Administration of teriparatide for four years cyclically compared to two years daily in treatment Naïve and alendronate treated women

Highlights

• Spine and hip BMD increase when TPTD is given in 3-month cycles over 4 years to both untreated and alendronate-treated women.

• BMD gains are not greater when TPTD is given cyclically over 4 years compared with standard daily treatment over 2 years.

• Over 2-years of daily TPTD, BMD gains in women who added TPTD to ALN were similar to those in previously untreated women.

• Biochemical markers suggest that bone formation was stimulated with each teriparatide cycle over 4 years.

Abstract

Purpose

We evaluated if equivalent doses of TPTD given cyclically over 4-years could increase BMD >2-years of daily TPTD in 2 cohorts of women; previously untreated (Rx-Naïve) and women previously treated with ALN (ALN-Rx).

Methods

In Rx-Naïve, women were randomized to daily TPTD for 24 months (Daily; n = 23) or cyclic TPTD for 48 months (3 months on, 3 months off; Cyclic; n = 25). In ALN-Rx, women were randomized to continued ALN plus daily TPTD for 24 months, followed by ALN alone for 24 months (Daily; n = 21) or TPTD for 48 months (3 months on, 3 months off) while ALN was continued (Cyclic; n = 20). BMD (DXA) was measured at spine (LS), total hip (TH) and femoral neck (FN). The primary analysis compared 4 years of cyclic therapy to 2 years of daily therapy in RX-naïve and ALN-RX cohorts.

Results

In Rx-Naïve, BMD changes at 24 months after Daily TPTD vs. 48 months after Cyclic TPTD were: LS 8.6% vs. 6.9%; TH 2.5% vs. 2.6%, and FN 1.6% vs. 2.2%. None of the BMD changes differed significantly between groups but all changes were significant over time within each group (p < 0.01 except for FN where p = 0.17 Daily; p = 0.09 Cyclic). In ALN-Rx, BMD changes at 24 months after Daily TPTD vs. 48 months after Cyclic TPTD were: LS 7.5% vs. 7.2%; TH 3.8% vs. 4.1%, and FN 3.2% vs. 2.5%. There were no differences between groups but all changes were significant within each group (p < 0.01).

Conclusion

The same cumulative dose of TPTD given cyclically for 4-years, does not increase BMD more than standard daily TPTD over 2-years in either Rx-Naïve or ALN-Rx women.

Trial Registration: NCT00668941

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.