Dr. Tashjian serves as a consultant to Eli Lilly and Company. Dr. Chabner has financial interests in the form of equity interests in Eli Lilly, Immunex, Johnson and Johnson, Gilead and Pfizer. Dr. Chabner serves as a board member for Kosan Bioscience and Vion. In addition, he serves as a consultant for Eli Lilly and PharmaMar.
Bruce A. Chabner
Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
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).
IMPORTANCE OF PTH AS AN AGENT FOR THE TREATMENT OF OSTEOPOROSIS
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 age(16) and to prevent estrogen deficiency-related bone loss in women 21-45 years old.(17)
USE OF rhPTH(1-34) IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS
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.
Table Table 1.. Clinical Studies With PTH(1-34) or PTH(1-38) of 6 Months Duration or Longer
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.
TWO-YEAR RAT BIOASSAY
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 age(35) or for 18 months to 9- to 11-year-old monkeys(12) 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 communication(36,37)) and humans(38) indicated that the magnitude of the effect in rats is much greater and occurs after a much shorter treatment period than in humans.
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 preosteoblast) cells.(46) Because of the predominance of osteonal remodeling, particularly along the endocortical surfaces, treatment with rhPTH(1-34) does not cause loss of marrow space in primates.(11,47)
In the 2-year rat study, rhPTH(1-34) did not increase the incidence of tumors in any other tissue, including nonosseous target organs for PTH such as the kidney.(3)
ADDITIONAL INFORMATION REGARDING THE SAFETY OF rhPTH(1-34) PROVIDED BY OTHER ANIMAL AND HUMAN STUDIES
In addition to the 2-year rodent bioassay, a number of shorter-duration pharmacology studies have been performed in rats to assess the bone anabolic effects of once daily or intermittent PTH(1-34) administration.(48,49) These published studies have all been of 9 months or less in duration, using several different rat strains, and daily doses of PTH(1-34) ranging from 0.03 to 100 μg/kg. Both male and female rats have been studied at various ages. In shorter-term experiments (Table 2), the anabolic effects of PTH(1-34) on the rat skeleton were still exaggerated but of lesser magnitude than those observed in the 2-year study. There have been no reports of osteosarcoma or evidence of bone proliferative lesions in any previous study in which histological evaluation was performed. In short-term (4-19 days) experiments designed to assess the action of PTH(1-34) (human and bovine) on cell proliferation in bone; it is noteworthy that intermittent administration, using anabolic protocols, did not stimulate osteoblast proliferation but rather increased osteoblast numbers by a mechanism that increased differentiation of precursors or activation of preexisting bone lining cells.(56–58)
Table Table 2.. Studies in Rats of 6 Months Duration or Longer
The bone formation-enhancing effects of rhPTH(1-34) have been examined extensively in nonhuman primates.(12,59) In an 18-month study of adult ovariectomized cynomolgus monkeys, rhPTH(1-34), 5 μg/kg per day (20 animals/group), increased volumetric BMD and bone mineral content, increased vertebral strength, stimulated bone apposition, and improved cancellous bone mass and architecture in both axial and appendicular skeletal sites.(10,12,59) Compared with the 5-μg/kg per day dose in the rat study, systemic exposure in monkeys was about two times greater based on area under the curve (AUC). Doses >5 μg/kg per day are not tolerated in monkeys. At the end of the monkey study radiographic and histological examination of the spine and upper and lower extremities showed no evidence of neoplasia. Histological and histomorphometric evaluation of sections from vertebra, proximal femur, femoral midshaft, distal radius, radius midshaft, humerus midshaft, and iliac crest biopsy specimens showed no evidence of proliferative lesions or any other anomalies that were related to treatment with rhPTH(1-34). The consensus opinion of a panel of independent bone histomorphometry experts and veterinary pathologists who evaluated sections from all treatment groups and controls was that treatment with rhPTH(1-34) stimulated the formation of normal bone in ovariectomized monkeys (unpublished information available in NDA 21-318 submission to the U.S. FDA under Non-Clinical Pharmacology Report X-95-11, Appendix D, Attachment D-1 Supplement, and Appendix F, 2001). Monkeys treated with rhPTH(1-34,) 5 μg/kg, were exposed to ∼8-fold greater concentrations (based on AUC) and 10-fold greater concentrations (based on peak blood levels) than postmenopausal women who received 20 μg/day of rhPTH(1-34. Biologically, 18 months in monkeys corresponds to 4.5-6 years in humans, in terms of bone remodeling or life span.
A variety of human osteoporosis trials have been performed with PTH(1-34), PTH(1-38), and PTH(1-84) at doses up to 240 μg/day. These studies generally have included small numbers of subjects in both observational and controlled trials of durations up to 3 years, administering PTH alone or in combination with a bone resorption-inhibiting agent(1,13,49,61,62) (Table 1). Although difficult to ascertain precisely, this experience involves several hundred patients with an estimated minimum follow-up after cessation of treatment of ∼5 years. These studies consistently show that PTH increases BMD, especially in the axial skeleton, in subjects with osteoporosis. Using histomorphometric analysis, PTH(1-34) has been shown to increase bone formation rate and the activation frequency of bone remodeling in osteoporotic patients as soon as 2 weeks after initiating therapy.(60) There have been no published reports of osteosarcomas in patients who have been treated with PTH(1-34) for any reason. Subsequent contact with most of the clinical investigators who have performed these studies revealed no knowledge of the occurrence of osteosarcomas in any PTH-treated patient, although this follow-up cannot be considered exhaustive.
In the recently reported clinical trial with 1637 subjects, 1093 post menopausal women received either 20 μg/day or 40 μg/day of rhPTH(1-34) for a median of 19 months; adverse events were monitored.(2) There was no increase in cancer incidence between subjects receiving rhPTH(1-34) and placebo, and no woman developed an osteosarcoma. Furthermore, no skeletal tumors have been noted in the ongoing follow-up observational study of 848 women from this trial monitored thus far for a median of 43 months after initiating treatment with rhPTH(1-34).
INTERPRETATION OF THE 2-YEAR RAT BIOASSAY
In the 2-year rat study, the pharmacodynamic effects of rhPTH(1-34) on BMD and bone mass were highly exaggerated compared with the effects observed in monkeys and humans. Even at the lowest dose used in the rat study (5 μg/kg), the effects on bone architecture greatly exceeded those observed in monkeys at 5 μg/kg and humans at 20 μg/day (∼0.3 μg/kg). Tumors in the rats were detected grossly after 17 months of treatment (75 μg/kg for ∼70% of lifetime) or after 18-20 months of treatment (5 μg/kg and 30 μg/kg for ∼80% of lifetime). Furthermore, treatment in rats began when the animals were 6-8 weeks of age and were actively growing. The marked response of the rat skeleton including marrow space reduction, appeared to result, at least in part, from stimulation of osteoblast function in the absence of osteonal remodeling, a characteristic of rodent bone that differentiates it from primate bone.(37) Figure 1 shows QCT images of midshaft femurs from male rats treated with 5, 30, or 75 μg/kg PTH(1-34) and a control femur. These findings are in marked contrast to the cortical bone images from monkeys treated with rhPTH(1-34) at 5 μg/kg.(11,47)
Under the conditions of the 2-year rat study, the magnitude of the skeletal anabolic effect was markedly greater than those effects observed in monkeys and humans. The systemic exposures in the carcinogenesis study as measured by plasma concentrations of rhPTH(1-34) provided multiples of 5.4-97 for peak blood level or 1.6-43 for AUC relative to the intended clinical exposure (20 μg/day). However, the plasma concentrations vastly underpredicted the skeletal response in the rat, challenging the usefulness of risk extrapolation from rats to humans, based on measures of drug exposure, either peak blood level, or AUC (Fig. 2). Thus, although both the relative duration of treatment (as a percentage of life span) and the magnitude of systemic exposure (peak blood level and AUC) were greater in the 2-year rat study than in monkey and human studies, the oncogenic response of the rat appears to be associated with the disproportionately large pharmacodynamic response in the rodent (Fig. 2).
In rats treated with rhPTH(1-34) for up to 2 years, there was no increase in the incidence of neoplasms in any nonosseous tissue, findings consistent with the hypothesis that the bone neoplasms were the result of the profound bone formation-enhancing effect of rhPTH(1-34) on the specific target tissue bone and were not related to a more generalized mechanism of tumorigenesis.
In conventional genotoxicity tests (Ames assay, mouse lymphoma assay, chromosome aberration assay in Chinese hamster ovary cells, and an in vivo micronucleus test in the mouse) rhPTH(1-34) was neither mutagenic nor clastogenic (Eli Lilly and Company, unpublished data, 2001), further evidence that the tumors resulted from a specific interaction of PTH and rat osteoblasts.
OTHER CLINICALLY RELEVANT INFORMATION
It is well recognized that the mode of hormone administration can dramatically affect the biological response. For example, continuous administration of gonadotropin-releasing hormone (GnRH) greatly diminishes gonadotropin secretion whereas intermittent pulsatile GnRH enhances secretion. In humans exposed continuously to elevated plasma levels of PTH for many years because of parathyroid adenomas or parathyroid gland hyperplasia, there is enhanced bone turnover with an increase in the bone-forming activity of osteoblasts, especially in trabecular bone, and a concomitant increase in osteoclastic bone resorption.(63) In human hyperparathyroidism, with continuous exposure to elevated concentrations of circulating PTH, the balance in bone turnover favors resorption, often leading to a net decrease in bone mass.(63) Although not yet fully understood at the biochemical and molecular levels, intermittent (once per day), transient (1-2 h in duration) elevation of plasma PTH concentrations (not exceeding the range observed in hyperparathyroidism) induced by exogenous administration enhances bone turnover with the balance favoring anabolism. Because enhanced bone formation occurs in primary hyperparathyroidism as it does in response to intermittently administered PTH, it is reasonable to evaluate any evidence for an increased incidence of osteosarcoma in patients with hyperparathyroidism recognizing, nonetheless, that the net skeletal outcome in people with this disease is not the same as that obtained when exogenous PTH is administered once daily to patients with osteoporosis.
Published epidemiological studies have reported no increase in the incidence of osteosarcoma in patients with primary hyperparathyroidism.(64,65) Recently, O. Johnell, A. Oden, and B.H. Mitlak (unpublished data, 2001) have searched the National Swedish Cancer Registry database from its inception in 1958 through 1998 and have identified a total of 12,644 patients reported because of a parathyroid adenoma (114,000 person years of observation, mean follow-up 9.5 ± 7.5 years). For these patients, the co-occurrence of malignant diseases was determined by linkage to the entire Cancer Registry. Overall, there was a slight increase in the risk of any cancer in men, RR 1.35 (95% CI, 1.08-1.65), and women, RR 1.45 (95% CI, 1.29-1.62), with a history of parathyroid adenoma. There was no increase in the risk for primary tumors of bone. The risk for nonosseous tumors metastatic to bone was not assessed. An additional search of a registry that includes information on all hospitalizations in Sweden was performed for the years 1987-1997 to obtain information on patients with parathyroid neoplasia. The search identified 5397 subjects with parathyroid hyperplasia (41,556 patient-years) and 4117 patients with the diagnosis of parathyroid adenoma (27,996 patient-years). These cases were then linked to the Swedish Cancer Registry. Based on this analysis, there is a slightly increased risk for the co-occurrence of malignant disease for patients with parathyroid adenoma, RR 1.35 (CI, 1.08-1.65) in men and RR 1.45 (CI, 1.29-1.62) in women, and for parathyroid hyperplasia in women, RR 1.24 (CI, 1.11-1.37), but not in men, RR 1.13 (CI, 0.91-1.38). Given the incidence rate of primary hyperparathyroidism in the general population (5-25 cases/100,000 population)(66–68) and the incidence of osteosarcoma (∼0.8 cases/100,000),(69) which occurs with highest frequency in young males, there appears to be no epidemiological evidence for an increase in osteosarcoma risk in patients with increased osteoblastic activity due to primary hyperparathyroidism.
The lack of association of osteosarcoma with hyperparathyroidism also appears to be true for patients with activating mutations of the PTH receptor, who have a genetic basis for lifelong PTH receptor-mediated increased bone turnover.(70) There are no published reports of osteosarcoma in patients with Jansen's metaphyseal chondrodysplasia, despite marked increases in trabecular bone, although there are only 10 patients in long-term follow-up evaluation (H.W. Jueppner, personal communication, 2001). Finally, secondary hyperparathyroidism with markedly elevated concentrations of PTH in plasma occurs frequently in patients with chronic renal failure, many of whom are maintained for years on dialysis. Despite long-term exposure (years) to elevated PTH and enhanced bone turnover with increases in both bone formation and resorption, an increase in the risk of osteosarcoma has not been reported in this patient population.
It can be argued that endogenous circulating hormone in hyperparathyroidism is the full-length polypeptide PTH(1-84) and that long-term exposure to constantly elevated levels of PTH(1-84) might elicit a different spectrum of biological responses than those produced by rhPTH(1-34). It is well established that both PTH(1-84) and PTH(1-34) act via the same PTH receptor on bone and essentially have equivalent biological activities in vivo on the skeleton at equimolar concentrations.(6,8,44,71) Although a receptor for the carboxy-terminal portion of the PTH(1-84) has been postulated,(72,73) it has not yet been isolated or cloned. If activation of this putative carboxy-terminal receptor somehow protects the skeleton against the development of osteosarcoma, despite the anabolic actions of PTH(1-84) data supporting such a hypothesis are entirely lacking.
Although 2-year rat carcinogenesis bioassays are standard practice for most drug candidates with new chemical structure, they have not been uniformly performed for chronic hormone replacement agents. Therefore, for a number of hormones administered chronically to humans, it is unclear how the target organs in rats would respond. With this background, it is useful to discuss the outcome of the 2-year rat study with rhPTH(1-34) in relation to other examples wherein chronic hormonal stimulation of target cell populations in the rat led to cell proliferation, clonal expansion, and, ultimately, neoplastic changes. A well-known example occurs in the rat thyroid gland. Chronic drug-induced elevation of thyroid-stimulating hormone (TSH) in the rat leads to thyroid follicular cell hyperplasia and neoplasia.(74,75) In humans, prolonged elevation of TSH does not result in an increased incidence of thyroid neoplasia.(76) In the rat, omeprazole (a gastric proton pump inhibitor) induces a chronic increase in endogenous gastrin concentrations leading to neoplasia of enterochromaffin-like cells.(77) Such neoplastic events have not been reported in humans receiving chronic therapy with proton pump inhibitors.(78) Tamoxifen administered chronically to rats leads to hepatic carcinomas, but not in humans, possibly as the result of differences between rats and humans in the balance between agonist and antagonist effects of the drug in rats and people (Gag TC, Letter to Physicians. Stuart Pharmaceuticals, July 1, 1987).
These examples illustrate biologically important differences in the responses of rats and humans to chronic or persistent hormone excess and emphasize that neoplastic responses in the rat are not uniformly predictive of similar effects in humans.
We wish to assess the relevance of the bone proliferative responses observed in the 2-year rat bioassay to postmenopausal women or adult men who might receive therapy with rhPTH(1-34) for osteoporosis. In this context, it is important to summarize the differences between the effect of PTH(1-34) in the rat and its proposed use in humans and to note physiological differences in skeletal metabolism between rats and primates.
Rats were treated with rhPTH(1-34), beginning at the age of 6-8 weeks for up to 2 years, which is 80-90% of their life span. Anticipated duration of therapy for humans is 2 years or less, which represents ∼2-3% of the life span for most postmenopausal women and men.
Rats were treated during rapid longitudinal growth for a total of ∼25-30 bone turnover cycles. Patients with osteoporosis have closed growth plates, are no longer growing longitudinally, and would be treated for only 1-2 bone turnover cycles.
There are fundamental differences in bone physiology between rats and humans. The near-lifetime skeletal growth and lack of osteonal remodeling in the rat appears to lead to a profoundly exaggerated anabolic response in the rodent, resulting in reduced bone marrow space and a bone density that approaches the density of bovine cortical bone. Because primate bone has a different remodeling process, the exaggerated anabolic response observed in cortical bone in rats does not occur in monkeys treated with rhPTH(1-34) for up to 18 months (approximately six bone turnover cycles)(11) or in humans treated for up to 3 years.(29)
Although the cellular and molecular mechanisms for development of bone proliferative lesions in rats treated with rhPTH(1-34) are not known, the available evidence is consistent with a mechanism involving long-term stimulation of osteoblasts in the context of a cellular remodeling process that is not capable of attenuating or modulating the anabolic response. The effect in the rat depends on both dose and duration of treatment and possibly, as well, on the stage of the life cycle in which the drug is given. Therefore, we suggest that the findings in the 2-year rat bioassay are unlikely to predict an increased risk of osteosarcoma in patients with osteoporosis receiving rhPTH(1-34) therapy for 2 years or less.
Because a no-effect level of PTH(1-34) on the osteosarcoma occurrence was not observed in the 2-year rat study,(3) it is not possible to estimate an overall safety margin for PTH(1-34) in terms of relative rat to human doses. For nongenotoxic (epigenetic) carcinogens, establishment of a no-effect level provides information regarding the dose and exposure at which risk increases, and thus allows an estimate of risk based on extrapolation of the dose-dependent effect in the rat to a dose in humans. Lima and Van der Laan(79) have presented a thorough description of the dose-related interpretation of threshold in regulatory decision making. Because the neoplastic response in rat bone was both a function of dose and time related to onset,(3) a threshold might be estimated from the duration of exposure at a given dose of PTH(1-34) rather than as an explicit dose. If duration of exposure were considered to be the threshold event, the lack of tumors in rats treated with any dose of PTH(1-34) for 6 months(3) would indicate that duration of exposure is an important, possibly essential, factor in the development of osteosarcomas in the rat. Thus, a given dose used in the rat study could be interpreted as a no-effect dose for a threshold model that takes duration of exposure into the calculation. As such, the mid-dose of 30 μg/kg per day for 6 months would be interpreted as a no-effect level for rats. If one then extrapolates to humans from percentage of life span the rat was exposed to PTH(1-34), we suggest the findings in the 2-year rat bioassay are unlikely to predict an increase risk of osteosarcomas in patients with osteoporosis receiving PTH(1-34) therapy for 2 years or less.
The substantial impact of osteoporosis on morbidity and mortality in postmenopausal women and in men would appear to justify the use of this potent and unique bone formation-enhancing agent in the affected population, although because of the uncertainty and importance of the risk, careful postmarketing surveillance for any evidence of bone tumors would necessarily accompany its use. Given the low incidence of osteosarcoma in adults >50 years of age, 0.4-0.8 cases per 100,000 person-years, detecting a doubling of risk will be extremely challenging.