Diana Frey

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 bone mineral density (BMD) in the first year after kidney transplantation. Ninety kidney transplant recipients were randomized 1:1 2 weeks after surgery to receive denosumab (60 mg at baseline and 6 months) or no treatment. After 12 months, total lumbar spine areal BMD (aBMD) increased by 4.6% (95% confidence interval [CI] 3.3–5.9%) in 46 patients in the denosumab group and decreased by −0.5% (95% CI −1.8% to 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, 0.1–3.7%; p = 0.035) over that in the control group at 12 months. High‐resolution peripheral quantitative computed tomography in a subgroup of 24 patients showed that denosumab increased volumetric BMD at the distal tibia and radius (all p < 0.05). Biomarkers of bone turnover (C‐terminal telopeptide of type I collagen, procollagen type I N‐terminal propeptide) 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.

Prediction of low bone mineral density in patients with inflammatory bowel diseases

Background Low bone mineral density (BMD) remains a frequent problem in patients with inflammatory bowel diseases (IBD). There is no general agreement regarding osteoporosis screening in IBD patients. Methods Cases of low BMD and disease characteristics were retrieved from 3172 patients of the Swiss IBD cohort study. Multivariate logistic regression analysis was conducted for predictive modeling. In a subgroup of 877 patients, 253 dual-energy X-ray absorptiometry (DXA) scans were available for validation. Results Low BMD was prevalent in 19% of patients. We identified seven predictive factors: type of IBD, age, recent steroid usage, low body mass index, perianal disease, recent high disease activity and malabsorption syndrome. Low BMD could be predicted with a sensitivity of 79% and a specificity of 64%, a positive predictive value (PPV) of 35% and a negative predictive value (NPV) of 93%. The area under the curve of the receiver operating characteristics was 0.78. In the validation cohort we calculated a PPV of 26% and an NPV of 88%. Conclusion We provide a comprehensive analysis of risk factors for low BMD and propose a predictive model with seven clinical variables. The high NPV of models such as ours might help in excluding low BMD to prevent futile investigations.

Osteoporosebehandlung: Bisphosphonate, SERM’s, Teriparatide und Strontium

Zusammenfassung.Zur Therapie der Osteoporose stehen hauptsächlich antiresorptive Substanzen, insbesondere Bisphosphonate, zur Verfügung. Aus dieser Gruppe sind aktuell Alendronat und Risedronat als Wochentabletten auf dem Markt, die gegenüber der täglichen Verabreichung den Vorteil von weniger unerwünschten Wirkungen wie Unverträglichkeiten des oberen Gastrointestinaltrakts, aufweisen. Diese Medikamente sind sowohl bei postmenopausalen Frauen als auch bei Männern einsetzbar. Für beide Substanzen konnte eine signifikante Zunahme der Knochendichte und Abnahme neuer Wirbelfrakturen dokumentiert werden. Intravenös verabreichte Bisphosphonate (Zoledronat, Ibandronat, Pamidronat) bleiben in der Regel speziellen Indikationen vorbehalten (Skelettmetastasen, Unverträglichkeit der peroralen Therapie). Die selektiven Oestrogenrezeptor-Modulatoren (SERMs), von denen Raloxifen als Antiresorptivum gut dokumentiert ist, bewirken bei postmenopausalen Frauen mit Osteoporose nicht nur eine Reduktion von Wirbelkörperfrakturen, sondern als günstigen Nebeneffekt auch eine signifikante Senkung der Mammakarzinomrate.Teriparatide, die rekombinante Form des humanen Parathormons rhPTH (1–34), ist ein Vertreter einer knochenaufbaustimulierenden Substanz. Teriparatide führt bei postmenopausalen Frauen sowohl zu einer signifikanten Erhöhung der lumbalen und femoralen Knochendichte als auch zu einer Reduktion von Wirbel- und Nicht-Wirbelfrakturen. Die genaue Rolle von Teriparatide für den klinischen Alltag ist vorläufig noch nicht ganz klar; durch seinen schnellen Wirkungseintritt könnte es jedoch zu einer wichtigen Therapiemöglichkeit bei Osteoporose werden.Neue Resultate mit Strontiumranelate, einem komplexen Salz mit gleichzeitig antiresorptiven und knochenaufbaustimulierenden Effekten sind auch für den Kliniker sehr interessant, wobei die Wirksamkeit dieser Substanz in weiteren kontrollierten Studien spezifisch geprüft werden sollte.Summary.The therapy of osteoporosis is mostly based upon the use of drugs which inhibit bone resorption. Among these, the bisphosphonate family is the best known and mostly used by clinicians. Both second and third generation bisphosphonates, like alendronate and risedronate, are now available as weekly tablets which have facilitated the patient compliance to treatment together with a decreased occurrence of gastrointestinal side effects. These compounds are used efficiently to treat postmenopausal osteoporosis and osteoporosis of men as well. Their use did provide good evidence of increased bone mineral density (BMD) and a reduction in fracture rates. The use of intravenous bisphosphonates such as Zoledronate, Ibandronate and Pamidronate remains in most of the cases limited to special indications such as intolerance to the oral formulations and treatment of patients with bone metastases. The selective estrogen modulators (SERM’s) family is limited to a single product on the market as of now, Raloxifene, which does inhibit bone resorption and is well documented by postmenopausal women to increase BMD and reduce vertebral fractures. In addition, a large range of positive nonosseous effects have been documented such as the reduction of the incidence of breast cancer. Other substances do have a strong anabolic effect such as Teriparatide, a recombinant human formulation of PTH 1–34. This compound has demonstrated good efficacy in postmenopausal women, increasing vertebral and hip BMD and reducing the incidence of fractures at both sites. The exact role of Teriparatide in the clinical setting is still open but its overall impact in the therapy of osteoporosis could be major due to its major efficiency over shorter periods of time. Strontium ranelate, a new divalent Strontium salt taken orally, acts both as an anti-catabolic and anabolic agent. The first results provided with strontium ranelate are very promising due to its major effect on the increase in BMD both at the vertebral and hip sites and its ability to reduce the incidence of fractures at both locations. Additional data are awaited to confirm these initial positive results.

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 post hoc 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%), cytomegalovirus 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.

Osteoporosis drug treatment: duration and management after discontinuation. A position statement from the SVGO/ASCO.

Antiosteoporotic drugs are recommended in patients with fragility fractures and in patients considered to be at high fracture risk on the basis of clinical risk factors and/or low bone mineral density. As first-line treatment most patients are started with an antiresorptive treatment, i.e. drugs that inhibit osteoclast development and/or function (bisphosphonates, denosumab, oestrogens or selective oestrogen receptor modulators). In the balance between benefits and risks of antiresorptive treatment, uncertainties remain regarding the optimal treatment duration and the management of patients after drug discontinuation. Based on the available evidence, this position statement will focus on the long-term management of osteoporosis therapy, formulating decision criteria for clinical practice.

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; 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.

[Therapy of osteoporosis: bisphosphonates, SERM's, teriparatide and strontium].

Zusammenfassung.Zur Therapie der Osteoporose stehen hauptsächlich antiresorptive Substanzen, insbesondere Bisphosphonate, zur Verfügung. Aus dieser Gruppe sind aktuell Alendronat und Risedronat als Wochentabletten auf dem Markt, die gegenüber der täglichen Verabreichung den Vorteil von weniger unerwünschten Wirkungen wie Unverträglichkeiten des oberen Gastrointestinaltrakts, aufweisen. Diese Medikamente sind sowohl bei postmenopausalen Frauen als auch bei Männern einsetzbar. Für beide Substanzen konnte eine signifikante Zunahme der Knochendichte und Abnahme neuer Wirbelfrakturen dokumentiert werden. Intravenös verabreichte Bisphosphonate (Zoledronat, Ibandronat, Pamidronat) bleiben in der Regel speziellen Indikationen vorbehalten (Skelettmetastasen, Unverträglichkeit der peroralen Therapie). Die selektiven Oestrogenrezeptor-Modulatoren (SERMs), von denen Raloxifen als Antiresorptivum gut dokumentiert ist, bewirken bei postmenopausalen Frauen mit Osteoporose nicht nur eine Reduktion von Wirbelkörperfrakturen, sondern als günstigen Nebeneffekt auch eine signifikante Senkung der Mammakarzinomrate.Teriparatide, die rekombinante Form des humanen Parathormons rhPTH (1–34), ist ein Vertreter einer knochenaufbaustimulierenden Substanz. Teriparatide führt bei postmenopausalen Frauen sowohl zu einer signifikanten Erhöhung der lumbalen und femoralen Knochendichte als auch zu einer Reduktion von Wirbel- und Nicht-Wirbelfrakturen. Die genaue Rolle von Teriparatide für den klinischen Alltag ist vorläufig noch nicht ganz klar; durch seinen schnellen Wirkungseintritt könnte es jedoch zu einer wichtigen Therapiemöglichkeit bei Osteoporose werden.Neue Resultate mit Strontiumranelate, einem komplexen Salz mit gleichzeitig antiresorptiven und knochenaufbaustimulierenden Effekten sind auch für den Kliniker sehr interessant, wobei die Wirksamkeit dieser Substanz in weiteren kontrollierten Studien spezifisch geprüft werden sollte.Summary.The therapy of osteoporosis is mostly based upon the use of drugs which inhibit bone resorption. Among these, the bisphosphonate family is the best known and mostly used by clinicians. Both second and third generation bisphosphonates, like alendronate and risedronate, are now available as weekly tablets which have facilitated the patient compliance to treatment together with a decreased occurrence of gastrointestinal side effects. These compounds are used efficiently to treat postmenopausal osteoporosis and osteoporosis of men as well. Their use did provide good evidence of increased bone mineral density (BMD) and a reduction in fracture rates. The use of intravenous bisphosphonates such as Zoledronate, Ibandronate and Pamidronate remains in most of the cases limited to special indications such as intolerance to the oral formulations and treatment of patients with bone metastases. The selective estrogen modulators (SERM’s) family is limited to a single product on the market as of now, Raloxifene, which does inhibit bone resorption and is well documented by postmenopausal women to increase BMD and reduce vertebral fractures. In addition, a large range of positive nonosseous effects have been documented such as the reduction of the incidence of breast cancer. Other substances do have a strong anabolic effect such as Teriparatide, a recombinant human formulation of PTH 1–34. This compound has demonstrated good efficacy in postmenopausal women, increasing vertebral and hip BMD and reducing the incidence of fractures at both sites. The exact role of Teriparatide in the clinical setting is still open but its overall impact in the therapy of osteoporosis could be major due to its major efficiency over shorter periods of time. Strontium ranelate, a new divalent Strontium salt taken orally, acts both as an anti-catabolic and anabolic agent. The first results provided with strontium ranelate are very promising due to its major effect on the increase in BMD both at the vertebral and hip sites and its ability to reduce the incidence of fractures at both locations. Additional data are awaited to confirm these initial positive results.

Widely differing screening and treatment practice for osteoporosis in patients with inflammatory bowel diseases in the Swiss IBD cohort study

Abstract Low bone mineral density (BMD) and osteoporosis remain frequent problems in patients with inflammatory bowel diseases (IBDs). Several guidelines with nonidentical recommendations exist and there is no general agreement regarding the optimal approach for osteoporosis screening in IBD patients. Clinical practice of osteoporosis screening and treatment remains insufficiently investigated. In the year 2014, a chart review of 877 patients included in the Swiss IBD Cohort study was performed to assess details of osteoporosis diagnostics and treatment. BMD measurements, osteoporosis treatment, and IBD medication were recorded. Our chart review revealed 253 dual-energy x-ray absorptiometry (DXA) scans in 877 IBD patients; osteoporosis was prevalent in 20% of tested patients. We identified widely differing osteoporosis screening rates among centers (11%–62%). A multivariate logistic regression analysis identified predictive factors for screening including steroid usage, long disease duration, and perianal disease; even after correction for all risk factors, the study center remained a strong independent predictor (odds ratio 2.3–21 compared to the center with the lowest screening rate). Treatment rates for patients with osteoporosis were suboptimal (55% for calcium, 65% for vitamin D) at the time of chart review. Similarly, a significant fraction of patients with current steroid medication were not treated with vitamin D or calcium (treatment rates 53% for calcium, 58% for vitamin D). For only 29% of patients with osteoporosis bisphosphonate treatment was started. Treatment rates also differed among centers, generally following screening rates. In patients with longitudinal DXA scans, calcium and vitamin D usage was significantly associated with improvement of BMD over time. Our analysis identified inconsistent usage of osteoporosis screening and underuse of osteoporosis treatment in IBD patients. Increasing awareness of osteoporosis as a significant clinical problem in IBD patients might improve patient care.

Metabolic response to three different diets in lean cats and cats predisposed to overweight

BackgroundThe existence of a genetic predisposition to obesity is commonly recognized in humans and rodents. Recently, a link between genetics and overweight was shown in cats. The goal of this study was to identify the effect of diet composition on plasma levels of glucose, insulin, free fatty acids and triglycerides in cats receiving different diets (high-carbohydrate, high-fat and high-protein diets).ResultsInsulin and leptin concentrations were significantly correlated with phenotype. Insulin levels were lower, whereas leptin levels were higher in cats predisposed to overweight. The other blood parameters were not correlated with phenotype. Intake of the high-carbohydrate diet resulted in higher insulin concentrations compared with the two other diets. Insulin levels were within the values described for non-obese cats in previous studies.ConclusionsThere was no difference in metabolic response between the two groups. As the high-carbohydrate diet led to the highest insulin blood concentrations, it might be useful to avoid such diets in cats predisposed to overweight. In addition, even cats with genetically linked obesity can regain insulin sensitivity after weight loss.