Teriparatide [Human PTH(1‐34)]: 2.5 Years of Experience on the Use and Safety of the Drug for the Treatment of Osteoporosis

IN NOVEMBER 2002, the Food and Drug Administration (FDA) approved teriparatide (Forteo) for the treatment of osteoporosis. Teriparatide contains the first 34 amino acids of human PTH. We will use the term teriparatide to describe PTH(1-34) produced by recombinant DNA technology by Eli Lilly & Co. (Indianapolis, IN, USA) and marketed as Forteo. The peptide produced by any other technology will be called PTH(1-34). The approval of teriparatide came after an eventful period of preclinical and clinical studies and was not without controversy. The approval process required the FDA to balance the potential oncologic risks with the clearly established benefits of this unique pharmacologic agent. This situation was created by preclinical data that showed the development of osteosarcomas in a high percentage of rodents treated with large doses of teriparatide for most of their lifespan. Aligned on the side advocating approval of teriparatide was the pharmaceutical maker (Eli Lilly & Co.), some patient groups representing those patients with severe osteoporosis, and a sizable component of basic and clinical investigators studying bone disease. Aligned against approval were several citizen watch groups who vigorously opposed human use of this agent because of concern regarding the potential development of osteosarcoma. Most vociferous was Public Citizen (www.publiccitizen.org), an organization actively opposed to use of this agent because of its potential carcinogenicity. The FDA had been under fire because of recalls of several previously approved pharmaceutical agents; the ensuing criticism created a tense regulatory environment. Perhaps the most interesting role was that of the metabolic bone disease community. After an initial period of surprise regarding the osteosarcoma data, researchers performing studies with teriparatide or other preparations of PTH(134) or PTH(1-84) examined their own patient populations treated with the hormone, and no reports of an association of osteosarcoma with PTH therapy have appeared. After a 1to 2-year period of sorting through their experiences, some extending to the mid-1980s, the reality set in that a novel pharmaceutical agent with shown effectiveness to stimulate new bone formation and little evidence of toxicity in humans might be disapproved. Furthermore, the absence of long-term patent protection for this agent created minimal incentive for the manufacturer to perform the longterm studies that would be necessary to prove safety in a definitive manner. Indeed, as events throughout the pharmaceutical industry have shown, the financial returns from the marketing of this agent (net revenue of $5.6 million in 2002, $56 million in 2003, and $239 million in 2004) would have to be balanced against the potential impact of litigation in the event that there was an adverse effect. More importantly, investigators in the field understood that disapproval of this agent would likely suppress future research using the PTH receptor system and its downstream signaling pathways as a pharmacologic target to stimulate bone formation. The prospect that research on the one signaling system that, at the time, was proven to increase bone formation and had no demonstrable toxicity in humans, was alarming to many basic and clinical researchers in the bone field and led to an advocacy role on behalf of teriparatide from a normally nonpolitical group once the company made a decision to move forward with a request for approval. The FDA chose a middle ground, one that permitted use of this agent for patients with severe forms of osteoporosis, accepting the time-tested tenet that the reduction in morbidity from the use of this agent in highrisk groups far outweighed the hypothetical risks. The FDA approved teriparatide for treatment of osteoporosis in men and women but placed significant limitations on its application. Use of the drug was limited to a 2-year period and exclusion of patients considered at high risk for osteosarcoma (those with a history of radiation exposure to bone, Paget’s disease of bone, and children with open epiphyses) and a recommendation that the pharmacologic agent be used only for those with substantial fracture risk. Despite these limitations, the decision was discussed broadly by experts in the bone community and was strongly supported by many academic and clinical investigators. In Dr Tashjian serves as a consultant for Eli Lilly and Company. Dr Gagel serves as a consultant for Proctor & Gamble, received speaker’s fee from Eli Lilly and Company, Merck, Novartis, Pfizer, and Proctor & Gamble, and received grants and research funding from Novartis and Pfizer.