Teriparatide
Teriparatide 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 used in the treatment of some forms of osteoporosis. 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. Recombinant teriparatide is sold by Eli Lilly and Company under the brand name Forteo/Forsteo. On June 11, 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) on October 4, 2019. 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. Teriparatide was approved for medical use in the European Union in June 2003. A synthetic teriparatide from Teva Generics has been authorised for marketing in the European Union. Biosimilar product from Gedeon Richter plc has been authorised in the European Union. On October 4, 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. Medical uses. It is effective in growing bone (e.g., 8% increase in bone density in the spine after one year) and reducing the risk of fragility fractures. 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 although repeat administration has been used in hypophosphatasia, where bisphosphonates are contraindicated. Teriparatide cuts the risk of hip fracture by more than half but does not reduce the risk of arm or wrist fracture. Other. Teriparatide can be used off-label to speed fracture repair and treat fracture nonunions. It has been reported to have been successfully used to heal fracture nonunions. Generally, due to HIPAA regulations, it is not publicized when American athletes receive this treatment to improve fracture recovery. 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. It has been reportedly used by Mark Mulder of the Oakland A's to recover from a hip fracture before the 2003 MLB playoffs and Terrell Owens to recover from an ankle fracture before the 2005 Super Bowl. 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. 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. Patients should not start teriparatide until any vitamin D deficiency is corrected. Adverse effects. Adverse effects of teriparatide include headache, nausea, dizziness, and limb pain. Teriparatide has a theoretical risk of osteosarcoma, which was found in rat studies but not confirmed in humans. This may be because, unlike humans, rat bones  grow for their entire life. The tumors found in the rat studies were located on the end of the bones which grew after the injections began. After nine years on the market, there were only two cases of osteosarcoma reported. This risk was considered by the FDA as "extremely rare" (1 in 100,000 people) and is only slightly more than the incidence in the population over 60 years old (0.4 in 100,000). 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. Teriparatide is the first FDA approved agent for the treatment of osteoporosis that stimulates new bone formation. FDA approval. 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. 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. 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.