Gastroenterology

Gastroenterology

Volume 156, Issue 4, March 2019, Pages 926-934.e6
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Dexlansoprazole and Esomeprazole Do Not Affect Bone Homeostasis in Healthy Postmenopausal Women

https://doi.org/10.1053/j.gastro.2018.11.023Get rights and content

Background & Aims

Epidemiological studies have associated proton pump inhibitor (PPI) therapy with osteoporotic fractures, but it is not clear if PPIs directly cause osteoporosis. We evaluated the effect of dexlansoprazole and esomeprazole on bone turnover, bone mineral density (BMD), true fractional calcium absorption (TFCA), serum and urine levels of minerals, and levels of parathyroid hormone (PTH) in healthy postmenopausal women.

Methods

We performed a prospective, multicenter, double-blind study of 115 healthy, postmenopausal women (45 to 75 years of age) from November 4, 2010, through August 7, 2014. Women were randomly assigned to groups given dexlansoprazole (60 mg), esomeprazole (40 mg), or placebo daily for 26 weeks. We measured plasma levels of procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) at 0 (baseline), 13, and 26 weeks. Primary outcomes were percent change in P1NP and CTX between weeks 0 and 26. We also measured changes in serum and urine levels of mineral, BMD, PTH (all subjects), and TFCA (n = 30).

Results

Between baseline and week 26, there were no significant within-group differences in markers of bone turnover; there was a nonsignificant increase in CTX levels in the dexlansoprazole group (0.12 ng/mL). The esomeprazole and dexlansoprazole groups had significantly increased levels of P1NP (18.2% and 19.2%, respectively) and CTX (22.0% and 27.4%, respectively) at week 26 compared with the placebo group, although these values remained within normal ranges. There were no statistically significant differences between groups in serum or urine levels of minerals, BMD, or PTH at week 26. PPI therapy did not reduce TFCA.

Conclusions

In a prospective study of postmenopausal women, we found significant increases in markers of bone turnover in women given PPI therapy compared with women given placebo, but levels remained within the normal reference range. We found no significant differences among groups in changes in BMD, PTH, serum or urine levels of minerals, or TFCA. Our findings indicate that 26 weeks of treatment with a PPI has no clinically meaningful effects on bone homeostasis. Clinicaltrials.gov no: NCT01216293

Section snippets

Study Design

We conducted a phase 4, randomized, double-blind, placebo-controlled study in healthy postmenopausal women from November 4, 2010 (first participant in) to August 7, 2014 (last participant out), at 12 US centers. Institutional review board approval and participant consent were obtained before the study. This study was funded by Takeda Pharmaceuticals International, Inc. Takeda Pharmaceuticals International, Inc., was responsible for and sponsored the study design, data collection, data

Subjects

Of the 556 women screened at 11 centers, 115 were enrolled, and 93 participants completed the study (Supplementary Figure 1). No substantial differences in baseline demographics were observed between treatment groups (Table 1). Most participants (>90%) were white, with mean age of 62 ± 6 years, and mean body mass index of 25.2 ± 2.8 kg/m2. Subjects’ serum 25(OH)D levels were 39 ± 10 ng/mL at randomization. The calcium absorption substudy enrolled 34 participants (30 completing) with

Discussion

Recent population-based epidemiological studies have generated conflicting results about a relationship between chronic PPI therapy and fracture risk.4, 5, 11, 12, 13, 36 Low odds ratios (<2), lack of dose response, biological implausibility, and uncontrolled potential confounders limit any firm conclusions about the causal nature between PPI therapy and osteoporosis.37, 38 Although some studies have detected an association between PPI use and fractures in postmenopausal women, prospective

Conclusions

Overall, this prospective, randomized, double-blind clinical trial detected minimal changes in bone homeostasis related to 26 weeks of PPI therapy. Increases in bone turnover were detected, but formation and resorption both increased and remained coupled. There were no PPI-associated declines in BMD, serum or urine mineral levels, PTH, or TFCA. Our study provides strong evidence against PPI-mediated alterations in calcium absorption or mineral homeostasis. If there is a causal relationship

Acknowledgments

This study was supported by Takeda Development Center Americas, Inc, Deerfield, Illinois. Medical writing assistance was provided by Nikhilesh Sanyal, PhD, and Jacob Edelstein, PhD, of inVentiv Medical Communications, LLC, a Syneos Health group company, and supported by Takeda Development Center Americas, Inc.

Sai Nudurupati’s current affiliation: AbbVie Inc, North Chicago, Illinois.

Author contributions: Drs Hansen, Nudurupati, Metz, and Perez contributed to the study design. Drs Hansen and

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    Conflicts of interest Dr Hansen was paid for her work as a consultant in the design and conduct of the study and received a grant to conduct the study. Dr Nieves received a research grant from Takeda to conduct this research. Dr Nudurupati was an employee of Takeda Pharmaceuticals at the time this study was conducted. Dr Metz received administrative and editorial support for study design and analysis of the data. Dr Perez is employed by Takeda Pharmaceuticals.

    Funding This study was funded by Takeda Pharmaceuticals International, Inc. Takeda Pharmaceuticals International, Inc., was responsible for and sponsored the study design, data collection, data interpretation, and writing of this manuscript.

    Authors share co-first authorship

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