]

History

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.[21] The drug is also approved to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture. On October 4, 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.

Teriparatide injection was developed by Pfenex Inc and approved by the US Food and Drug Administration (FDA) on October 4, 2019.[22]Biosimilar product from Gedeon Richter plc has been authorised in the European Union.[23] On October 4, 2019, the US FDA approved a recombinant teriparatide product.[22]

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.[24][25] Qutavina and Livogiva were approved for medical use in the European Union in August 2020.[26][27]

Research

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]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Teriparatide". drugs.com. American Society of Health-System Pharmacists. Retrieved 1 October 2021.
  2. 2.0 2.1 "Teriparatide Use During Pregnancy". Drugs.com. 25 November 2019. Retrieved 14 September 2020.
  3. 3.0 3.1 3.2 3.3 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 774. ISBN 978-0-85711-369-6.CS1 maint: date format (link)
  4. 4.0 4.1 "Forsteo EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 26 June 2020.
  5. "Forteo". Goodrx.com. Retrieved 1 October 2021.
  6. 6.0 6.1 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.
  7. 7.0 7.1 7.2 7.3 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.
  8. 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.
  9. O'Connor KM (July 2016). "Evaluation and Treatment of Osteoporosis". The Medical Clinics of North America. 100 (4): 807–26. doi:10.1016/j.mcna.2016.03.016. PMID 27235616.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 15.0 15.1 "Forteo". drugs.com.
  16. 16.0 16.1 Riek AE, Towler DA (2011). "The pharmacological management of osteoporosis". Missouri Medicine. 108 (2): 118–23. PMC 3597219. PMID 21568234.
  17. 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.
  18. 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.
  19. Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R (December 1993). "Anabolic actions of parathyroid hormone on bone". Endocrine Reviews. 14 (6): 690–709. doi:10.1210/edrv-14-6-690. PMID 8119233.
  20. "Fortéo: teriparatide (rDNA origin) injection". Archived from the original on 2009-12-27.
  21. "Drug Approval Package: Forteo [teriparatide (rDNA origin)] Injection; NDA #021318". U.S. Food and Drug Administration (FDA). Retrieved 14 September 2020.
  22. 22.0 22.1 "Drug Approval Package: Bonsity". U.S. Food and Drug Administration (FDA). 26 February 2020. Retrieved 14 September 2020.
  23. "Summary of the European public assessment report (EPAR) for Terrosa". Retrieved 2019-08-14.
  24. "Qutavina: Pending EC decision". European Medicines Agency (EMA). 25 June 2020. Retrieved 26 June 2020.
  25. "Livogiva: Pending EC decision". European Medicines Agency (EMA). 25 June 2020. Retrieved 26 June 2020.
  26. "Qutavina EPAR". European Medicines Agency (EMA). Retrieved 25 January 2021.
  27. "Livogiva EPAR". European Medicines Agency (EMA). Retrieved 25 January 2021.
  28. Leder, Benjamin Z.; Tsai, Joy N.; Uihlein, Alexander V.; Burnett-Bowie, Sherri-Ann M.; Zhu, Yuli; Foley, Katelyn; Lee, Hang; Neer, Robert M. (2014-05-01). "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.
  29. 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.

External links

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