Safety of osteoanabolic therapy: A decade of experience

Osteoporosis is a prevalent disease that affects more than 10 million Americans. The lifetime risk of an osteoporosis-related fracture is 50% for Caucasian women and 25% for men. Hip fractures carry a 10% to 20% increase in mortality rate within the first year after fracture.1 The burden of the hip and other fractures can result in chronic pain, disability and other indices of reduced quality of life. Amidst these sobering statistics is the welcome advent over the past two decades of effective pharmacological therapies that reduce fracture risk. The therapies approved for the management of osteoporosis include bisphosphonates, raloxifene (a selective estrogen-receptor modulator), calcitonin, denosumab, strontium ranelate, and parathyroid hormone [teriparatide (recombinant PTH(1–34) and PTH(1–84)]. The full-length PTH molecule and its foreshortened amino-terminal fragment (teriparatide) are currently the only osteoanabolic agents approved for use. PTH(1–84) is not available in the United States. In November, 2002, teriparatide was approved by the U.S. Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis and, later, in men. The approval came with restrictions in duration of therapy (18–24 months) and was limited to individuals with advanced osteoporosis at high risk for fracture. Reasons for these limitations relate, at least in part, to the unexpected occurrence of osteosarcoma and other bone neoplasms in Fischer 344 rat toxicity studies. In fact, the pivotal phase 3 trial of teriparatide was suspended when these rat toxicity data became available. The effects on rats was dose- and duration-dependent, with rats being treated for approximately 80% of their lifetime and at doses three to 58 times the currently approved human dose.2 Similar toxicity was seen for PTH(1–84)3 Given the clear-cut efficacy data when the results of the abbreviated clinical trial results for teriparatide were analyzed, the FDA and equivalent other agencies in Europe and elsewhere granted approval of teriparatide with the stipulations that it should be used for no longer than 2 years. In the United States, the drug carries a “black box warning” and contraindicates its use in patients with existing risk factors for osteosarcoma, including Paget's disease of bone, prior skeletal radiation, and children with open epiphyses. Teriparatide has now been used in the United States for 10 years. With a decade of experience, it is timely to review the efficacy and safety profile of this medication. PTH(1–84) will also be reviewed. This perspective will be limited to PTH formulations that are available for the treatment of osteoporosis; we will not be discussing other anabolic agents that are currently being studied but are not yet approved, such as the sclerostin antibody (http://clinicaltrials.gov/ct2/results?term = sclerostin + antibody). Teriparatide is an amino-terminal fragment of PTH that is biologically identical to the amino-terminal fragment of human PTH. This fragment contains all the classical biological and biochemical actions of the full-length molecule, PTH(1–84). Unlike other osteoporosis agents, PTH is an osteoanabolic that actually promotes bone formation when administered at low doses intermittently. Although the cellular mechanisms by which this occurs are still unclear, it is likely that the Wnt signaling pathway (via suppression of sclerostin),4, 5 Runx2, receptor activator of NF-κB ligand (RANKL), osteoprotegerin, and insulin-like growth factor are all involved.6-8 The stimulation of bone formation that results may first occur on quiescent bone surfaces, akin to bone modeling that occurs in the growing skeleton. Subsequently, bone turnover is stimulated through activation of bone remodeling units. It would appear that most of PTH's osteoanabolic effects are due to the stimulation of bone remodeling, with osteoblast activity exceeding osteoclast activity, and 30% being due to the modeling effect. The initial effect, namely the stimulation of bone modeling, is seen clinically by an increase in bone formation markers such as amino-terminal propeptide of type I procollagen (P1NP) and osteocalcin. The subsequent stimulation of bone remodeling is seen clinically by an increase in bone resorption markers such as serum cross-linked C-telopeptide (CTX) and urinary cross-linked N-telopeptide of type I collagen (NTX). This sequence gives rise to an anabolic window during which the osteoanabolic actions of PTH are optimized (Fig. 1).9 Since the stimulation of bone turnover is a predominant effect of PTH, areas of the skeleton that show an intrinsically high rate of bone turnover, such as the cancellous skeleton (e.g., lumbar spine) will show that greatest accrual of bone density. Skeletal microstructure is improved, with increases in trabecular thickness, connectivity density, and a reduction in trabecular separation.10 An initial increase in cortical porosity is seen; however, this increase does not persist beyond 24 months,11 and one study showed no difference in cortical porosity in iliac crest biopsies between 18 and 24 months.12 Initial declines in bone mineral density (BMD) at cortical sites have also been shown.13-15 However, the net effect on cortical bone is an improvement in both cortical structure and thickness.16-19 These results clearly establish teriparatide and PTH(1–84) as osteoanabolic agents for both trabecular and cortical bone. The anabolic window. This figure demonstrates the window between the rise in bone formation markers and the subsequent rise in bone turnover markers; the effects of PTH actions are optimized during this interval (adapted from Ref. 9). PTH reduces fracture risk. The international pivotal Fracture Prevention Trial assigned 1637 postmenopausal women to daily teriparatide (20 or 40 µg) or placebo injections. After an average of 18 months, subjects who received teriparatide at the daily 20-µg dose showed a 9% increase in lumbar spine BMD, a 65% reduction in risk of new vertebral fractures, and a 35% reduction in risk of nonvertebral fractures; there was also a 53% reduction in nonvertebral fractures that were specifically classified as fragility fractures.20 Several other clinical trials have supported these results since the pivotal trial was originally published. For example, a recent meta-analysis of eight clinical trials (n = 2388) that used teriparatide to treat postmenopausal osteoporosis found that lumbar spine BMD increased by 8.14% (95% confidence interval [CI], 6.72%–9.55%) and by 2.48% in the hip (95% CI, 1.67%–3.29%). In trials that included fracture data, vertebral and nonvertebral fractures were reduced by 70% and 38%, respectively. Limitations of this meta-analysis, according to the authors, included the participation of patients with postmenopausal osteoporosis only, excluding all secondary causes, as well as the clinical heterogeneity present in any broad review, which can confound results.21 In another recent meta-analysis, Murad and colleagues22 compared the effectiveness of the following therapeutic approaches: teriparatide, bisphosphonates, raloxifene, denosumab, and calcium and vitamin D. One hundred and sixteen (116) studies were included in the final analysis, with a total 139,647 patients. Teriparatide had the highest reduction in vertebral fracture incidence (odds ratio [OR] 0.30), hip fracture (OR 0.42), and nonvertebral fracture (OR 0.50), and had the highest probability of being ranked most effective in all three categories (49%, 42%, and 79%, respectively) when compared to the other treatments. Murad and colleagues22 noted limitations of their study that included the small number of fracture events in the trials, which could lead to imprecise estimates and indirect comparisons that are intrinsically not as accurate as head-to-head comparisons. In an update of the 2007 systematic review examining the effectiveness and safety of osteoporosis treatments, Crandall and colleagues23 reported a relative risk of vertebral fractures with teriparatide ranging from 0.31 to 0.36 and a relative risk in nonvertebral fractures ranging from 0.60 to 0.65 when compared to placebo or no treatment after pooling data from two systematic reviews. They also included data from randomized controlled trials (RCTs) not included in the meta-analyses and found an 84% statistically significant reduction in all fractures, reduced risk of vertebral fractures with relative risks (RRs) ranging from 0.34 to 0.44 (with the exception of one RCT that had the fewest vertebral fractures and did not show a statistical difference between PTH and placebo). Nonvertebral fracture risk reduction results were mixed, with several RCTs showing no statistically significant difference when compared with placebo, whereas a pooled analysis of other RCTs showed a statistically significant risk reduction with teriparatide treatment = was that teriparatide is with a reduced risk of both vertebral and nonvertebral fractures in postmenopausal a that was statistically by the pivotal clinical trial of teriparatide by and prevalent in osteoporosis carries an mortality rate after hip fracture than in trials in are in and are not to in fracture markers such as BMD are The first randomized trial examining the efficacy of teriparatide in was by and in The teriparatide showed BMD increases of at the lumbar spine and at the after 18 but trial with osteoporosis showed a increase in lumbar spine BMD and increase at the The duration of this clinical only months, was due to the of the results of the rat toxicity studies. The increase in BMD over this the in the pivotal clinical trial in postmenopausal after the of of these study subjects (n = were after the treatment was was a significant = in new or vertebral fractures at after the of It should be noted that of these patients did other osteoporosis therapies during the however, the of the patients that received other therapies were in the placebo and, the results are likely still to be Teriparatide was approved for the treatment of osteoporosis in for both and are the most secondary of fracture risk when bone density is not osteoanabolic activity is to the effects of such as reduced bone formation and increased In and a head-to-head study daily teriparatide (20 µg) with daily in patients who had received for at least 3 daily or between the were by months, and by 18 the teriparatide showed lumbar spine BMD increases of the which showed increases of only hip BMD also showed increases with teriparatide than with the by were new vertebral fractures in the teriparatide than in the = In the significant in BMD and fracture risk between the two were PTH has also efficacy in postmenopausal osteoporosis and is approved for use in and the first trial that compared or PTH(1–84) daily with placebo over was found to be with the highest dose showing increases in BMD in the lumbar spine and a increase in the total hip at and a trial PTH(1–84) placebo in postmenopausal women for 18 in BMD were in the treatment by in the lumbar spine and in the PTH treatment also first vertebral fractures CI, and incidence of vertebral fractures in women with fractures CI, An study was by and the effect of PTH(1–84) after in patients who were originally in the placebo of the to lumbar spine BMD increased by total hip by and by for all three spine and data showed initial increases and between 24 and months, whereas the total hip showed improvement the duration of the Although the trial was not to vertebral fracture the rate did to only one a vertebral fracture after treatment had a vertebral fracture at the of the from these pivotal trials have been showing that these two PTH are effective in subjects who have or have not or have a fracture or fractures, and that of are is by low or PTH in individuals serum calcium is It is most by or the parathyroid during or other An can be with The treatment for of high doses of calcium and vitamin including the D. However, these high doses can as well as and other is currently the only disease for which the namely PTH, is not Several small teriparatide studies ranging from to 3 have of serum calcium with reduced for calcium and vitamin when compared to calcium and vitamin PTH(1–84) has also results for the treatment of Several recent clinical trials have a reduced for vitamin calcium as well as improvement in bone remodeling and on daily or other patients in the PTH(1–84) treatment were to their and results from a study examining 18 patients treated with PTH(1–84) at a dose of other or showed that serum and calcium and were for the duration of the for calcium were reduced by were also with three subjects PTH(1–84) was found to be effective with teriparatide daily results were also reported in an trial teriparatide in In PTH has been to be in fracture by and formation and the of the fracture study examining the of PTH to fracture in human postmenopausal showed a reduction in the to The effect was seen at the 20-µg dose of teriparatide, but not the Similar results were reported by in a study with PTH(1–84) in women more than who a study of teriparatide to after hip fracture is currently being from randomized controlled trials is to that to effects in this include the use of the approved teriparatide in one of fracture and two of of the In the first the improvement with the of the fracture one after and and and reported bone at sites and the of in two patients with after 10 of anabolic of the to the safety of PTH in human subjects to the rat toxicity data, clearly that osteosarcoma occurs in a dose- and In the United States, the FDA safety with a “black a to teriparatide with to The the use of teriparatide in any in which the risk of osteosarcoma is teriparatide and PTH(1–84) are in with a of osteosarcoma or any bone or at risk for osteosarcoma disease of bone, therapy to the skeleton or to other skeletal is or children and with open epiphyses. In the osteosarcoma is the most bone incidence a by with a first and a in subjects over of 58 the incidence of osteosarcoma is than of all in the United The incidence between 3 and in and 2 in individuals to and to in subjects over the of 58 The FDA and the osteosarcoma is to the of the disease in 344 rats during the study for This study reported a incidence of osteosarcoma in 344 rats that received teriparatide at doses of or at to of The occurrence of osteosarcoma was with the first and clinical after and months, bone including and osteoblast were It was noted that the duration of to to 2 most of their the doses were to of the human dose.2 The rat study by and that the of bone in rats was on the dose and the duration of whereas the at had only a effect. were reported in the PTH(1–84) which 344 rats doses of or for 24 with a of was also showed bone in treated and small bone in the highest dose a significant and increase in bone in the and and in the compared to was first at in the from the FDA on the of PTH for the and treatment of osteoporosis reported data on the occurrence of osteosarcoma in two of rat and one of treated with PTH and from to 18 of whereas no bone was in the recent study by and the of teriparatide in and The reported data from studies the effect of teriparatide doses and treatment and the results in 344 significant increase in the incidence of osteosarcoma was found in the compared to as for the 344 a dose- and of bone was of at of treatment was The study also the and the dose of teriparatide as and The the of teriparatide at these doses were to and to the in the would be the dose of The osteoanabolic effect of PTH has also been studied in has not in this with of to of teriparatide or PTH(1–84) for to 18 of treatment and of For the 5 dose is approximately eight times the human The of for osteosarcoma these to and Although studies in are not in the of the effect of these data to to a effect of PTH in than in such as The studies may also have more to human In human results from clinical trials with both PTH(1–34) and PTH(1–84) have not reported any skeletal The number of patients in these trials and studies to more than and to 3 of The with teriparatide and PTH(1–84) has The has 10 for teriparatide and for PTH(1–84). The is well over million subjects for teriparatide and of for respectively. of osteosarcoma in patients treated with teriparatide have been other of osteosarcoma in patients teriparatide have been and are currently no of osteosarcoma have been reported with the use of The first of osteosarcoma in a treated with teriparatide was reported in The postmenopausal was a in during year of teriparatide was found to have a that was as was in bone and no was with the the was to be an The was a with a past of and subsequent therapy for who was with osteosarcoma of the 2 after The was an who the growth of an after teriparatide The of treatment and of the are not the in the of the the was as an These three and included the of osteosarcoma in patients teriparatide, not appear to a and effect of PTH therapy in the of These of osteosarcoma would appear to be with the of osteosarcoma in The incidence is to of who osteosarcoma and are not PTH. In this of and the first data from the study of osteosarcoma and teriparatide in the United States. This study was by the FDA in with the to a on the to teriparatide in patients with and from U.S. of patients with osteosarcoma were It was that by the number of patients who osteosarcoma and were teriparatide would to one or would an that was than on The by and does not any of teriparatide prior to the of The three of osteosarcoma were not included in the were not in the and in the This which and data, will for another to are other that one could to there is an increased risk of osteosarcoma in subjects who are to PTH. An is a chronic in which patients can be to of PTH for years. The reported no increase in the incidence of bone patients with who did not in patients with with secondary such as chronic no increase in osteosarcoma has been and a analysis of all of osteosarcoma at between and the three patients also the of In two was a whereas in the both were The of in these patients with osteosarcoma did not from the in a The increase in osteosarcoma when rats are to PTH as to the rat and the and it would appear not the human or the are at risk. could be the a and the high doses human subjects could such high doses of PTH over their would This is a that will be to this was by and They bone mineral data from and to of PTH and reported a pharmacological effect of teriparatide in both trabecular and cortical bone in This the that there are other dose and duration of for the of for a between PTH and osteosarcoma in and in The rat is a that its skeleton for its life. The modeling is with lifetime skeletal to an osteoanabolic PTH, the rat with a increase in and trabecular bone and a significant reduction in studies from the showed that the can be by chronic of rats to The rat is a and that to PTH with its for modeling or In to rat skeletal the human skeleton on a as a occurrence after skeletal has been are on quiescent but are found in the bone remodeling to the of the An exception to this at least in part, is the human skeleton to PTH. modeling is stimulated but this phase is limited in and in is by PTH to a than the modeling This difference in between rats and is an to be and may have to the of PTH and It should be that the with teriparatide and PTH(1–84) is still limited in and in It is but that after a longer of therapy and with of subjects a PTH with osteosarcoma in human subjects will be The of data would that this is an clinical on the use of PTH in patients with a of in other than bone. The studies in 344 rats did not any The effect of PTH in rats to be to In the clinical trials with teriparatide and no increase in was However, and could the it has been that patients with a of in the past 5 PTH may be in this for such as and However, there is no in in to PTH. are data that mortality from in are actually than and are relative to PTH use. This is classified by FDA as that no data are available. The and actions of PTH on bone, and are all in the of calcium and serum calcium used as a pharmacological however, PTH has the to the serum calcium and, by of a calcium to increase urinary calcium PTH is used to treat the serum calcium will rise but is within the The increase in serum calcium after PTH occurs after teriparatide and a with PTH(1–84) the 24 later, the administered PTH is no longer in the and the small rise in serum calcium has to In the pivotal fracture trial of teriparatide, an incidence of in postmenopausal women was to after The rate was being in only of It was to the PTH of Similar results were reported in other clinical trials, which also showed or no incidence of within 24 after teriparatide In a analysis, and showed a incidence of in patients with rate The incidence of in women was to within the first of teriparatide compared to at However, there was a significant difference between the treatment and the placebo only when calcium was by at urinary calcium was a was and were found in than of women on teriparatide, with a significant between serum and urinary calcium data have that and are seen in subjects treated with and reported an incidence of calcium of than of patients treated with teriparatide in the United States in a The pivotal trial for PTH(1–84) in however, showed and were found in and of These high are to a significant of the study was to their serum calcium urinary calcium were With an and incidence of and it is not that and would be seen from other clinical trials with PTH(1–84) in which and were did not show these relative high of and They were not from the of the teriparatide In both the teriparatide and the PTH(1–84) trials, of calcium and, reduction in PTH dose were reported as effective in the incidence of In the of calcium when teriparatide is being to no more than It should be that serum and urinary calcium should be prior to PTH as FDA and It is also that PTH should not be used in patients with of any the incidence of was in patients with is also a as the by PTH trials clinical on and management of in patients are currently It is to the serum calcium within the first after the calcium is it should be the serum calcium to be the calcium should be reduced or to from the incidence of of was found in the teriparatide pivotal fracture trial in patients with with the highest occurrence in patients with In the pivotal fracture trial of serum within the In trial was there any increased risk of clinical such as or in patients with a of or or of would it to the serum prior to The most and but not events that have been in clinical over the past 10 are and such as and Although the incidence of such events between and in the two pivotal not appear to be as with clinical PTH is a can be by but can also occur any in are no in rate with use of PTH. other of (e.g., in or or have been trials of both teriparatide and PTH(1–84) in patients with have not after a treatment of to and in one of a treated for any of osteosarcoma or other and reported no of high serum or urinary calcium in patients treated with teriparatide daily over a from PTH(1–84) trials showed of for only of all and a significant but and increase in urinary calcium subjects the hormone at the dose of other for 24 The data reported three of in three of 18 subjects and no of teriparatide and well high of and The trial by and found that only of patients teriparatide the of the high of have also been found in subsequent studies in the United States and that have reported of PTH(1–84) a of to in the of the and 70% of the placebo the study showed a rate of at of this was likely by the and to on Similar results were seen in a study at in postmenopausal patients in an and and found that were still on treatment at and have that who with therapy of PTH(1–84) show With a decade of with teriparatide and more than of with PTH these two have been to be effective for the treatment of osteoporosis for both and women at high risk for fracture and for The has not safety that were not during the clinical The fracture risk and low profile these for in which are such as in and to fracture are osteosarcoma to be a the clinical with both of PTH has not such is a for and and from and and that have no of and were all in the and of this