Comparison of Teriparatide and Calcitonin Treatment in Postmenopausal Korean Women with Osteoporosis

(1)

Comparison of Teriparatide and Calcitonin Treatment in Postmenopausal Korean Women with Osteoporosis

Woong Hwan Choi

¹

, Ghi Su Kim

²

, Sung Kil Lim

³

, Moo Il Kang

⁴

, Hyun Koo Yoon

⁵

, Yong Ki Min

⁶

, Chan Soo Shin

⁷

, Maria Yu

⁸

, Belinda J Hall

⁸

, Daniel Thiebaud

⁹

Division of Endocrinology, College of Medicine, Hanyang University, Seoul, Korea¹, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea²,

College of Medicine, Yonsei University, Seoul, Korea³, Catholic University of Korea, St. Mary’s Hospital, Seoul, Korea⁴,

School of Medicine, Sungkyunkwan University, Seoul, Korea⁵,

Samsung Medical Center, Seoul, Korea⁶, Seoul National University, Seoul, Korea⁷ Intercontinental Information Sciences (ICIS)⁸, Eli Lilly Australia Pty Limited⁹

목적: 이 연구의 목적은 골다공증으로 확진된 폐경 후 여성에서 teriparatide와 calcitonin치료가 요추와 대퇴골 골밀도와 생화학적 골 표지자 (bone-specific alkaline phosphatase [BSAP] and osteocalcin)에 미치는 효과와 안정성을 비교하는 것이다.

방법: 한국에서 시행된 이 개방 표지, 다기관, 대조군 연구에서 골다공증이 있는 70명의 폐경 후 여성이 teripa- ratide 20μg/일 (n=35) 또는, calcitonin 100 IU/일 (n=35)을 6개월 간 피하로 투여 받는 군으로 임의로 나누어졌 다. 모든 환자들은 연구 기간 동안 칼슘 (≥500 mg/일)과 비타민 D (200 to 400 IU/day)를 투여 받았다.

결과: 모든 환자들은 한국인으로, 연령은 55세에서 82세 사이로 (66±5 years; mean±SD) 이전에 1회 이상 골절을 경험한 적이 있었다. teriparatide군에서는, calcitonin군의 23명 (66%)의 환자에 비해 31명 (81%)의 환자가 이 연 구 계획을 모두 수행하였다 (P=.044). teriparatide 치료를 받은 환자들에서, 요추 골밀도가 4.2±5.9% (mean±SD;

P=.555) 증가하였고, calcitonin 치료를 받은 환자들에서 0.6±5.5% (mean±SD; P=.555)가 증가하였다. 양 군에서 치료 시작부터 종결 시점까지 요추 골밀도 변화의 보정된 평균 차이는 3.8% (95% CI: 0.94～6.57, P=.010)였다.

Teriparatide 치료는 전체 대퇴골 (P=.658), 전자 (P=.056), 또는 경부 (P=.442) 골밀도에 통계적으로 의미 있는 영향 을 미치지는 못했다. Calcitonin 치료는 전체 대퇴골 골밀도에서 2.2±4.6% (mean±SD; P=.029)의 통계적으로 의 미 있는 감소를 초래한 반면, 전자 (P=.641) 또는 대퇴골 경부 (P=.216) 골밀도에는 의미 있는 감소를 초래하지 않았 다. Teriparatide 치료는 혈청 bone-specific alkaline phosphatase (BSAP) and osteocalcin의 농도를 치료 시작 전보다 각각 116% (median change, range-31 to 599%; P＜.001)와 172% (median change, range-62 to 571%; P＜.001) 증가시켰다. Calcitonin 치료는 혈청 BSAP 또는 osteocalcin 농도에 통계적으로 의미 있는 영향을 미치지는 않았다. teriparatide 치료 군에서, calcitonin 치료 군에서는 85%에 비해, 69%의 환자가 1가지 이상의 치료와 연관된 부작용을 경험하였다 (P=.154). 양 치료 군에서 가장 흔한 치료와 연관된 부작용은 오심이었고, teri- paratide 치료 군에 비해 calcitonin 치료 군에서 더 많이 나타났다 (41% versus 17% respectively; P=.036). 양 치료군에서 기타 실험실 검사 또는 활력 징후의 임상적으로 의미 있는 차이는 관찰되지 않았다.

결론: 이 연구는 teriparatide가 요추 골밀도뿐만 아니라, 골형성 생화학적 표지자인 BSAP and osteocalcin의 증 가를 일으킨 것으로 보아, 한국의 폐경 후 여성의 골다공증에 효과적인 치료제라는 것을 보여준다. teriparatide 치료는 calcitonin치료에 비해 요추골 골밀도의 의미 있는 증가를 가져왔다. 두 치료 모두 모든 환자에서 안전하였 고, 특별한 부작용이 없었다.

중심단어: Teriparatide, Calcitonin, 골다공증, 폐경 후 여성

책임저자 : Daniel Thiebaud, Eli Lilly Australia Pty Limited

Tel: ⁺61-2-93254606, Fax: ⁺61-2-93254699, E-mail: [email protected]

* This study was supported by funding from Eli Lilly & Co.

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Osteoporosis is a disease characterised by compro- mised bone strength leading to increased fracture susceptibility. Currently, the most common treatments for osteoporosis include calcium and vitamin D supplementation, estrogens, bisphosphonates, raloxi- fene, and calcitonin

^1,2

. These agents are all antire- sorptive, thus they stabilise bone mass and prevent further bone loss. This means that antiresorptive treat- ments can increase BMD and reduce fracture risk, however they do not usually produce large increases in bone mass.

Recently, the effects of the bone formation- stimu- lating agent teriparatide, biosynthetic human parathy- roid hormone (rhPTH [1-34]), have been demonstrated in women with postmenopausal osteoporosis. Teri- paratide treatment has been associated with increases in BMD and bone formation markers and importantly, a reduced fracture risk in these patients due to its anabolic action on bone

^3,4

. Dramatic increases in BMD have also been observed in postmenopausal women with osteoporosis receiving a combination of hormone replacement therapy (HRT) and teriparatide compared with HRT alone

^5,6

.

Calcitonin is a widely used treatment for osteo- porosis. It is a natural peptide secreted by the thyroid gland and has a well known role in humans in the short-term fine tuning of calcium homeostasis. Calci- tonin binds to high-affinity receptors on osteoclasts and causes an inhibition of activity

⁷

. Clinical experi- ence has shown that the most effective form of calcitonin for osteoporosis treatment is salmon calci- tonin, available as a subcutaneous injection or nasal spray

^8-10

. Some early studies supported the use of calcitonin in the prevention and treatment of involu- tioal osteoporosis with the use of 100 IU of salmon calcitonin injected subcutaneousl y

^11,12

. Salmon calci- tonin is usually relatively safe, with some reports of transient facial flushing, nausea, mild inflammation at the injection site, and very rarely, vomiting and dia- rrhoea.

The current study was part of a registration study and it is the first study to compare teriparatide treat- ment with calcitonin treatment in Korean patients. The aims of this study were to compare in postmeno- pausal Korean women with established osteoporosis the effect of treatment with teriparatide 20μg/day administered subcutaneously with the effect of salmon calcitonin 100 IU/day administered subcutaneously on changes in BMD, biochemical bone markers (bone- specific alkaline phosphatase [BSAP] and osteocal- cin), and safety.

Methods 1. Study Design

This was an open-label, controlled, randomised study with two treatment arms conducted in seven centres in Korea (study code B3D-KL-GHCC). Se- venty postmenopausal women with established osteo- porosis, as determined by at least one prevalent vertebral or nonvertebral osteoporotic fracture, were enrolled. The study included a 6-month treatment phase after a screening period of 2 months. Eligibility requirements were fulfilled and baseline procedures were carried out during the screening phase. At this time, all patients began taking supplements of at least 500 mg/day of elemental calcium and 200 to 400 IU/day of vitamin D.

During the treatment phase, study visits occurred at 0 (baseline), 1, 3, and 6 months. Patients were ran- domised to treatment with either teriparatide (20μ g/day) or calcitonin (100 IU/day) at the baseline visit using the Interactive Voice Response System (IVRS).

Teriparatide 20μg (Forteo

^Ⓡ

, Eli Lilly & Co., Ltd.)

was provided in pre-filled cartridges placed in Gemini

PTH pen injection devices. Calcitonin was provided in

prefilled disposable syringes containing 100 IU of

salmon calcitonin (Miacalcic

^Ⓡ

, Novartis). Each pa-

tient was instructed to inject either teriparatide or

(3)

calcitonin into her left or right lower abdomen or outer thigh in the early morning on a daily basis during the study treatment. At the baseline visit, the patient administered the first dose of teriparatide or calcitonin under supervision at the study site. The last injection of teriparatide or calcitonin took place the day before the last visit (6 months).

2. Study Population

Postmenopausal women aged 55 to 85 years (at least 3 years had elapsed after menopause), inclusive, with established osteoporosis as defined by a previous, documented (X-ray), vertebral (evaluated on lateral views of the thoracic and lumbar spine) or nonvertebral osteoporotic fragility fracture (excluding major trauma), and who were free of severe or chronically disabling conditions other than osteo- porosis, were eligible for inclusion in this study. L-1 through L-4 vertebrae were required to be without artefacts or multiple vertebral fractures, and the reading of the BMD T-score was required to be in the range of -2.0 and -4.0 for at least one of the two sites measured (spine or hip). Patients with a history of diseases which affect bone metabolism, any secondary causes of osteoporosis, an increased base- line risk of osteosarcoma, significantly impaired hepa- tic, renal, or gastric function, a history of other malig- nant neoplasms in the 5 years prior to screening, a history of nephrolithiasis or urolithiasis in the 2 years prior to Visit 2, or treatment with any drug known to significantly affect bone metabolism in the 6 months prior to Visit 2, were excluded from the study.

3. Measures

The primary measure of efficacy was the percent change in lumbar spine BMD from baseline to endpoint measured by dual energy x-ray absorp- tiometry (DXA) at the end of 6 months or at the early

termination visit. Secondary measures of efficacy were the percent changes from baseline to endpoint in total hip, femoral neck, and trochanter BMD. All BMD measurements were performed using DXA using Hologic or Lunar equipment. Further secondary measures of efficacy were percent changes from baseline to 3 months and from baseline to endpoint (6 months or last observation carried forward [LOCF]) in the biochemical bone markers bone- specific alkaline phosphatase (BSAP) and osteocalcin. Adverse events were collected at every visit, regardless of relationship to study drug. These events were captured as actual terms and coded to Medical Dictionary for Regulatory Activities (MedDRA) terms. Physical examinations, including measurement of heart rate and blood pressure, and the recording of self-reported fractures were also carried out at each visit. Quantification of returned study materials at each visit allowed percent compliance to be calculated based on the amount of medication injected as a percentage of the total amount prescribed for that period. Any patient who missed more than 50% of the injectable study medi- cation in any one of the visit intervals was considered noncompliant.

4. Statistical Analyses

All efficacy analyses were performed on an

intention-to-treat (ITT) basis, and were based on data

from patients with at least one observation post-

randomisation. Safety analyses were performed on

patients who had taken at least one dose of study

medication. For confirmatory purposes, a per-protocol

population was used to assess the robustness of the

results from the analysis of the primary and secondary

efficacy variables. This population excluded patients

who violated the inclusion/exclusion criteria, who did

not complete the study, or who received prohibited

concomitant medications. A LOCF approach was used

for patients who discontinued prior to the end of the

(4)

treatment period.

For the BMD data, standardised values for lumbar spine and total hip (sBMD) were used for analysis.

For femoral neck and trochanter BMD, raw values were used for analysis. For change from baseline analysis, both change and percent change from base- line were calculated. The initial analysis of covariance (ANCOVA) model for BMD measures included effects of treatment, baseline value, centre, and treat- ment by centre interaction. None of the BMD vari- ables had significant treatment by centre interaction at a 0.10 level of significance. Therefore, all analyses were performed using ANCOVA without the interac- tion. Rank analysis of covariance was used for the biochemical bone marker (BSAP and osteocalcin) analysis since the data were generally not normally distributed. To analyse the changes from baseline within treatment groups, a paired t-test or signed-rank test was used. All statistical tests were two-sided and conducted at 0.05 level of significance.

The targeted number of patients to be included in this study was 64, as this was the number required (based on a dropout rate of approximately 20%) to provide 80% power to detect a treatment group difference of 4% at a two-sided 0.05 alpha level. No adjustments for multiple comparisons were made.

Results

1. Patient Disposition and Baseline Demo- graphics

A total of 156 patients were entered into the screening phase. Of these, 70 patients were enrolled into the study and randomly assigned to receive study treatment (n=35 teriparatide, n=35 calcitonin), compri- sing the ITT population. Efficacy analyses were carried out on ITT patients with at least one post- baseline measurement and were repeated on the per- protocol population for confirmatory purposes (n=51

overall; n=29 teriparatide, n=22 calcitonin). One patient in the calcitonin group did not meet protocol entry criteria and was withdrawn without receiving study medication, thus safety analyses were carried out on 69 patients.

The specific characteristics of the patients that were examined at study enrolment were age, origin, height, and baseline fracture data. The mean age of all randomised patients was 66.2 years (66.2 years in the teriparatide group and 66.3 years in the calcitonin group). All randomised patients were Korean, with a mean height and weight prior to treatment of 151.16

cm (151.04 cm in the teriparatide group and 151.27 cm in the calcitonin group) and 57.03 kg (57.79 kg in the teriparatide group and 56.27 kg in the calcitonin group) respectively. The number of fractures present prior to study treatment was 61 in the teriparatide group and 59 in the calcitonin group, with the number of fractures per patient ranging from one to five in each group. These data as well as other baseline medical characteristics are summarised in Table 1.

The two treatment groups were generally well ba- lanced at baseline in terms of historical diagnoses, pre- existing conditions, previous osteoporosis medi- cation, and concomitant medication.

Of the 35 patients in the teriparatide group, 31 (88.6%) patients completed the protocol compared with 23 of the 35 (65.7%) patients in the calcitonin group (Table 2). This difference was statistically signi- ficant (P=.044). Patients who received calcitonin on average spent fewer days on therapy (131.9 days) than patients who received teriparatide (166.9 days). At the end of Month 1, average percentage compliance was lower in the calcitonin treatment group compared with the teriparatide treatment group, with values of 97.9%

and 78.3% respectively. Month 3 compliance was si-

milar for both treatment groups (90.3% and 90.2% for

teriparatide and calcitonin respectively), however, by

this time, 10 patients from the calcitonin group had

discontinued compared with one patient from the

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Table 1. Patient characteristics

Baseline Characteristic Teriparatide

N=35

Calcitonin N=35 Age, (years) (mean±SD)

Height, (cm) (mean±SD) Weight, (kg) (mean±SD)

Years since menopause (mean±SD) Hysterectomy, n (%)

Baseline Fractures (mean±SD) BMD, (g/cm²) (mean±SD)

Lumbar spine Total Hip Femoral Neck Trochanter

66.2±5.0 151.0±6.1 57.8±7.8 17.5±6.5 3 (8.6) 1.7±1.0

0.687±0.075 0.670±0.073 0.560±0.074 0.460±0.061

66.3±5.6 151.3±6.4 56.3±7.2 17.9±6.4 6 (17.1) 1.7±1.1

0.700±0.099 0.664±0.093 0.546±0.084 0.457±0.077 Abbreviations, BMD=bone mineral density, SD=standard deviation.

Table 2. Completion rates and reasons for discontinuation

Teriparatide (N=35)

n, %

Calcitonin (N=35)

n, %

P-value^a

Completion Rate

Reason for discontinuation, Adverse Event

Personal conflict or other patient decision Protocol entry criteria not met

31 (88.6)

1 (2.9) 3 (8.6) 0 (0)

23 (65.7)

3 (8.6) 8 (22.9)

1 (2.9)

0.044

aFisher’s Exact Test

Fig. 1. Mean percent change in BMD from baseline to endpoint.

teriparatide group. Month 6 compliance was 95.8%

and 88.7% for the teriparatide and calcitonin treatment groups respectively.

2. Bone Mineral Density

The primary efficacy endpoint of this study was to compare the percentage change from baseline to endpoint in lumbar spine BMD. Teriparatide treatment was associated with a mean percentage increase from baseline in lumbar spine BMD of 4.2±5.9% (mean±

SD, P＜.001). No statistically significant change in lumbar spine BMD was observed in the calcitonin treatment group (mean change from baseline of 0.6±5.5%, P=.555; Fig. 1). There was a statistically significant difference between the two treatment

groups in the percentage change from baseline to endpoint (adjusted mean difference of 3.8%, 95% CI:

0.94, 6.57, P=.010). Table 3 shows the adjusted mean

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Table 3. Adjusted mean difference (AMD) between treatment groups for the percent change from baseline to endpoint in BMD superscript

Area ITT Population Per protocol population

AMD 95% CI P-value^a AMD 95% CI P-value^a

Lumbar Spine 3.76 0.94-6.57 0.0098 3.70 0.18-7.22 0.0399

Total Hip 1.85 -0.10-3.81 0.0629 2.44 0.14-4.74 0.0380

Femoral Neck 0.38 -2.28-3.04 0.7764 0.82 -2.30-3.94 0.6000

Trochanter 1.44 -0.64-3.51 0.1711 1.22 -1.36-3.80 0.3460

aP-value from ANCOVA with treatment, baseline and centre in the model, Abbreviations: BMD=bone mineral density.

Fig. 2. Median percentage change (± interquartile range (IQR)) in serum levels of (a) BSAP and (b) osteocalcin, from baseline to 3 and 6 months post-treatment.

difference between the two treatment groups for each of the BMD measurements for both the ITT and the per- protocol populations.

Teriparatide treatment had no significant effect on total hip BMD while calcitonin treatment was associated with a slight yet statistically significant mean decrease in total hip BMD of 2.2 ± 4.6%

compared to baseline (mean ± SD, P=.029; Fig. 1).

The difference between the two treatment groups in the mean percentage change from baseline to endpoint was not statistically significant in the ITT population

(adjusted mean difference of 1.9%, 95% CI: -0.10, 3.81, P=.063), however, it was statistically significant in the per-protocol population (adjusted mean diffe- rence of 2.4%, 95% CI: 0.14, 4.74, P=.038; Table 3).

No statistically significant differences were observed in either treatment group for the mean change from baseline to endpoint in femoral neck or trochanter BMD.

3. Bone Markers

Median baseline values for serum BSAP were 11.9 μg/L and 14.2μg/L in the teriparatide and calcitonin treatment groups respectively. In the teriparatide treat- ment group, there were median percentage increases in BSAP of 85% at 3 months (P＜.001) and 116% at 6 months (P＜.001) compared to baseline (Fig. 2a). In the calcitonin treatment group, the median percentage increases in BSAP were not statistically significant

(3.9% at 3 months and 3.5% at 6 months compared to baseline; P=.157 and P=.725 respectively). In addition, a statistically significant median percentage difference between the two treatment groups was observed at Months 3 and 6 (P＜.001 for both periods).

Median baseline values for serum osteocalcin were

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Table 4. Adverse events

Treatment Emergent Adverse Event^a(TEAE), n (%)

Teriparatide (N=35)

Calcitonin (N=34) Patients with at least 1

TEAE Nausea Cough

Pain in extremity Headache Arthralgia Paraesthesia Constipation Contusion Dyspepsia Nasopharyngitis Productive cough Pruritus Rhinorrhoea Back pain Cataract Dizziness Flushing Hypertension Injection site pruritus Palmar erythema Vomiting

24 (68.6) 6 (17.1) 5 (14.3) 5 (14.3) 4 (11.4) 3 (8.6) 3 (8.6) 2 (5.7) 2 (5.7) 2 (5.7) 2 (5.7) 2 (5.7) 2 (5.7) 2 (5.7) 1 (2.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

29 (85.3) 14 (41.2) 2 (5.9) 1 (2.9) 7 (20.6)

2 (5.9) 1 (2.9) 2 (5.9) 1 (2.9) 1 (2.9) 1 (2.9) 1 (2.9) 1 (2.9) 0 (0.0) 2 (5.9) 2 (5.9) 4 (11.8)

3 (8.8) 2 (5.9) 2 (5.9) 2 (5.9) 6 (17.6)

aReported by at least 5% of patients from either treatment group.

13.3 ng/L and 14.2 ng/L in the teriparatide and calci- tonin treatment groups respectively. In the teriparatide treatment group, there was a median percentage increase in osteocalcin of 124% at 3 months (P＜.001) and 172% at 6 months (P＜.001) compared to base- line (Fig. 2b). In the calcitonin treatment group, there were median percentage decreases in osteocalcin of 11% at 3 months and 1.4% at 6 months that were not statistically significant (P=.361 and P=.513 respecti- vely). In addition, a statistically significant mean per- centage difference between the two treatment groups was observed at Months 3 and 6 (P＜.001 for both periods).

4. Safety

The numbers of patients experiencing at least one adverse event during the study were 33 (94%) and 32 (94%) in the teriparatide and calcitonin treatment groups respectively. At least one treatment-emergent adverse event (TEAE) was reported by 24 of the 35 patients on teriparatide (69%), compared with 29 of the 34 patients on calcitonin (85%; P=.154). Table 4 shows that the most common TEAEs reported by patients (≥5%) receiving teriparatide treatment were nausea, cough, pain in extremity, headache, arthralgia, paraesthesia, constipation, contusion, dyspepsia, naso- pharyngitis, productive cough, pruritis, and rhino- rrhoea. Of these, more patients from the calcitonin treatment group reported nausea compared with the teri- paratide treatment group (41% versus 17%; P=.036).

A total of three patients in this study reported four serious adverse events: two (5.7%) patients from the teriparatide group and one (2.9%) patient from the calcitonin group. From the teriparatide group, one patient reported pain in extremity and one patient reported pneumonia twice. From the calcitonin group, one patient reported stage II breast cancer. These events were judged by the investigators to be unrelated to the study treatment.

A total of four patients discontinued from the study early due to an adverse event: one (2.9%) from the teriparatide group and three (8.8%) from the calcitonin group (P=.614). The patient treated with teriparatide discontinued because of hypercalcaemia. From the calcitonin group, one discontinued because of head- ache, one because of nausea, and one because of vomiting. No clinically significant changes in heart rate, blood pressure, height, or weight were observed and no new fractures were reported at any time during the study.

Discussion

In the current study, subcutaneous injection of

(8)

teriparatide 20μg/day (with calcium and vitamin D supplementation) was effective in increasing lumbar spine BMD over a 6-month treatment period in postmenopausal Korean women with established osteoporosis. This is consistent with previous studies which have shown similar increases in lumbar spine BMD with teriparatide treatment in women with postmenopausal osteoporosis

^13～15

. After 6 months, teriparatide treatment has been reported to increase lumbar spine BMD by 4.5% to 5% at a dose of 20 μg/day

^16,17

. Furthermore, teriparatide has been shown to produce a 4% increase in lumbar spine BMD in men with osteoporosis

¹⁸

. In contrast, calcitonin 100 IU/day plus calcium and vitamin D over the same treatment period had no significant effect on lumbar spine BMD in the current study. This is similar to previous studies reporting that calcitonin treatment produced very little change in lumbar spine BMD at 6 months

^16,17

.

Teriparatide treatment had no statistically significant effect on total hip BMD, trochanter BMD, or femoral neck BMD, while calcitonin treatment resulted in a slight, yet statistically significant, decrease in total hip BMD. Calcitonin treatment had no statistically signi- ficant effect on trochanter or femoral neck BMD. A placebo- controlled study of teriparatide treatment in women with postmenopausal osteoporosis found that at last visit, the mean increase in total hip BMD was 2.6±4.9% which was statistically significant com- pared to placebo (P＜.001)

³

. This study was longer than the current study with a median duration of treatment of 19 months. No BMD measurements were carried out at 6 months, so it is not possible to compare the data directly to that from the current study. However, it is possible that if the current study were continued for a longer period of time, similar increases in total hip BMD measurements compared to baseline may be observed. Similarly, in another previous study, increases in femoral neck BMD associated with teriparatide treatment only reached

statistical significance at 18 months when measured at 0, 12, and 18 months

¹⁷

.

Teriparatide treatment was associated with increased levels of the biochemical markers of bone formation, BSAP and osteocalcin, as measured after 3 months and 6 months of treatment, while calcitonin did not significantly affect the levels of these bone markers.

The differing effects of teriparatide and calcitonin treatment on the levels of bone markers are consistent with the differing mechanisms of action of these com- pounds, since teriparatide stimulates osteoblasts while calcitonin inhibits osteoclasts. Decreases in the levels of biochemical markers of bone formation or bone turnover are expected with calcitonin treatment as it is known to act by decreasing bone remodelling, and has been shown to result in significantly reduced levels of BSAP and osteocalcin

⁸

. The positive changes in the levels of BSAP and osteocalcin with teriparatide treatment are consistent with previously discovered evidence that teriparatide has anabolic effects on bone. Teriparatide treatment is expected to increase formation markers to a greater extent than it would resorption markers in the first 6 months of treatment, since it is known to increase the number of bone multicellular units (BMUs) and effect a positive BMU balance (where formation is greater than resorp- tion)

^8,19

. Teriparatide treatment is also reported to be associated with increased levels of the bone turnover markers, PINP and NTx

^17,20

. Increases in the levels of both formation and resorption markers resulting from teriparatide treatment usually peak at about 6 months.

This aligns with the dramatic increases in BSAP and osteocalcin observed in the current study.

Teriparatide was well tolerated by most patients.

Study drug compliance appeared to be higher in the

group receiving teriparatide treatment than in the

group receiving calcitonin treatment and the number

of patients who completed the protocol was stati-

stically significantly higher in the teriparatide group

compared with the calcitonin group. No statistically

(9)

significant differences were found between the two treatment groups in terms of the overall incidence of TEAEs or serious adverse events (SAEs). The most common TEAE reported by all patients was nausea, and there was a statistically significant difference between the two treatment groups in the number of patients reporting this TEAE (n=6 for teriparatide, n=14 for calcitonin).

No clinically relevant changes in vital signs, height, or weight were observed in either treatment group. No new fractures were reported at any time during the study and this was probably due to the relatively short study duration as well as the fact that this data was self-reported by the patients, therefore some fractures may have gone undetected. A longer study duration would be more likely to allow a comparison between the effects of teriparatide and calcitonin on fracture incidence. The efficacy and safety results observed in this study are very similar to and consistent with previously published data for both treatments in other patient populations

^3,10,12,13

.

In conclusion, teriparatide is an effective treatment for osteoporosis in postmenopausal Korean women as measured by an increase in lumbar spine BMD as well as increases in the levels of biochemical markers of bone formation, BSAP and osteocalcin. Treatment with teriparatide was associated with a statistically significantly greater increase in lumbar spine BMD than calcitonin treatment. Both treatments were safe and well tolerated in this patient population.

Abstract

Objectives: The objectives of this study were to compare the effects of teriparatide and calcitonin treatment on changes in lumbar spine and hip bone mineral density (BMD), changes in biochemical bone markers (bone-specific alkaline phosphatase [BSAP]

and osteocalcin), and safety in postmenopausal women with established osteoporosis.

Methods: In this open-label, multicenter, controlled trial conducted in Korea, 70 postmenopausal women with osteoporosis were randomised to receive teripa- ratide 20μg/day (n=35) or calcitonin 100 IU/day (n=

35) subcutaneously for 6 months. All patients received calcium (≥500 mg/day) and vitamin D (200 to 400 IU/day) supplements throughout the study.

Results: All randomised patients were Korean, aged between 55 and 82 years (66±5 years; mean±

SD) with at least one previous fracture. From the teri- paratide group, 31 (89%) patients completed the pro- tocol compared with 23 (66%) patients from the calci- tonin group (P=.044). Lumbar spine BMD increased by 4.2±5.9% (mean±SD; P＜.001) with teriparatide treatment and by 0.6±5.5% (mean±SD; P=.555) with calcitonin treatment. The adjusted mean difference between the two treatment groups for the percent change from baseline to endpoint in lumbar spine BMD was 3.8% (95% CI: 0.94～6.57, P=0.10). Teri- paratide treatment had no statistically significant effect on the percent change in total hip (P=.658), trochanter (P=.056), or femoral neck (P=.442) BMD. Calcitonin treatment resulted in a slight yet statistically signi- ficant decrease of 2.2±4.6% (mean±SD; P=.029) in total hip BMD, while having no statistically signifi- cant effect on trochanter (P=.641) or femoral neck (P=.216) BMD. Teriparatide treatment resulted in serum levels of bone-specific alkaline phosphatase (BSAP) and osteocalcin increasing by 116% (median change, range -31 to 599%; P＜.001) and 172% (me- dian change, range -62 to 571%; P＜.001) from base- line respectively. Calcitonin treatment had no statis- tically significant effect on serum levels of BSAP or osteocalcin. From the teriparatide treatment group, 69% of patients experienced at least one treatment- emergent adverse event (TEAE) compared with 85%

from the calcitonin treatment group (P=.154). The

most common TEAE with both treatments was

nausea, and this was reported by more patients in the

calcitonin group compared with the teriparatide group

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(41% versus 17% respectively; P=.036). No clinically significant changes in laboratory values or vital signs were observed in either of the teatment groups.

Conclusion: This study shows that teriparatide is an effective treatment for osteoporosis in postmeno- pausal Korean women as measured by an increase in lumbar spine BMD as well as increases in the levels of biochemical markers of bone formation, BSAP and osteocalcin. Treatment with teriparatide produced a significantly greater increase in lumbar spine BMD than calcitonin treatment. Both treatments were safe and well tolerated in this patient population.

Key Words: Teriparatide, Calcitonin, Osteoporosis, Postmenopausal women

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