Teriparatide

Last updated

Teriparatide
Teriparatide structure.svg
Clinical data
Trade names Forteo, Forsteo
Biosimilars Bonsity, [1] Kauliv, [2] Livogiva, [3] Osnuvo, [4] Qutavina, [5] Sondelbay, [6] Teribone, [7]
AHFS/Drugs.com Monograph
MedlinePlus a603018
License data
Pregnancy
category
Routes of
administration 		Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 95%
Metabolism Liver (nonspecific proteolysis)
Elimination half-life Subcutaneous: 1 hour
Excretion Kidney (metabolites)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.168.733 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C181H291N55O51S2
Molar mass 4117.77 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 X mark.svgN
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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. [13] It is an effective anabolic (promoting bone formation) agent [15] used in the treatment of some forms of osteoporosis. [13] [16] Teriparatide is a recombinant human parathyroid hormone analog (PTH 1-34). [13] It has an identical sequence to the 34 N-terminal amino acids of the 84-amino acid human parathyroid hormone. [13]

Contents

Medical uses

Teriparatide is indicated for the treatment of postmenopausal women with osteoporosis; [13] for the increase of bone mass in men with primary or hypogonadal osteoporosis; [13] and treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy. [13]

It is effective in growing bone (e.g., 8% increase in bone density in the spine after one year) [17] and reducing the risk of fragility fractures. [18] [19]

Teriparatide cuts the risk of hip fracture by more than half but does not reduce the risk of arm or wrist fracture. [20]

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. [13] 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. [21]

Adverse effects

Adverse effects of teriparatide include headache, nausea, dizziness, and limb pain. [18] Teriparatide has a theoretical risk of osteosarcoma, which was found in rat studies but not confirmed in humans. [15] This may be because, unlike humans, rat bones grow for their entire life. [15] The tumors found in the rat studies were located on the end of the bones which grew after the injections began. [22] After nine years on the market, there were only two cases of osteosarcoma reported. [17] This risk was considered by the FDA as "extremely rare" (1 in 100,000 people) [18] and is only slightly more than the incidence in the population over 60 years old (0.4 in 100,000). [18]

Adverse effects - Teriparatide versus Placebo Teriparatide versus Placebo Adverse effects.png
Adverse effects - Teriparatide versus Placebo


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. [24] [25] [26]

Society and culture

Teriparatide was approved for medical use in the United States in 1987. [13] [23] 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. [27] In October 2019, the US FDA approved the recombinant teriparatide product with brand name Bonsity. [1]

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. [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. [28]

Teriparatide was approved for medical use in the European Union in June 2003. [14] A synthetic teriparatide from Teva Generics has been authorized for marketing in the European Union. [29] Biosimilar product from Gedeon Richter plc has been authorized in the European Union. [30] 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. [5] [3] Qutavina and Livogiva were approved for medical use in the European Union in August 2020. [5] [3]

Osnuvo was approved for medical use in Canada in January 2020. [4]

Sondelbay was approved for medical use in the European Union in March 2022. [6] [31]

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. [32] The applicant for this medicinal product is Strides Pharma Cyprus. [32] Kauliv was approved for medical use in the European Union in February 2023. [33] [2]

Research

Teriparatide is undergoing a clinical trial with zoledronic acid as a treatment for osteogenesis imperfecta to reduce the risk of broken bones. [34]

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. [35] [36]

Related Research Articles

<span class="mw-page-title-main">Osteoporosis</span> Skeletal disorder

Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in fracture risk.

<span class="mw-page-title-main">Parathyroid hormone</span> Mammalian protein found in humans

Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.

<span class="mw-page-title-main">Filgrastim</span> Medication

Filgrastim, sold under the brand name Neupogen among others, is a medication used to treat low neutrophil count. Low neutrophil counts may occur with HIV/AIDS, following chemotherapy or radiation poisoning, or be of an unknown cause. It may also be used to increase white blood cells for gathering during leukapheresis. It is given either by injection into a vein or under the skin. Filgrastim is a leukocyte growth factor.

<span class="mw-page-title-main">Fluticasone/salmeterol</span> Formulation used in the management of asthma and chronic obstructive pulmonary disease

Fluticasone/salmeterol, sold under the brand name Advair among others, is a fixed-dose combination medication containing fluticasone propionate, an inhaled corticosteroid; and salmeterol, a long-acting beta2‑adrenergic agonist. It is used in the management of asthma and chronic obstructive pulmonary disease (COPD). It is used by inhaling the medication into the lungs.

Bevacizumab, sold under the brand name Avastin among others, is a monoclonal antibody medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, lung cancer, ovarian cancer, glioblastoma, hepatocellular carcinoma, and renal-cell carcinoma. In many of these diseases it is used as a first-line therapy. For age-related macular degeneration it is given by injection into the eye (intravitreal).

<span class="mw-page-title-main">Zoledronic acid</span> Chemical compound

Zoledronic acid, also known as zoledronate and sold under the brand name Zometa among others, by Novartis among others, is a medication used to treat a number of bone diseases. These include osteoporosis, high blood calcium due to cancer, bone breakdown due to cancer, Paget's disease of bone and Duchenne muscular dystrophy (DMD). It is given by injection into a vein.

<span class="mw-page-title-main">Bazedoxifene</span> Chemical compound

Bazedoxifene, used as bazedoxifene acetate, is a medication for bone problems and possibly for cancer. It is a third-generation selective estrogen receptor modulator (SERM). Since late 2013 it has had U.S. FDA approval for bazedoxifene as part of the combination drug Duavee in the prevention of postmenopausal osteoporosis. It is also being studied for possible treatment of breast cancer and pancreatic cancer.

<span class="mw-page-title-main">Ibandronic acid</span> Chemical compound

Ibandronic acid is a bisphosphonate medication used in the prevention and treatment of osteoporosis and metastasis-associated skeletal fractures in people with cancer. It may also be used to treat hypercalcemia. It is typically formulated as its sodium salt ibandronate sodium.

<span class="mw-page-title-main">Denosumab</span> Human monoclonal antibody

Denosumab, sold under the brand names Prolia among others, is a human monoclonal antibody used for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone.

<span class="mw-page-title-main">Strontium ranelate</span> Chemical compound

Strontium ranelate, a strontium(II) salt of ranelic acid, is a medication for osteoporosis marketed as Protelos or Protos by Servier. Studies indicate it can also slow the course of osteoarthritis of the knee. The drug is unusual in that it both increases deposition of new bone by osteoblasts and reduces the resorption of bone by osteoclasts. It is therefore promoted as a "dual action bone agent" (DABA).

A biosimilar is a biologic medical product that is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved versions of original "innovator" products and can be manufactured when the original product's patent expires. Reference to the innovator product is an integral component of the approval.

Aflibercept, sold under the brand names Eylea and Zaltrap among others, is a medication used to treat wet macular degeneration and metastatic colorectal cancer. It was developed by Regeneron Pharmaceuticals.

Romosozumab, sold under the brand name Evenity, is a medication used to treat osteoporosis. It has been found to decrease the risk of fractures of the spine.

Abaloparatide, sold under the brand name Tymlos among others, is a parathyroid hormone-related protein (PTHrP) analog medication used to treat osteoporosis. It is an anabolic agent.

<span class="mw-page-title-main">Cabotegravir</span> Medication for HIV/AIDS

Cabotegravir, sold under the brand name Vocabria among others, is a antiretroviral medication used for the treatment of HIV/AIDS. It is available in the form of tablets and as an intramuscular injection, as well as in an injectable combination with rilpivirine under the brand name Cabenuva.

Recombinant human parathyroid hormone, sold under the brand name Preotact among others, is an artificially manufactured form of the parathyroid hormone used to treat hypoparathyroidism. Recombinant human parathyroid hormone is used in the treatment of osteoporosis in postmenopausal women at high risk of osteoporotic fractures. A significant reduction in the incidence of vertebral fractures has been demonstrated. It is used in combination with calcium and vitamin D supplements.

<span class="mw-page-title-main">Etelcalcetide</span> Chemical compound

Etelcalcetide, sold under the brand name Parsabiv, is a calcimimetic medication for the treatment of secondary hyperparathyroidism in people undergoing hemodialysis. It is administered intravenously at the end of each dialysis session. Etelcalcetide functions by binding to and activating the calcium-sensing receptor in the parathyroid gland. Parsabiv is currently owned by Amgen and Ono Pharmaceuticals in Japan.

<span class="mw-page-title-main">Alpelisib</span> Chemical compound

Alpelisib, sold under the brand name Piqray among others, is a medication used to treat certain types of breast cancer. It is used together with fulvestrant. It is taken by mouth. It is marketed by Novartis.

Somapacitan, sold under the brand name Sogroya, is a growth hormone medication. Somapacitan is a human growth hormone analog. Somapacitan-beco is produced in Escherichia coli by recombinant DNA technology.

<span class="mw-page-title-main">Palopegteriparatide</span> Medication

Palopegteriparatide, sold under the brand name Yorvipath, is a hormone replacement therapy used for the treatment of hypoparathyroidism. It is a transiently pegylated parathyroid hormone. It is a parathyroid hormone analog.

References

  1. 1 2 3 4 "Drug Approval Package: Bonsity". U.S. Food and Drug Administration (FDA). 26 February 2020. Archived from the original on 2 April 2021. Retrieved 14 September 2020.
  2. 1 2 3 "Kauliv EPAR". European Medicines Agency (EMA). 18 July 2022. Archived from the original on 9 March 2023. Retrieved 8 March 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. 1 2 3 "Livogiva EPAR". European Medicines Agency (EMA). 26 May 2020. Archived from the original on 30 January 2021. Retrieved 25 January 2021.
  4. 1 2 "Summary Basis of Decision (SBD) for Osnuvo". Health Canada . 23 October 2014. Archived from the original on 30 May 2022. Retrieved 29 May 2022.
  5. 1 2 3 "Qutavina EPAR". European Medicines Agency (EMA). 26 May 2020. Archived from the original on 30 January 2021. Retrieved 25 January 2021.
  6. 1 2 3 "Sondelbay EPAR". European Medicines Agency. 24 January 2022. Archived from the original on 4 March 2023. Retrieved 3 March 2023.
  7. ↑ Lisbeth Tristan de Brea (18 September 2018). "Nota de Seguridad de Medicamentos" (PDF). Panama: Directora Nacional de Farmacia y Drogas. Archived (PDF) from the original on 4 December 2020. Retrieved 30 September 2018.
  8. ↑ "Terrosa". Therapeutic Goods Administration (TGA). 26 May 2022. Archived from the original on 30 September 2022. Retrieved 7 July 2024.
  9. ↑ "Teriparatide Use During Pregnancy". Drugs.com. 25 November 2019. Archived from the original on 27 October 2020. Retrieved 14 September 2020.
  10. ↑ "Forteo teriparatide (rbe) 250 microgram solution for injection cartridge, Eli Lilly Australia Pty Ltd, CON-1240". Therapeutic Goods Administration (TGA). 17 June 2024. Archived from the original on 17 June 2024. Retrieved 17 June 2024.
  11. ↑ "Ritosa teriparatide 250 microgram/mL solution for injection pre-filled cartridge (408423)". Therapeutic Goods Administration (TGA). 3 May 2024. Archived from the original on 17 June 2024. Retrieved 17 June 2024.
  12. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  13. 1 2 3 4 5 6 7 8 9 10 "Forteo- teriparatide injection, solution". DailyMed. 29 April 2021. Archived from the original on 19 January 2022. Retrieved 8 March 2023.
  14. 1 2 "Forsteo EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 27 June 2020. Retrieved 26 June 2020.
  15. 1 2 3 Riek AE, Towler DA (2011). "The pharmacological management of osteoporosis". Missouri Medicine. 108 (2): 118–23. PMC   3597219 . PMID   21568234.
  16. ↑ 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.
  17. 1 2 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.
  18. 1 2 3 4 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.
  19. ↑ 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.
  20. ↑ 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 . hdl: 10230/36878 . PMID   30268814.
  21. ↑ 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.
  22. ↑ "Forteo". drugs.com. Archived from the original on 15 June 2018. Retrieved 23 January 2018.
  23. 1 2 "Teriparatide injection, solution". DailyMed. 1 November 2019. Archived from the original on 25 May 2022. Retrieved 8 March 2023.
  24. ↑ 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.
  25. ↑ 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 .
  26. ↑ 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.
  27. ↑ "Drug Approval Package: Forteo [teriparatide (rDNA origin)] Injection; NDA #021318". U.S. Food and Drug Administration (FDA). Archived from the original on 31 March 2021. Retrieved 14 September 2020.
  28. ↑ "Pfenex Announces U.S. Commercial Launch of Teriparatide Injection" (Press release). Pfenex Inc. 12 June 2020. Archived from the original on 7 April 2021. Retrieved 13 October 2020– via GlobeNewswire.
  29. ↑ BfArM (8 May 2017). "PUBLIC ASSESSMENT REPORT - Decentralised Procedure - Teriparatid-ratiopharm 20 µg / 80ml, Solution for injection" (PDF). Archived (PDF) from the original on 24 June 2021. Retrieved 24 June 2019.
  30. ↑ "Summary of the European public assessment report (EPAR) for Terrosa". 17 September 2018. Archived from the original on 14 August 2019. Retrieved 14 August 2019.
  31. ↑ "Sondelbay Product information". Union Register of medicinal products. Archived from the original on 4 March 2023. Retrieved 3 March 2023.
  32. 1 2 "Kauliv: Pending EC decision". European Medicines Agency. 11 November 2022. Archived from the original on 31 December 2022. Retrieved 3 March 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  33. ↑ "Kauliv Product information". Union Register of medicinal products. Archived from the original on 27 January 2023. Retrieved 3 March 2023.
  34. ↑ "New trial for people with brittle bone disease". BBC News. 16 January 2017. Archived from the original on 31 August 2021. Retrieved 31 August 2021.
  35. ↑ Leder BZ, Tsai JN, Uihlein AV, Burnett-Bowie SA, Zhu Y, Foley K, et al. (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. doi:10.1210/jc.2013-4440. PMC   4010689 . PMID   24517156.
  36. ↑ Tsai JN, Uihlein AV, Lee H, Kumbhani R, Siwila-Sackman E, McKay EA, et al. (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. PMC   4083737 . PMID   23683600.
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