Elsevier

Bone

Volume 130, January 2020, 115113
Bone

Full length article
Psychotropic medications and proton pump inhibitors and the risk of fractures in the teriparatide versus risedronate VERO clinical trial

https://doi.org/10.1016/j.bone.2019.115113Get rights and content

Highlights

Abstract

Background

VERO is a fracture endpoint study in women with established osteoporosis that showed reduction in the risks of new vertebral fractures (VFx) and clinical fractures in women randomized to teriparatide compared with risedronate. Patients on psychotropic drugs (hypnotics, benzodiazepines and antidepressants [selective serotonin- and norepinephrine-reuptake inhibitors: SSRIs and SNRIs]) and proton pump inhibitors (PPIs) may be at a higher risk of fractures. We studied the association of exposure to these medications with the risk of fractures in the VERO study cohort, including an assessment of their potential interactions with the assigned clinical trial drugs.

Methods

A total of 1360 postmenopausal women with at least 2 moderate or 1 severe VFx and bone mineral density T-score ≤-1.50 were randomized to subcutaneous daily teriparatide (20 μg) or oral weekly risedronate (35 mg) in a double-blind, double-dummy, 2-year trial. In thispost-hoc analysis, multivariable log-binomial and Cox proportional hazards regression models were used to estimate adjusted risk ratios (RR) or hazard ratios (HR) for the exposure to these concomitant medications with the occurrence of incident fractures. We also assessed treatment effect modifications on anti-fracture efficacy driven by the use of these medications.

Results

There were 406 (29.9 %), 347 (25.5 %) and 176 (12.9 %) subjects taking PPIs, benzodiazepines/hypnotics, and SSRIs/SNRIs during the study, respectively. For all fracture endpoints, the greater risk reduction of teriparatide versus risedronate did not significantly differ within the categories of psychotropic drugs and PPIs. Multivariable analysis showed that the risk of pooled new and worsened VFx was higher in PPI users than in non-PPI users (RR: 1.57; p = 0.032), regardless of the study treatment. Benzodiazepine/hypnotic drug users showed an increased risk of clinical fractures (HR: 1.71; p = 0.026) and non-vertebral fragility fractures (NVFFx, HR: 1.89; p = 0.017), regardless of the study treatment. Increases in the risk of clinical fractures (HR: 1.93; p = 0.018) and NVFFx (HR: 2.16; p = 0.011) were also observed in SSRI/SNRI users, regardless of the study treatment.

Conclusion

In postmenopausal women with severe osteoporosis, the superior anti-fracture efficacy of teriparatide compared with risedronate was consistent regardless of psychotropic or PPI drugs use. Patients taking psychotropic drugs and PPIs showed a higher risk for NVFFx and VFx respectively, compared to those not on these medications.

Introduction

Although glucocorticoids are most frequently associated with increased osteoporotic fractures, other prescription drugs have been linked with increased fracture risk. These include aromatase inhibitors, antiandrogens, gonadotropin-releasing hormone agonists to treat hormone-dependent cancers or endometriosis, thiazolidinediones, antiretroviral drugs, selective inhibitors of serotonin and noradrenaline reuptake, morphine and opiates, antiepileptics, benzodiazepines, antipsychotic drugs, antihypertensives, heparin and warfarin, suppressive l-thyroxine, and proton pump inhibitors (PPIs) [[1], [2], [3], [4]]. The reason of the increased fracture risk may be an increased risk of falls and/or decreased bone mineral density (BMD).

Most studies that have analyzed the association of different types of medications with adverse skeletal effects are observational studies [5,6].

The VERtebral fracture treatment comparisons in Osteoporotic women (VERO) trial is the first active-controlled, double-dummy, fracture endpoint study in postmenopausal women with established osteoporosis designed to compare the effects of the bone-forming drug teriparatide with that of an anti-resorptive risedronate, with fractures as the primary outcome [7]. Compared with risedronate-treated patients, teriparatide-treated patients showed the following: a 56 % reduction in the risk of new morphometric vertebral fractures (VFx, p < 0.0001); a 54 % reduction in the risk of pooled new and worsened VFx (p < 0.0001); a 52 % reduction in the risk of clinical fractures (clinical vertebral and non-vertebral fragility fractures [NVFFx], p = 0.0009); and a 34 % non-significant reduction in the risk of NVFFx (p = 0.1). A predefined analysis of nine clinically relevant subgroups of the VERO trial revealed no evidence of heterogeneity of the treatment effect on fracture endpoints across the examined subgroups, including the subjects receiving glucocorticoids [8].

Fragility fractures are frequently observed in patients on psychotropic medications and PPIs [5,6]. These medications are commonly used representing a potentially modifiable risk factor, with a likely significant impact on the prognosis of patients at high risk of fracture. In this post-hoc analysis, we investigated whether the concomitant use of psychotropic drugs (benzodiazepines, hypnotics, and antidepressants [selective serotonin- or norepinephrine-reuptake inhibitors: SSRIs and SNRIs]), and PPIs were associated with a higher risk of incident fractures during the VERO study. Additionally, we analyzed potential differences in the treatment effect on the incidence of fractures observed in the VERO trial cohort driven by the use of these types of concomitant drugs.

Section snippets

Study design

The VERO trial was an international, multicenter, randomized, double-blind, active-controlled, parallel-group, 24-month trial. It enrolled ambulatory postmenopausal women over 45 years of age with a BMD T-score ≤-1.5 standard deviations at the femoral neck, total hip, or lumbar spine, and radiographic evidence of at least 2 moderate or 1 severe prevalent vertebral fragility fractures according to the classification of Genant et al. [9]. Exclusion criteria included low serum 25-hydroxy-vitamin D

Results

A total of 406 (29.9 %), 347 (25.5 %), and 176 (12.9 %) subjects took PPIs, benzodiazepines/hypnotics, and SSRIs/SNRIs during the study, respectively. The frequency of concomitant drug users was balanced by the treatment arm (PPIs: teriparatide, 32.2 %, risedronate, 27.5 %; benzodiazepines/hypnotics: teriparatide, 25.7 %, risedronate, 25.3 %; SSRIs/SNRIs: teriparatide, 12.4 %, risedronate, 13.5 %). Three patients started treatment with PPIs only after the first incident fracture occurred, and

Discussion

Our results from a 2-year, prospective, randomized clinical trial in postmenopausal women with severe osteoporosis confirm the association between an increased risk for fractures and the use of several commonly used medications in this patient population. Patients who were exposed to either of the analyzed psychotropic drugs (benzodiazepines/hypnotics or antidepressants) had a statistically significant increased risk of clinical and non-vertebral fractures, while users of PPIs had an increased

Credit author statement

David L. Kendler: recruited patients, collected, analysed and interpreted the data, and wrote, jointly with FM, the first draft of the manuscript.

Fernando Marin: conceived and designed the study, analysed and interpreted the data, and wrote, jointly with DLK, the first draft of the manuscript.

Piet Geusens: recruited patients, collected, analysed and interpreted the data, and revised the report for important intellectual content.

Pedro López-Romero: designed the study, did the statistical

Funding

The Eli Lilly and Company funded the VERO clinical trial.

Declaration of Competing Interest

Dr. Kendler received honoraria, research grants, and/or consultant fees from Amgen, Lilly, and UCB. Drs. Marin and López-Romero are employees and shareholder of Lilly. Dr. Geusens received consultant and/or speaker fees from Lilly, and research support from Pfizer, Abbott, Lilly, Amgen, MSD, Roche, UCB, BMS and Novartis. Dr. Lespessailles received speaker and consultant fees from Amgen, Expanscience, Lilly and MSD, and research grants from Abbvie, Amgen, Lilly, MSD and UCB. Dr. Body received

Acknowledgements

We are indebted to Anja Gentzel-Jorczyk (Clinical Trial Coordinator), Estrella Crespo and Laura Briones (Data Management) for their contribution to the study, Richi Taneja, Eli Lilly Services India Pvt Ltd, for the editorial assistance, the members of the investigational teams at the study centers, and the women who participated in the study.

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  • Cited by (0)

    1

    Prohealth Clinical Research, 150-943 West Broadway, Vancouver, British Columbia V5Z 4E1, Canada.

    2

    Department of Medical Research, Eli Lilly and Company, Avda. de la Industria 30, 28108-Alcobendas, Madrid, Spain.

    3

    Maastricht University Medical Center, Department of Internal Medicine, subdivision of Rheumatology, P. Debyelaan 25, 6229 HX Maastricht, Netherlands.

    4

    Regional Hospital of Orleans and University of Orleans, 14 Avenue de L'Hôpital, 45067 Orleans CEDEX 2, France.

    5

    Hôpital Universitaire Brugmann Brussel, Place Arthur Van Gehuchten 4, 1020 Brussels, Belgium.

    6

    Ambulatorio Osteoporosi e Osteopatie Fragilizzanti, Sapienza" Università di Roma, Via del Policlinico 155, 00161 Rome, Italy.

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