Elevated Bone Hardness Under Denosumab Treatment, With Persisting Lower Osteocyte Viability During Discontinuation.

Katharina Jähn-Rickert,Mathias Werner,Björn Jobke,Maya Hellmich,Christoph Riedel,Björn Busse,Eva M Wölfel,Michelle M Mcdonald

doi:10.3389/fendo.2020.00250

Abstract

Denosumab is a potent osteoclast inhibitor targeted to prevent osteoporotic bone loss and thereby reduce fractures in the aging population. Recently, an elevated risk of rebound fractures following denosumab discontinuation was identified, unless patients were transitioned to an alternative antiresorptive medication. How denosumab affects the interaction of mechanosensitive osteocytes and bone quality remains unknown. We hypothesized that denosumab influences osteocyte function contributing to bone reorganization and increased fractures during discontinuation. Bone quality and osteocytes were assessed in archived iliac crest bone biopsies obtained from patients with high fracture occurrence from 2011 to 2016. Biopsies were obtained due to high fracture occurrence prior and during osteoporosis therapy from (i) patients with at least two semiannual subcutaneous injections of 60 mg denosumab, (ii) patients with rebound fractures during discontinuation, and (iii) patients of a treatment-naive group. In total, biopsies from 43 individuals were analyzed (mean age, 65.5 ± 12.1 years). Our results showed that during denosumab treatment, iliac cortical bone had a higher bone tissue hardness compared to treatment-naive bone (p = 0.0077) and a higher percentage of mineralized osteocyte lacunae (p = 0.0095). The density of empty osteocyte lacunae was higher with denosumab compared to treatment-naive (p = 0.014) and remained high in trabecular bone during discontinuation (p = 0.0071). We conclude that during denosumab treatment, increased bone hardness may contribute to improved fracture resistance. In biopsies from patients with high fracture occurrence, denosumab treatment reduced osteocyte viability, an effect that persisted during treatment discontinuation. High-resolution imaging of osteocyte viability indicates a role for osteocytes as a potential future mechanistic target to understand rebound bone loss and increased fractures with denosumab discontinuation.

Highlights

One in two women and one in five men aged 50 years or older will experience a fracture as a result of agerelated bone loss, defining osteoporosis as major health burden in the growing aged population [1, 2]
We present a comprehensive bone quality assessment utilizing bone biopsies obtained from (i) aged patients with high fracture occurrence under denosumab treatment, (ii) from patients whose denosumab treatment was halted afflicted with rebound fractures, and (iii) from an age-matched treatmentnaive group
It is of clinical relevance to understand the changes in bone quality at the tissue level when fractures occur during denosumab treatment but importantly during its discontinuation

Summary

Introduction

One in two women and one in five men aged 50 years or older will experience a fracture as a result of agerelated bone loss (osteoporosis), defining osteoporosis as major health burden in the growing aged population [1, 2]. The lacuno-canalicular system creates a permeability within the dense bone matrix, enabling the cellular exchange of signaling molecules This extensive network spans throughout the bone matrix, connecting osteocytes to bone surface cells and enabling osteocytes to regulate bone remodeling activities [8,9,10]. We have previously shown that in aged human bone, osteocyte lacunar hypermineralization (micropetrosis) accumulates, impacting osteocyte canalicular signaling [15, 16]. In this context, the osteocyte network in osteoporosis patients is impaired showing lower connectivity and permeability, confirming a role for osteocyte pathology in osteoporotic bone loss [17,18,19,20]

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