Quantitative metrics of bone quality determined at the distal radius using photon-counting CT.

OBJECTIVE: To determine the accuracy of photon-counting-detector CT (PCD-CT) at deriving bone morphometric indices and demonstrate utility in vivo in the distal radius. METHODS: Ten cadaver wrists were scanned using PCD-CT and high-resolution peripheral quantitative CT (HRpQCT). Correlation between PCD-CT and HRpQCT morphometric indices was determined. Agreement was assessed by Lin's concordance correlation coefficient (Lin's CCC). Wrist PCD-CTs of patients between 02/2022 and 08/2023 were also evaluated for clinical utility. Morphometric indices of the in vivo distal radii were extracted and compared between patients with or without osteoporosis. RESULTS: In cadavers, strong correlation between PCD-CT and HRpQCT was observed for cortical thickness (Spearman correlation, ρ, 0.85), trabecular spacing (ρ = 0.98), and trabecular bone volume fraction (ρ = 0.68). Moderate negative correlation (ρ = - 0.49) was observed for trabecular thickness. PCD-CT shows good agreement to HRpQCT for cortical thickness, trabecular spacing, and trabecular bone volume fraction (Lin's CCC = 0.80, 0.94, and 0.86, respectively) but poor agreement (Lin's CCC = - 0.1) for trabecular thickness. In forty participants (31 adults and 9 pediatric), bone morphometrics indices for cortical thickness, trabecular thickness, trabecular spacing, and trabecular bone volume fraction were 0.99 mm (IQR, 0.89-1.06), 0.38 mm (IQR, 0.25-0.40), 0.82 mm (IQR, 0.72-1.05), and 0.28 (IQR, 0.25-0.33), respectively. Patients with osteoporosis had statistically significantly larger trabecular spacing (p = 0.025) and lower trabecular volumetric bone mineral density (p = 0.042). CONCLUSION: This study demonstrates the agreement of PCD-CT to HRpQCT in cadavers of most cortical and bone morphometrics examined and provide in vivo quantitative metrics of bone microarchitecture from routine clinical PCD-CT images of the distal radius.

Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial.

Preclinical evidence demonstrates that senescent cells accumulate with aging and that senolytics delay multiple age-related morbidities, including bone loss. Thus, we conducted a phase 2 randomized controlled trial of intermittent administration of the senolytic combination dasatinib plus quercetin (D + Q) in postmenopausal women (n = 60 participants). The primary endpoint, percentage changes at 20 weeks in the bone resorption marker C-terminal telopeptide of type 1 collagen (CTx), did not differ between groups (median (interquartile range), D + Q -4.1% (-13.2, 2.6), control -7.7% (-20.1, 14.3); P = 0.611). The secondary endpoint, percentage changes in the bone formation marker procollagen type 1 N-terminal propeptide (P1NP), increased significantly (relative to control) in the D + Q group at both 2 weeks (+16%, P = 0.020) and 4 weeks (+16%, P = 0.024), but was not different from control at 20 weeks (-9%, P = 0.149). No serious adverse events were observed. In exploratory analyses, the skeletal response to D + Q was driven principally by women with a high senescent cell burden (highest tertile for T cell p16 (also known as CDKN2A) mRNA levels) in which D + Q concomitantly increased P1NP (+34%, P = 0.035) and reduced CTx (-11%, P = 0.049) at 2 weeks, and increased radius bone mineral density (+2.7%, P = 0.004) at 20 weeks. Thus, intermittent D + Q treatment did not reduce bone resorption in the overall group of postmenopausal women. However, our exploratory analyses indicate that further studies are needed testing the hypothesis that the underlying senescent cell burden may dictate the clinical response to senolytics. ClinicalTrials.gov identifier: NCT04313634 .

Treatment of hypercalcaemia of malignancy in adults.

Hypercalcaemia of malignancy (HCM) is a common metabolic complication of advanced malignancies with a prevalence varying from 2-30%, depending on cancer type and disease stage. HCM is associated with impaired quality of life, increased risk of hospitalisation and limited survival. Evidence-based guidelines for management of HCM have been lacking to date, despite its prevalence and detrimental impact. This concise guidance highlights key recommendations from the recent Endocrine Society Clinical Practice Guidelines on Treatment of Hypercalcaemia of Malignancy in Adults, published in December 2022. A systematic review and meta-analysis was commissioned to support the guideline development process. Key suggestions include the use of denosumab in preference to intravenous bisphosphonates as first-line treatment for HCM and the use of denosumab in cases of recurrent or refractory HCM in patients previously treated with intravenous bisphosphonates. The guideline also identifies priority areas for future research.

An atlas of the bone marrow bone proteome in patients with dysproteinemias.

Multiple myeloma (MM) bone disease is a significant cause of morbidity but there is a paucity of data on the impact of malignant plasma cells on adjacent trabecular bone within the BM. Here, we characterize the proteome of trabecular bone tissue from BM biopsies of 56 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM), newly diagnosed (NDMM), relapsed MM (RMM), and normal controls. Proteins involved in extracellular matrix (ECM) formation and immunity pathways were decreased in SMM and active MM. Among the proteins most decreased were immunoglobulins, type IV collagen, and TIMP3, suggesting increased immunoparesis and decreased ECM remodelling within trabecular bone. Proteins most increased in SMM/MM were APP (enhances osteoclast activity), ENPP1 (enhances bone mineralization), and MZB1 (required for normal plasmablast differentiation). Pathway analyses showed that proteins involved in gamma -carboxylation, a pathway implicated in osteocalcin function, osteoblast differentiation, and normal hematopoiesis, were also overexpressed in SMM/MM. This study is the first comprehensive proteomic atlas of the BM bone proteome in dysproteinemias. We identify new key proteins and pathways for MM bone disease and potentially impaired hematopoiesis, and show for the first time that gamma -carboxylation pathways are increased in the bone tissue of SMM/MM.

Patient and Physician Decisional Factors Regarding Hypercalcemia of Malignancy Treatment: A Novel Mixed-Methods Study.

BACKGROUND: Integrating shared decision making between patients and physicians and incorporating their values and preferences in the development of clinical practice guidelines (CPGs) is of critical importance to optimize CPG implementation and treatment adherence. This applies to many debilitating diseases, including hypercalcemia of malignancy (HCM). OBJECTIVE: Evaluate patient and physician values, preferences, and attitudes to better inform CPGs to treat HCM in adults. METHODS: We followed a mixed-methods approach. We conducted a systematic review using 5 databases to identify studies reporting on patient and physician values, costs and resources, feasibility, acceptability, and equity regarding HCM treatment. We also gathered data from different countries on the cost of multiple treatment modalities. We collected data on outcome prioritization from the CPG Working Group. Similarly, we collected data from patients with HCM regarding outcome prioritization and administered a questionnaire to evaluate their attitudes and perceptions toward treatment as well as treatment acceptability and feasibility. RESULTS: In the systematic review, we included 2 cross-sectional surveys conducted on the same population of physicians who agreed that treating HCM alleviates symptoms and improves quality of life; however, harms and benefits should be thoroughly considered when deciding on the duration of treatment. We also included 2 studies on cost showing that intravenous (IV) bisphosphonate is more cost-effective than a combination of IV bisphosphonate and calcitonin and administration of IV zoledronic acid at home is more cost-effective than other IV bisphosphonates. The cost of zoledronic acid, denosumab, and cinacalcet varied widely among countries and types (brand vs generic). Both the CPG Working Group and patients with HCM agreed that the most important outcomes when deciding on treatment were survival and resolution of HCM, but there was some variability in the ratings for other outcomes. CONCLUSION: Using mixed methods, CPG developers can obtain meaningful information regarding evidence to decision criteria. In the case of HCM CPGs, this approach has provided the required contextual information and supported the development of evidence-based recommendations.

A Systematic Review Supporting the Endocrine Society Clinical Practice Guideline on the Treatment of Hypercalcemia of Malignancy in Adults.

CONTEXT: Hypercalcemia is a common complication of malignancy that is associated with high morbidity and mortality. OBJECTIVE: To support development of the Endocrine Society Clinical Practice Guideline for the treatment of hypercalcemia of malignancy in adults. METHODS: We searched multiple databases for studies that addressed 8 clinical questions prioritized by a guideline panel from the Endocrine Society. Quantitative and qualitative synthesis was performed. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess certainty of evidence. RESULTS: We reviewed 1949 citations, from which we included 21 studies. The risk of bias for most of the included studies was moderate. A higher proportion of patients who received bisphosphonate achieved resolution of hypercalcemia when compared to placebo. The incidence rate of adverse events was significantly higher in the bisphosphonate group. Comparing denosumab to bisphosphonate, there was no significant difference in the rate of patients who achieved resolution of hypercalcemia. Two-thirds of patients with refractory/recurrent hypercalcemia of malignancy who received denosumab following bisphosphonate therapy achieved resolution of hypercalcemia. Addition of calcitonin to bisphosphonate therapy did not affect the resolution of hypercalcemia, time to normocalcemia, or hypocalcemia. Only indirect evidence was available to address questions on the management of hypercalcemia in tumors associated with high calcitriol levels, refractory/recurrent hypercalcemia of malignancy following the use of bisphosphonates, and the use of calcimimetics in the treatment of hypercalcemia associated with parathyroid carcinoma. The certainty of the evidence to address all 8 clinical questions was low to very low. CONCLUSION: The evidence summarized in this systematic review addresses the benefits and harms of treatments of hypercalcemia of malignancy. Additional information about patients' values and preferences, and other important decisional and contextual factors is needed to facilitate the development of clinical recommendations.

Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline.

BACKGROUND: Hypercalcemia of malignancy (HCM) is the most common metabolic complication of malignancies, but its incidence may be declining due to potent chemotherapeutic agents. The high mortality associated with HCM has declined markedly due to the introduction of increasingly effective chemotherapeutic drugs. Despite the widespread availability of efficacious medications to treat HCM, evidence-based recommendations to manage this debilitating condition are lacking. OBJECTIVE: To develop guidelines for the treatment of adults with HCM. METHODS: A multidisciplinary panel of clinical experts, together with experts in systematic literature review, identified and prioritized 8 clinical questions related to the treatment of HCM in adult patients. The systematic reviews (SRs) queried electronic databases for studies relevant to the selected questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. An independent SR was conducted in parallel to assess patients' and physicians' values and preferences, costs, resources needed, acceptability, feasibility, equity, and other domains relevant to the Evidence-to-Decision framework as well as to enable judgements and recommendations. RESULTS: The panel recommends (strong recommendation) in adults with HCM treatment with denosumab (Dmab) or an intravenous (IV) bisphosphonate (BP). The following recommendations were based on low certainty of the evidence. The panel suggests (conditional recommendation) (1) in adults with HCM, the use of Dmab rather than an IV BP; (2) in adults with severe HCM, a combination of calcitonin and an IV BP or Dmab therapy as initial treatment; and (3) in adults with refractory/recurrent HCM despite treatment with BP, the use of Dmab. The panel suggests (conditional recommendation) the addition of an IV BP or Dmab in adult patients with hypercalcemia due to tumors associated with high calcitriol levels who are already receiving glucocorticoid therapy but continue to have severe or symptomatic HCM. The panel suggests (conditional recommendation) in adult patients with hypercalcemia due to parathyroid carcinoma, treatment with either a calcimimetic or an antiresorptive (IV BP or Dmab). The panel judges the treatments as probably accessible and feasible for most recommendations but noted variability in costs, resources required, and their impact on equity. CONCLUSIONS: The panel's recommendations are based on currently available evidence considering the most important outcomes in HCM to patients and key stakeholders. Treatment of the primary malignancy is instrumental for controlling hypercalcemia and preventing its recurrence. The recommendations provide a framework for the medical management of adults with HCM and incorporate important decisional and contextual factors. The guidelines underscore current knowledge gaps that can be used to establish future research agendas.

Proceedings of the 2022 Santa Fe Bone Symposium: Current Concepts in the Care of Patients with Osteoporosis and Metabolic Bone Diseases.

The 22nd Annual Santa Fe Bone Symposium (SFBS) was a hybrid meeting held August 5-6, 2022, with in-person and virtual attendees. Altogether, over 400 individuals registered, a majority of whom attended in-person, representing many states in the USA plus 7 other countries. The SFBS included 10 plenary presentations, 2 faculty panel discussions, satellite symposia, Bone Health & Osteoporosis Foundation Fracture Liaison Service Boot Camp, and a Project ECHO workshop, with lively interactive discussions for all events. Topics of interest included fracture prevention at different stages of life; how to treat and when to change therapy; skeletal health in cancer patients; advanced imaging to assess bone strength; the state of healthcare in the USA; osteosarcopenia; vitamin D update; perioperative bone health care; new guidelines for managing primary hyperparathyroidism; new concepts on bone modeling and remodeling; and an overview on the care of rare bone diseases, including hypophosphatasia, X-linked hypophosphatemia, tumor induced osteomalacia, osteogenesis imperfecta, fibrodysplasia ossificans progressiva, and osteopetrosis. The SFBS was preceded by the Santa Fe Fellows Workshop on Osteoporosis and Metabolic Bone Diseases, a collaboration of the Endocrine Fellows Foundation and the Osteoporosis Foundation of New Mexico. From the Workshop, 4 participating fellows were selected to give oral presentations at the bone symposium. These proceedings represent the clinical highlights of 2022 SFBS presentations and the discussions that followed, all with the aim of optimizing skeletal health and minimizing the consequences of fragile bones.

Pros and Cons of Skeletal Medications in the COVID-19 Era.

Purpose of Review: This review provides an overview regarding osteoporosis therapies during the COVID-19 pandemic. Recent Findings: The COVID-19 pandemic has disrupted treatments for osteoporosis and resulted in decreased adherence particularly for parenteral regimens. Osteoporosis medications are safe and effective during the pandemic and should be continued whenever possible. Bisphosphonates have long-lasting effects on bone turnover such that delays in their administration are unlikely to be harmful to skeletal health. In contrast, interruption of denosumab treatment is strongly discouraged because of rapid loss of bone mass and an associated increased risk for rebound vertebral fractures. When osteoanabolic treatments cannot be continued during the pandemic, change to an oral bisphosphonate is advised. Preclinical data suggest possible beneficial effects of some therapies against COVID-19, but require validation in clinical studies. Vitamin D deficiency is associated with a more severe COVID-19 clinical course but data supporting improvements in outcomes with vitamin D supplementation are lacking. Summary: The impact of the COVID-19 pandemic on long-term bone health remains unknown but focused interventions to ensure osteoporosis treatment initiation/maintenance should be implemented. Future studies are needed to determine whether osteoporosis medications have an impact on SARS-CoV-2 pathophysiology and COVID-19 clinical outcomes.

Tumour-induced osteomalacia: a rare cause of chronic pain and weakness.

Tumor-induced osteomalacia is a rare and often misdiagnosed condition that presents with progressively worsening unexplained chronic pain and proximal muscle weakness. The osteomalacia leads to multiple stress fractures which do not heal properly, leading to progressive disability. It is caused by chronic hypophosphatemia due to inappropriate urinary phosphate wasting. This is due to a typically benign mesenchymal tumor that over-secretes a phospaturic hormone. Neurologists need to appreciate the relevance of chronic hypophosphatemia in people with chronic unexplained pain, as timely diagnosis and treatment of tumour-induced osteomalacia can be curative.

Hypovitaminosis D Is Prevalent in Patients With Renal AL Amyloidosis and Associated With Renal Outcome.

Introduction: Vitamin D deficiency is common, but no data have been reported on vitamin D levels in light chain (AL) amyloidosis. Patients and Methods: In this exploratory study, stored serum samples from 173 patients with newly diagnosed AL amyloidosis were analyzed for vitamin studies which included 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D] and vitamin D binding protein (DBP). Measurements were made by liquid chromatography-tandem mass spectrometry. Kidney survival and overall survival (OS) were assessed in association to vitamin D status. Results: Cardiac and kidney involvement occurred in 69% and 63% of patients, respectively. 25(OH)D deficiency (<20 ng/mL) was seen in 56.6% of the patients and was notably found among patients with heavy proteinuria (96%), hypoalbuminemia (84.3%) and morbidly obese patients (68.3%). Heavy proteinuria (>5 gr/24-h) and vitamin D supplementation were independent predictors of 25(OH)D level on nominal multivariate regression analysis. 1,25(0H)2D deficiency was noted in 37.6% of patients and was independently associated with low eGFR and hypoalbuminemia. Progression to ESRD occurred in 23.7% of evaluable patients. Patients who progressed to ESRD had lower serum 25(OH)D and 1,25(OH)2D levels compared to those who did not progress to ESRD. On a multivariate analysis, severe 25(OH)D deficiency was an independent predictor of progression to ESRD as was renal stage, while 1,25(OH)2D deficiency was not. Conclusions: Hypovitaminosis D is common in AL amyloidosis, particularly among patients with heavy proteinuria. Severe 25(OH)D deficiency at time of diagnosis predicts progression to ESRD.

Skeletal Aging.

Aging represents the single greatest risk factor for chronic diseases, including osteoporosis, a skeletal fragility syndrome that increases fracture risk. Optimizing bone strength throughout life reduces fracture risk. Factors critical for bone strength include nutrition, physical activity, and vitamin D status, whereas unhealthy lifestyles, illnesses, and certain medications (eg, glucocorticoids) are detrimental. Hormonal status is another important determinant of skeletal health, with sex steroid concentrations, particularly estrogen, having major effects on bone remodeling. Aging exacerbates bone loss in both sexes and results in imbalanced bone resorption relative to formation; it is associated with increased marrow adiposity, osteoblast/osteocyte apoptosis, and accumulation of senescent cells. The mechanisms underlying skeletal aging are as diverse as the factors that determine the strength (and thus fragility) of bone. This review updates our current understanding of the epidemiology, pathophysiology, and treatment of osteoporosis and provides an overview of the underlying hallmark mechanisms that drive skeletal aging.

Enhancing the Trustworthiness of the Endocrine Society's Clinical Practice Guidelines.

In an effort to enhance the trustworthiness of its clinical practice guidelines, the Endocrine Society has recently adopted new policies and more rigorous methodologies for its guideline program. In this Clinical Practice Guideline Communication, we describe these recent enhancements-many of which reflect greater adherence to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to guideline development-in addition to the rationale for such changes. Improvements to the Society's guideline development practices include, but are not limited to, enhanced inclusion of nonendocrinologist experts, including patient representatives, on guideline development panels; implementation of a more rigorous conflict/duality of interest policy; a requirement that all formal recommendations must be demonstrably underpinned by systematic evidence review; the explicit use of GRADE Evidence-to-Decision frameworks; greater use and explanation of standardized guideline language; and a more intentional approach to guideline updating. Lastly, we describe some of the experiential differences our guideline readers are most likely to notice.

Antidiabetic Effects of the Senolytic Agent Dasatinib.

OBJECTIVE: To evaluate the antidiabetic effects of the senolytic agent dasatinib in older patients with type 2 diabetes mellitus. METHODS: This retrospective cohort study included enterprise-wide Mayo Clinic patients using Informatics for Integrating Biology at the Bedside from January 1994 through December 2019. The antidiabetic outcomes (change in hemoglobin A1c value, serum glucose concentration, and diabetic medications) after 1 year of a strongly senolytic tyrosine kinase inhibitor, dasatinib (n=16), was compared with a weakly senolytic tyrosine kinase inhibitor, imatinib (n=32). RESULTS: Relative to imatinib, patients treated with dasatinib had a mean reduction of 43.7 mg/dL (P=.005) in serum glucose concentration (to convert glucose values to mmol/L, multiply by 0.0555) and required 28.8 fewer total daily insulin units (P=.08) in the setting of a 4.8-kg relative weight loss (5.3% of total body weight; P=.045). Linear regression analysis suggests that the relative difference in weight accounts for 8.4 mg/dL of the 43.7 mg/dL blood glucose value decrease, or 19.2%. Relative to imatinib, patients treated with dasatinib had a mean 0.80 absolute point (P=.05) reduction in hemoglobin A1c and required 18.2 fewer total daily insulin units (P=.16) in the setting of a 5.9-kg relative weight loss (6.3% of total body weight; P=.06). CONCLUSION: Dasatinib may have antidiabetic effects comparable to contemporary diabetic treatments and may be considered for use as a novel diabetic therapy. Future studies are needed to determine whether these results are translatable to patients with type 2 diabetes mellitus without underlying malignant diseases and to determine whether the antidiabetic effects of dasatinib are due to its senolytic properties.

Update on Approved Osteoporosis Therapies Including Combination and Sequential Use of Agents.

Osteoporosis is characterized by reduced bone mass leading to diminished skeletal integrity and an increased risk for fracture. Multiple agents exist that are effective for the treatment of osteoporosis. These can be broadly categorized into those that reduce the risk for additional loss of bone mass (anti-resorptive agents) and those that augment existing bone mass (anabolic agents). This article reviews the different medications within each class, and discusses more recent data regarding the combination and sequential use of these medications for optimization of skeletal health in patients at high risk for fracture.

Vaccination for Coronavirus Disease 2019 (COVID-19) and Relationship to Osteoporosis Care: Current Evidence and Suggested Approaches.

The development of coronavirus disease 2019 (COVID-19) vaccines has proceeded at an unprecedented pace, with numerous trials conducted simultaneously across the world as a result of massive technological and financial resource expenditures. With multiple vaccines having now received regulatory approval, public health efforts to promote widespread vaccine dissemination are currently underway. There has been particular emphasis placed on vaccination of older populations, the age group in which COVID-19 infection has been most lethal. However, such widespread vaccination approaches have necessarily raised important questions related to potential interactions with underlying diseases and concomitant treatments among persons to be vaccinated. Osteoporosis is a chronic condition marked by reduced bone strength and an associated increased risk for fracture that generally requires sustained medical intervention(s). Osteoporosis is neither associated with a higher risk of COVID-19 infection nor by more pronounced disease severity following infection, such that individuals with osteoporosis need not be more highly prioritized for COVID-19 vaccination. Osteoporosis therapies do not interfere with the efficacy or side effect profiles of COVID-19 vaccines and should not be stopped or indefinitely delayed because of vaccination. Depending on the specific drug profile within an anti-osteoporosis medication category, minor adjustments to the timing of drug administration may be considered with respect to the patient's COVID-19 vaccination schedule. Herein we provide practical recommendations for the care of patients requiring treatment for osteoporosis in the setting of COVID-19 vaccination. © 2021 American Society for Bone and Mineral Research (ASBMR).