Gonadal Hormones in the Pathogenesis and Treatment of Bone Health in Patients with Chronic Kidney Disease: a Systematic Review and Meta-Analysis

Purpose of Review

Patients with chronic kidney disease (CKD) have a greatly increased fracture risk compared with the general population. Gonadal hormones have an important influence on bone mineral density (BMD) and fracture risk, and hormone therapies can significantly improve these outcomes. Gonadal dysfunction is a frequent finding in patients with CKD; yet, little is known about the impact of gonadal hormones in the pathogenesis and treatment of bone health in patients with CKD. This systematic review and meta-analysis aimed to examine the effects of gonadal hormones and hormone therapies on bone outcomes in men and women with CKD.

Methods

EMBASE, MEDLINE, SCOPUS, and clinical trial registries were systematically searched from inception to February 14, 2018 for studies that assessed gonadal hormones or hormone treatments with bone outcomes in patients with CKD stage 3–5D. Two independent reviewers screened the titles and abstracts of search results according to inclusion criteria and assessed study quality and risk of bias using validated assessment tools.

Recent Findings

Thirteen studies met the inclusion criteria. Six moderate-to-high quality observational studies showed inconsistent association between any gonadal hormone and bone outcomes, limited by significant study heterogeneity. Five moderate-high risk of bias interventional studies examined treatment with selective oestrogen receptor modulators in post-menopausal women (four using raloxifene and one bazedoxifene) and demonstrated variable effects on BMD and fracture outcomes. Meta-analysis of raloxifene treatment in post-menopausal women demonstrated improvement in lumbar spine (SMD 3.30; 95% CI 3.21–3.38) and femoral neck (SMD 3.29; 95% CI 3.21–3.36) BMD compared with placebo. Transdermal oestradiol/norethisterone in pre-menopausal women receiving dialysis (n?=?1 study), demonstrated BMD improvement over 12 months. Testosterone treatment for 6 months in dialysis-dependant men (n?=?1 study) did not improve BMD.

Summary

There is evidence that raloxifene treatment may be beneficial in improving BMD in post-menopausal women with CKD. There is insufficient evidence for other hormone treatments in men or women. Despite high fracture rates and frequent gonadal dysfunction in patients with CKD, significant evidence gaps exist, and well-designed studies are required to specifically assess the impact of gonadal status in the pathogenesis of CKD-related bone fragility and its treatment.

     

Comparison of catheter tip migration using flexible and stimulating catheters inserted into the adductor canal in a cadaver model

Use of adductor canal blocks and catheters for perioperative pain management following total knee arthroplasty is becoming increasingly common. However, the optimal equipment, timing of catheter insertion, and catheter dislodgement rate remain unknown. A previous study has suggested, but not proven, that non-tunneled stimulating catheters may be at increased risk for catheter migration and dislodgement after knee manipulation. We designed this follow-up study to directly compare tip migration of two catheter types after knee range of motion exercises. In a male unembalmed human cadaver, 30 catheter insertion trials were randomly assigned to one of two catheter types: flexible or stimulating. All catheters were inserted using an ultrasound-guided short-axis in-plane technique. Intraoperative knee manipulation similar to that performed during surgery was simulated by five sequential range of motion exercises. A blinded regional anesthesiologist performed caliper measurements on the ultrasound images before and after exercise. Changes in catheter tip to nerve distance (p = 0.547) and catheter length within the adductor canal (p = 0.498) were not different between groups. Therefore, catheter type may not affect the risk of catheter tip migration when placed prior to knee arthroplasty.     

A Phase II Study of Telisotuzumab Vedotin in Patients With c–MET-positive Stage IV or Recurrent Squamous Cell Lung Cancer (LUNG-MAP Sub-study S1400K,NCT03574753)

IntroductionLung-MAP S1400K was designed to evaluate the response to telisotuzumab vedotin, an antibody-drug conjugate targeting c-MET, in patients with c-MET–positive squamous cell carcinoma (SCC).Patients and MethodsPatients with previously treated SCC with c-MET–positive tumors (H score ≥ 150, Ventana SP44 assay) were enrolled into 2 cohorts: Cohort 1 (immune checkpoint inhibitor-naive) and Cohort 2 (immune checkpoint inhibitor refractory). Telisotuzumab vedotin 2.7 mg/kg was administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Response assessments were performed every 6 weeks. The primary endpoint was response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included progression-free survival, overall survival, response within cohort, duration of response, and toxicities. Interim analysis was planned after 20 evaluable patients, with ≥ 3 responses needed to continue enrollment.ResultsForty-nine patients (14% of screened patients) were assigned to S1400K, 28 patients enrolled (15 in Cohort 1 and 13 in Cohort 2), and 23 were eligible. S1400K closed on December 21, 2018 owing to lack of efficacy. Two responses (response rate of 9%; 95% confidence interval, 0%-20%) were reported in cohort 1 (1 complete and 1 unconfirmed partial response), whereas 10 patients had stable disease, with a disease control rate of 52%. The median overall and progression-free survival was 5.6 and 2.4 months, respectively. There were 3 grade 5 events (2 pneumonitis, in Cohort 2, and 1 bronchopulmonary hemorrhage, in Cohort 1).ConclusionTelisotuzumab vedotin failed to meet the pre-specified response needed to justify continuing enrollment to S1400K. Pneumonitis was an unanticipated toxicity observed in patients with SCC.