Full Length ArticleAdministration of teriparatide for four years cyclically compared to two years daily in treatment Naïve and alendronate treated women
Introduction
Parathyroid hormone 1-34 (teriparatide, TPTD) stimulates bone formation and bone remodeling, with positive net bone balance resulting in increased bone mass, improved bone architecture, increased bone strength and reduced risk of fracture [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]]. The biochemical response to TPTD follows a consistent pattern, with a brisk increase in markers of bone formation upon initiating TPTD treatment [2,6,10,11], peak levels within the year and decline toward baseline thereafter [12]. Increases in serum markers of bone resorption are delayed, but also peak and decline toward baseline during the second year of TPTD [2,4,10,12]. The increase in spine bone density (BMD) following TPTD is also most rapid within the first 6 months of treatment [[2], [3], [4],6,10,11]. Histomorphometric analyses of iliac crest biopsies indicate dramatic direct stimulation of bone formation (modeling-based formation) and stimulation of bone remodeling (remodeling-based formation) at 1 to 6 months [8,[13], [14], [15]]. These effects are continued but somewhat dampened at 18–36 months [7,[16], [17], [18]]. Taken together, the biochemical turnover marker levels, BMD, and histomorphometric data suggest that there is a developing resistance to the effects of continued TPTD administration during the second year. This could be due to depletion of the osteoblast progenitor pool or the induction of bone formation inhibitors [19,20].
Considering the data summarized above, the concept of administering TPTD cyclically (in 3 month cycles) was based on two hypotheses. The first was that early direct stimulation of bone formation without prior resorption [21] might be more important to the ultimate accrual of BMD than later activation of bone remodeling. The second hypothesis was that repeated short cycles of TPTD might surmount the partial tachyphylaxis that develops after 6–15 months of continuous daily therapy. Short TPTD cycles could potentially dissociate the early modeling-based anabolic effect from the latter remodeling-based effect.
We previously published results from the first two years of this trial [22]. Cyclic TPTD over two years increased BMD similarly to daily treatment in women who remained on alendronate (ALN-Rx). However, in treatment naïve women (Rx-Naïve), BMD increments in the cyclic group were about half those in the standard daily group, consistent with the cumulative dose of TPTD administered. In the current study, we determine, in a group of Rx-Naïve women, if continued cyclic TPTD administration over four years increases BMD more than standard daily TPTD administration for two years (same cumulative dose of TPTD). Since both Rx-Naïve women and ALN-Rx women can be candidates for TPTD, we also tested equivalent cumulative doses of TPTD given cyclically vs. a 2-year standard daily TPTD regimen in the ALN-Rx.
To keep the time period equal in the 2 arms, a secondary analysis was also performed, comparing the daily group with the cyclic group at 4 years. Note that in the Rx-Naïve cohort, for the secondary 4-year analysis, the daily group received 2 years of ALN that the cyclic did not receive. In the ALN-Rx cohort, cumulative doses of TPTD and ALN were the same over 4 years.
Section snippets
Methods
This was a randomized, open label study in postmenopausal women with osteoporosis. Subjects were recruited concurrently into 2 parallel cohorts: women on ALN (70 mg/week) for at least one year (ALN-Rx; n = 64) and women with minimal or no prior osteoporosis therapy (Rx-Naïve; n = 86). In both cohorts, volunteers were randomized to daily TPTD (20 μg daily subcutaneously for 24 months) or cyclic TPTD given in 3 month cycles (3 months on TPTD 20 μg/day and 3 months off TPTD) [22]. After two years,
Results
One-hundred-fifteen women completed the 2 year parent study and 89 (75%) enrolled in the extension study, including 48 in Rx-Naïve and 41 in ALN-Rx cohorts (Fig. 1). Seventy-four women (83% of enrolled) completed the 2-year extension: 9 withdrew consent for personal reasons, 4 were lost to follow-up, and 2 withdrew due to an SAE/AE. There were no deaths during the extension study (Fig. 1).
Discussion
The hypothesis underlying this study was that cyclic administration might be a more effective way to build skeletal mass rather than daily therapy for 2 years, based on the concepts of maximizing formation over resorption and avoiding skeletal tachyphylaxis to TPTD with short therapy cycles. In our prior manuscript, based on the 2 year parent study [22], we showed that TPTD administered either daily or cyclically over 24 months in both Rx-Naïve and ALN-Rx women increased BMD in the spine and
Conflict of interest disclosures
Felicia Cosman: Advisory Board/Consulting Fees for Amgen, Eli Lilly, Merck, Radius and Tarsa; lecture fees from Amgen, Eli Lilly and Radius; grant support from Amgen and Eli Lilly.
Jeri W. Nieves: Grant support from Eli Lilly.
Simon Neubort and Donald Mcmahon: Nothing to report.
David W. Dempster: Consulting/advisory board fees from Eli Lilly, Merck, Amgen, Radius and Tarsa; lecture fees from Amgen, Eli Lilly, Radius; grant support from Amgen and Eli Lilly.
Robert Lindsay: Consulting/advisory
Acknowledgements
Source of Funding: National Institutes of Health AR056651. We thank Eli Lilly and Company for generously supplying Teriparatide for this trial. Eli Lilly had no role in the design or conduct of the trial, nor in the data interpretation or manuscript preparation. We also thank Roche Diagnostics for providing the assay reagents for the biochemical turnover markers free of charge for the purpose of conducting this research study.
Authors' roles: Study design: FC, RL. Study conduct: FC, JWN CR. Data
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