Effect of teriparatide on bone mineral density and bioc1hemical markers

J Bone Miner Metab (2008) 26:624–634 ? The Japanese Society for Bone and Mineral Research and Springer 2008

DOI 10.1007/s00774-008-0871-3

A. Miyauchi (*) · H. Shigeta · M. Tsujimoto

Lilly Research Laboratories Japan, Eli Lilly Japan K.K., Sannomiya Plaza Bldg., 7-1-5 Isogamidori, Chuo-ku, Kobe 651-0086, Japan Tel. +81-78-242-8157; Fax +81-78-242-9526e-mail: miyauchi_akimitsu@https://www.wendangku.net/doc/fd3871952.html,

T. Matsumoto

Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan

D. Thiebaud

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

T. Nakamura

Department of Orthopedics, University of Occupational and Environmental Health, Kitakyushu, Japan

Akimitsu Miyauchi · Toshio Matsumoto

Hirofumi Shigeta · Mika Tsujimoto · Daniel Thiebaud Toshitaka Nakamura

Effect of teriparatide on bone mineral density and biochemical markers in Japanese women with postmenopausal osteoporosis: a 6-month dose–response study

Abstract The dose–response ef? cacy and safety with three doses of teriparatide and placebo was assessed, using once-daily subcutaneous injections for 24 weeks, in Japanese postmenopausal women with osteoporosis at high risk of fracture for reasons of preexisting fracture(s), advanced age, and/or low bone mineral density (BMD). In this mul-ticenter, randomized, placebo-controlled study, 159 subjects were randomized and 154 subjects were included for analy-sis. Teriparatide (10-μg, 20-μg, and 40-μg doses) showed a statistically signi? cant increase with increasing treatment dose as assessed by the percent change of lumbar spine BMD from baseline to endpoint using Williams’ test when compared with placebo (P < 0.001). The mean (±SD) percent change in lumbar spine, femoral neck, and total hip BMD with the 20-μg dose from baseline to endpoint was 6.40% ± 4.76%, 1.83% ± 7.13%, and 1.91% ± 3.60%, respec-tively. Rapid and sustained increases in bone formation markers [type I procollagen N-terminal propeptide (PINP), type I procollagen C-terminal propeptide (PICP), and bone-speci? c alkaline phosphatase (BAP)], followed by late increases in a bone resorption marker [type I collagen cross-linked C-telopeptide (CTX)], were observed for the teriparatide treatment groups (20-μg, 40-μg), suggesting a persistent, positive, balanced anabolic effect of teriparatide. Optimal adherence was achieved by this daily self-injection treatment. Regarding safety, most of the adverse events

were mild to moderate in severity. No study drug- or study procedure-related serious adverse events were reported during the treatment period. These results observed in Jap-anese patients may support the observation that teripara-tide stimulates bone formation in patients with osteoporosis at a high risk of fracture.

Key words teriparatide · parathyroid hormone · osteoporo-sis · bone mineral density · bone turnover marker

Introduction

Osteoporosis is a skeletal disease associated with increased risk of fracture. Recent health outcomes research indicates that effectively reducing fractures will eventually decrease the public burden of this disease [1]. In Japan, osteoporosis is becoming a major concern in the graying society. The introduction of new antiresorptive agents with strong ef? -cacy such as bisphosphonates or raloxifene has contributed to reducing fractures. However, for patients with a high risk of fracture, a potent drug that could effectively prevent fractures in the short term would be particularly useful.Teriparatide is the recombinant N-terminal fragment (1-34) of endogenous human parathyroid hormone (PTH). It has been approved and used in more than 50 countries, including the United States, Europe, and recently in Asian countries including Korea and Taiwan. A large-scale pro-spective study conducted in several countries, the Fracture Prevention Trial (FPT), demonstrated that treatment with teriparatide (20 μg/day) for approximately 2 years [mean (±SD) duration of treatment, 18 ± 6 months] increased lumbar spine bone mineral density (BMD) by 9.7%, and reduced the risk of new vertebral fractures by 65% and that of nonvertebral fragility fractures by 53%, compared with those of the placebo group [2].

A head-to-head study (Forteo Alendronate Comparator Trial) compared teriparatide and alendronate, the most commonly used potent antiresorptive agent, and showed that teriparatide (20 μg/day) signi? cantly increased areal

Received: November 7, 2007 / Accepted: March 12, 2008

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and volumetric lumbar spine BMD compared with alendro-nate (10 mg/day) [3]. Using ? nite element analysis of quan-titative CT (QCT) scans performed in this trial, Keaveney et al. reported that teriparatide showed a signi? cant ? ve-fold-greater percentage increase in bone strength : density ratio compared with alendronate [4]. One explanation for the greater increase in the strength of the trabecular com-ponent by teriparatide is that it stimulates bone formation and improves microarchitecture by increasing cortical thick-ness and trabecular connectivity, as observed in paired iliac bone biopsy analyses [5,6].

The primary objective of our study was to assess the dose–response ef? cacy and safety with three doses of terip-aratide (10 μg, 20 μg, and 40 μg) and placebo, using once-daily subcutaneous injections for 24 weeks, based on measurements of lumbar spine BMD in Japanese post-menopausal women with osteoporosis at a high risk of fracture.

Materials and methods

Study subjects

This study was conducted at 19 study centers in Japan. Japanese women diagnosed with osteoporosis were eligible for enrollment if they were ambulatory, if they were at least 55 years old, if at least 5 years had elapsed since menopause, if they were able to use a pen injector properly, and if they had a high risk of fracture(s), which was de? ned as follows: (1) BMD at L2–L4 was less than 80% of young adult mean (YAM) and had a minimum of either one moderate or two mild prevalent fragility vertebral fractures; (2) BMD at L2–L4 was less than 70% of YAM and age was 65 years or older, and (3) BMD at L2–L4 was less than 60% of YAM. Subjects were excluded if they had severe or chronically disabling conditions other than osteoporosis, pathological fractures caused by diseases other than osteoporosis, history of metabolic bone disorders other than postmenopausal osteoporosis, abnormal thyroid function, or history of sprue, in?ammatory bowel disease, or malabsorption syndrome. Subjects were also excluded if they had a history of neph-rolithiasis or urolithiasis in the 2 years before enrollment, clinically signi?cant abnormal laboratory values, signi? -cantly impaired hepatic function, a serum creatinine con-centration exceeding 2 mg per deciliter, alcohol or drug abuse, or treatment with drugs or methods that alter bone metabolism within 1 to 24 months (depending on drugs) before the study. All subjects signed informed consent doc-uments for the treatment and investigation protocol, which was approved by the institutional review board at each study center.

Treatment protocol

All subjects received calcium/vitamin D supplements (pro-viding up to 610 mg/day of calcium and up to 400 IU/day of vitamin D) on a daily basis. The subjects were randomly assigned to receive placebo, or 10, 20, or 40 μg teriparatide, in a regimen of daily, subcutaneous self-injections for 24 weeks. The subject registration center (Bell System 24, Tokyo, Japan) divided subjects into three groups based on lumbar spine BMD (<60%, <70%, and <80% of YAM) at the time of screening and assigned each eligible subject to a treatment group in accordance with the algorithm for dynamic allocation of the subject with nondeterministic schemes.

This study was a partial double-blind study. During the treatment phase, although the investigator, subinvestigator, study coordinator, sponsor, and subjects knew or could ascertain the injection volume of the clinical study drug, neither the investigator, subinvestigator, study coordinator, sponsor, nor subject knew which was the placebo or active study drug for each injection volume of the study drug. To preserve the blindness of the study, the randomization table was not disclosed until all computer data, except for the assignment data of subjects to treatments, were locked. To keep active doses and placebo blinded, the results of BMD measurements and the laboratory assessments that could re? ect the effects of teriparatide were not reported to the investigator, subinvestigator, study coordinator, or sponsor after randomization.

Subject compliance with treatment by self-injection was evaluated by the proportion of administered days between two consecutive visits.

BMD was measured using dual X-ray absorptiometry (DXA). Densitometry laboratories used only Hologic equipment (QDR or Delphi). Quality control of all equip-ment was conducted based on the manufacturer’s standard anthropomorphic spine phantom. To ensure further unifor-mity, the traveling phantom from the BMD central reading center was used for across-site calibration. All BMD mea-surements were read and evaluated centrally. Only cen-trally read BMD measurements were included in the ? nal analyses. Lumbar spine BMD was measured at baseline and at 12 and 24 weeks, or at the early discontinuation visit if the subject had taken the study drug for 2 months or more, or if it had been more than 2 months since the previous BMD was measured.

Serum type I procollagen N-terminal propeptide (PINP), type I procollagen C-terminal propeptide (PICP), and bone-speci? c alkaline phosphatase (BAP) (markers of bone formation) and type I collagen cross-linked C-telopeptide (CTX) (a marker of bone resorption) were measured at baseline and at 4, 12, and 24 weeks, or at the early discon-tinuation visit if the subject had taken the study drug for 1 month or more, and the last dose of the study drug had been taken within 1 week of blood collection. Serum PINP was measured using a radioimmunoassay (Orion Diagnostica, Espoo, Finland); serum PICP was measured using an enzyme immunoassay (Quidel, San Diego, CA, USA); serum BAP was measured with the use of Ostase assay (Beckman Coulter, Brea, CA, USA); and serum CTX was measured with the use of a enzyme-linked immunosorbent assay (Nordic Bioscience Diagnostics, Herlev, Denmark).

At each visit, all subjects were questioned about adverse events by investigators. The adverse events were classi? ed using the preferred terms from MedDRA (Medical

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Dictionary for Regulatory Activities) version 9.0 and the site-reported severity level (mild, moderate, or severe) for each adverse event. Treatment-emergent adverse events (TEAEs) were de? ned as those adverse events that emerged or deteriorated during the administration period of the study drug.

Clinical laboratory tests including blood chemistry, hematology, and urinalysis were performed at baseline and at 2, 4, 12, and 24 weeks. Serum calcium was assessed at predose and 4-h postdose, and corrected using the following formula: corrected value of serum calcium (mg/dl) = actual value of serum calcium (mg/dl)—actual value of serum albumin (g/dl) + 4.0 [7]. This correction applied to serum calcium data with a serum albumin value less than 4 g/dl. The critical values for the elevated corrected serum calcium were set at 11 mg/dl for predose and 13.5 mg/dl for post-dose. If the corrected serum calcium level was higher these values, the investigator was required to stop calcium/vitamin D supplements or to repeat the serum calcium laboratory test. If the investigator received information that the predose corrected serum calcium value was still above 11 mg/dl after discontinuation of calcium supplement administration, administration of the injectable study drug was to be dis-continued. Radioimmunoassay (Immunodiagnostic Systems, Boldon, UK) was used to assess 1,25-dihydroxy vitamin D. Each test was analyzed by a central laboratory. Twenty-four-hour urine calcium and creatinine were measured in a subset population. Vital signs were measured at baseline, and at 4, 12, and 24 weeks. Twelve-lead electrocardiogram (ECG) was recorded at baseline and 24 weeks. Determination of sample size

Sample size calculation was performed using the results of the global pivotal study [Fracture Prevention Trial (FPT)]. From an ef?cacy point of view, mean percent changes of lumbar spine BMD at 24 weeks in the placebo, 10-μg, 20-μg, and 40-μg teriparatide groups were assumed to be 1.87, 4.13, 6.38, and 7.33, respectively. At a common standard devia-tion of 5.27, 24 subjects per group were needed to detect a statistically signi?cant difference between 20 μg, and placebo with more than 80% power and 5% of statistical signi? cance level (two-sided) using Williams’ test. From a safety point of view, assuming that a proportion of subjects with an adverse event would be 5.0%, the chance of more than 1 subject of 40 experiencing the adverse event is 87.1%. Also, assuming that the prevalence rate of nausea at the 40-μg dose in a Japanese population of 40 subjects would be 18.0%, the expected width of the 90% con? dence inter-val is ±10%.

A total of 160 subjects (40 subjects per treatment group) was set as a sample size of the Full Analysis Set (FAS). Statistical analysis

The subset of randomized subjects used for all statistical analyses was designated the FAS. Randomized but not-treated subjects were excluded from the FAS. The analyses of ef? cacy variables were conducted using subjects in the FAS with at least one baseline and at least one postbaseline measurement. The endpoint measurements were de? ned as last observation after randomization. For time-point-speci?c analyses, only subjects who had both a baseline measurement and a measurement at the speci? c visit post-baseline were used for analysis. The percent change in each ef? cacy variable from baseline to study endpoint was ana-lyzed with Williams’ test to detect the smallest dose that was signi? cantly different from the placebo group.

Basically, all safety analyses were conducted using the FAS. The incidences of treatment-emergent adverse events (TEAEs) among the treatment groups were tested using Fisher’s exact test. Changes from baseline in laboratory results and vital signs were tested separately for each treat-ment group using Wilcoxon’s signed-rank test. Pairwise contrasts between each of the teriparatide doses and placebo in change from predose to 4-h postdose in corrected serum calcium, urinary calcium/creatinine ratio, and 1,25-dihy-droxy vitamin D were examined using Wilcoxon’s rank sum test. Changes from baseline to endpoint in ECG values were tested using one-way analysis of variance (ANOVA) with ? xed effect of treatment.

Results

Subject disposition and characteristics

Figure 1 shows subject disposition in this study. This mul-ticenter study screened 332 subjects, with 159 of these subjects randomly assigned to treatment groups (the placebo group, the 10-μg group, the 20-μg group, and the 40-μg group). As the injection volumes were different for each of the three teriparatide dosage groups, the placebo treatment group was divided into three subgroups by injec-tion volume in accordance with active treatment groups to ensure nonpredictability of treatment group. Some results from placebo group were pooled for analysis. Of these randomized subjects, 134 subjects completed the study. Three subjects who were randomized but did not receive any treatment with the study drug, and 2 subjects who had reports of incorrect dispensing of study drug kits, were excluded from the FAS. The ef?cacy and safety analyses included 154 subjects (age range, 58–85 years old) in the FAS.

Table 1 summarizes the demographic and other baseline characteristics of the subjects. No statistically signi? cant difference was observed across the four treatment groups for any of the measured demographic and baseline char-acteristics except for years since natural menopause (P= 0.048); this was considered to be partially dependent on age because a similar tendency was also observed in age across the four treatment groups (P= 0.091). There was no tendency in the other variables that depended on age or years since natural menopause. No statistically signi? cant difference was observed in lumbar spine BMD and the number of previous vertebral fractures at baseline.

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In all treatment groups, total compliance with treatment was high. The proportions of the subjects categorized as having good compliance (≥70%) during the total treatment period were 97.4% in the placebo group, 97.4% in the 10-μg group, 100% in the 20-μg group, and 92.3% in the 40-μg group.

Ef? cacy

Lumbar spine BMD (L2–L4) increased in subjects treated with teriparatide 10 μg/day, 20 μg/day, and 40 μg/day at study endpoint (Table 2, Fig. 2). All subjects in the 40-μg group showed positive increases of lumbar spine BMD

Fig. 1. Subject disposition. N , number of subjects

Table 1. Demographics and baseline characteristics Variable

Placebo (N = 38)TPTD10 (N = 38)TPTD20 (N = 39)TPTD40 (N = 39)Age [in years] (n ) Mean ± SD

(38) 69.9 ± 3.6(38) 70.3 ± 4.8(39) 71.5 ± 5.1(39) 72.5 ± 6.1Years since menopause (natural) (n ) Mean ± SD (34) 19.49 ± 3.80(34) 20.21 ± 6.05(36) 22.23 ± 7.30(32) 23.32 ± 7.10Smoking history No

35 (92.1)32 (84.2)33 (84.6)29 (74.4) Past smoker

0 (0.0) 1 (2.6) 3 (7.7) 6 (15.4) Continuous smoker 3 (7.9) 5 (13.2) 3 (7.7) 4 (10.3)Alcohol consumption No 34 (89.5)33 (86.8)35 (89.7)33 (84.6) Yes

4 (10.5)

5 (13.2) 4 (10.3)

6 (15.4)Previous therapy for osteoporosis No 30 (78.9)2

7 (71.1)29 (74.4)30 (76.9) Yes

8 (21.1)11 (28.9)10 (25.6)9 (23.1)No. of previous vertebral fractures 021 (55.3)23 (60.5)23 (59.0)21 (53.8) 111 (28.9)8 (21.1)8 (20.5)10 (25.6) 2

3 (7.9)

4 (10.5) 4 (10.3)

5 (12.8) 3 or more 3 (7.9)

3 (7.9)

4 (10.3) 3 (7.7)

Height [cm]

(n ) Mean ± SD (38) 149.64 ± 5.76(38) 150.05 ± 5.93(39) 149.00 ± 5.82(39) 149.31 ± 4.53Weight [kg]

(n ) Mean ± SD (38) 47.82 ± 6.18(38) 47.91 ± 6.63(39) 48.82 ± 7.15(39) 48.14 ± 8.49BMI [kg/m 2]

(n ) Mean ± SD (38) 21.36 ± 2.61(38) 21.26 ± 2.50(39) 21.99 ± 2.88(39) 21.59 ± 3.6825(OH)-VD [ng/ml] (n ) Mean ± SD (38) 23.28 ± 3.80(38) 23.19 ± 5.17(39) 23.24 ± 4.46(39) 23.11 ± 5.54Creatinine [mg/dl] (n ) Mean ± SD (38) 0.64 ± 0.08(38) 0.61 ± 0.10(39) 0.65 ± 0.10(39) 0.65 ± 0.13Corrected Ca [mg/dl] (n ) Mean ± SD

(38) 9.26 ± 0.38

(38) 9.29 ± 0.36

(39) 9.38 ± 0.37

(39) 9.37 ± 0.32

TPTD10, teriparatide 10 μg/day; TPTD20, teriparatide 20 μg/day; TPTD40, teriparatide 40 μg/day; N , total number of subjects; n , number of subjects who have the measurement; BMI, body mass index; 25(OH)-VD, 25-hydroxy vitamin D

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(L2–L4) at study endpoint. Teriparatide at 10-μg, 20-μg, and 40-μg doses showed a statistically signi? cant increase with increasing treatment dose, as assessed by the percent change of lumbar spine BMD from baseline to endpoint using Williams’ test when compared with placebo (P < 0.001 in all teriparatide treatment groups).

Femoral neck and total hip BMD were also evaluated as exploratory variables (see Table 2). The mean (±SD) percent changes of femoral neck and total hip BMD with 20 μg teriparatide from baseline to endpoint were 1.83% ± 7.13% (n = 39) and 1.91% ± 3.60% (n = 39), respectively. Teriparatide increased PICP , PINP , BAP and CTX. Median actual values are shown over time for all four biochemical markers in Fig. 3. All teriparatide treatment groups showed a rapid increase in PICP to peak levels at week 4 (Fig. 3a). At week 24, the actual values of PICP decreased below baseline in the 10-μg group and returned to values similar to baseline in the 20-μg group; however, PICP in the 40-μg group remained at higher levels than baseline in the 40-μg treated group (Fig. 3a). Increases in PINP were observed at week 4 in all teriparatide treatment groups (Fig. 3b). Thereafter, PINP gradually declined and returned to values similar to baseline at week 24 in the 10-μg group. In the 20-μg group and the 40-μg group, PINP remained at higher levels than baseline at week 24. Increases in BAP and CTX were also observed in the 20-μg group and the 40-μg group (Fig. 3c,d). In contrast, no increase in BAP or CTX was

Table 2. Bone mineral density: descriptive statistics of percent change from baseline to weeks 12, 24, and endpoint

Placebo (N = 38)

TPTD10 (N = 38)

TPTD20 (N = 39)

TPTD40 (N = 39)

Lumbar spine (L2–L4)

Actual value at baseline [g/cm 2] (n ) Mean ± SD

(37) 0.6299 ± 0.0784(38) 0.6202 ± 0.0607(39) 0.6270 ± 0.0823(39) 0.6262 ± 0.0752Percent change to week 12 [%] (n ) Mean ± SD

(36) 0.83 ± 2.57(37) 3.72 ± 3.92(39) 4.65 ± 3.63(32) 7.45 ± 4.27Percent change to week 24 [%] (n ) Mean ± SD

(34) 0.95 ± 2.71(36) 6.13 ± 4.09(37) 6.54 ± 4.72(27) 12.06 ± 5.75Percent change to endpoint [%] (n ) Mean ± SD (37) 0.66 ± 2.85(37) 5.80 ± 4.50(39) 6.40 ± 4.76(33) 11.47 ± 5.45 Williams’ test*–

t = 4.95, P = 0.000t = 5.60, P = 0.000t = 10.10, P = 0.000Femoral neck

Actual value at baseline [g/cm 2] (n ) Mean ± SD

(38) 0.5068 ± 0.0802(38) 0.5161 ± 0.0663(38) 0.5168 ± 0.0927(38) 0.5112 ± 0.0903Percent change to week 12 [%] (n ) Mean ± SD

(37) ?0.75 ± 6.04(37) 0.15 ± 4.39(38) 0.98 ± 6.87(31) 1.76 ± 5.40Percent change to week 24 [%] (n ) Mean ± SD

(34) ?0.71 ± 4.68(36) 1.18 ± 4.78(36) 0.96 ± 4.86(26) 3.61 ± 8.32Percent change to endpoint [%] (n ) Mean ± SD (38) ?0.39 ± 4.70(37) 1.23 ± 4.73(38) 1.83 ± 7.13(32) 2.80 ± 7.73Total hip

Actual value at baseline [g/cm 2] (n ) Mean ± SD

(38) 0.6193 ± 0.0884(38) 0.6261 ± 0.0784(38) 0.6223 ± 0.1116(38) 0.6020 ± 0.1125Percent change to week 12 [%] (n ) Mean ± SD

(37) ?0.43 ± 3.40(37) 1.00 ± 2.78(38) 0.96 ± 3.48(31) 2.25 ± 3.73Percent change to week 24 [%] (n ) Mean ± SD

(34) 0.32 ± 3.16(36) 1.65 ± 2.94(36) 1.70 ± 3.49(26) 3.58 ± 5.72Percent change to endpoint [%] (n ) Mean ± SD

(38) 0.23 ± 3.08

(37) 1.71 ± 2.92

(38) 1.91 ± 3.60

(32) 3.19 ± 5.26

The endpoint measurements were obtained using the last observation obtained after randomization; for time-point speci? c analyses, measure-ments at the speci? c visit were used

TPTD10, teriparatide 10 μg/day; TPTD20, teriparatide 20 μg/day; TPTD40, teriparatide 40 μg/day; N , total number of subjects; n , number of subjects who were included in the analysis at the particular time point * One-sided test,

step-down

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observed in the 10-μg group during the study. Increases in CTX reached maximum values at week 24 in the 20-μg group and at week 12 in the 40-μg group (Fig. 3d).

Safety

No subject deaths occurred in this study. Three subjects experienced serious treatment-emergent adverse events during the study: hand fracture in the 10-μg group, transient ischemic attack in the 20-μg group, and decreased appetite in the 40-μg group. All serious treatment-emergent adverse events in this study were considered not to be related to the study drug, study procedure, or study device. Six subjects (two in the 20-μg group and four in the 40-μg group) were discontinued from the study because of TEAEs. The TEAEs that led to discontinuation were as follows: increased blood potassium (one subject), and osteoarthritis (one subject) in the 20-μg group, nausea (two subjects), dyspnea (one subject) and malaise (one subject) in the 40-μg group. The events other than osteoarthritis were considered to be pos-sibly related to the study drug.

The number of subjects with at least one TEAE was 29 (76.3%) in the placebo group, 30 (78.9%) in the 10-μg group, 33 (84.6%) in the 20-μg group, and 32 (82.1%) in the 40-μg group. No statistically signi? cant difference was noted among the four treatment groups in the overall incidence of TEAEs. Table 3 shows the TEAEs that occurred in the teriparatide treatment groups in more than 2% of the sub-jects. The TEAEs that occurred in the teriparatide treat-ment groups in more than 5% of the subjects and were

reported more frequently than in the placebo group were

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nausea, eczema, headache, fall, muscle spasms, and increased blood uric acid (Table 3). Of these TEAEs, the incidences of nausea and headache were higher in the 40-μg group than in the other treatment groups. There was a statistically sig-ni? cant difference among the four treatment groups in the incidences of fall and chest pain (P= 0.045 and P= 0.029, respectively), which were higher in the 10-μg group than in the other treatment groups. TEAEs were generally mild to moderate in severity.

According to the pharmacological effect of PTH, there was the possibility that serum calcium would be elevated after the administration of teriparatide. Compared with the placebo group, the changes in corrected serum calcium from predose to 4-h postdose were statistically signi? cant at all time points after baseline in the 20-μg group and the 40-μg group (Table 4). Furthermore, compared with base-line, the changes in corrected serum calcium from predose to 4-h postdose were also statistically signi? cant at weeks 2 and 12 in the 20-μg group and at weeks 2, 12, and 24 in the 40-μg group (Table 4). However, these changes in corrected serum calcium were considered to be small and not clini-cally signi? cant. No subject was discontinued from the study because of elevated serum calcium level. Teriparatide had no effect on the urinary calcium/creatinine ratio.

In the laboratory tests, signi? cant increases in blood uric acid were also observed, but these changes were not associ-ated with adverse events such as gout, arthralgia, or urinary calculus that might be attributable to increases in blood uric acid. Statistically signi? cant changes from baseline in 1,25-dihydroxy vitamin D were observed in all teriparatide treatment groups, but not in the placebo group. The percent changes in 1,25-dihydroxy vitamin D from baseline were dose dependent and reached a maximum at week 4 [54.59% ± 57.59% (mean ± SD, n= 39) increase from base-line in the 20-μg group]. No clinically signi? cant changes from baseline to week 24 were observed in vital signs or electrocardiograms.

Discussion

This study is the ?rst randomized, double-blind, placebo-controlled clinical trial to evaluate the ef? cacy and safety of teriparatide daily injection in Japan. This phase 2 study demonstrated that teriparatide daily subcutaneous injection for a 6-month period is well tolerated and effective for the treatment of Japanese postmenopausal women with osteo-porosis at a high risk of fracture. Teriparatide treatment signi?cantly increased lumbar spine BMD and tended to increase femoral BMD, together with increases of bone formation markers such as PINP, PICP, and BAP, indicat-ing the unique mechanism of bone formation, which is not found with other antiresorptive agents.

Table 3.Treatment-emergent adverse events (TEAEs) (preferred term) observed in >2% subjects who were treated with teriparatide

Treatment-emergent adverse events

?preferred term?a Placebo

(N= 38)

n (%)

TPTD10

(N= 38)

n (%)

TPTD20

(N= 39)

n (%)

TPTD40

(N= 39)

n (%)

ALL_TPTD

(N= 116)

n (%)

Fisher’s test

result (P value)

Nasopharyngitis10 (26.3)7 (18.4)9 (23.1)12 (30.8)28 (24.1)0.634

Nausea 4 (10.5) 2 (5.3) 4 (10.3)7 (17.9)13 (11.2)0.397

Eczema 1 (2.6) 4 (10.5) 2 (5.1) 2 (5.1)8 (6.9)0.541 Headache 1 (2.6) 1 (2.6) 1 (2.6) 6 (15.4)8 (6.9)0.057 Diarrhea 3 (7.9) 3 (7.9) 1 (2.6) 3 (7.7)7 (6.0)0.732

Fall 1 (2.6) 5 (13.2)0 (0.0) 2 (5.1)7 (6.0)0.045

Muscle spasms0 (0.0) 4 (10.5) 1 (2.6) 2 (5.1)7 (6.0)0.138

Blood uric acid

increased

0 (0.0) 1 (2.6) 3 (7.7) 2 (5.1) 6 (5.2)0.515

Back pain 4 (10.5) 4 (10.5)0 (0.0) 1 (2.6) 5 (4.3)0.082

Chest pain0 (0.0) 4 (10.5)0 (0.0) 1 (2.6) 5 (4.3)0.029 Contusion0 (0.0) 3 (7.9) 1 (2.6) 1 (2.6) 5 (4.3)0.281 Osteoarthritis0 (0.0) 3 (7.9) 1 (2.6) 1 (2.6) 5 (4.3)0.281

Pain in extremity0 (0.0)0 (0.0) 3 (7.7) 2 (5.1) 5 (4.3)0.169 Vomiting 2 (5.3) 1 (2.6) 2 (5.1) 2 (5.1) 5 (4.3) 1.000 Abdominal pain

upper

1 (2.6) 1 (2.6) 3 (7.7)0 (0.0) 4 (3.4)0.320 Decreased appetite0 (0.0)0 (0.0)0 (0.0) 4 (10.3) 4 (3.4)–

Injection site

hemorrhage

0 (0.0)0 (0.0) 2 (5.1) 2 (5.1) 4 (3.4)–

Joint sprain0 (0.0) 4 (10.5)0 (0.0)0 (0.0) 4 (3.4)–

Stomach discomfort0 (0.0) 1 (2.6)0 (0.0) 3 (7.7) 4 (3.4)–Constipation 1 (2.6) 1 (2.6) 2 (5.1)0 (0.0) 3 (2.6)–

Dental caries0 (0.0)0 (0.0) 2 (5.1) 1 (2.6) 3 (2.6)–

Dermatitis contact0 (0.0)0 (0.0) 1 (2.6) 2 (5.1) 3 (2.6)–

Dizziness 1 (2.6)0 (0.0) 3 (7.7)0 (0.0) 3 (2.6)–

Rash0 (0.0) 1 (2.6) 1 (2.6) 1 (2.6) 3 (2.6)–

Tooth extraction0 (0.0) 1 (2.6) 1 (2.6) 1 (2.6) 3 (2.6)–

a MedDRA version 9.0

TPTD10, teriparatide 10 μg/day; TPTD20, teriparatide 20 μg/day; TPTD40, teriparatide 40 μg/day; ALL_TPTD, all teriparatide-treatments; N, total number of subjects; n, number of subjects with each adverse event

631

Recent evidence by the WHO Osteoporosis Research Group indicates the importance of risk factors of fractures [8]. They de? ned several risk factors using the worldwide various cohort studies including a Japanese Hiroshima cohort [9]. Among those, prevalent fractures, low BMD, and advanced age are also well-known independent risk factors of fractures in the Japanese population [9,10]. According to this evidence, the inclusion criteria of this study was de? ned for patients at a high risk of fracture(s) as being at least 55 years old and having either of the fol-lowing three categories: (1) lumbar spine BMD <80% YAM, with a minimum of either one moderate or two mild prevalent fragility vertebral fractures, (2) lumbar spine BMD <70% of YAM, and age ≥65, and (3) lumbar spine BMD <60% of YAM.

Approximately 8 million postmenopausal women in Japan have osteoporosis; however, less than 30% of them are receiving any treatment. From an epidemiological anal-ysis, it is estimated that the total number of patients with hip fracture in Japan will increase from 15 900 per year in 2010 to 25 500 in 2030 [11]. It is suggested that fracture reduction by agents with high effectiveness to prevent frac-tures may eventually reduce the burden on society.

Intermittent treatment with PTH has been shown to have an anabolic effect on bone. PTH stimulates the prolif-eration and differentiation of osteoprogenitor cells leading to bone formation [12]. In addition, PTH has been shown to inhibit apoptosis of osteoblasts, leading to an increase in the number of osteoblasts [13]. A combination of modeling- and remodeling-based formation enhanced by PTH treat-ment resulted in increased bone mass [14–17] and improved bone microarchitecture by increasing trabecular thickness and connectivity as well as cortical thickness [5]. Regarding the development of PTH for osteoporosis treatment in Japan, Fujita et al. reported lumbar spine BMD increased from baseline [less than 6.0% at 24 weeks and 8.1% at 48 weeks in the highest dose group (mean value, 200 U)] by intermittent weekly injection of hPTH (1-34) [18]. These results were also reproduced by daily nasal spray of hPTH (1-34) [2.4% mean increase in lumbar spine BMD from baseline in the highest dose group (1000 μg) at 3 months] [19]. These values at each time point (12 and 24 weeks) are less than those reported here for the middle dose, 20 μg daily injection [mean percent increase of lumbar spine BMD, 4.65% at 12 weeks and 6.54% at 24 weeks (see Table 2)], although it is dif? cult to compare the results obtained at different studies using different formulation, drug deliv-ery, and dosing regimen. Fracture risk reduction by inter-mittent weekly injection of hPTH (1-34) and daily nasal spray of hPTH (1-34) has not been demonstrated. Teripa-

Table 4.Corrected serum calcium predose and 4-h postdose: descriptive statistics of actual value and change at baseline and weeks 2, 4, 12, and 24

Placebo (N= 38)TPTD10 (N= 38)TPTD20 (N= 39)TPTD40 (N= 39) Baseline

n38383938

Predose: median (Min–Max) [mg/dl]9.20 (8.30–10.20)9.30 (8.70–10.30)9.30 (8.60–10.30)9.40 (8.30–10.00) Change: median (Min–Max) [mg/dl]?0.10 (?0.60–0.50)0.00 (?0.60–0.60)0.00 (?0.80–0.60)?0.05 (?0.60–0.70) Wilcoxon’s rank sum*–P= 0.168P= 0.095P= 0.074

Week 2

n38353836

Predose: median (Min–Max) [mg/dl]9.30 (8.60–10.10)9.30 (8.60–10.20)9.40 (8.80–10.30)9.30 (8.60–10.20) Change: median (Min–Max) [mg/dl]?0.10 (?0.60–0.50)?0.10 (?0.60–0.80)0.15 (?0.40–0.50)0.30 (?0.20–1.10) Wilcoxon’s rank sum*–P= 0.179P= 0.005P= 0.000

Wilcoxon’s signed-rank**P= 0.590P= 0.389P= 0.032P= 0.000

Week 4

n38373935

Predose: median (Min–Max) [mg/dl]9.40 (8.90–10.60)9.50 (8.90–10.10)9.40 (8.60–10.30)9.40 (8.60–10.30) Change: median (Min–Max) [mg/dl]?0.20 (?0.90–0.40)?0.10 (?0.60–0.60)0.00 (?1.40–0.60)0.10 (?0.50–0.70) Wilcoxon’s rank sum*–P= 0.151P= 0.001P= 0.000

Wilcoxon’s signed-rank**P= 0.306P= 0.328P= 0.257P= 0.175

Week 12

n37373830

Predose: median (Min–Max) [mg/dl]9.40 (8.70–10.20)9.40 (8.60–10.50)9.55 (9.00–10.10)9.60 (8.90–10.70) Change: median (Min–Max) [mg/dl]?0.10 (?0.60–0.50)?0.10 (?0.80–0.60)0.10 (?0.70–1.00)0.20 (?0.50–1.00) Wilcoxon’s rank sum*–P= 0.220P= 0.000P= 0.001

Wilcoxon’s signed-rank**P= 0.861P= 0.752P= 0.005P= 0.002

Week 24

n33363627

Predose: median (Min–Max) [mg/dl]9.50 (8.90–11.10)9.65 (8.90–10.50)9.70 (8.80–10.50)9.70 (8.90–10.60) Change: median (Min–Max) [mg/dl]?0.20 (?0.90–0.60)?0.10 (?0.60–0.40)0.00 (?0.60–1.10)0.30 (?1.50–1.10) Wilcoxon’s rank sum*–P= 0.171P= 0.004P= 0.000

Wilcoxon’s signed-rank**P= 0.551P= 0.389P= 0.191P= 0.009

TPTD10, teriparatide 10 μg/day; TPTD20, teriparatide 20 μg/day; TPTD40, teriparatide 40 μg/day; N, total number of subjects; n, number of subjects who were included in the analysis at a particular time point

* W ilcoxon’s rank sum test of change value compared with placebo

** W ilcoxon’s signed-rank test of change value compared with baseline

632

ratide daily injection showed great ef? cacy in the reduction of fracture risk in a large-scale trial, the Fracture Prevention Trial (FPT) [2].

From the analysis of the FPT trial, the increase in lumbar spine BMD accounts for 30%–41% of the vertebral fracture risk reduction with teriparatide treatment [20]. Changes in lumbar spine BMD at 12 months were signi? cantly corre-lated with the improvements in trabecular bone structure at 22 months [21].

In our study, teriparatide induced a dose-dependent increase in lumbar spine BMD. The mean percent change in lumbar spine BMD from baseline was 6.54% with the 20-μg dose at 6 months. The increase of lumbar spine BMD at 6 months with 20 μg teriparatide was similar to that observed in the FPT trial [22], although patient character-istics in the FPT 20-μg group [mean (±SD) age, 70 ± 7, mean (±SD) baseline lumbar spine BMD, 0.82 ± 0.167 g/cm2, 91% of patients with prevalent vertebral fracture] were slightly different from those of our study [mean (±SD) age, 70.3 ±4.8, mean (±SD) baseline lumbar spine BMD, 0.63 ± 0.08 g/ cm2, 41% of patients with prevalent vertebral fracture].

In an Asian study comparing teriparatide with calcitonin [23], teriparatide showed a statistically signi? cant increase of 5.03% from baseline in lumbar spine BMD [mean (±SD) age, 70.6 ± 7.1, mean (±SD) baseline lumbar spine BMD, 0.755 ± 0.123 g/cm2, all with prevalent vertebral or nonver-tebral fracture]. In a similar study in Taiwan [24], teripara-tide was associated with a statistically signi? cant 4.5% increase from baseline in lumbar spine BMD [mean (±SD) age, 68.06 ± 1.07, mean (±SD) baseline lumbar spine BMD, 0.751 ± 0.018 g/cm2, all with prevalent vertebral or nonver-tebral fracture].

Although there are some differences in patient charac-teristics, the increase in lumbar spine BMD with teripara-tide treatment observed in our study is consistent with previous studies of teriparatide conducted in both Cauca-sian and Asian populations.

In the 20-μg group, PINP rapidly increased at 4 weeks and remained at a higher level than baseline at 24 weeks, suggesting a persistent anabolic effect of teriparatide. In contrast, PINP in the 10-μg group gradually declined and returned to values similar to baseline level at 24 weeks, suggesting weaker anabolic action compared with the 20-μg and 40-μg groups.

In the FPT trial, increase in PICP at 1 month and PINP at 3 months has been shown to be the best predictor of BMD response at 18 months [25]. In our study, the increase in PICP peaked at 4 weeks for each dose, whereas PINP and BAP were more sustained. The increase in PINP at 12 weeks in the 20-μg and 40-μg groups may predict the sustained lumbar spine BMD increase. In another analysis of the FPT trial, changes in the bone formation markers (BAP and PICP) correlated with improvements in bone structure after 22 months of teriparatide treatment [26]. The difference in the time-course of the responses of bone formation markers (PINP, PICP, and BAP) following teriparatide treatment observed in our study was similarly observed in the other global trials [3,25,26]. However among these bone formation markers, PINP has the best signal-to-noise ratio [27], superior to PICP or BAP, and is considered suitable in monitoring skeletal response to teriparatide [3,27].

Regarding the bone resorption marker, teriparatide sig-ni? cantly increased urinary NTX compared with placebo in the FPT trial at 3, 6, and 12 months after the administration of teriparatide in both the 20-μg and 40-μg groups [25]. A similar increase of urinary NTX from baseline by teripara-tide at 20 μg daily treatment was reported in a trial that compared teriparatide with alendronate [3]. In our study, the serum bone resorption marker CTX increased at 4 weeks in the 40-μg group, and a lesser increase was observed at 24 weeks in the 20-μg group. This increase in CTX was slow compared with the increase of bone formation markers. It may re?ect that remodeling-based formation mainly occurred after the initial modeling-based formation, and the increased bone turnover with a positive bone balance led to an increase in bone mass [17,28,29].

It is generally considered that agents that require daily self-injection may have a disadvantage for patient compli-ance. However, in this study, high compliance of the treat-ment was observed. The compliance was slightly higher compared with that reported in the FPT trial [2].

Regarding safety, most of the adverse events were mild to moderate in severity. No study drug- or study procedure-related serious adverse events were reported during the treatment period. These characteristics of TEAEs are com-parable to those of the FPT or Asian trials [2,23,24]. The incidences of nausea and headache were higher in the 40-μg group, as similarly reported in the FPT trial [2].

Although there was a slight but statistically signi? cant increase in the serum calcium concentration from predose to 4-h postdose, predose and postdose serum calcium level never exceeded 11 mg/dl in the teriparatide treatment groups at either time point, and no subject was discontinued from the study because of elevated serum calcium level.

Our study has some limitations. The 6-month observa-tional period was considered appropriate as a phase 2 dose–response study; however, it was not long enough to acquire long-term ef?cacy and safety data. We have chosen the lumbar spine BMD as the primary ef?cacy measure and BMD at femoral neck and total hip as exploratory vari-ables. However, we have not evaluated the change of BMD at the one-third distal radius (shaft of radius) in Japanese subjects, where a small reduction was reported following 40-μg teriparatide treatment compared to the placebo group in FPT [2]. In contrast to this observation, the teriparatide-treated patients in the FPT trial reported about half the incidence of wrist fracture compared to placebo [2]. In a cross-sectional study using three-dimensional peripheral quantitative computed tomography (pQCT), total bone mineral content, total and cortical bone area, and periosteal circumference of the distal radius in teriparatide-treated groups (20-μg and 40-μg) were all higher than in the placebo group, with greater polar cross-sectional moments of inertia [30]. These ? ndings could support the consistent bene? cial effects of teriparatide treatment at this site. Occasional decreases in BMD that were observed in the distal radius by two-dimensional areal DXA measurement could be

633

explained by the increased bone size with newly formed, relatively undermineralized bone tissue.

In conclusion, daily subcutaneous injection teriparatide treatment increased bone formation markers and lumbar spine BMD within 6 months in Japanese postmenopausal women with osteoporosis at a high risk of fracture. This daily self-injection treatment was safe, well tolerated, and showed optimal adherence. These results observed in Japa-nese subjects may support the observation that teriparatide stimulates bone formation in patients with osteoporosis at a high risk of fracture.

Acknowledgments This study was supported by funding from Eli Lilly and Company, as a phase 2 clinical trial for registration in Japan. The following investigators participated in this trial: Dr. Hikaru Ishii, Shin Nihonbashi Ishii Clinic, Tokyo; Dr. Masanari Omata, Ohimachi Orthopedic Surgery Clinic, Tokyo; Dr. Masataka Karube, New Medical Research System Clinic, Tokyo; Dr. Yukio Nakatsuchi, Nagano National Hospital, Nagano; Dr. Kentaro Suzuki, Iida Hospital, Nagano; Dr. Yasuaki Miki, Nankou Hospital, Osaka; Dr. Shu Ohta, Ohta Clinic, Hiroshima; Dr. Ryu Yamamoto, Southern Clinic, Hiroshima; Dr. Yoshifumi Oda, Takanohashi Chuo Hospital, Hiroshima; Dr. Masaki Ito, Hiroshima Park Building Internal Medicine, Hiroshima; Dr. Kenji Oda, Oda Internal Medicine Clinic, Hiroshima; Dr. Hiroshi Ito, Ito Orthopedics Clinic, Kagoshima; Dr. Koji Yonemori, Orthopedic Hos-pital Yonemori, Kagoshima; Dr, Hidetoshi Kawamura, San-Ai Hospi-tal, Kagoshima; Dr. Shohachiro Hidaka, Hidaka Hospital, Kagoshima; Dr. Daiki Nakaoka, Nakaoka Clinic, Osaka; Dr. Hideyone Kanaumi, Yuuaikai Hospital, Osaka; Dr. Hiroji Miyake, Nishinomiya Kyoritsu Neurosurgical Hospital, Hyogo; Dr. Ryosuke Ikegami, Shonan Memo-rial Hospital, Kanagawa. We thank Atsuko Iwata for assistance in the preparation of the manuscript. We also thank Haruo Kitado, Tomomi Goto, Hiroko Furumoto, Yoko Hashimoto, Souta Mizumoto, Naohiko Wakayama, Yoshihiro Higashiuchi, and Yukihito Kuwagaki for helpful discussions, and Dr. Kiyoshi Nakatsuka, Dr. Shigeru Tai, and Dr. Juan Carlos Gomez for their contributions to the design and execution of this study.

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