Commentary on Clinical Safety of Recombinant Human Parathyroid Hormone 1-34 in the Treatment of Osteoporosis in Men and Postmenopausal Women

RECOMBINANT HUMAN parathyroid hormone 1-34 [rhPTH(1-34)], currently under the Food and Drug Administration (FDA) review for marketing approval as FORTEO (teriparatide injection [rDNA origin]), is a promising addition to agents used for the treatment of osteoporosis.1, 2 When administered once daily rhPTH(1-34) stimulates rapidly the formation of new bone matrix, which does not occur with other currently available therapies. In addition, it was well tolerated in phase III clinical trials.2 However, there are concerns, based on studies in rats,3 about the long-term clinical safety, particularly the tumorigenic potential, of PTH as a therapeutic agent. This commentary (1) reviews briefly the human experience with PTH as a treatment for osteoporosis; (2) summarizes the most important results from a 2-year carcinogenesis bioassay in rats; (3) analyzes the differences in the biological responses to rhPTH(1-34) among rats, monkeys, and humans; (4) interprets the findings in the 2-year rat study in terms of human safety; (5) reviews the data from patients with hyperparathyroidism to determine whether there is evidence for increased risk of osteosarcoma associated with chronic exposure to excess PTH; and (6) offers an assessment of the likely risk-to-benefit ratio for treatment of osteoporosis in humans with rhPTH(1-34). Current approved therapies for the prevention and treatment of osteoporosis in men and postmenopausal women all act primarily by inhibiting bone resorption. These include calcium and vitamin D supplementation, bisphosphonates, hormone-replacement therapy (HRT), a selective estrogen receptor modulator (raloxifene), and calcitonin.4 rhPTH(1-34), with an entirely different mode of action, may be available soon for treatment of patients with osteoporosis. This polypeptide is composed of the first 34 amino acids of the native 84-amino acid hPTH molecule and usually is referred to as rhPTH(1-34). rhPTH(1-34) and PTH(1-84) act via the PTH-1 receptor (also called the PTH/PTHrP receptor) in target tissues to mediate the same spectrum of biological effects.5-8 When administered to animals and humans as a single subcutaneous injection once daily, rhPTH(1-34) stimulates bone turnover with a substantial net increase in bone formation leading to an increase in bone mass and improved architecture.4, 9-12 The biomechanical properties of bone also are improved,10, 12 resulting in a substantial decrease in the risk of both vertebral and nonvertebral fractures.2 In rats, monkeys, and humans, these bone formation-stimulating effects differ from those of resorption inhibitors, which act mainly to increase bonemineral density (BMD) by reducing bone resorption and by enhancing the state of mineralization; they do not increase matrix deposition and overall bone volume.1, 13, 14 rhPTH(1-34) appears to increase BMD by 8-9% in the first year of treatment while estrogen and bisphosphonates increase BMD 3-5% during this same period.15 rhPTH(1-34) also has been reported to reverse corticosteroid-induced osteoporosis in women 50-82 years of age16 and to prevent estrogen deficiency-related bone loss in women 21-45 years old.17 Results of a double-blinded placebo-controlled, prospective clinical trial with rhPTH(1-34) in 1637 postmenopausal women with at least one moderate or two mild atraumatic vertebral fractures has been published recently and has shown a strongly positive effect on BMD and decrease in the risk of new osteoporotic fractures.2 With a self-administered daily dose of 20 μg of rhPTH(1-34), the relative risk (RR) for a new vertebral fracture was 0.35 (95% CI, 0.22-0.55) and 0.47 (95% CI, 0.28-0.79) for nonvertebral fragility fractures compared with the risk in placebo-treated women. Fracture prevention effects were observed after 10-12 months of treatment and the fracture risk was reduced compared with control subjects through the duration of the study (median exposure of 19 months). BMD was increased 9.7% (p < 0.001) at the lumbar spine and 2.6% (p < 0.001) at the total hip as compared with placebo-treated subjects. Overall, rhPTH(1-34) was well tolerated, with high compliance, a low dropout rate [6% in the placebo group and 6% in the 20 μg-PTH(1-34) group], and relatively minor adverse events including transient (<24-h duration) low-level increases in serum calcium in 11% of subjects receiving 20 μg/day of rhPTH(1-34). Patients did not experience persistent hypercalcemia, hypercalciuria, or renal calculi.2 Iliac crest bone biopsy specimens in a subset of 38 patients treated with PTH(1-34) in this study showed no evidence of woven bone or bone cell proliferative lesions when evaluated at endpoint. Histomorphometric analysis of these specimens showed an increase in trabecular bone volume and an increase in mineral apposition rate (U.S. FDA NDA 21-318 submission, unpublished data, 2001). Data from other human studies of 6 months duration or longer consistently showed an increase in bone mass and are summarized in Table 1. Thus, rhPTH(1-34) is a well-tolerated therapeutic agent that has the unique ability to add new lamellar bone matrix rapidly in the osteoporotic human skeleton and decrease the risk of vertebral and nonvertebral fractures. As is standard practice for new chemical agents to be used in humans for long periods of treatment, rhPTH(1-34) was tested in a conventional 2-year carcinogenesis bioassay in rats. The design of the experiment, including the testing of three different daily doses of rhPTH(1-34) (5, 30, or 75 μg/kg), was planned in consultation with the U.S. FDA. The Fischer 344 rat is a common strain used for 2-year rodent bioassays. As in most rat strains, Fischer 344 rats have a low spontaneous incidence (<0.2%) of primary bone tumors including osteosarcomas. The study with rhPTH(1-34) revealed a high incidence of osteosarcomas after 2 years of treatment, and, therefore, initially raised serious concerns regarding the safety of PTH use in humans. In this commentary, we attempt to place the rodent findings in context, providing additional data and analyses. We conclude that the occurrence of such tumors in patients with osteoporosis treated with rhPTH(1-34) is unlikely. Fischer 344 rats, beginning at 6-8 weeks of age, were given subcutaneous injections of rhPTH(1-34) daily for 2 years (60/sex per group, intact female and male rats). Unexpectedly, they developed osteosarcomas that were first detected by gross examination in the high-dose group (75 μg/kg) after ∼17 months of treatment. By the end of the study, osteosarcomas occurred with increasing frequency in a dose-related manner at all three doses (75, 30, and 5 μg/kg) in the rhPTH(1-34)-treated groups of rats of both sexes.3 The highest incidence (48%) occurred in animals that received the 75-μg/kg dose.3 As soon as these tumors were first identified in rats, administration of rhPTH(1-34) to subjects in the clinical trials was stopped, and the results from the study were analyzed at that point. To attempt to understand and explain the unexpected neoplasms in rats, the pharmacodynamic and toxicologic effects of rhPTH(1-34) in this and other animal studies were analyzed in detail. The tumors were unexpected for several reasons. In shorter-duration toxicology and pharmacology studies, administration of rhPTH(1-34) for 12 months to rats beginning at 6 months of age35 or for 18 months to 9- to 11-year-old monkeys12 resulted in no osteosarcomas or other bone tumors, and osteosarcomas had not been reported in any of the patients treated with daily rhPTH(1-34) in all reported trials to date. Further, in patients with hyperparathyroidism, proliferative bone lesions have not been linked to chronic exposure to elevated circulating concentrations of PTH. In the 2-year bioassay, a comprehensive histological evaluation of the rats at the end of the study disclosed that animals treated for up to 2 years with rhPTH(1-34) had profound skeletal changes at all three doses. As evaluated by quantitative computed tomography (QCT; Fig. 1) and qualitative histology, bone mass in the rats was increased greatly beyond normally attained peak levels. Expansion of endocortical and trabecular bone resulted in substantial reduction in the marrow space with altered bone architecture in these rats (M. Sato, Eli Lilly and Company, personal communication, 2001). The skeletal responses were so dramatic that the BMD, in rats treated with rhPTH(1-34) at 75 μg/kg, was 1418 mg/cc for the whole femur of female rats, a value that was similar to that of a rod of pure cortical bone from the bovine femoral midshaft (1393 mg/cc), as compared with the BMD in a control female rat femur (967 mg/cc) or male rat femur (882 mg/cc). Comparison of the effects of daily PTH treatment on bone in rats (M. Sato, Eli Lilly and Company, personal communication36, 37) and humans38 indicated that the magnitude of the effect in rats is much greater and occurs after a much shorter treatment period than in humans. QCT images of the midshaft of femurs from male rats at the end of the 2-year bioassay. Shown are representative images from a control, vehicle-treated rat and bones from rats treated with 5, 30, or 75 μg/kg of rhPTH(1-34). The dose-dependent increase in BMD and bone mineral content is evident as is the progressive loss of marrow space. All images are at the same magnification showing the dose-dependent increase in cross-sectional area. Possible explanations for the greater sensitivity of the rat skeleton may be related to the important differences in skeletal physiology between rodents and primates.37 Skeletal growth occurs in rats throughout most of their lives.37, 39 PTH stimulates longitudinal bone growth in rats, resulting in longer, wider bones, even in aged rats.40, 41 In contrast, humans typically cease longitudinal skeletal growth by ∼18-24 years of age, achieving peak bone mass at ∼30-35 years of age.42 Thus, the natural history of the adult human skeleton is dominated by osteonal remodeling and not by growth, and that of the rat skeleton is dominated by skeletal growth (modeling) that is not coupled to resorption. In humans and other large animal species with osteonal cortical bone, PTH stimulates turnover at multiple sites, so that old bone is replaced by new bone; thus, cortical bone mass does not increase.11, 29, 43 In rats, which lack Haversian systems, PTH increases cortical bone mass by extensively layering new bone on endocortical and periosteal surfaces, in addition to trabecular bone surfaces.6, 44, 45 Thus, marked gains in bone mass and deformity of bone geometry were induced by PTH in rats, particularly when it was given for nearly the entire life span. As a result of the massive bone formation, it was not possible to distinguish between trabecular and cortical bone for most of the skeletal sites in many of the animals from the 2-year bioassay. Interestingly, elimination or drastic reduction of the marrow space in rats occurred at all three doses of rhPTH(1-34). The time after initiating treatment at which marrow exclusion took place was inversely dose related.3 It was estimated from radiographic data that marrow space decline with extramedullary hematopoiesis occurred at about 12, 15, and 21 months with rhPTH(1-34) at doses of 75, 30, and 5 μg/kg, respectively. These times correspond to approximately the times at which early (microscopic) osteosarcomas were first identified in rhPTH(1-34)-treated rats. This association raises the question as to whether loss of marrow elements in response to rhPTH(1-34) is somehow related etiologically to the onset of osteosarcoma in the rat. It is well recognized that substantial cell-to-cell communication occurs between hematopoietic stroma and bone lining (or of the of osteonal particularly the endocortical surfaces, treatment with rhPTH(1-34) does not loss of marrow space in In the 2-year rat study, rhPTH(1-34) did not increase the incidence of tumors in any other including target for PTH such as the In addition to the 2-year rodent bioassay, a of shorter-duration pharmacology studies have been in rats to the bone effects of once daily or PTH(1-34) These published studies have all been of months or in several different rat strains, and daily doses of PTH(1-34) from to male and female rats have been at In the effects of PTH(1-34) on the rat skeleton were of magnitude than those observed in the 2-year have been no of osteosarcoma or evidence of bone proliferative lesions in any study in which histological evaluation was In to the of PTH(1-34) and on cell in bone; it is that did not increased by a that increased of or of bone lining The bone effects of rhPTH(1-34) have been extensively in In an study of adult monkeys, rhPTH(1-34), 5 μg/kg per increased BMD and bone mineral increased vertebral bone and improved bone mass and architecture in both and skeletal 12, with the per dose in the rat study, exposure in was about two times greater based on under the μg/kg per are not tolerated in the end of the study radiographic and histological examination of the spine and and showed no evidence of and evaluation of from femoral and crest biopsy specimens showed no evidence of proliferative lesions or any other that were related to treatment with rhPTH(1-34). The of a of bone and evaluated from all treatment groups and was that treatment with rhPTH(1-34) the formation of bone in available in NDA 21-318 to the U.S. FDA under and 2001). treated with 5 μg/kg, were to greater concentrations on and greater concentrations on peak than postmenopausal women received 20 μg/day of 18 months in to years in humans, in terms of bone remodeling or life span. of human osteoporosis trials have been with and PTH(1-84) at doses up to These studies have of subjects in both and trials of up to PTH or in with a bone 13, to this experience several patients with an estimated after of treatment of These studies consistently that PTH increases BMD, in the in subjects with osteoporosis. PTH(1-34) has been shown to increase bone formation rate and the frequency of bone remodeling in osteoporotic patients as soon as 2 weeks after initiating have been no published of osteosarcomas in patients have been treated with PTH(1-34) for any with most of the clinical have these studies revealed no of the occurrence of osteosarcomas in any this be In the recently reported clinical trial with 1637 women received 20 μg/day or μg/day of rhPTH(1-34) for a of 19 adverse events were was no increase in incidence between subjects receiving rhPTH(1-34) and and no developed an no skeletal tumors have been in the study of women from this trial for a of 43 months after initiating treatment with rhPTH(1-34). In the 2-year rat study, the pharmacodynamic effects of rhPTH(1-34) on BMD and bone mass were compared with the effects observed in and humans. at the dose used in the rat study μg/kg), the effects on bone architecture greatly those observed in at 5 μg/kg and humans at 20 μg/day in the rats were detected after months of treatment (75 μg/kg for of or after months of treatment μg/kg and μg/kg for of treatment in rats when the animals were 6-8 weeks of and were The marked response of the rat skeleton including marrow space to at least in from of in the of osteonal a of rodent bone that it from QCT images of midshaft femurs from male rats treated with 5, 30, or 75 μg/kg PTH(1-34) and a control These findings are in marked to the cortical bone images from treated with rhPTH(1-34) at 5 the of the 2-year rat study, the magnitude of the skeletal effect was greater than those effects observed in and humans. The in the carcinogenesis study as by concentrations of rhPTH(1-34) of for peak or for relative to the clinical exposure However, the concentrations the skeletal response in the the of risk from rats to humans, based on of peak or Thus, both the relative duration of treatment a of life and the magnitude of exposure and were greater in the 2-year rat study than in and human studies, the response of the rat appears to be associated with the large pharmacodynamic response in the rodent Skeletal effects of rhPTH(1-34) as bone mineral content in the 2-year rat bioassay compared with effects in humans and after months of treatment. bone data from the of the or Data for trabecular The a of bone as the The exposure to rhPTH(1-34) as The data are for women given μg of rhPTH(1-34) for a duration of 19 months in the phase III rats given 5 μg/kg in the 2-year and given 5 μg/kg in the These data were the most in terms of treatment duration exposure to rhPTH(1-34), and skeletal rhPTH(1-34) the bone effects in humans and are of similar the other rats a much greater increase in bone mass at both cortical and trabecular It is important to that in the the increase in is or peak bone and in women the increase is osteoporotic In women the increase in BMD was from about to about rats greater than bone mass at in 2 and were after a of 19 months of treatment with In rats treated with rhPTH(1-34) for up to 2 there was no increase in the incidence of neoplasms in any findings with the that the bone neoplasms were the result of the profound bone effect of rhPTH(1-34) on the target bone and were not related to a of In conventional in and an in in the rhPTH(1-34) was Lilly and Company, unpublished data, evidence that the tumors resulted from a of PTH and rat It is well recognized that the mode of hormone administration the biological administration of hormone greatly In humans to elevated of PTH for many years of parathyroid or parathyroid there is bone turnover with an increase in the of in trabecular bone, and a increase in bone In human hyperparathyroidism, with exposure to elevated concentrations of circulating the in bone turnover leading to a net decrease in bone not at the and per transient in duration) of PTH concentrations the observed in induced by administration bone turnover with the bone formation occurs in primary hyperparathyroidism as it does in response to administered it is to any evidence for an increased incidence of osteosarcoma in patients with hyperparathyroidism that the net skeletal in with this is not the same as that when PTH is administered once daily to patients with osteoporosis. studies have reported no increase in the incidence of osteosarcoma in patients with primary and data, have the from in through and have identified a total of patients reported of a parathyroid years of these the of was by to the entire Overall, there was a increase in the risk of any in (95% CI, and (95% CI, with a history of parathyroid was no increase in the risk for primary tumors of The risk for tumors to bone was not additional of a that on all in was for the years to on patients with parathyroid The identified subjects with parathyroid and patients with the of parathyroid These were linked to the on this there is a increased risk for the of for patients with parathyroid in men and in and for parathyroid in not in the incidence rate of primary hyperparathyroidism in the and the incidence of osteosarcoma which occurs with highest frequency in there appears to be no evidence for an increase in osteosarcoma risk in patients with increased to primary The lack of association of osteosarcoma with hyperparathyroidism also appears to be for patients with of the PTH have a for PTH increased bone are no published of osteosarcoma in patients with marked increases in trabecular bone, there are patients in long-term evaluation personal communication, 2001). hyperparathyroidism with elevated concentrations of PTH in occurs in patients with chronic renal many of are for years on long-term exposure to elevated PTH and bone turnover with increases in both bone formation and an increase in the risk of osteosarcoma has not been reported in this It be that circulating hormone in hyperparathyroidism is the polypeptide PTH(1-84) and that long-term exposure to elevated of PTH(1-84) a different spectrum of biological responses than those by rhPTH(1-34). It is well that both PTH(1-84) and PTH(1-34) act via the same PTH receptor on bone and have biological in on the skeleton at 44, a receptor for the of the PTH(1-84) has been it has not been or of this receptor somehow the skeleton the of the of PTH(1-84) data such a are entirely 2-year rat carcinogenesis are standard practice for most with new chemical they have not been for chronic hormone for a of administered to humans, it is the target in rats With this it is to the of the 2-year rat study with rhPTH(1-34) in to other chronic of target cell in the rat to cell and, occurs in the rat of hormone in the rat to cell and 75 In humans, of does not result in an increased incidence of In the a chronic increase in concentrations leading to of events have not been reported in humans receiving chronic therapy with administered to rats to not in humans, as the result of differences between rats and humans in the between and effects of the in rats and to These important differences in the responses of rats and humans to chronic or persistent hormone excess and that responses in the rat are not of similar effects in humans. were treated with rhPTH(1-34), beginning at the of 6-8 weeks for up to 2 which is of their life span. duration of therapy for humans is 2 years or which of the life for most postmenopausal women and were treated during longitudinal growth for a total of bone turnover Patients with osteoporosis have growth are no longer and be treated for bone turnover are differences in bone physiology between rats and humans. The skeletal growth and lack of osteonal remodeling in the rat appears to to a response in the resulting in reduced bone marrow space and a bone density that the density of bovine cortical bone has a different remodeling the response observed in cortical bone in rats does not occur in treated with rhPTH(1-34) for up to 18 months bone turnover or in humans treated for up to the and for of bone proliferative lesions in rats treated with rhPTH(1-34) are not the available evidence is with a long-term of in the of a remodeling that is not of or the The effect in the rat on both dose and duration of treatment and as on the of the life in which the is we that the findings in the 2-year rat bioassay are to an increased risk of osteosarcoma in patients with osteoporosis receiving rhPTH(1-34) therapy for 2 years or a of PTH(1-34) on the osteosarcoma occurrence was not observed in the 2-year rat it is not possible to an overall safety for PTH(1-34) in terms of relative rat to human doses. of a regarding the dose and exposure at which risk and an of risk based on of the dose-dependent effect in the rat to a dose in humans. and have a of the dose-related of in the response in rat bone was both a of dose and time related to a be estimated from the duration of exposure at a given dose of PTH(1-34) than as an duration of exposure were to be the the lack of tumors in rats treated with any dose of PTH(1-34) for 6 that duration of exposure is an in the of osteosarcomas in the rat. Thus, a given dose used in the rat study be as a dose for a that duration of exposure the As the of μg/kg per for 6 months be as a for rats. one to humans from of life the rat was to we the findings in the 2-year rat bioassay are to an increase risk of osteosarcomas in patients with osteoporosis receiving PTH(1-34) therapy for 2 years or The substantial of osteoporosis on and in postmenopausal women and in men to the use of this and unique bone agent in the of the and of the for any evidence of bone tumors the low incidence of osteosarcoma in years of age, per a of risk be