Colorado Center for Bone Research

To provide expert recommendations for side effect management in patients with bladder cancer receiving intravesical-drug releasing system (iDRS) treatment and for optimizing iDRS insertion procedure success. Indwelling iDRS are designed to provide sustained local exposure to therapy. In clinical trials, frequent side effects of iDRS treatment were lower urinary tract symptoms (LUTS) (e.g., dysuria, pollakiuria, micturition urgency), urinary tract infections (UTIs), and hematuria. These side effects are generally low grade, but if not properly managed, may lead to treatment interruptions or discontinuations. As data are limited, practical recommendations based on expert opinion for the management of common side effects and best practices for iDRS insertion procedures may improve treatment adherence and optimize outcomes in patients with bladder cancer receiving iDRS. Two separate expert panels were convened to develop recommendations for side effect management with iDRS and optimizing iDRS insertion procedure success. Stepwise treatment-specific management strategies for LUTS, UTIs, and hematuria in patients receiving iDRS treatment that are familiar to practicing urologists are presented, including considerations for continuation or discontinuation of iDRS treatment. Several advanced techniques can be considered to improve iDRS insertions based on variations in patient anatomy.

With the aim to develop a novel multifunctional gene delivery system that may overcome the common barriers of gene transfection, near-infrared fluorescent triphenylamine-pyrazine was modified with a DNA condensing triazole-[12]aneN3 moiety through different length alkyl ester linkages to afford three new non-viral gene vectors, TDM-A/B/C. All compounds showed prominent solvatochromic fluorescence (Stokes shift of up to 383 nm) and two-photon absorption properties (σ2P to 101 GM), and exhibited strong aggregation-induced emission (AIE). Gel electrophoresis demonstrated that plasmid DNA was completely condensed at a concentration of 10 μM (TDM-A), 14 μM (TDM-B) and 16 μM (TDM-C), and released in esterase and acidic environment. SEM demonstrated that the three compounds were able to self-assemble and co-aggregate with DNA to form regular nanoparticles. Experiments demonstrated that TDM-A/B/C was able to integrate with DNA through electrostatic interactions and supramolecular stacking, and the short alkyl linkage favored the strong interaction with DNA. Among the three compounds, TDM-B showed the best luciferase and GFP transfection activities in the presence of DOPE, which were 156% and 310% higher than those of Lipo2000, respectively. The transfection process of DNA was clearly traced through one- and two-photon fluorescence microscopy imaging. Cellular uptake inhibition assay indicated that the DNA complex entered the cell mainly via clathrin-independent endocytosis. Furthermore, the in vivo transfection experiments of TDM-B/DOPE were successfully implemented in zebra fish embryos, and the GFP gene expression level was superior to that of Lipo2000 (200%). Finally, this study clearly unraveled that the length of the alkyl linkage affected the DNA condensation and transfection activity, which can serve as a base for the future rational design of non-viral gene vectors.

The original version of this article, published on 21 March 2019, unfortunately contains some typos in Figs. 2, 3, 4, and Supplemental Fig. 1. The corrected figures are given below.

We conducted a patient-level pooled analysis of four studies to estimate the efficacy and safety of transitioning to denosumab vs. continuing bisphosphonate treatment in postmenopausal women who previously received oral bisphosphonates. Patients received 60mg denosumab once every 6months or a bisphosphonate (oral alendronate, risedronate, ibandronate, or intravenous zoledronic acid). Endpoints were change from baseline in lumbar spine, total hip, femoral neck, and 1/3 radius BMD at month 12, change from baseline in serum CTX-1 and P1NP, and incidence of adverse events. A total of 2850 randomized patients (1424 bisphosphonate:1426 denosumab) were included in the analysis. Percentage change in BMD was significantly greater (p < 0.001) for denosumab vs. bisphosphonate at each skeletal site; differences in BMD changes ranged from 0.6 to 2.0%. Percentage decrease in serum CTX-1 and P1NP was significantly greater (p < 0.0001) for denosumab vs. bisphosphonate at months 1, 6, and 12; in the denosumab group only, percentage change in serum CTX-1 at month 1 was significantly correlated with percentage change in lumbar spine and total hip BMD at month 12. The incidences of adverse events were similar between treatment groups. Three patients (one bisphosphonate and two denosumab) had atypical femoral fractures, all from the denosumab vs. zoledronic acid study. Postmenopausal women can safely transition from a bisphosphonate to denosumab, which is more effective at improving BMD than continuing with a bisphosphonate. NCT00377819, NCT00919711, NCT00936897, NCT01732770.

Dual-energy X-ray absorptiometry (DXA) is the most versatile technology for managing patients with osteoporosis. Non-bone mineral density (BMD) applications of DXA include assessments of hip geometry, diagnosis of vertebral fractures, analysis of body composition, and trabecular bone score. Quantitative ultrasound (QUS) devices have a more limited role in managing osteoporosis, but may be clinically useful in locations where DXA is not available. DXA technologists and interpreters can be trained in high-quality DXA through courses in bone densitometry; familiarity with a basic skill set can be demonstrated by passing a certification test in bone densitometry and maintaining a valid certification. Each DXA technologist should perform in vivo precision assessment, analogous to what is done for BMD measurements, for all body composition measures of interest, using patients who are representative of the clinic's patient population.

To the Editor: We were pleased to read and are delighted to acknowledge the Editorial of Cummings and Eastell1 that reviewed the history of pivotal advances in clinical research into bone and mineral disease in connection with the 40th anniversary celebration of the ASBMR. The article provides a succinct review of several key epidemiological, technological, biochemical, and therapeutic advances that, overall, have signaled landmark achievements in our field. The importance of the combined effects of enhanced study design, analysis, and capability coupled with knowledge of how to apply different research methods to most appropriately address relevant research questions over the past 40 years cannot be overemphasized.2-7 It was a daunting task to cover everything and, while the Editorial includes many issues, it omits several key points. These include references to key advances, such as the prevalence and importance of fractures in postmenopausal women relative to other diseases,8 specific delineation of risk factors in postmenopausal women with and without prior fracture,9-11 age-, sex-, and ethnicity-matched normative reference values for bone mineral density,12 and the timing, location, and mechanism of fragility fractures among postmenopausal women in many countries.13 Multiple societies, including the ASBMR, National Osteoporosis Foundation (NOF), International Society for Clinical Densitometry (ISCD), Endocrine Society (ES), American Association of Clinical Endocrinology (AACE), International Osteoporosis Foundation (IOF), European Calcified Tissue Society (ECTS), and Asian Federation of Osteoporosis Societies (AFOS), have embraced the field and expanded our own society, so small and modest in the late 1970s, to one of international stature. Global and regional experts now regularly meet and collaborate in ways that wouldn't have seemed likely when ASBMR began. An example among many of these collaborative societies is the ISCD, which has clarified many issues related to bone densitometry and is dedicated to educating, training, and certifying technologists, clinicians, and scientists around the world. Its multiple internationally respected Position Development Statements and courses14, 15 have, along with ASBMR Task Forces, literally changed the way we think about key and controversial issues. Cummings and Eastell omitted to mention in their section on advances in therapeutics the recently FDA-approved (but EMA-rejected) osteoanabolic agent for postmenopausal osteoporosis, abaloparatide,16 while they prominently discuss romosozumab, a drug that is still in development.17 Although the Editorial focuses upon advances, it omits one of the most important issues that has been brewing over the past decade, namely the increasingly wide gap that has developed between evidence-based guidelines of diagnosis and therapy of osteoporosis and the alarming reduction in adherence to such guidelines.(18–22) Many barriers exist to get educated health care professionals to do what is recommended,23 and many different guidelines exist, some with conflicting recommendations.24 Contemporaneous inclusion of patient education, active engagement, and shared decision-making, in tandem with professionals, will likely reap the greatest benefits.25, 26 Our greatest advancement over the next 40 years will be to develop effective solutions to close this gap and to harmonize guidelines and societies in the field in order to bring best evidence into best practice and universal quality care to the forefront of clinical care everywhere. This would be a deeply satisfying outcome for our field.

Context:Denosumab and zoledronic acid (ZOL) are parenteral treatments for patients with osteoporosis.Objective:The objective of the study was to compare the effect of transitioning from oral bisphosphonates to denosumab or ZOL on bone mineral density (BMD) and bone turnover.Design and Setting:This was an international, multicenter, randomized, double-blind trial.Participants:A total of 643 postmenopausal women with osteoporosis previously treated with oral bisphosphonates participated in the study.Interventions:Subjects were randomized 1:1 to sc denosumab 60 mg every 6 months plus iv placebo once or ZOL 5 mg iv once plus sc placebo every 6 months for 12 months.Main Outcome Measures:Changes in BMD and bone turnover markers were measured.Results:BMD change from baseline at month 12 was significantly greater with denosumab compared with ZOL at the lumbar spine (primary end point; 3.2% vs 1.1%; P < .0001), total hip (1.9% vs 0.6%; P < .0001), femoral neck (1.2% vs −0.1%; P < .0001), and one-third radius (0.6% vs 0.0%; P < .05). The median decrease from baseline was greater with denosumab than ZOL for serum C-telopeptide of type 1 collagen at all time points after day 10 and for serum procollagen type 1 N-terminal propeptide at month 1 and at all time points after month 3 (all P < .05). Median percentage changes from baseline in serum intact PTH were significantly greater at months 3 and 9 with denosumab compared with ZOL (all P < .05). Adverse events were similar between groups. Three events consistent with the definition of atypical femoral fracture were observed (two denosumab and one ZOL).Conclusions:In postmenopausal women with osteoporosis previously treated with oral bisphosphonates, denosumab was associated with greater BMD increases at all measured skeletal sites and greater inhibition of bone remodeling compared with ZOL.