Author’s Response to Letter to the Editor

Re: Anagnostis P, Karras SN, Goulis DG. Monitoring the efficacy of once-weekly teriparatide. Are bone turnover markers useful in predicting fracture risk? Curr Med Res Opin 2014;30:1177-8

Dear Editor,

We appreciate the important suggestions raised by Drs. Anagnostis, Karras, and Goulis1 related to our analysis of bone mineral density (BMD) and bone turnover markers (BTMs) as surrogate endpoints for incident vertebral fracture2,3. The proportion of the treatment effect of once-weekly teriparatide on vertebral fracture explained by the change in lumbar BMD was estimated to be 83% (Freedman’s method) or 66% (Chen’s method) in our study2, and the estimate of the recent meta-analysis was 25–32% (Chen’s method)4 for the once-daily teriparatide formulation, although the magnitude of lumbar BMD changes after teriparatide treatment for 1 year was larger with the once-daily than with the once-weekly preparation (8% in the FPT study5 versus 6% in TOWER study3). In addition, the fracture risk reduction in the TOWER trial (RR 0.20, 95% CI 0.09–0.45) was equal to that in the FPT study (RR 0.29, 95% CI 0.20–0.436). These differences in the two formulations of teriparatide may be explained by plausible factors, such as differences in ethnicity, improvement of bone quality, or changes in BTMs.

Firstly, Tsujimoto et al. examined whether the pharmacokinetics of once-daily teriparatide and the effects of the drug on BMD differ between Japanese and non-Japanese populations5. The pharmacokinetic parameters (AUC and Cmax) were not different between Japanese and Caucasian postmenopausal women. Similarly, the time course and dose–response change in BMD between Japanese and Caucasian populations were not significantly different. Therefore, no ethnic difference in teriparatide effects was observed, at least with once-daily teriparatide.

Once-weekly teriparatide treatment is associated with improved material properties (mineral contents and collagen cross-links) of bone in ovariectomized monkeys7. Moreover, increases of bone strength parameters (section modulus and buckling ratio) were observed in humans by CT analysis8. Therefore, it is theoretically reasonable to expect that the bone quality improvements produced by once-weekly teriparatide may account for the anti-fracture efficacy.

The change in BTMs by once-daily teriparatide treatment has been well established as the ‘anabolic window’9. However, a significant relationship between the change in BTMs and anti-fracture efficacy was not observed with once-weekly teriparatide2 and was not reported with once-daily teriparatide treatment. The meaning of the change in BTMs produced by teriparatide treatment may be different between the once-weekly and once-daily treatment regimens. However, we would like to emphasize that a difference in the timing of sampling exists between once-daily and once-weekly preparations. In the case of once-daily teriparatide, the BTM samples were taken 24 hours after the injection, while with once-weekly teriparatide, they were taken one week after the injection. These differences arise because it has been reported that bone resorption markers were increased shortly after the injection, followed by around a 10% decrease during the subsequent 14 days, while bone formation markers were decreased shortly after the injection, followed by a 10% increase during the subsequent 14 days10. These changes were repeatedly observed at every weekly injection for 24 weeks11. Therefore, measurements of BTMs with once-weekly teriparatide could not represent the total bone turnover changes after the injection.

In conclusion, both once-weekly and once-daily teriparatide treatments increase lumbar BMD (by 6% and 8%, respectively). Changes in BTMs after once-weekly teriparatide were spiky, and the changes were repeated to the same extent during the treatment. On the other hand, the changes in formation markers with once-daily teriparatide increase in a time-dependent manner. The changes in bone resorption markers also increase in a time-dependent manner with a slight delay from the changes in bone formation markers. Therefore, the effects of teriparatide on BTMs are quite different between the once-daily and once-weekly preparations. Although differences in bone effects exist between the two teriparatide preparations, fracture risk reduction seems to be the same with both preparations. Further study is needed to explore the mechanisms of action on fracture risk reduction with both preparations.

Transparency

Declaration of funding

This letter received no funding.

Declaration of financial/other relationships

As previously reported: S.T. has disclosed that he received a research grant from Asahi Kasei Pharma Corporation. T.K. has disclosed that he is an employee of Asahi Kasei Pharma Corporation. T.S. has disclosed that he received research grants and consulting fees from the following pharmaceutical companies: Asahi Kasei Pharma and Daiichi Sankyo. T.N. has disclosed that he received research grants and consulting fees from the following pharmaceutical companies: Chugai, Teijin, Asahi Kasei Pharma and Daiichi Sankyo. M.S. has disclosed that he received consulting fees from the following pharmaceutical companies: Chugai, Daiichi Sankyo, Asahi Kasei Pharma, Teijin, and MSD.