Full Length ArticleDenosumab effects on bone density and turnover in postmenopausal women with low bone mass with or without previous treatment
Introduction
Denosumab, a monoclonal antibody against the receptor activator of nuclear factor κB ligand (RANKL), is a potent antiresorptive agent, which profoundly suppresses bone turnover markers (BTMs), increases bone mineral density (BMD), and reduces fracture risk [1]. The effects on BTMs and BMD are completely reversible after denosumab discontinuation, including a rise of BTMs, a rapid reduction of BMD, and a potential risk of multiple vertebral fractures (VFx) [2,3]. Zoledronic acid (ZOL) is a potent bisphosphonate that exerts antiresorptive activity, while teriparatide (TPTD) is an osteoanabolic agent. Both ZOL and TPTD significantly improve BMD and decrease vertebral and non-vertebral fractures [4,5], although they exert opposite effects on BTMs. Upon discontinuation, ZOL displays a sustained effect on bone metabolism [6], while TPTD gradually loses its effects on BMD and BTMs [7].
During the last years, BTMs have gained importance as surrogate markers to monitor both anti-resorptive and anabolic treatment, and may be used in conjunction with BMD measurements in clinical practice [8]. The two most widely utilized BTMs are pro-collagen type 1 N-terminal propeptide (PINP), which reflects osteoblast activity, and C-terminal-cross-linking telopeptide of type 1 collagen (CTX), which corresponds to the osteoclastic function [8]. While prior treatment with bisphosphonates results in smaller BMD and BTM changes in patients transitioning to denosumab as compared to treatment-naïve patients beginning denosumab therapy [9,10], it has also been proposed to blunt enhanced bone turnover and/or attenuate BMD loss after denosumab discontinuation [11]. On the contrary, postmenopausal women switching from TPTD to denosumab depicted a continued increase in BMD, with bone resorption maximally suppressed after 1-month of denosumab and a delayed suppression of bone formation with maximal effects after 12–24 months of denosumab treatment [12].
ZOL, denosumab, and TPTD are characterized by the coupling effect in their action, the former two agents decreasing both bone resorption and formation, and the latter stimulating both formation and resorption. Interactions between these agents and the (Wnt)/β-catenin signaling pathway, which constitutes a major promoter of bone formation, have been documented [13]. Serum concentrations of Wnt-antagonists sclerostin and dickkopf-1 (Dkk-1) have been reported in both pre-treated and treatment-naïve patients with postmenopausal osteoporosis, and are believed to reflect their expression in the bone microenvironment [14,15]. Myostatin is a member of the transforming growth factor beta (TGF-beta) superfamily, with major effects on muscle, fat, and bone homeostasis [16]. Next to the pivotal finding that myostatin deficiency is associated with increased muscle mass [17], animal studies report that inhibition of the myostatin pathway is associated with enhanced bone turnover and bone mass accrual [18,19]. In a placebo-controlled multiple dose human study, inhibition of myostatin led to a significant increase of muscle mass, while also causing an up-regulation of bone specific alkaline phosphatase and down-regulation of CTX [20], implying uncoupling of bone remodeling.
In this study, we compared the effects of denosumab following previous treatment with ZOL, TPTD, or no treatment, on spinal BMD and serum concentrations of PINP, CTX, sclerostin, Dkk-1, and myostatin in postmenopausal women with low bone mass.
Section snippets
Patients
This was a 12-month, observational, monocentric, longitudinal study of 82 postmenopausal women with low bone mass. All data was obtained from patients who were treated and regularly monitored at the outpatient clinics for Metabolic Bone Diseases of 424 General Military Hospital, Thessaloniki, Greece. At the time of the first s.c. injection of 60 mg denosumab, patients were either treatment-naïve (n = 30), or had received 1–2 yearly i.v. infusions of 5 mg ZOL (n = 30), or had completed 24 months
Methods
Baseline assessment was defined as the day of the first s.c. injection of 60 mg denosumab, and comprised of history (including history of previous VFx), physical examination, blood sampling, measurement of bone mineral density at the lumbar spine (lumbar spine BMD), and lateral spine radiographs for the presence of VFx. Areal BMD was measured by dual energy X-ray absorptiometry (DXA) at the lumbar spine (LS) (L1–L4) using a Lunar Prodigy densitometer (Lunar Corporation, Madison, WI, USA) at
Results
Baseline anthropometric and lumbar spine BMD data, as well as VFx history is summarized in Table 1. Baseline characteristics were similar between treatment-naïve patients (n = 30), and patients pre-treated with ZOL [After ZOL] (n = 30), or TPTD [After TPTD] (n = 22).
In treatment-naïve patients BMD at the lumbar spine increased by 4.4% ± 0.6% (p < 0.001) at 12 months of denosumab treatment. The respective change for patients pre-treated with ZOL increased by 4.1% ± 0.8% (p < 0.001), and for
Discussion
In this study lumbar spine BMD increased equivalently in the three groups of patients, seemingly not being affected by previous anti-osteoporotic treatment or absence of treatment. These findings were in line with previous studies highlighting the potent BMD increase achieved with denosumab in treatment-naïve [21], or TPTD pre-treated patients [12]. Conversely, a course of bisphosphonate pre-treatment has been shown to diminish denosumab's effect on BMD in most [[22], [23], [24]], but not all
Grant support
This work was supported by the MedDrive Starting Grant and the Frauenhabilitationsstipendium of Technische Universität Dresden to ET and the DFG SPP μBONE to TDR, MR, and LCH.
Disclosure statement
Dr. Tsourdi reports honoraria for lectures from Amgen. Dr. Makras reports honoraria for lectures and research grants from Amgen; lecture fees from Glaxo, Lilly, Pfizer, Leo, Genesis, Elpen, and Vianex. Dr. Rachner reports honoraria for lectures from Amgen and Roche and advisory boards from Merck. Dr. Polyzos reports a lecture fee from Amgen. Dr. Rauner reports honoraria for lectures from Amgen. Dr. Mandanas has nothing to declare. Dr. Hofbauer reports reports honoraria for lectures and
Acknowledgments
We thank the technical assistants of the Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden Medical Center, as well as Mrs. Dorit Breining and Mrs. Bärbel Zeiler of the Bone Lab Dresden for performing the serum measurements of all afore-mentioned parameters.
Study design, study conduct, data collection: ADA. Data analysis and data interpretation: ET, PM, TDR, SAP, MR, SM, LCH, and ADA. Drafting manuscript and revising manuscript content: ET, PM, SAP, MR, TDR,
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