A randomised controlled trial to examine the effects of cinacalcet on bone and cardiovascular parameters in haemodialysis patients with advanced secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism may lead to increased cardiovascular risk. The use of cinacalcet may improve bone and cardiovascular health with improved parathormone (PTH) and phosphate control. METHODS: This is an open-label prospective randomised controlled trial to compare progression of cardiovascular and chronic kidney disease mineral and bone disorder (CKD-MBD) parameters. Patients were randomised to receive cinacalcet alongside standard therapy or standard therapy alone. Thirty-six haemodialysis patients who had > 90 days on dialysis, iPTH > 300 pg/mL, calcium > 2.1 mmol/L and age 18-75 years were included. Following randomization, all 36 patients underwent an intensive 12-week period of bone disease management aiming for iPTH 150-300 pg/mL. The primary outcome was change in vascular calcification using CT agatston score. Secondary outcomes included pulse wave velocity (PWV), left ventricular mass index (LVMI), carotid intima-media thickness (CIMT), augmentation index (Aix) and bone measurements. The above measurements were obtained at baseline and 12 months. RESULTS: There was no evidence of a group difference in the progression of calcification (median change (IQR) cinacalcet: 488 (0 to1539); standard therapy: 563 (50 to 1214)). In a post hoc analysis combining groups there was a mean (SD) phosphate reduction of 0.3 mmol/L (0.7) and median (IQR) iPTH reduction of 380 pg/mL (- 754, 120). Regression of LVMI and CIMT was seen (P = 0.03 and P = 0.001) and was significantly associated with change of phosphate on multi-factorial analyses. CONCLUSIONS: With a policy of intense CKD-MBD parameter control, no significant benefit in bone and cardiovascular markers was seen with the addition of cinacalcet to standard therapy over one year. Tight control of hyperphosphataemia and secondary hyperparathyroidism may lead to a reduction in LVMI and CIMT but this needs further investigation. Although the sample size was small, meticulous trial supervision resulted in very few protocol deviations with therapy.

[Iatrogenic non uremic calciphylaxis: A case report]. / Calciphylaxie non urémique iatrogène : une nouvelle observation.

Calciphylaxis is a rare and severe condition, characterized by calcification and thrombosis of small vessels, mainly affecting the skin. It is most often described in patients with end-stage renal disease on dialysis. Rarer cases of non-uremic calciphylaxis are reported. The prognosis is grim and the treatment is not well codified. Sodium thiosulfate has been used for more than a decade in the treatment of uremic calciphylaxis and has been shown to be effective. Its use in non-uremic cases has been reported in a few rare observations. Rheopheresis is a technique very recently used as an adjuvant treatment in uremic calciphylaxis. We describe a case of non-uremic calciphylaxis in a patient with normal renal function and with calcium supplementation. Sodium thiosulfate was introduced, then discontinued due to the patient's poor tolerance for this treatment. Rheopheresis was then used and allowed the acceleration of healing process and a significant reduction in pain. These two treatments are promising, larger studies are needed to establish their effectiveness in non-uremic calciphylaxis.

Case report of a cystic parathyroidal adenoma with rapid growth induced by cinacalcet.

BACKGROUND: Primary hyperparathyroidism is a rare condition of disease which can seldomly present as giant retrotrhyroideal cysts, complicating the localization of the adenoma to resect. CASE PRESENTATION: A 56-year old female presented with hypercalcaemia of 3.38 mmol/L (2.2-2.65 mmol/L) and a history of breast cancer. A fast growing cystic parathyroidal adenoma was diagnosed by a multimodal approach including comprehensive diagnostic imaging (ultrasonography, scintigraphies, dynamic MRI) and cytopathological investigations after ultrasonography-guided puncture. The patient was cured by surgical extraction of the whole adenoma. In retrospect, the rapid growth was most likely induced by cinacalcet (initially 30 mg/d, later 60 mg/d) therapy which the patient received for few months only. Primary hyperparathyroidism was ascertained because surgical removal of the solitary adenoma cured the patient. Furthermore, there was no relevant renal insufficiency or history of prolonged calcium-level deregulation. CONCLUSIONS: This phenomenon of cystic degeneration of parathyroidal adenoma under therapy with cinacalcet has previously been described in secondary hyperparathyroidism, but not in primary hyperparathyroidism and should be considered in diagnostic approach.

Complications of Phosphate and Vitamin D Treatment in X-Linked Hypophosphataemia.

Conventional treatment of X-linked hypophosphataemia (XLH) consists in the oral administration of phosphate plus calcitriol supplements. Although this therapy has reduced bone deformities and even achieved adequate patient growth, overtreatment or low adherence could lead to subsequent consequences that may compromise the efficacy of the therapy. Some of the complications associated with phosphate and vitamin D treatment are abdominal discomfort, diarrhoea, hypokalaemia, hyperparathyroidism, hypercalcaemia or hypercalciuria, nephrocalcinosis or nephrolithiasis, and ectopic calcifications. Therefore, constant multidisciplinary monitoring of patients with XLH is necessary to prevent the manifestation of these complications and to deal with them as soon as they appear. The main objective of this article is to review the main complications arising from conventional treatment of XLH and how to deal with them.

Flash Fabrication of Orally Targeted Nanocomplexes for Improved Transport of Salmon Calcitonin across the Intestine.

Salmon calcitonin (sCT) is a potent calcium-regulating peptide hormone and widely applied for the treatment of some bone diseases clinically. However, the therapeutic usefulness of sCT is hindered by the frequent injection required, owing to its short plasma half-life and therapeutic need for a high dose. Oral delivery is a popular modality of administration for patients because of its convenience to self-administration and high patient compliance, while orally administered sCT remains a great challenge currently due to the existence of multiple barriers in the gastrointestinal (GI) tract. Here, we introduced an orally targeted delivery system to increase the transport of sCT across the intestine through both the paracellular permeation route and the bile acid pathway. In this system, sCT-based glycol chitosan-taurocholic acid conjugate (GC-T)/dextran sulfate (DS) ternary nanocomplexes (NC-T) were produced by a flash nanocomplexation (FNC) process in a kinetically controlled mode. The optimized NC-T exhibited well-controlled properties with a uniform and sub-60 nm hydrodynamic diameter, high batch-to-batch reproducibility, good physical or chemical stability, as well as sustained drug release behaviors. The studies revealed that NC-T could effectively improve the intestinal uptake and permeability, owing to its surface functionalization with the taurocholic acid ligand. In the rat model, orally administered NC-T showed an obvious hypocalcemia effect and a relative oral bioavailability of 10.9%. An in vivo assay also demonstrated that NC-T induced no observable side effect after long-term oral administration. As a result, the orally targeted nanocomplex might be a promising candidate for improving the oral transport of therapeutic peptides.

Effects of teriparatide in Chinese and Caucasian women with osteoporosis: bridging study on efficacy.

OBJECTIVE: To bridge the efficacy and compare the safety of the 24-week teriparatide treatment in a Chinese osteoporosis study (NCT00414973) to a large international trial (FPT, NCT00670501) to determine whether long-term results from the international study were applicable to Chinese patients. METHODS: In this post-hoc analysis, a propensity score matching method was used to select patients with similar baseline characteristics. Patients were female with osteoporosis at high risk of fracture, aged ≥55 years, and had no history of rheumatoid arthritis or corticosteroid use. Outcomes included percentage changes in lumbar-spine bone mineral density (LS-BMD) from baseline to 24 weeks, safety in matched-pair patients, and long-term percentage changes in LS-BMD and fragility fracture incidence in the matched fracture prevention trial (FPT) population. The determination of the acceptability of bridging results was based on the International Conference on Harmonization E5 guidelines. RESULTS: A total number of 228 patients from each study were matched and paired. Patients were similar at baseline (P-values >0.33) except for ethnicity (98% Caucasian for FPT). For changes in LS-BMD from baseline to week 24, treatment with teriparatide showed significantly greater increases (P-values <0.001; least-squares mean difference: 5.0% in the Chinese study and 5.4% in FPT) than comparator (calcitonin/placebo). The safety profiles over 24 weeks were similar between two studies. For matched-pair FPT patients, long-term changes in LS-BMD were significantly greater (least-squares mean difference: 11.5%, P<0.001) and the fragility fracture rate was marginally lower in the teriparatide group compared with the placebo group (13.1% vs 22.3%, P=0.070). CONCLUSION: Assuming similar pharmacokinetic profiles for teriparatide between populations, comparable increases in LS-BMD and consistent safety profiles within 24 weeks of the treatment suggest long-term LS-BMD results from the FPT may be applicable to Chinese population.

Efficacy and safety of elcatonin in postmenopausal women with osteoporosis: a systematic review with network meta-analysis of randomized clinical trials.

The present systematic review aimed to evaluate bone mineral density (BMD) change and complication rates of elcatonin on treating postmenopausal osteoporosis. The result confirmed efficacy of elcatonin and safety in combination therapies of elcatonin (C-E). INTRODUCTION: Postmenopausal osteoporosis is an important issue in global aging trends. One treatment of osteoporosis is elcatonin, a kind of calcitonin. However, it has been challenged for long time because of safety. Many trials investigated on this topic, but they were designed differently. Those designs can be categorized in monotherapy of elcatonin (M-E) and C-E. Unfortunately, no synthesized evidence dealt this topic. METHODS: This study systematically identified target trials from six important databases and only included randomized controlled trial for synthesis. Two investigators assessed quality of eligible trials using the Cochrane Risk of Bias Tool, and they independently extracted data. Network meta-analysis performed Peto odds ratio (POR, used for dealing with zero cell) or weighted mean difference (WMD, for continuous data) with 95% confidence intervals (CI) and consistency H. RESULTS: Sixteen trials recruiting 2754 women with postmenopausal osteoporosis were included in our study. Elcatonin therapies and non-elcatonin medications had comparable fracture rates and bone mineral density change. Yet, C-E (WMD, - 18.93; 95% CI, - 23.97 to - 13.89) and M-E (WMD, - 13.72; 95% CI, - 19.51 to - 7.94) had significantly lower pain score than non-elcatonin medications. However, M-E (POR = 8.413, 95% CI, 2.031 to 34.859) and non-elcatonin medication (Peto OR, 7.450; 95% CI, 1.479 to 37.530) had significantly higher complication rates than placebo. No evidence detected inconsistency and small study effect in this network model. CONCLUSIONS: Based on current evidence, C-E may be considered for treating postmenopausal osteoporosis because it benefits on pain relief and complications. Moreover, it shows comparable fracture rate and bone mineral density change as compared with anti-osteoporosis and calcium supplements. Nevertheless, further trials are needed to investigate formula and dosages of elcatonin.

Pharmacokinetics of a New Pharmaceutical Form of Vitamin D3 100,000 IU in Soft Capsule.

Vitamin D deficiency is frequent in the general population and both subjects and health professionals could benefit from a broader range of vitamin D3 formulations. We conducted a single-dose, open-label, parallel-group, randomized bioequivalence study to compare a single dose of a newly developed vitamin D3 100,000 IU in a soft capsule (Group 1) with the reference drug vitamin D3 100,000 IU oral solution in ampoule (Group 2) in healthy volunteers over a four-month period. The primary endpoint was the area under the curve (AUC) of serum 25-hydroxyvitamin-D (25(OH)D) concentrations on Day 112. This study was conducted in France from February to June 2014 in 53 young adults with a mean age of 26.9 years. At baseline, low mean serum 25(OH)D levels were observed in both groups (10.6 ng/mL in Group 1 and 9.0 ng/mL in Group 2). On Day 112, the AUC of serum 25(OH)D concentration was 2499.4 ± 463.8 nmol/mL (7.8 ± 0.2 for LogAUC) for Group 1 and 2152.3 ± 479.8 nmol/mL (7.6 ± 0.2 for LogAUC) for Group 2. Bioequivalence of the two treatments was not demonstrated. Superiority of vitamin D3 100,000 IU soft capsule was observed with p = 0.029 for AUC and p = 0.03 for LogAUC using a non-parametric Wilcoxon test. The profile of the serum 25(OH)D concentration showed a significant difference in favor of Group 1 on Days 1, 3, 7, 14 and 90. Mean serum 25(OH)D concentrations in Group 1 were between 20 and 30 ng/mL during the four-month period and under 20 ng/mL throughout the study in Group 2, except on Day 112. Mean Cmax for Group 1 was significantly higher (p = 0.002). Fourteen days were needed to reach Tmax by more than half the subjects in Group 1 compared to 45 days in Group 2. Both treatments were well tolerated, with no severe or related adverse events reported. In conclusion, the pharmacokinetic profile of the new formulation of vitamin D3 100,000 IU soft capsule is superior to that of the oral solution in ampoule. The new formulation increased serum 25(OH)D levels to above 20 ng/mL and maintained levels from 20 ng/mL to 30 ng/mL for four months in late winter and spring.