Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2013.879440
Vol. 30, No. 5, 2014, 931–936
Article FT-0436.R1/879440 All rights reserved: reproduction in whole or part not permitted
py Un t rig au fo t ht di hor r S sp ize a la d le © y, u s 20 vi e o ew p r 14 r C o an h d p ibi om In rin ted m fo rm t a . Au e si th rc aU ng or i le is al K co ed D py us is Lim fo ers tr ite rp c i b a er n d so d ut na ow io l u nl n se oa d,
Shiro Tanaka
Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan
Tatsuhiko Kuroda
Asahi Kasei Pharma Corporation, Tokyo, Japan
Toshitsugu Sugimoto
Shimane University Faculty of Medicine, Shimane, Japan
Toshitaka Nakamura
National Center for Global Health and Medicine, Tokyo, Japan
Masataka Shiraki
Research Institute and Practice for Involutional Diseases, Nagano, Japan
Address for correspondence: Masataka Shiraki MD PhD, Department of Internal Medicine, Research Institute and Practice for Involutional Diseases, 1610-1 Meisei, Misato, Azumino, Nagano 399-8101, Japan. Tel: +81 263-77-2134; Fax: +81 263-77-6963; [email protected]
No
Co
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/28/14 For personal use only.
Original article Changes in bone mineral density, bone turnover markers, and vertebral fracture risk reduction with once weekly teriparatide
Keywords: Bone mineral density – Fracture – Proportion of treatment effect – Teriparatide
Accepted: 26 December 2013; published online: 13 January 2014 Citation: Curr Med Res Opin 2014; 30:931–6
Abstract
Objective: We aimed to evaluate the surrogacy of bone mineral density and bone turnover markers for incident vertebral fracture using data from 237 patients treated with once weekly 56.5 mg teriparatide or placebo. Methods: This analysis was conducted using data from the Teriparatide Once-Weekly Efficacy Research trial, a randomized, double-blind, placebo-controlled trial for patients with severe osteoporosis in Japan. A total of 237 subjects (placebo group, n ¼ 130; teriparatide group, n ¼ 107) were assessed at baseline and at 72 weeks. Main outcome measures included estimation of the treatment effects of once weekly teriparatide on vertebral fracture risk reduction using percentage changes in lumbar bone mineral density and bone turnover markers. Results: The percentage change in lumbar bone mineral density was 6.69% in the teriparatide group compared with 0.28% in the placebo group (p50.01). One incident vertebral fracture occurred in the teriparatide group compared with 16 in the placebo group. The unadjusted and adjusted hazard ratios of the teriparatide group compared with the placebo group were 0.07 (95% confidence interval: 0.01 to 0.56) and 0.64 (95% confidence interval: 0.06 to 6.36), respectively. The proportion of treatment effect explained by changes in lumbar bone mineral density was 83% (Freedman’s method) and 66% (Chen’s method). There were no notable changes in hazard ratios if we adjusted for bone turnover markers. Conclusions: Most of the vertebral fracture risk reduction with once weekly 56.5 mg teriparatide is explained by changes in lumbar bone mineral density rather than changes in bone turnover markers.
Introduction Bone mineral density (BMD) is the major risk factor for fracture in patients with osteoporosis1. Changes in BMD are a potential surrogate marker for fracture endpoints in clinical trials, and using BMD values reduces costs and accelerates the pace of drug development2. Changes in BMD are also used as a treatment goal for osteoporosis3. The surrogacy of BMD for anti-fracture efficacy has been intensively investigated in patients treated by antiresorptive agents4–8, although results are conflicting. Therefore, the surrogacy of each drug should be investigated individually. However, little is known about the use of BMD as a surrogate endpoint in patients treated with teriparatide. To our knowledge, only the
! 2014 Informa UK Ltd www.cmrojournal.com
Weekly teriparatide treatment effect proportion explained Tanaka et al.
931
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/28/14 For personal use only.
Current Medical Research & Opinion Volume 30, Number 5
May 2014
Fracture Prevention Trial performed a posthoc analysis that showed that increases in lumbar BMD after daily teriparatide accounted for 30% to 41% of the observed reduction in the risk of vertebral fracture9. Some researchers have explored non-BMD determinants of fracture risk that explain the remaining fracture risk reduction, such as levels of type I collagen cross-linked N-telopeptides (NTX) and type I collagen cross-linked C-telopeptides (CTX)10–12. Once weekly 56.5 mg teriparatide (human PTH 1-34) was shown to be efficacious for increasing lumbar BMD by 6.7% at 72 weeks and reducing the risk of vertebral fracture by 80% in postmenopausal women and elderly men with osteoporosis in the Teriparatide Once-Weekly Efficacy Research (TOWER) trial13. In this analysis, we aimed to evaluate the surrogacy of BMD and bone turnover markers for vertebral fracture using data from 237 patients from the TOWER trial. Bone turnover markers included serum levels of bone alkaline phosphatase (BAP), osteocalcin, procollagen type 1 amino-terminal propeptide (P1NP), and urinary levels of NTX.
Patients and methods Ethics statement This analysis was conducted with data from the TOWER trial, which was a randomized, multicenter, double-blind, placebo-controlled trial in Japan13. The protocol of the TOWER trial was approved by the Institutional Review Boards at each participating institution and was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice (GCP). Written informed consent was obtained from all participants prior to their participation in the study.
Patients and intervention The original eligibility criteria of the TOWER trial included men and postmenopausal women between 65 and 91 years of age with primary osteoporosis, who had up to five prevalent vertebral fractures, and low BMD (T-score51.67) at the lumbar spine (L2 to L4), femoral neck, total hip, or distal radius. Patients were randomly assigned to receive weekly subcutaneous injections of placebo (n ¼ 290) or 56.5 mg of teriparatide (n ¼ 288) for 72 weeks. All patients received daily oral supplements of calcium 610 mg, vitamin D 400 IU, and magnesium 30 mg. A total of 237 patients were included in this analysis after excluding patients whose measurements of lumbar BMD at baseline and end of study were not available. 932
Weekly teriparatide treatment effect proportion explained Tanaka et al.
Data collection At baseline, age, height, weight, and vertebral fracture number and grade were investigated. The lumbar spine BMD was measured at baseline and end of the study using dual-energy x-ray absorptiometry (DXA) with QDR (Hologic, Bedford, MA, USA) or DPX (GE Healthcare, Fairfield, CT, USA). A central facility performed quality assurance of the longitudinal adjustment by calibrating each machine with standardized phantoms. All DXA measurements were analyzed at a central site by a radiologist blinded to treatment group assignment. Serum and urine samples were obtained under nonfasting conditions at baseline and at 4, 12, 24, 48, and 72 weeks. Bone turnover markers were measured centrally in a single batch at a validated institution (Mitsubishi Chemical Medience, Tokyo, Japan). Serum levels of osteocalcin were measured with an immunoradiometric assay (BGP-IRMA Mitsubishi; Mitsubishi Chemical Medience); P1NP was measured by RIA (Orion Diagnostica, Espoo, Finland); NTX was measured with an enzyme-linked immunoassay (Osteomark; Inverness Medical Innovations Inc., Waltham, MA, USA). The coefficients of variation for DXA and details of other data collection and methods of bone turnover markers appear in the original trial publication13. Vertebral fracture from Th4 to L4 was defined by a semi-quantitative and quantitative morphometric method using X-ray films of the thoracic and lumbar spine taken at baseline, 24, 48, and 72 weeks14. The assessment of incident vertebral fractures was conducted by an independent committee of three experts who were blinded to treatment. Incident vertebral fracture was defined as a vertebral fracture that was normal (semi-quantitative grade 0) at baseline of the original trial.
Statistical analysis The primary endpoint was time from randomization to incidence of new, radiographically confirmed vertebral fractures (Th4 to L4). Hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of vertebral fracture were estimated by Cox regression. We evaluated the association between vertebral fracture and changes in BMD and bone turnover markers using two statistical criteria for surrogate endpoints, namely Freedman’s proportion of treatment effect explained (PTE)15 and Chen’s PTE9. Freedman’s PTE is defined as PTE ¼ 1 / , where is a log HR for treatment effect adjusted for surrogates and is a log HR for treatment effect unadjusted for surrogates. Chen’s PTE is defined as (A B)/(A C), where A is the fracture risk of patients in the placebo group with a change in lumbar BMD observed in the placebo group at 72 weeks, B is the fracture risk of patients in the placebo group with a change in lumbar BMD observed in www.cmrojournal.com ! 2014 Informa UK Ltd
Current Medical Research & Opinion Volume 30, Number 5 May 2014
Table 1. Baseline characteristics of 237 patients with osteoporosis.
PTE = (A-B)/(A-C) = 66%
Placebo group (n ¼ 130)
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/28/14 For personal use only.
Risk of vetebral fracture
0.15
0.10
0.05
Age (years) Men (number [%]) Body mass index (kg/m2) Lumbar BMD (g/cm2) Serum BAP (U/L) Serum osteocalcin (ng/mL) Serum PINP (ng/mL) Serum NTX (nmol BCE/L) Urinary NTX (nmol BCE/mmol Cr)
A B C
0.00 −5
0
5
10
Percent change in lumbar BMD
Figure 1. Proportion of treatment effect explained by Chen’s method. Solid line: teriparatide group; dashed line: placebo group. Proportion of treatment effect explained (PTE) is defined by (A B)/(A C)8. A: The fracture risk of patients in the placebo group with a change in lumbar bone mineral density (BMD) of placebo group level at 72 weeks. B: The fracture risk of patients in the placebo group with a change in lumbar BMD of teriparatide group level at 72 weeks. C: The fracture risk of patients in the teriparatide group with a change in lumbar BMD of teriparatide group level at 72 weeks.
the teriparatide group at 72 weeks, and C is the fracture risk of patients in the teriparatide group with a change in lumbar BMD observed in the teriparatide group at 72 weeks, respectively (Figure 1). The vertebral fracture risks at the three points (A, B, and C) were estimated as a spline function, a smooth curve of vertebral fracture risk depending on percentage change in lumbar BMD using generalized additive models. All p-values were two-sided, and the significance level was 0.05. All statistical analyses and data management were conducted at a central data center using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA).
Results There were no significant differences in age, body mass index, BMD, and bone turnover markers between groups (Table 1). Longitudinal profiles of BMD and bone markers in percentage change from baseline at 4, 12, 24, 48, and 72 weeks are presented in Figure 2. BMD increased from 0.709 0.123 at baseline to 0.755 0.133 g/cm2 at 72 weeks in the teriparatide group, representing a 6.69% increase. In the placebo group, BMD increased from 0.721 0.117 at baseline to 0.724 0.128 g/cm2 at 72 weeks, representing a 0.28% increase. Differences between treatment groups were significantly different (p50.01). Serum BAP decreased from 33.9 12.9 to ! 2014 Informa UK Ltd www.cmrojournal.com
Teriparatide group (n ¼ 107)
Mean
SD
Mean
SD
74.7 6 23.1 0.721 32.9 8.0
5.6 [5.6%] 3.2 0.117 11.6 3.3
74.4 4 23.1 0.709 33.9 7.7
5.5 [5.6%] 3.2 0.123 12.9 2.6
51.7 13.7 41.4
1.8 5.3 23.3
52.5 13.5 42.9
2.4 4.8 21.5
BMD, bone mineral density; BAP, bone specific alkaline phosphatase; P1NP, procollagen type 1 amino-terminal propeptide; NTX, type I collagen crosslinked N-telopeptides.
24.8 7.8 U/L in the teriparatide group and 32.9 11.6 to 27.4 8.8 U/L in the placebo group (p50.01). Serum P1NP decreased from 52.5 25.1 to 38.5 18.1 ng/mL in the teriparatide group and 51.7 20.8 to 45.6 20.0 ng/mL in the placebo group (p50.01). Serum osteocalcin decreased from 7.69 2.60 to 7.56 2.37 ng/mL in the teriparatide group and 8.02 3.30 to 7.62 2.73 ng/mL in the placebo group (p ¼ 0.79). Urinary NTX decreased from 42.9 21.5 to 35.4 18.2 nmolBCE/mmolCr in the teriparatide group and increased from 41.4 23.3 to 47.8 25.4 nmolBCE/ mmolCr in the placebo group (p50.01). Serum NTX increased from 13.5 4.8 to 15.4 6.3 nmolBCE/L in the teriparatide group and 13.7 5.3 to 17.3 6.6 nmolBCE/L in the placebo group (p50.01). During a follow-up of 72 weeks, one incident vertebral fracture was observed in the teriparatide group and 16 incident vertebral fractures were observed in the placebo group. The HR of the teriparatide group compared with the placebo group was 0.07 (95% CI: 0.01 to 0.56, p ¼ 0.01). Table 2 shows the HRs of teriparatide unadjusted and adjusted for percentage change in BMD at the lumbar spine and the criteria for surrogacy using Freedman’s PTE. As shown, the unadjusted and adjusted HRs were 0.07 (95% CI: 0.01 to 0.56) and 0.64 (95% CI: 0.06 to 6.36), respectively. Freedman’s PTE was 83%, indicating that most of the effects of teriparatide for fracture risk reduction were explained by the percentage change in lumbar BMD. The results were similar if we used absolute changes in lumbar BMD (Freedman’s PTE ¼ 76%). Figure 1 shows the spline curves for vertebral fracture risks according to treatment groups estimated by generalized additive models. The vertebral fracture risk in the teriparatide group was consistently low, whereas that in Weekly teriparatide treatment effect proportion explained Tanaka et al.
933
Current Medical Research & Opinion Volume 30, Number 5
Teriparatide
May 2014
Placebo
Placebo
Teriparatide
Teriparatide
(B) 20
(A) 10
Placebo
(C) 40
6 4 2
% Serum P1NP
% Serum BAP
% Lumbar BMD
8 0
−20
20
0
−20
0
0
24
48
−40
72
0 4 12
24
(Weeks) Teriparatide
48
−40
72
Teriparatide
0
48 (Weeks)
72
20 0
−40
Placebo
40
20
0
−20 −20
72
(F) 60
% Serum NTX
% Urinary NTX
20
48
Teriparatide
Placebo
40
24
24
(Weeks)
(E) 60
0 4 12
0 4 12
(Weeks) Placebo
(D) 40
% Serum osteocalcin
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/28/14 For personal use only.
−2
0 4 12
24
48 (Weeks)
−20
72
0 4 12
24 48 (Weeks)
72
Figure 2. Changes by group from baseline to 72 weeks in lumbar BMD and bone turnover markers. Solid lines: teriparatide group; dashed lines: placebo group. (A) BMD; (B) bone-specific alkaline phosphatase (BAP); (C), procollagen type 1 amino-terminal propeptide (P1NP); (D) osteocalcin; (E) and (F), type I collagen cross-linked N-telopeptides (NTX). Table 2. Proportion of treatment effect explained by lumbar BMD. Unadjusted HR Teriparatide vs. placebo Change in lumbar BMD per 5% PTE*
0.07
95% CI 0.01
0.56
Adjusted for lumbar BMD p
HR
0.01
0.64 0.32
95% CI 0.06 0.13
p 6.36 0.77
0.70 0.01
83%
HR, hazard ratio; CI, confidence interval; BMD, bone mineral density; PTE, proportion of treatment effect explained. *PTE was calculated as one minus log adjusted hazard ratio for treatment divided by log unadjusted hazard ratio for treatment.
the placebo group decreased as the percentage change in lumbar BMD increased. The vertebral fracture risks at the three points were A ¼ 0.04, B ¼ 0.0135, C ¼ 0.00, respectively (Chen’s PTE ¼ 66%). On the other hand, adjustment for each bone marker alone instead of BMD did not increase the HRs of teriparatide toward null, yielding PTEs for bone markers of approximately 0%. Table 3 shows the HRs of teriparatide further adjusted for bone markers and Freedman’s PTEs for each adjustment factor. The HR of teriparatide increased from 0.64 (Table 2) to 0.83 (Table 3) if we adjusted for serum P1NP additionally, and Freedman’s PTE increased from 83% to 93%. There 934
Weekly teriparatide treatment effect proportion explained Tanaka et al.
were no notable changes in HRs for other bone turnover markers.
Discussion Changes in BMD are a potential surrogate marker for antifracture efficacy in long-term treatment of osteoporosis. Because the surrogacies of change in BMD to anti-fracture efficacy differ by drug4–8, the relationship should be evaluated in each drug. www.cmrojournal.com ! 2014 Informa UK Ltd
Current Medical Research & Opinion Volume 30, Number 5 May 2014
Table 3. Proportion of treatment effect explained by combinations of lumbar BMD and bone markers. Serum BAP HR Teriparatide vs. placebo Change in lumbar BMD per 5% Change in bone markers per 5% PTE*
0.73 0.18 0.76
95% CI 0.07 0.06 0.62
7.57 0.54 0.93
Serum osteocalcin p
HR
0.79 50.01 0.01
0.65 0.31 1.00
0.83 0.18 0.89
95% CI 0.08 0.06 0.79
p 6.57 0.78 1.06
0.72 0.01 0.90
84%
Serum P1NP
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/28/14 For personal use only.
0.06 0.12 0.93
88%
HR Teriparatide vs. placebo Change in lumbar BMD per 5% Change in bone markers per 5% PTE*
95% CI
8.47 0.57 1.01
Urinary NTX p
HR
0.97 50.01 0.07
0.51 0.28 0.96
93%
95% CI 0.05 0.11 0.90
p 4.93 0.70 1.03
0.56 0.01 0.27
74%
BMD, bone mineral density; BAP, bone specific alkaline phosphatase; HR, hazard ratio; CI, confidence interval; PTE, proportion of treatment effect explained; P1NP, procollagen type 1 amino-terminal propeptide; NTX, type I collagen cross-linked N-telopeptides. *Four separate bivariate Cox regression models were fitted to each combination of BMD and bone markers. PTEs were calculated as one minus log adjusted hazard ratio for treatment divided by log unadjusted hazard ratio for treatment.
The current analysis of data from a randomized placebocontrolled trial in Japan demonstrated that most of the vertebral fracture risk reduction by once weekly 56.5 mg teriparatide is explained by the change in lumbar BMD: 83% using Freedman’s method and 66% using Chen’s method. These estimates for PTE at the vertebra are not only higher than those seen in a previous study using antiresorptive agents such as alendronate (16%)6 or risedronate (18%)16 but are also higher than with strontium (no significant association)8 or with daily teriparatide (30 to 41%)9. The major difference between the current study and previous studies of patients treated with teriparatide9,13,17 is the dose and schedule (once weekly 56.5 mg vs. daily 20 mg). Another difference between these studies is in the patients’ characteristics, that is, the TOWER trial comprised Japanese patients with a mean age and BMI of 76 years and 23 kg/m2, respectively, while the previous study was conducted mainly with Western patients who were slightly younger and more obese. Furthermore, the relative risk for once weekly 56.5 mg teriparatide treatment observed in the TOWER trial was 0.20, which is lower than that seen with 20 mg teriparatide daily (RR ¼ 0.47), alendronate (RR ¼ 0.52), or risedronate (RR ¼ 0.64)17–20. These factors have the potential to influence the relationship between change in lumbar BMD and vertebral fracture risk reduction. Moreover, once weekly teriparatide administration is associated not only with an increase in BMD but with improved bone material properties and collagen deterioration, as observed in ovariectomized monkeys21. The bone quality improvements produced by new bone with once weekly teriparatide may contribute to a higher correlation of fracture reduction. The explained values adjusted for bone formation markers (P1NP and BAP) only slightly increased the PTE ! 2014 Informa UK Ltd www.cmrojournal.com
value from the change of BMD. It was reported that greater reductions of bone turnover markers in response to bisphosphonate treatment were associated with a lower risk of spinal, hip, and non-spinal fractures12, but the relationship between changes in bone turnover markers and fracture risk reduction has not been seen with bone formation agents such as teriparatide. Changes in bone turnover markers with teriparatide may not contribute to fracture risk reduction. Several limitations warrant mention. First, in the original TOWER trial, a total of 542 participants were evaluated for fracture incidence, and incident vertebral fracture occurred in seven cases (2.7%, 7/261) in the teriparatide group and 37 cases (13.2%, 37/281) in the placebo group. However, not all study sites measured BMD using DXA. Therefore, the number of participants in this analysis was limited. Second, the PTE value to incident hip fracture was not evaluated in this analysis. In the original TOWER trial, only one hip fracture in the teriparatide group and three hip fractures in the placebo group were observed, although measurement of BMD by DXA was not carried out in sites where fractures were observed.
Conclusion We conclude that most of the vertebral fracture risk reduction by once weekly 56.5 mg teriparatide is explained by the change in lumbar BMD.
Transparency Declaration of funding This study was supported by the Asahi Kasei Pharma Corporation.
Weekly teriparatide treatment effect proportion explained Tanaka et al.
935
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/28/14 For personal use only.
Current Medical Research & Opinion Volume 30, Number 5
May 2014
Declaration of financial/other relationships S.T. received a research grant from Asahi Kasei Pharma Corporation. T.K. is an employee of Asahi Kasei Pharma Corporation. T.S. received research grants and consulting fees from the following pharmaceutical companies: Asahi Kasei Pharma and Daiichi Sankyo. T.N. received research grants and/or consulting fees from the following pharmaceutical companies: Chugai, Teijin, Asahi Kasei Pharma, and Daiichi Sankyo. M.S. received consulting fees from the following pharmaceutical companies: Chugai, Daiichi Sankyo, Asahi Kasei Pharma, Teijin, and MSD. CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.
References 1. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996;312:1254-9 2. Khosla S. Surrogates for fracture endpoints in clinical trials. J Bone Miner Res 2003;18:1146-9 3. Cummings SR, Cosman F, Eastell R, et al. Goal-directed treatment of osteoporosis. J Bone Miner Res 2013;28:433-8 4. Hochberg MC, Ross PD, Black D, et al. Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Fracture Intervention Trial Research Group. Arthritis Rheum 1999;42:1246-54 5. Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive agents is related to changes in bone density. J Clin Endocrinol Metab 2000;85:231-6 6. Cummings SR, Karpf DB, Harris F, et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med 2002;112:281-9 7. Sarkar S, Mitlak BH, Wong M, et al. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res 2002;17:1-10 8. Bruyere O, Roux C, Detilleux J, et al. Relationship between bone mineral density changes and fracture risk reduction in patients treated with strontium ranelate. J Clin Endocrinol Metab 2007;92:3076-81 9. Chen P, Miller PD, Delmas PD, et al. Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatide-treated postmenopausal women with osteoporosis. J Bone Miner Res 2006;21:1785-90
936
Weekly teriparatide treatment effect proportion explained Tanaka et al.
10. Eastell R, Barton I, Hannon RA, et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res 2003;18:1051-6 11. Sarkar S, Reginster JY, Crans GG, et al. Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res 2004;19:394-401 12. Bauer DC, Black DM, Garnero P, et al. Change in bone turnover and hip, nonspine, and vertebral fracture in alendronate-treated women: The Fracture Intervention Trial. J Bone Miner Res 2004;19:1250-8 13. Nakamura T, Sugimoto T, Nakano T, et al. Randomized Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk. J Clin Endocrinol Metab 2012;97:3097-106 14. Genant HK, Jergas M, Palermo L, et al. Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis. J Bone Miner Res 1996;11:984-6 15. Freedman LS, Graubard BI, Schatzkin A. Statistical validation of intermediate endpoints for chronic diseases. Stat Med 1992;11:167-78 16. Watts NB, Cooper C, Lindsay R, et al. Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom 2004;7:255-61 17. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41 18. Miyauchi A, Matsumoto T, Sugimoto T, et al. Effects of teriparatide on bone mineral density and bone turnover markers in Japanese subjects with osteoporosis at high risk of fracture in a 24-month clinical study: 12-month, randomized, placebo-controlled, double-blind and 12-month open-label phases. Bone 2010;47:493-502 19. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: The Fracture Intervention Trial. J Clin Endocrinol Metab 2000;85:4118-24 20. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 1999;282:1344-52 21. Saito M, Marumo K, Kida Y, et al. Changes in the contents of enzymatic immature, mature, and non-enzymatic senescent cross-links of collagen after once-weekly treatment with human parathyroid hormone (1-34) for 18 months contribute to improvement of bone strength in ovariectomized monkeys. Osteoporos Int 2010;22:2373-83
www.cmrojournal.com ! 2014 Informa UK Ltd
Vol. 30, No. 5, 2014, 931–936
Article FT-0436.R1/879440 All rights reserved: reproduction in whole or part not permitted
py Un t rig au fo t ht di hor r S sp ize a la d le © y, u s 20 vi e o ew p r 14 r C o an h d p ibi om In rin ted m fo rm t a . Au e si th rc aU ng or i le is al K co ed D py us is Lim fo ers tr ite rp c i b a er n d so d ut na ow io l u nl n se oa d,
Shiro Tanaka
Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan
Tatsuhiko Kuroda
Asahi Kasei Pharma Corporation, Tokyo, Japan
Toshitsugu Sugimoto
Shimane University Faculty of Medicine, Shimane, Japan
Toshitaka Nakamura
National Center for Global Health and Medicine, Tokyo, Japan
Masataka Shiraki
Research Institute and Practice for Involutional Diseases, Nagano, Japan
Address for correspondence: Masataka Shiraki MD PhD, Department of Internal Medicine, Research Institute and Practice for Involutional Diseases, 1610-1 Meisei, Misato, Azumino, Nagano 399-8101, Japan. Tel: +81 263-77-2134; Fax: +81 263-77-6963; [email protected]
No
Co
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/28/14 For personal use only.
Original article Changes in bone mineral density, bone turnover markers, and vertebral fracture risk reduction with once weekly teriparatide
Keywords: Bone mineral density – Fracture – Proportion of treatment effect – Teriparatide
Accepted: 26 December 2013; published online: 13 January 2014 Citation: Curr Med Res Opin 2014; 30:931–6
Abstract
Objective: We aimed to evaluate the surrogacy of bone mineral density and bone turnover markers for incident vertebral fracture using data from 237 patients treated with once weekly 56.5 mg teriparatide or placebo. Methods: This analysis was conducted using data from the Teriparatide Once-Weekly Efficacy Research trial, a randomized, double-blind, placebo-controlled trial for patients with severe osteoporosis in Japan. A total of 237 subjects (placebo group, n ¼ 130; teriparatide group, n ¼ 107) were assessed at baseline and at 72 weeks. Main outcome measures included estimation of the treatment effects of once weekly teriparatide on vertebral fracture risk reduction using percentage changes in lumbar bone mineral density and bone turnover markers. Results: The percentage change in lumbar bone mineral density was 6.69% in the teriparatide group compared with 0.28% in the placebo group (p50.01). One incident vertebral fracture occurred in the teriparatide group compared with 16 in the placebo group. The unadjusted and adjusted hazard ratios of the teriparatide group compared with the placebo group were 0.07 (95% confidence interval: 0.01 to 0.56) and 0.64 (95% confidence interval: 0.06 to 6.36), respectively. The proportion of treatment effect explained by changes in lumbar bone mineral density was 83% (Freedman’s method) and 66% (Chen’s method). There were no notable changes in hazard ratios if we adjusted for bone turnover markers. Conclusions: Most of the vertebral fracture risk reduction with once weekly 56.5 mg teriparatide is explained by changes in lumbar bone mineral density rather than changes in bone turnover markers.
Introduction Bone mineral density (BMD) is the major risk factor for fracture in patients with osteoporosis1. Changes in BMD are a potential surrogate marker for fracture endpoints in clinical trials, and using BMD values reduces costs and accelerates the pace of drug development2. Changes in BMD are also used as a treatment goal for osteoporosis3. The surrogacy of BMD for anti-fracture efficacy has been intensively investigated in patients treated by antiresorptive agents4–8, although results are conflicting. Therefore, the surrogacy of each drug should be investigated individually. However, little is known about the use of BMD as a surrogate endpoint in patients treated with teriparatide. To our knowledge, only the
! 2014 Informa UK Ltd www.cmrojournal.com
Weekly teriparatide treatment effect proportion explained Tanaka et al.
931
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/28/14 For personal use only.
Current Medical Research & Opinion Volume 30, Number 5
May 2014
Fracture Prevention Trial performed a posthoc analysis that showed that increases in lumbar BMD after daily teriparatide accounted for 30% to 41% of the observed reduction in the risk of vertebral fracture9. Some researchers have explored non-BMD determinants of fracture risk that explain the remaining fracture risk reduction, such as levels of type I collagen cross-linked N-telopeptides (NTX) and type I collagen cross-linked C-telopeptides (CTX)10–12. Once weekly 56.5 mg teriparatide (human PTH 1-34) was shown to be efficacious for increasing lumbar BMD by 6.7% at 72 weeks and reducing the risk of vertebral fracture by 80% in postmenopausal women and elderly men with osteoporosis in the Teriparatide Once-Weekly Efficacy Research (TOWER) trial13. In this analysis, we aimed to evaluate the surrogacy of BMD and bone turnover markers for vertebral fracture using data from 237 patients from the TOWER trial. Bone turnover markers included serum levels of bone alkaline phosphatase (BAP), osteocalcin, procollagen type 1 amino-terminal propeptide (P1NP), and urinary levels of NTX.
Patients and methods Ethics statement This analysis was conducted with data from the TOWER trial, which was a randomized, multicenter, double-blind, placebo-controlled trial in Japan13. The protocol of the TOWER trial was approved by the Institutional Review Boards at each participating institution and was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice (GCP). Written informed consent was obtained from all participants prior to their participation in the study.
Patients and intervention The original eligibility criteria of the TOWER trial included men and postmenopausal women between 65 and 91 years of age with primary osteoporosis, who had up to five prevalent vertebral fractures, and low BMD (T-score51.67) at the lumbar spine (L2 to L4), femoral neck, total hip, or distal radius. Patients were randomly assigned to receive weekly subcutaneous injections of placebo (n ¼ 290) or 56.5 mg of teriparatide (n ¼ 288) for 72 weeks. All patients received daily oral supplements of calcium 610 mg, vitamin D 400 IU, and magnesium 30 mg. A total of 237 patients were included in this analysis after excluding patients whose measurements of lumbar BMD at baseline and end of study were not available. 932
Weekly teriparatide treatment effect proportion explained Tanaka et al.
Data collection At baseline, age, height, weight, and vertebral fracture number and grade were investigated. The lumbar spine BMD was measured at baseline and end of the study using dual-energy x-ray absorptiometry (DXA) with QDR (Hologic, Bedford, MA, USA) or DPX (GE Healthcare, Fairfield, CT, USA). A central facility performed quality assurance of the longitudinal adjustment by calibrating each machine with standardized phantoms. All DXA measurements were analyzed at a central site by a radiologist blinded to treatment group assignment. Serum and urine samples were obtained under nonfasting conditions at baseline and at 4, 12, 24, 48, and 72 weeks. Bone turnover markers were measured centrally in a single batch at a validated institution (Mitsubishi Chemical Medience, Tokyo, Japan). Serum levels of osteocalcin were measured with an immunoradiometric assay (BGP-IRMA Mitsubishi; Mitsubishi Chemical Medience); P1NP was measured by RIA (Orion Diagnostica, Espoo, Finland); NTX was measured with an enzyme-linked immunoassay (Osteomark; Inverness Medical Innovations Inc., Waltham, MA, USA). The coefficients of variation for DXA and details of other data collection and methods of bone turnover markers appear in the original trial publication13. Vertebral fracture from Th4 to L4 was defined by a semi-quantitative and quantitative morphometric method using X-ray films of the thoracic and lumbar spine taken at baseline, 24, 48, and 72 weeks14. The assessment of incident vertebral fractures was conducted by an independent committee of three experts who were blinded to treatment. Incident vertebral fracture was defined as a vertebral fracture that was normal (semi-quantitative grade 0) at baseline of the original trial.
Statistical analysis The primary endpoint was time from randomization to incidence of new, radiographically confirmed vertebral fractures (Th4 to L4). Hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of vertebral fracture were estimated by Cox regression. We evaluated the association between vertebral fracture and changes in BMD and bone turnover markers using two statistical criteria for surrogate endpoints, namely Freedman’s proportion of treatment effect explained (PTE)15 and Chen’s PTE9. Freedman’s PTE is defined as PTE ¼ 1 / , where is a log HR for treatment effect adjusted for surrogates and is a log HR for treatment effect unadjusted for surrogates. Chen’s PTE is defined as (A B)/(A C), where A is the fracture risk of patients in the placebo group with a change in lumbar BMD observed in the placebo group at 72 weeks, B is the fracture risk of patients in the placebo group with a change in lumbar BMD observed in www.cmrojournal.com ! 2014 Informa UK Ltd
Current Medical Research & Opinion Volume 30, Number 5 May 2014
Table 1. Baseline characteristics of 237 patients with osteoporosis.
PTE = (A-B)/(A-C) = 66%
Placebo group (n ¼ 130)
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/28/14 For personal use only.
Risk of vetebral fracture
0.15
0.10
0.05
Age (years) Men (number [%]) Body mass index (kg/m2) Lumbar BMD (g/cm2) Serum BAP (U/L) Serum osteocalcin (ng/mL) Serum PINP (ng/mL) Serum NTX (nmol BCE/L) Urinary NTX (nmol BCE/mmol Cr)
A B C
0.00 −5
0
5
10
Percent change in lumbar BMD
Figure 1. Proportion of treatment effect explained by Chen’s method. Solid line: teriparatide group; dashed line: placebo group. Proportion of treatment effect explained (PTE) is defined by (A B)/(A C)8. A: The fracture risk of patients in the placebo group with a change in lumbar bone mineral density (BMD) of placebo group level at 72 weeks. B: The fracture risk of patients in the placebo group with a change in lumbar BMD of teriparatide group level at 72 weeks. C: The fracture risk of patients in the teriparatide group with a change in lumbar BMD of teriparatide group level at 72 weeks.
the teriparatide group at 72 weeks, and C is the fracture risk of patients in the teriparatide group with a change in lumbar BMD observed in the teriparatide group at 72 weeks, respectively (Figure 1). The vertebral fracture risks at the three points (A, B, and C) were estimated as a spline function, a smooth curve of vertebral fracture risk depending on percentage change in lumbar BMD using generalized additive models. All p-values were two-sided, and the significance level was 0.05. All statistical analyses and data management were conducted at a central data center using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA).
Results There were no significant differences in age, body mass index, BMD, and bone turnover markers between groups (Table 1). Longitudinal profiles of BMD and bone markers in percentage change from baseline at 4, 12, 24, 48, and 72 weeks are presented in Figure 2. BMD increased from 0.709 0.123 at baseline to 0.755 0.133 g/cm2 at 72 weeks in the teriparatide group, representing a 6.69% increase. In the placebo group, BMD increased from 0.721 0.117 at baseline to 0.724 0.128 g/cm2 at 72 weeks, representing a 0.28% increase. Differences between treatment groups were significantly different (p50.01). Serum BAP decreased from 33.9 12.9 to ! 2014 Informa UK Ltd www.cmrojournal.com
Teriparatide group (n ¼ 107)
Mean
SD
Mean
SD
74.7 6 23.1 0.721 32.9 8.0
5.6 [5.6%] 3.2 0.117 11.6 3.3
74.4 4 23.1 0.709 33.9 7.7
5.5 [5.6%] 3.2 0.123 12.9 2.6
51.7 13.7 41.4
1.8 5.3 23.3
52.5 13.5 42.9
2.4 4.8 21.5
BMD, bone mineral density; BAP, bone specific alkaline phosphatase; P1NP, procollagen type 1 amino-terminal propeptide; NTX, type I collagen crosslinked N-telopeptides.
24.8 7.8 U/L in the teriparatide group and 32.9 11.6 to 27.4 8.8 U/L in the placebo group (p50.01). Serum P1NP decreased from 52.5 25.1 to 38.5 18.1 ng/mL in the teriparatide group and 51.7 20.8 to 45.6 20.0 ng/mL in the placebo group (p50.01). Serum osteocalcin decreased from 7.69 2.60 to 7.56 2.37 ng/mL in the teriparatide group and 8.02 3.30 to 7.62 2.73 ng/mL in the placebo group (p ¼ 0.79). Urinary NTX decreased from 42.9 21.5 to 35.4 18.2 nmolBCE/mmolCr in the teriparatide group and increased from 41.4 23.3 to 47.8 25.4 nmolBCE/ mmolCr in the placebo group (p50.01). Serum NTX increased from 13.5 4.8 to 15.4 6.3 nmolBCE/L in the teriparatide group and 13.7 5.3 to 17.3 6.6 nmolBCE/L in the placebo group (p50.01). During a follow-up of 72 weeks, one incident vertebral fracture was observed in the teriparatide group and 16 incident vertebral fractures were observed in the placebo group. The HR of the teriparatide group compared with the placebo group was 0.07 (95% CI: 0.01 to 0.56, p ¼ 0.01). Table 2 shows the HRs of teriparatide unadjusted and adjusted for percentage change in BMD at the lumbar spine and the criteria for surrogacy using Freedman’s PTE. As shown, the unadjusted and adjusted HRs were 0.07 (95% CI: 0.01 to 0.56) and 0.64 (95% CI: 0.06 to 6.36), respectively. Freedman’s PTE was 83%, indicating that most of the effects of teriparatide for fracture risk reduction were explained by the percentage change in lumbar BMD. The results were similar if we used absolute changes in lumbar BMD (Freedman’s PTE ¼ 76%). Figure 1 shows the spline curves for vertebral fracture risks according to treatment groups estimated by generalized additive models. The vertebral fracture risk in the teriparatide group was consistently low, whereas that in Weekly teriparatide treatment effect proportion explained Tanaka et al.
933
Current Medical Research & Opinion Volume 30, Number 5
Teriparatide
May 2014
Placebo
Placebo
Teriparatide
Teriparatide
(B) 20
(A) 10
Placebo
(C) 40
6 4 2
% Serum P1NP
% Serum BAP
% Lumbar BMD
8 0
−20
20
0
−20
0
0
24
48
−40
72
0 4 12
24
(Weeks) Teriparatide
48
−40
72
Teriparatide
0
48 (Weeks)
72
20 0
−40
Placebo
40
20
0
−20 −20
72
(F) 60
% Serum NTX
% Urinary NTX
20
48
Teriparatide
Placebo
40
24
24
(Weeks)
(E) 60
0 4 12
0 4 12
(Weeks) Placebo
(D) 40
% Serum osteocalcin
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/28/14 For personal use only.
−2
0 4 12
24
48 (Weeks)
−20
72
0 4 12
24 48 (Weeks)
72
Figure 2. Changes by group from baseline to 72 weeks in lumbar BMD and bone turnover markers. Solid lines: teriparatide group; dashed lines: placebo group. (A) BMD; (B) bone-specific alkaline phosphatase (BAP); (C), procollagen type 1 amino-terminal propeptide (P1NP); (D) osteocalcin; (E) and (F), type I collagen cross-linked N-telopeptides (NTX). Table 2. Proportion of treatment effect explained by lumbar BMD. Unadjusted HR Teriparatide vs. placebo Change in lumbar BMD per 5% PTE*
0.07
95% CI 0.01
0.56
Adjusted for lumbar BMD p
HR
0.01
0.64 0.32
95% CI 0.06 0.13
p 6.36 0.77
0.70 0.01
83%
HR, hazard ratio; CI, confidence interval; BMD, bone mineral density; PTE, proportion of treatment effect explained. *PTE was calculated as one minus log adjusted hazard ratio for treatment divided by log unadjusted hazard ratio for treatment.
the placebo group decreased as the percentage change in lumbar BMD increased. The vertebral fracture risks at the three points were A ¼ 0.04, B ¼ 0.0135, C ¼ 0.00, respectively (Chen’s PTE ¼ 66%). On the other hand, adjustment for each bone marker alone instead of BMD did not increase the HRs of teriparatide toward null, yielding PTEs for bone markers of approximately 0%. Table 3 shows the HRs of teriparatide further adjusted for bone markers and Freedman’s PTEs for each adjustment factor. The HR of teriparatide increased from 0.64 (Table 2) to 0.83 (Table 3) if we adjusted for serum P1NP additionally, and Freedman’s PTE increased from 83% to 93%. There 934
Weekly teriparatide treatment effect proportion explained Tanaka et al.
were no notable changes in HRs for other bone turnover markers.
Discussion Changes in BMD are a potential surrogate marker for antifracture efficacy in long-term treatment of osteoporosis. Because the surrogacies of change in BMD to anti-fracture efficacy differ by drug4–8, the relationship should be evaluated in each drug. www.cmrojournal.com ! 2014 Informa UK Ltd
Current Medical Research & Opinion Volume 30, Number 5 May 2014
Table 3. Proportion of treatment effect explained by combinations of lumbar BMD and bone markers. Serum BAP HR Teriparatide vs. placebo Change in lumbar BMD per 5% Change in bone markers per 5% PTE*
0.73 0.18 0.76
95% CI 0.07 0.06 0.62
7.57 0.54 0.93
Serum osteocalcin p
HR
0.79 50.01 0.01
0.65 0.31 1.00
0.83 0.18 0.89
95% CI 0.08 0.06 0.79
p 6.57 0.78 1.06
0.72 0.01 0.90
84%
Serum P1NP
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/28/14 For personal use only.
0.06 0.12 0.93
88%
HR Teriparatide vs. placebo Change in lumbar BMD per 5% Change in bone markers per 5% PTE*
95% CI
8.47 0.57 1.01
Urinary NTX p
HR
0.97 50.01 0.07
0.51 0.28 0.96
93%
95% CI 0.05 0.11 0.90
p 4.93 0.70 1.03
0.56 0.01 0.27
74%
BMD, bone mineral density; BAP, bone specific alkaline phosphatase; HR, hazard ratio; CI, confidence interval; PTE, proportion of treatment effect explained; P1NP, procollagen type 1 amino-terminal propeptide; NTX, type I collagen cross-linked N-telopeptides. *Four separate bivariate Cox regression models were fitted to each combination of BMD and bone markers. PTEs were calculated as one minus log adjusted hazard ratio for treatment divided by log unadjusted hazard ratio for treatment.
The current analysis of data from a randomized placebocontrolled trial in Japan demonstrated that most of the vertebral fracture risk reduction by once weekly 56.5 mg teriparatide is explained by the change in lumbar BMD: 83% using Freedman’s method and 66% using Chen’s method. These estimates for PTE at the vertebra are not only higher than those seen in a previous study using antiresorptive agents such as alendronate (16%)6 or risedronate (18%)16 but are also higher than with strontium (no significant association)8 or with daily teriparatide (30 to 41%)9. The major difference between the current study and previous studies of patients treated with teriparatide9,13,17 is the dose and schedule (once weekly 56.5 mg vs. daily 20 mg). Another difference between these studies is in the patients’ characteristics, that is, the TOWER trial comprised Japanese patients with a mean age and BMI of 76 years and 23 kg/m2, respectively, while the previous study was conducted mainly with Western patients who were slightly younger and more obese. Furthermore, the relative risk for once weekly 56.5 mg teriparatide treatment observed in the TOWER trial was 0.20, which is lower than that seen with 20 mg teriparatide daily (RR ¼ 0.47), alendronate (RR ¼ 0.52), or risedronate (RR ¼ 0.64)17–20. These factors have the potential to influence the relationship between change in lumbar BMD and vertebral fracture risk reduction. Moreover, once weekly teriparatide administration is associated not only with an increase in BMD but with improved bone material properties and collagen deterioration, as observed in ovariectomized monkeys21. The bone quality improvements produced by new bone with once weekly teriparatide may contribute to a higher correlation of fracture reduction. The explained values adjusted for bone formation markers (P1NP and BAP) only slightly increased the PTE ! 2014 Informa UK Ltd www.cmrojournal.com
value from the change of BMD. It was reported that greater reductions of bone turnover markers in response to bisphosphonate treatment were associated with a lower risk of spinal, hip, and non-spinal fractures12, but the relationship between changes in bone turnover markers and fracture risk reduction has not been seen with bone formation agents such as teriparatide. Changes in bone turnover markers with teriparatide may not contribute to fracture risk reduction. Several limitations warrant mention. First, in the original TOWER trial, a total of 542 participants were evaluated for fracture incidence, and incident vertebral fracture occurred in seven cases (2.7%, 7/261) in the teriparatide group and 37 cases (13.2%, 37/281) in the placebo group. However, not all study sites measured BMD using DXA. Therefore, the number of participants in this analysis was limited. Second, the PTE value to incident hip fracture was not evaluated in this analysis. In the original TOWER trial, only one hip fracture in the teriparatide group and three hip fractures in the placebo group were observed, although measurement of BMD by DXA was not carried out in sites where fractures were observed.
Conclusion We conclude that most of the vertebral fracture risk reduction by once weekly 56.5 mg teriparatide is explained by the change in lumbar BMD.
Transparency Declaration of funding This study was supported by the Asahi Kasei Pharma Corporation.
Weekly teriparatide treatment effect proportion explained Tanaka et al.
935
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/28/14 For personal use only.
Current Medical Research & Opinion Volume 30, Number 5
May 2014
Declaration of financial/other relationships S.T. received a research grant from Asahi Kasei Pharma Corporation. T.K. is an employee of Asahi Kasei Pharma Corporation. T.S. received research grants and consulting fees from the following pharmaceutical companies: Asahi Kasei Pharma and Daiichi Sankyo. T.N. received research grants and/or consulting fees from the following pharmaceutical companies: Chugai, Teijin, Asahi Kasei Pharma, and Daiichi Sankyo. M.S. received consulting fees from the following pharmaceutical companies: Chugai, Daiichi Sankyo, Asahi Kasei Pharma, Teijin, and MSD. CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.
References 1. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996;312:1254-9 2. Khosla S. Surrogates for fracture endpoints in clinical trials. J Bone Miner Res 2003;18:1146-9 3. Cummings SR, Cosman F, Eastell R, et al. Goal-directed treatment of osteoporosis. J Bone Miner Res 2013;28:433-8 4. Hochberg MC, Ross PD, Black D, et al. Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Fracture Intervention Trial Research Group. Arthritis Rheum 1999;42:1246-54 5. Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive agents is related to changes in bone density. J Clin Endocrinol Metab 2000;85:231-6 6. Cummings SR, Karpf DB, Harris F, et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med 2002;112:281-9 7. Sarkar S, Mitlak BH, Wong M, et al. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res 2002;17:1-10 8. Bruyere O, Roux C, Detilleux J, et al. Relationship between bone mineral density changes and fracture risk reduction in patients treated with strontium ranelate. J Clin Endocrinol Metab 2007;92:3076-81 9. Chen P, Miller PD, Delmas PD, et al. Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatide-treated postmenopausal women with osteoporosis. J Bone Miner Res 2006;21:1785-90
936
Weekly teriparatide treatment effect proportion explained Tanaka et al.
10. Eastell R, Barton I, Hannon RA, et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res 2003;18:1051-6 11. Sarkar S, Reginster JY, Crans GG, et al. Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res 2004;19:394-401 12. Bauer DC, Black DM, Garnero P, et al. Change in bone turnover and hip, nonspine, and vertebral fracture in alendronate-treated women: The Fracture Intervention Trial. J Bone Miner Res 2004;19:1250-8 13. Nakamura T, Sugimoto T, Nakano T, et al. Randomized Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk. J Clin Endocrinol Metab 2012;97:3097-106 14. Genant HK, Jergas M, Palermo L, et al. Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis. J Bone Miner Res 1996;11:984-6 15. Freedman LS, Graubard BI, Schatzkin A. Statistical validation of intermediate endpoints for chronic diseases. Stat Med 1992;11:167-78 16. Watts NB, Cooper C, Lindsay R, et al. Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom 2004;7:255-61 17. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41 18. Miyauchi A, Matsumoto T, Sugimoto T, et al. Effects of teriparatide on bone mineral density and bone turnover markers in Japanese subjects with osteoporosis at high risk of fracture in a 24-month clinical study: 12-month, randomized, placebo-controlled, double-blind and 12-month open-label phases. Bone 2010;47:493-502 19. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: The Fracture Intervention Trial. J Clin Endocrinol Metab 2000;85:4118-24 20. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 1999;282:1344-52 21. Saito M, Marumo K, Kida Y, et al. Changes in the contents of enzymatic immature, mature, and non-enzymatic senescent cross-links of collagen after once-weekly treatment with human parathyroid hormone (1-34) for 18 months contribute to improvement of bone strength in ovariectomized monkeys. Osteoporos Int 2010;22:2373-83
www.cmrojournal.com ! 2014 Informa UK Ltd
