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

Abstract

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(1-34) 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 1- to 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 long-term 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 high-risk 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 addition to the availability of this agent for those patients with severe osteoporosis, implicit in the approval process was a strategy to establish that this agent was indeed as safe as most researchers in this field considered it to be. As a part of the approval process, the manufacturer agreed to conduct a long-term (10-year) surveillance study at several referral centers to assess whether any individuals who developed osteosarcoma had been previously treated with teriparatide. In June 2003, the European Agency for the Evaluation of Medicinal Products also approved teriparatide (Forsteo) for treatment of women with osteoporosis. We are now >2.5 years down the road. Through August 2005, the number of patients treated with teriparatide worldwide was estimated to be >205,000. Data collected from ∼15,000 retail pharmacies in the United States indicate that ∼90% of the patients are female, and the average age is 68 years (median, 71 years). The age group ≥70 years represent those who have the highest risk of fracture and would be expected to benefit most. Within the limitations of prescription audit data, 82% of patients receiving teriparatide had one or more prior fractures and ∼50% had previously filled a prescription for an antiresorptive drug (bisphosphonate, estrogen or estrogen/progestin combination, or a selective estrogen receptor modulator [SERM]). Among drugs used to treat osteoporosis in the United States, bisphosphonates constitute ∼77%; the remaining drugs (SERMs, calcitonin, teriparatide, or hormone replacement) constitute in aggregate the remaining 23%. Teriparatide prescriptions account for <3% of the total. Each patient in the United States who fills or renews a prescription for teriparatide receives a document called a “Medication Guide” that describes the drug, how it should be taken and used, and possible side effects. It is recommended that all patients treated with teriparatide receive vitamin D and calcium supplementation if dietary sources are likely to be of with the recommended treatment and of use are not the of teriparatide use a number that with the average of use for bisphosphonates of This be because the patients using teriparatide have more severe osteoporosis and are more In the will a number of and with the use of this agent. Teriparatide is by of in the or using a that many of the patients would be and some would be Lilly created an for patients who to use this agent. This by a or other use of the with in the of the group patients have been the first years This proven As might be for this with little or no with of in the use of the is the most of patients teriparatide and the most for patients to the in were in As in a studies in showed that teriparatide the formation of osteosarcomas at exposure the approved for human use of In the first bone were in all treatment In a study to treatment and age at no bone were at the human exposure in treated for of their this is a of of the PTH receptor and not unique to the first 34 amino acids of PTH is shown by the of osteosarcomas in treated for with human PTH(1-84) at doses of and representing clinical exposure of and that of the in humans to the from the were with no significant in treated with a clinical exposure of have been no studies teriparatide to recombinant PTH(1-84) these are with the that and of treatment with PTH are to the formation of osteosarcomas in in In clinical of teriparatide studying no patient treated with or developed osteosarcoma. human teriparatide studies were in at the that osteosarcomas were in these patients have been for years their exposure to teriparatide. In there have been no reports of osteosarcoma in any patient previously treated with teriparatide, or of these studies to the for osteosarcoma development there were a treatment and development of an it is how the investigators in these prior studies examined the of patients who in those The by in the bone and to the development of with use most patients to their to their bone or a regarding the of the side is there have been no reports of osteosarcoma in any of the patients treated through August teriparatide approval in the United States or It be estimated that of these patients have been on teriparatide for and an percentage of patients are now their of It is to that the first osteosarcomas in the treated with to clinical exposure of teriparatide not of exposure had been the absence of should be considered an initial of the long-term clinical safety of this pharmacologic agent. This also been examined from a have been reports of the of and osteosarcoma in that the long-term exposure of bone to PTH in would some of the exposure to an of with the of examined a of patients with osteosarcoma who to a referral a period to whether the of in this was expected in the of these patients had calcium their patients in this had osteosarcoma and a of the of in the osteosarcoma and populations showed no significant the these not a and osteosarcoma with that a if it is not it to be that exposure to PTH in not the pharmacologic with of the this a surveillance study is by Eli Lilly & Co. to whether a of men or years of age with have treatment with teriparatide or PTH(1-34). The FDA and the manufacturer have a regarding use of teriparatide in patients who might have a risk of osteosarcoma. Teriparatide use is in patients with Paget's disease of bone or of patients with a prior history of radiation to the children or with open or in patients with bone the manufacturer and FDA have the of to these of in a and whether radiation to for treatment of After several of osteosarcomas in the of patients to the manufacturer and the FDA that patients with any radiation should be from treatment with teriparatide. it will be to to regarding these is by The first is a patient treated by one of who had treatment years at and had had was by the and by the In a by a teriparatide had been by a a history of prior radiation to the As regarding the safety of teriparatide should the regarding its use in the regulatory that this is a safe agent for most it will be that in the bone field not the use of this pharmacologic agent by this therapy in patients at risk for osteosarcoma. The development of several of osteosarcoma in patient populations at risk for whether or not by teriparatide, the FDA to regulatory that would its use in the groups of patients with severe osteoporosis. Teriparatide is in patients with and bone It been established that bone an role in the and of bone is evidence that of by treatment with bisphosphonates the development of bone in treatment with teriparatide, in addition to bone also bone regarding the of bone with a role for peptide a peptide that to and the receptor as in the of is to to bone It been that of or other by bone and an these be with the of long-term clinical there is clearly evidence that patients with and with bone those not have now been to years of data, the for clinical be to and other with bone is evidence in that treatment the of to bone it is whether treatment with a that formation would be or these are in teriparatide should not be used in patients with or bone or in patients with with or other more is the patient with a history of who developed severe osteoporosis. of used teriparatide in several patients with severe osteoporosis fractures and treated for more a In of these been taken to a prior history of The absence of any clinical in patients that these should be on a because the percentage of patients with a history of will the several clinical should be in this The of patients treated with teriparatide been for a period of years to whether or or fractures with after of teriparatide. of these data by Eli Lilly & Co. no increase in any of these on Eli Lilly & Co. the teriparatide to a on This the of adverse events with events after in patients in patients in patients surveillance for is on safety reports to the company and not represent an calcium have been treated by of dietary calcium vitamin D drug also been and events and at the in patients have been and In a on was to the teriparatide there have been of in the to of the teriparatide have been as a events have and In some no adverse events as a of the with have been and a years have teriparatide was use in the United States and the of patients will have years of In most bone of will have are now the of to after of teriparatide. In there are regarding of teriparatide with other osteoporosis of these have been in by more by We to on several and definitive data are on a number of the clinical Teriparatide been approved for treatment of osteoporosis in women with osteoporosis and men with or osteoporosis. The evidence for been and only the of this will be in this In will the evidence for in osteoporosis. The highest of teriparatide been in women with osteoporosis. The women with a fracture who were not receiving hormone therapy or other antiresorptive patients were to teriparatide teriparatide or This study was after a of treatment of because of the of osteosarcomas in a 2-year of the data set showed a reduction in the risk of fractures in women of teriparatide and a reduction in the group treated with fractures were and in the and the number of fractures was the of teriparatide at any was not of this data set showed no in at the and doses and with the was approved by the The data in men were but the of the to establish fracture of fracture In this men were to teriparatide teriparatide or The study was because of the of osteosarcomas in as After of was by in the and in the by was to significant on fracture risk. to teriparatide were of had or on these and other studies that also showed of the FDA approved teriparatide for use in In a of the men who teriparatide and who have antiresorptive therapy had a risk of and severe is also evidence for of PTH(1-34) in study in women on estrogen or estrogen and PTH(1-34) showed on estrogen and PTH had a or increase in with or in the In this there were no significant or the treatment were no fracture This study is also interesting because it was the first to a of PTH with agent after of the The PTH was after of and groups were on estrogen and In the group treated with the first from to and from to This with a to or to in the were also at the in the group the only was the PTH but for some period of after The of teriparatide or PTH(1-84) on bone are are not only on and bone, but the of in these of bone also treatment with PTH an increase of and bone that is a 2-year period of of PTH after a of therapy is with of bone in some and in treatment with teriparatide or PTH(1-84) of bone at the and of the by or treatment in of bone on the and of bone on the with of PTH after or years of therapy in in of the bone and or of The in bone an period of treatment and a of at in this The addition of a agent those have been antiresorptive be in the of the studies have the of use of teriparatide or PTH(1-84) in with a In the most study of this examined the of PTH(1-84) and or a Evaluation of the data set was PTH(1-84) a increase of bone or PTH(1-84) and or The on bone or by were the was a increase with no with PTH(1-84) with and of bone with was for these groups in the of bone by at the of the an of fracture data were study by showed of PTH(1-34) and This study from the one in several of PTH(1-34) was used the approved of and PTH was at in the PTH and was by or the of was highest in the PTH(1-34) group the initial of in the and at the was highest in the or therapy group with PTH(1-34) was with all but there were no significant or with PTH(1-34) produced in the period of In PTH(1-34) of in the at the and were a the of the of the of PTH at and the more of PTH and a are studies a number of interesting regarding the of PTH and a The of on in bone, in the of PTH that PTH with a might protection for bone without with bone formation. in the absence of studies fracture data most in the osteoporosis field have to use bisphosphonates after PTH as will be is whether therapy should be for a period of of teriparatide In to the of therapy on bone formation and there is evidence that the of PTH therapy on bone is with its to increase of bone in at and at were the most and of the to teriparatide in Furthermore, a number of the more bisphosphonates have a and on of bone some to of therapy for a period the of teriparatide This was also in a from who all patients a study for with of this group on were treated with and PTH(1-34) and with a period of PTH(1-34) by a period without for or of PTH(1-34). were of PTH(1-34) an increase of bone formation and of the PTH The of increase in the PTH group was with but in the PTH there were in by at the and with the or and were with this study not any by it to whether there were on and In the increase in and was in of these groups in many other studies in PTH was by also that of PTH after of is with an bone formation a group of patients previously treated with PTH(1-34) by for a with a of PTH(1-34). formation and the exposure to PTH were to those the first of It is possible that of by bone formation by PTH(1-34). it been that of the to of bone without bone that selective pharmacologic of the but not of the be to this will be by or the that to and of the In of this by of bone but not bone to bone treatment of with to of there will be in humans is the of if there are in humans as in it would be to one of these with teriparatide. have been no studies that the of PTH and estrogen It be from the increase in in patients on estrogen therapy in PTH(1-34) was that estrogen not to the bone of use of teriparatide or PTH(1-34) and been examined in rodents and in rodents showed that with not in bone In other it been shown that a bone formation in in humans have shown that prior treatment with not the of The of and also indicate no of the of teriparatide used with long-term studies are are a number of potential that have not been in with teriparatide or are vitamin D D or have been shown in a of studies in rodents and humans to increase bone and also to studies of for treatment of osteoporosis have shown an increase in but no fracture data have been and there is a significant of and vitamin D with PTH in humans been limited or by the potential for development of in patients treated with The of vitamin D with and on bone formation an to study in with that bone formation and It is not whether these with PTH would be of that is now using this agent is whether to an antiresorptive drug after years of teriparatide In the previously using teriparatide, women with a who were not receiving or other antiresorptive were to teriparatide teriparatide or a In a to long-term a group of women from the was for after teriparatide. were treated to with osteoporosis drugs other teriparatide used in of the women in the reduction in new fracture risk was in women who had been treated with teriparatide in the in with women treated with in the a of teriparatide for at after the This study limitations in that in the and in the teriparatide also some other of osteoporosis treatment the the that it was some of teriparatide and osteoporosis agent a that to fracture reduction effect. the indicate that there not to be any of no data are More the of group by the of this Indeed, the at the that therapy the of teriparatide by data that bone by teriparatide are by the use of a of will be shown more in studies discussed More examined the fracture in the of patients in the after of teriparatide of group or were treated with a for some period of the and a percentage was on a at the of bone this period that patients treated with bisphosphonates after of teriparatide in those who no treatment had studies are also limited in the as the was to whether to the to the PTH or the of PTH and because of the of of In a by using treatment with in at of PTH(1-84) In the in this study that bone in the PTH(1-84) group by by and was the group by at the of the study after of that of PTH to increase bone after it is from in women or PTH or the first by the data represent the after of PTH or data represent the after an of with Data were from the with of the and The have for teriparatide. treated with or after PTH(1-34) therapy an those placed on no therapy after teriparatide Furthermore, the addition of or after PTH(1-34) a increase in bone with that in patients treated with a at the of of PTH(1-34). This study from of patients and the of a The most evidence for a of a is by the from were to one of PTH(1-84) the first with no therapy in the PTH(1-84) the first by in the PTH and the first by in the and for The from this showed clearly that PTH(1-84) by was with the in bone whether by or not from in at the and of the to treatment was used in these was with the use of for the with the group at for the with the represent the for the at and with from studies evidence that therapy after PTH(1-34) or PTH(1-84) there are no fracture is the use of other antiresorptive as after teriparatide there are data that use of estrogen or with PTH not impact the of with have for antiresorptive therapy after teriparatide teriparatide is the most therapy for bone and it is also the most and its use is limited to a of years of to and in bone because there is no for therapy if bone the initial years of teriparatide therapy is this with the data of antiresorptive after of teriparatide therapy a for or of antiresorptive was concern that teriparatide therapy might increase bone at the of reports this have on this The of that teriparatide in the with no on and studies of showed that PTH bone by by and by in women with osteoporosis. have been in the an of the might be expected to have a effect. of that bone formation with to bone with a and a with The of these is a bone that is studies that fracture will be to on this effect. is a substantial that exposure to teriparatide is with bone exposure to teriparatide In a by exposure to teriparatide of and exposure was with in and of This of the and teriparatide. from that of a is on the of through its to an of and In this the were to bone formation in the by of these It is possible that the new bone formation PTH treatment is by the of these It will be to these in other The potential to bone formation by the of only by other without of bone is an PTH and an increase in bone formation and bone In this PTH from all prior approved calcitonin, and are to bone with teriparatide, or PTH(1-84) of bone formation of bone and bone formation and bone of or and evidence of bone The increase in bone formation to the increase of Furthermore, in human studies of patients with osteoporosis treated with there is evidence that in with in bone to the on bone formation and have to been treatment with and PTH in a of bone treatment with PTH(1-34) or PTH(1-84) that is for bone formation or that the of by bisphosphonates some signaling process by the and evidence from a of by and for the of an from to necessary for bone formation. hypothetical have been The first that of the receptor system by PTH to a that bone formation. the is that of as from bone, bone The that teriparatide treatment of the of the bone It is possible that the of or or with a to bone formation. of the bone and formation would to to formation and the that bone formation by PTH be of The that PTH(1-34) and the that and treated with PTH more had a impact on the of bone Within after the of this investigators at had treatment to whether there are in are the that PTH PTH(1-34) was used to treat in the to are long-term treatment of is not an of be who have and for or of these patients the first after be a and is with a to a of a large doses of calcium of or calcium and vitamin D are required to are because of the of vitamin D and calcium therapy and of in of patients this to In this study of the potential for treatment with teriparatide in the a more and safe of calcium and vitamin D there are as no clinical data in patients on the potential use of teriparatide use in fracture or there are some In it been that of teriparatide increase of fracture and studies in have that treatment with teriparatide and and increase that limited clinical using teriparatide are in clinical to fracture or the of or In the years there been a increase in the use of teriparatide, patients with is but is and in in The of adverse events in the community of clinical is to those in the clinical with the most and of calcium have been in the clinical events have to be not and have been by calcium or vitamin D or of of use is have been no of osteosarcoma in patients teriparatide or any other of PTH. number of how to use this bone agent to benefit for women and men with osteoporosis, the and use of drugs that to bone clinical are to the potential use of teriparatide to stimulate and and to of bone in clinical as and The for