Follow-up of bone mineral density changes in de novo kidney transplant recipients treated with two doses of the receptor activator of nuclear factor κB ligand inhibitor denosumab

BACKGROUND: Studies in women with post-menopausal osteoporosis have shown that discontinuation of treatment with denosumab leads to an increased risk of vertebral fractures because of rebound bone turnover and rapid loss of bone mineral density (BMD). METHODS: In a post hoc analysis of the Prolia for Osteoporosis of Transplant Operated Patient study, we analyzed the effect of denosumab withdrawal on BMD changes. Twenty-five de novo kidney transplant recipients (KTR) who were treated for 1 year with 2 six-monthly doses of denosumab on top of standard treatment (daily calcium and vitamin D) were compared to a control group of 29 KTR who received standard treatment alone. BMD changes were analyzed by repeated dual-energy X-ray absorptiometry shortly after transplantation (baseline), after 6 and 12 months (active treatment phase) and after 2-6.5 years (follow-up phase). RESULTS: The average BMD at the lumbar spine declined markedly after discontinuation of treatment with denosumab but increased again thereafter. Thus, the average monthly change in lumbar spine BMD from month 12 onward was only 0.1 ± 2.8‰ in the denosumab group but 1.5 ± 1.9‰ in the control group (p = 0.021). The average monthly change in lumbar spine BMD from baseline to follow-up was similar in the control and denosumab group (1.1 ± 1.2‰ vs. 1.5 ± 2.4‰, p = 0.788). Similar results were seen at the total hip. CONCLUSIONS: In de novo KTR treated with 2 doses of denosumab, we detect a marked decrease in lumbar spine and hip BMD when denosumab is discontinued. Denosumab treatment should therefore not be discontinued without considering an alternative antiresorptive treatment

Relationship of serum bicarbonate levels with 1-year graft function in kidney transplant recipients in Switzerland

BACKGROUND: Metabolic acidosis (MA) is common in kidney transplant recipients (KTRs). Several studies have shown that MA is involved in the progression of chronic kidney disease. However, it is unclear if there is also a relationship between serum bicarbonate and graft function after kidney transplantation (KTx). We hypothesized that low serum bicarbonate is associated with a lower estimated glomerular filtration rate (eGFR) 1 year after KTx. METHODS: We performed a post hoc analysis of a single-center, open-label randomized trial in 90 KTRs and investigated the relationship of serum bicarbonate and graft function in the first year after KTx. RESULTS: Prevalence of MA was high after KTx (63%) and decreased to 28% after 1 year. Bicarbonate (20.6 ± 3.0 to 22.7 ± 2.7 mmol/L) increased in the first year after transplantation whereas eGFR (53.4 ± 15.8 to 56.9 ± 18.5 mL/min/1.73 m2) did not change significantly. Higher serum bicarbonate (p = 0.029) was associated with higher eGFR in the first year after KTx. CONCLUSION: Prevalence of MA is high in KTRs. In the first year after KTx, serum bicarbonate was positively correlated with eGFR, suggesting a potential role of MA in kidney graft function

Optimization of 68Ga production at an 18 MeV medical cyclotron with solid targets by means of cross-section measurement of 66Ga, 67Ga and 68Ga.

The future development of personalized nuclear medicine relies on the availability of novel medical radionuclides. In particular, radiometals are attracting considerable interest since they can be used to label both proteins and peptides. Among them, the β+-emitter 68Ga is widely used in nuclear medicine for positron emission tomography (PET). It is used in theranostics as the diagnostic partner of the therapeutic β--emitters 177Lu and 90Y for the treatment of a wide range of diseases, including prostate cancer. Currently, 68Ga is usually obtained via 68Ge/68Ga generators. However, their availability, high price and limited produced radioactivity per elution are a major barrier for a wider use of the 68Ga-based diagnostic radiotracers. A promising solution is the production of 68Ga by means of proton irradiation of enriched 68Zn liquid or solid targets. Along this line, a research program is ongoing at the Bern medical cyclotron, equipped with a solid target station. In this paper, we report on the measurements of 68Ga, 67Ga and 66Ga production cross-sections using natural Zn and enriched 68Zn material, which served as the basis to perform optimized 68Ga production tests with enriched 68Zn solid targets

Predictive Power of Bone Turnover Biomarkers to Estimate Bone Mineral Density after Kidney Transplantation with or without Denosumab: A post hoc Analysis of the POSTOP Study

BACKGROUND Low bone mineral density (BMD) represents a major risk factor for bone fractures in patients with chronic kidney disease (CKD) as well as after kidney transplantation. However, modalities to solidly predict patients at fracture risk are yet to be defined. Better understanding of bone turnover biomarkers (BTMs) may close this diagnostic gap. This study strives to correlate BTMs to BMD in kidney transplant recipients. METHODS Changes in BTMs - procollagen type I N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BSAP), β-isomer of the C-terminal telopeptide of type I collagen, and urine deoxypyridinoline/Cr - at the time of transplant and 3 months were correlated to changes in BMD measured by dual-energy X-ray absorptiometry at the time of transplant, 6, and 12 months, respectively. Half of the collective was treated with denosumab twice yearly in addition to the standard treatment with calcium and vitamin D. RESULTS Changes in bone formation markers BSAP and P1NP within 3 months showed a significant negative correlation to changes in BMD at the hip within 6 months in denosumab-naïve patients. This correlation was abrogated by denosumab treatment. CONCLUSIONS Changes in BSAP and P1NP showed promise in short-term prediction of BMD. We suggest further trials expanding on the knowledge of these BTMs with assessment of fracture risk, sequential measurements of BTMs within the first 6 months, and the additional use of computed tomography to assess BMD

Effect of denosumab on trabecular bone score in de novo kidney transplant recipients

BACKGROUND: Kidney transplant recipients (KTR) are at risk to lose bone mass. The trabecular bone score (TBS) represents a recently developed parameter of lumbar spine trabecular bone texture that correlates with the occurrence of fractures. METHODS: We analysed the 1-year changes in TBS in 44 de novo KTR that were randomized 1:1 to denosumab or no treatment. TBS was derived from dual energy X-ray absorptiometry and was correlated with 1-year areal bone mineral density (aBMD) changes at the lumbar spine and total hip. Correlations were also performed with parameters of peripheral bone microarchitecture and bone strength at the distal tibia and distal radius, as assessed by high-resolution peripheral quantitative computed tomography (HRpQCT) and micro-finite element analysis. RESULTS: The baseline TBS in KTR amounted to 1.312 ± 0.101, which is lower than the TBS of an age-matched normal control population (range 1.364-1.471). The TBS correlated positively with aBMD at the lumbar spine (Spearman's ρ = 0.56; P < 0.001) and total hip (ρ = 0.33; P < 0.05). The baseline TBS also correlated with HRpQCT-derived total (ρ = 0.49; P < 0.05) and trabecular volumetric BMD (ρ = 0.57; P < 0.01) and trabecular separation (ρ = -0.46; P < 0.05) at the tibia. Denosumab treatment led to an increase in TBS, paralleling the BMD changes at the lumbar spine. CONCLUSIONS: The TBS is a useful additional score of bone health, which may help to better define fracture risk. Treatment with denosumab led to improved trabecular bone texture in de novo KTR in addition to its beneficial effect on BMD

Effect of Denosumab on Peripheral Compartmental Bone Density, Microarchitecture and Estimated Bone Strength in De Novo Kidney Transplant Recipients

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; pConclusions: These findings demonstrate that denosumab improves bone density and bone quality in first-year kidney transplant recipients at risk to develop osteoporosis

Infections in de novo kidney transplant recipients treated with the RANKL inhibitor denosumab

BACKGROUND: Infections are a major cause of morbidity and mortality in kidney allograft recipients. In this posthoc analysis of a randomized clinical trial which tested the effect of denosumab on bone mineral density we assessed the impact of this drug on the incidence and severity of infections in the first year after kidney transplantation. METHODS: In this clinical trial we randomized 90 de novo kidney transplant recipients shortly after transplantation to either denosumab on top of standard treatment (calcium and vitamin D) (n=46), or to standard treatment alone (n=44). Among all adverse events we analyzed all infections that occurred within the first year after transplantation, and compared their incidence and severity in both groups. RESULTS: Overall we identified more infections (n=146) in the denosumab group than in the control group (n=99). The most common infections were urinary tract infection (cystitis) (34.9% vs 25.2%), CMV viremia (17.8% vs 24.2%), flu-like syndrome (11.6% vs 14.1%), polyoma (BK) viremia (8.2% vs 11.1%), and herpes simplex infections (5.5% vs 4.0%). Episodes of urinary tract infection (cystitis) occurred more often in the denosumab than in the control group (51 vs 25 episodes in 24 vs 11 patients, p=0.008), whereas episodes of transplant pyelonephritis or urosepsis were not more frequent (3 vs 5 episodes). CONCLUSIONS: This post-hoc analysis reveals that treatment with denosumab to prevent bone loss in first-year kidney transplant recipients was associated with more frequent episodes of urinary tract infections, whereas other infections occurred with similar frequency in both treatment groups

Sclerostin blood levels before and after kidney transplantation

BACKGROUND/AIMS: Sclerostin is secreted by osteocytes. As a circulating inhibitor of the Wnt-signaling pathway it inhibits bone formation and contributes to the development of osteoporosis. Sclerostin levels are elevated in patients with chronic kidney disease and end-stage renal disease. Since data for patients after kidney transplantation are scarce, we have prospectively measured sclerostin levels before and during the first year after renal transplantation and have examined the association of sclerostin with parameters of bone mineral metabolism and with bone mineral density. METHODS: Sclerostin levels were measured by ELISA in 42 consecutive renal transplant recipients before and at defined intervals in the first year after transplantation. Bone mineral density was measured by dual energy X-ray absorptiometry. RESULTS: Pre-transplant serum sclerostin levels were elevated in all patients (61.8 ± 32.3 pmol/l, normal range 20-30 pmol/l). Within 15 days after transplantation and correlating with the improvement of renal function, sclerostin levels dropped to 21.0 ± 14.7 pmol/l and subsequently increased to 23.8 ± 14.9 and 28.0 ± 16.8 pmol/l after 6 and 12 months, respectively (P<0.001). A linear mixed model indicated that pre-transplant sclerostin levels (P<0.001) and time after transplantation (P<0.001) were the most important predictors for the rise of post-transplant sclerostin levels. No correlation was found between post-transplant sclerostin levels and bone mineral density. CONCLUSIONS: The rapid reduction of elevated serum sclerostin levels shortly after kidney transplantation parallels the improvement of renal function, but contrasts with the more delayed improvement of hyperparathyroidism. The normalization of both hormones could contribute to improved bone health after renal transplantation

Effect of twice-yearly denosumab on prevention of bone mineral density loss in de novo kidney transplant recipients: a randomized controlled trial

We conducted an open-label, prospective, randomized trial to assess the efficacy and safety of RANKL inhibition with denosumab to prevent the loss of BMD in the first year after kidney transplantation. Ninety kidney transplant recipients were randomized 1:1 two weeks after surgery to receive denosumab (60 mg at baseline and 6 months) or no treatment. After 12 months, total lumbar spine aBMD increased by 4.6% (95% CI 3.3-5.9%) in 46 patients in the denosumab group and decreased by -0.5% (95% CI -1.8-0.9%) in 44 patients in the control group (between-group difference 5.1% (95% CI 3.1-7.0%), P<0.0001). Denosumab also increased aBMD at the total hip by 1.9% (95% CI, 0.1 to 3.7%; P=0.035) over that in the control group at 12 months. HR-pQCT in a subgroup of 24 patients showed that denosumab increased vBMD at the distal tibia and radius (all P<0.05). Biomarkers of bone turnover (β-CTX, P1NP) markedly decreased with denosumab (all P<0.0001). Episodes of cystitis and asymptomatic hypocalcemia occurred more often with denosumab, whereas graft function, rate of rejections and incidence of opportunistic infections were similar. In conclusion, denosumab increased BMD in the first year after kidney transplantation but was associated with more frequent episodes of urinary tract infection. This article is protected by copyright. All rights reserved