Effect of Denosumab on Peripheral Compartmental Bone Density, Microarchitecture and Estimated Bone Strength in <b><i>De Novo</i></b> Kidney Transplant Recipients

Abstract

Background/Aims: In a randomized controlled clinical trial in kidney transplant recipients (NCT01377467) we have recently shown that RANKL inhibition with denosumab significantly improved areal bone mineral density (aBMD) when given during the first year after transplantation. The effect of denosumab on skeletal microstructure and bone strength in kidney transplant recipients is not known. Methods: The purpose of the present bone microarchitecture ancillary study was to investigate high-resolution peripheral quantitative computed tomography (HRpQCT) data from the distal tibia and distal radius in 24 study patients that had been randomized to receive either two injections of denosumab 60 mg at baseline and after 6 months (n=10) or no treatment (n=14). Results: Consistent with the full trial findings, denosumab reduced biomarkers of bone turnover, and significantly increased aBMD at the lumbar spine (median difference of 4.7%; 95% confidence interval [CI] 2.6 - 7.8; p<0.001). Bone quality as assessed by total and cortical volumetric bone mineral density (Tot. vBMD, Ct.vBMD) and cortical thickness (Ct.Th) increased significantly at the tibia, while changes at the radius were less pronounced. The trabecular volumetric BMD (Tb.vBMD), thickness (Tb. Th), separation (Tb.Sp) and number (Tb.N) and the cortical porosity (Ct.Po) at the tibia and the radius did not significantly change in both treatment groups. Micro-finite element analysis (µFEA) showed that bone stiffness increased significantly at the tibia (median difference 5.6%; 95% CI 1.8% - 9.2%; p=0.002) but not at the radius (median difference 2.9%, 95% CI -3.7% - 9.1%; p=0.369). Likewise, failure load increased significantly at the tibia (median difference 5.1%; 95% CI 2.1% - 8.1%; p=0.002) but not at the radius (median difference 2.4%, 95% CI -3.2% - 8.5%; p=0.336). Conclusions: These findings demonstrate that denosumab improves bone density and bone quality in first-year kidney transplant recipients at risk to develop osteoporosis.

Knochenstoffwechsel nach Nierentransplantation

“…Ein neues Konzept in der Behandlung der TO stellt möglicherweise die RANK-Ligandenblockade mittels des monoklonalen Antikörpers Denosumab dar. Bonani et al (38,39) veröffentlichte 2016 zum ersten Mal dessen Anwendung in einer offenen, prospektiv randomisierten Studie über zwölf Monate in inzidenten (de novo) nierentransplantierten Patienten (n = 90). Diese Therapie führte zu einer signifikanten Erhöhung der Knochendichte an allen gemessen Arealen sowie zu einem Abfall der Serummarker für die Knochenformation und Knochenresorption, inklusive des Parathormons, im Vergleich zu Placebo.…”

“…Bei 24 Patienten aus dieser Studie wurde additiv eine hochauflösende periphere quantitative Computertomografie an der Tibia und am Radius durchgeführt. Knochenqualitativ zeigte sich allerdings nur eine Verbesserung der totalen und kortikalen volumetrischen Knochendichte (Tibia > Radius) sowie der Knochensteifigkeit insbesondere an der Tibia (39). Frakturanalysen liegen derzeit noch nicht vor.…”

“…Überblick über die Effekte der Therapieoptionen (25-32, 34-39)Table Overview of therapy options(25)(26)(27)(28)(29)(30)(31)(32)(34)(35)(36)(37)(38)(39) …”

New Molecules Modulating Bone Metabolism – New Perspectives in the Treatment of Osteoporosis

“…Biological therapy has a good potential for increasing bone mass. The monoclonal antibody against RANKL, denosumab has positive effects on the microarchitecture of the skeleton (inhibition of erosion development and increase in cortical thickness and bone stiffness) (Bonani et al 2016). Kamimura et al (2017) showed inhibition of bone resorption and an increase in lumbar and hip BMD after one year of treatment with denosumab in patients unresponsive to bisphosphonate.…”

Is there a practical role for a virtual bone biopsy using high‐resolution imaging of bone in patients with chronic kidney disease?

“…Bone loss occurred in all subjects in this study, but was significantly greater among those with incident fractures. The potential role of high resolution imaging and FEA in therapeutic interventional trials has been illustrated by Bonani et al in a small randomised controlled trial of the effect of denosumab on bone microarchitecture and mechanical competence, assessed by HR‐pQCT, in kidney transplant recipients. Participants in the treatment group showed increased total and cortical vBMD, cortical thickness and bone stiffness compared to control group.…”