Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies.

Steatotic liver disease (SLD) displays a dynamic and complex disease phenotype. Consequently, the metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) therapeutic pipeline is expanding rapidly and in multiple directions. In parallel, noninvasive tools for diagnosing and monitoring responses to therapeutic interventions are being studied, and clinically feasible findings are being explored as primary outcomes in interventional trials. The realization that distinct subgroups exist under the umbrella of SLD should guide more precise and personalized treatment recommendations and facilitate advancements in pharmacotherapeutics. This review summarizes recent updates of pathophysiology-based nomenclature and outlines both effective pharmacotherapeutics and those in the pipeline for MASLD/MASH, detailing their mode of action and the current status of phase 2 and 3 clinical trials. Of the extensive arsenal of pharmacotherapeutics in the MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, have shown only marginal benefits and are now being tested as part of combination therapies, yet others are still in development as monotherapies. Although the Food and Drug Administration (FDA) has recently approved resmetirom, additional therapeutic approaches in development will ideally target MASH and fibrosis while improving cardiometabolic risk factors. Due to the urgent need for the development of novel therapeutic strategies and the potential availability of safety and tolerability data, repurposing existing and approved drugs is an appealing option. Finally, it is essential to highlight that SLD and, by extension, MASLD should be recognized and approached as a systemic disease affecting multiple organs, with the vigorous implementation of interdisciplinary and coordinated action plans. SIGNIFICANCE STATEMENT: Steatotic liver disease (SLD), including metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, is the most prevalent chronic liver condition, affecting more than one-fourth of the global population. This review aims to provide the most recent information regarding SLD pathophysiology, diagnosis, and management according to the latest advancements in the guidelines and clinical trials. Collectively, it is hoped that the information provided furthers the understanding of the current state of SLD with direct clinical implications and stimulates research initiatives.

The impact of metformin on weight and metabolic parameters in patients with obesity: A systematic review and meta-analysis of randomized controlled trials.

There are conflicting data on the weight-reducing potential of metformin (MTF) in nondiabetic patients with obesity. The purpose of this systematic review and meta-analysis was to evaluate the effect of MTF on weight and cardiometabolic parameters in adults with overweight/obesity with or without nonalcoholic fatty liver disease (NAFLD) (CRD42018085512). We included randomized controlled trials (RCTs) in adults without diabetes mellitus, with mean body mass index (BMI) ≥ 25 kg/m2, with or without NAFLD, comparing MTF to placebo/control, lifestyle modification (LSM) or a US Food and Drug Administration-approved anti-obesity drug, reporting on weight or metabolic parameters, and extending over at least 3 months. We conducted a systematic search in MEDLINE, EMBASE, PubMed and the Cochrane Library without time limitation (until March 2022). We screened and selected eligible articles, abstracted relevant data, and assessed the risk of bias. All steps were in duplicate and independently. We conducted a random-effects model meta-analysis using Review Manager version 5.3, with prespecified subgroup analyses in case of heterogeneity. We identified 2650 citations and included 49 trials (55 publications). Compared to placebo, MTF was associated with a significant reduction in BMI (mean difference [MD] -0.56 [-0.74, -0.37] kg/m2; p < 0.0001), at doses ranging from 500 to 2550 mg/day, and with a significant percentage change in BMI of -2.53% (-2.90, -2.17) at the dose 1700 mg/day. There was no interaction by baseline BMI, MTF dose or duration, nor presence or absence of NAFLD. There was no significant difference between MTF and LSM. Orlistat was more effective than MTF (at doses of 1000-1700 mg/day) in terms of weight loss, with an MD in BMI of -3.17 (-5.88; -0.47) kg/m2, favouring the former. Compared to placebo/control, MTF improved insulin parameters, while no effect was detected when compared to LSM. A few small trials showed heterogenous effects on liver parameters in patients with NAFLD treated with MTF compared to placebo/control. There was a large variability in the expression of outcome measures and RCTs were of low quality. In conclusion, MTF was associated with a modest weight reduction in obese nondiabetic patients. Further high-quality and better powered studies are needed to examine the impact of MTF in patients with insulin resistance and NAFLD.

Mortality risk in patients with obesity and COVID-19 infection: a systematic review and meta-analysis.

Obesity is a risk factor for severe respiratory diseases, including COVID-19 infection. Meta-analyses on mortality risk were inconsistent. We systematically searched 3 databases (Medline, Embase, CINAHL) and assessed the quality of studies using the Newcastle-Ottawa tool (CRD42020220140). We included 199 studies from US and Europe, with a mean age of participants 41.8-78.2 years, and a variable prevalence of metabolic co-morbidities of 20-80 %. Exceptionally, one third of the studies had a low prevalence of obesity of <20 %. Compared to patients with normal weight, those with obesity had a 34 % relative increase in the odds of mortality (p-value 0.002), with a dose-dependent relationship. Subgroup analyses showed an interaction with the country income. There was a high heterogeneity in the results, explained by clinical and methodologic variability across studies. We identified one trial only comparing mortality rate in vaccinated compared to unvaccinated patients with obesity; there was a trend for a lower mortality in the former group. Mortality risk in COVID-19 infection increases in parallel to an increase in BMI. BMI should be included in the predictive models and stratification scores used when considering mortality as an outcome in patients with COVID-19 infections. Furthermore, patients with obesity might need to be prioritized for COVID-19 vaccination.

Vitamin D status and supplementation before and after Bariatric Surgery: Recommendations based on a systematic review and meta-analysis.

Bariatric surgery is associated with a postoperative reduction of 25(OH) vitamin D levels (25(OH)D) and with skeletal complications. Currently, guidelines for 25(OH)D assessment and vitamin D supplementation in bariatric patients, pre- and post-surgery, are still lacking. The aim of this work is to analyse systematically the published experience on 25(OH)D status and vitamin D supplementation, pre- and post-surgery, and to propose, on this basis, recommendations for management. Preoperatively, 18 studies including 2,869 patients were evaluated. Prevalence of vitamin D insufficiency as defined by 25(OH)D < 30 ng/mL (75 nmol/L) was 85%, whereas when defined by 25(OH)D < 20 ng/mL (50 nmol/L) was 57%. The median preoperative 25(OH)D level was 19.75 ng/mL. After surgery, 39 studies including 5,296 patients were analysed and among those undergoing either malabsorptive or restrictive procedures, a lower rate of vitamin D insufficiency and higher 25(OH)D levels postoperatively were observed in patients treated with high-dose oral vitamin D supplementation, defined as ≥ 2,000 IU/daily (mostly D3-formulation), compared with low-doses (< 2,000 IU/daily). Our recommendations based on this systematic review and meta-analysis should help clinical practice in the assessment and management of vitamin D status before and after bariatric surgery. Assessment of vitamin D should be performed pre- and postoperatively in all patients undergoing bariatric surgery. Regardless of the type of procedure, high-dose supplementation is recommended in patients after bariatric surgery.

The Genetic Architecture of Vitamin D Deficiency among an Elderly Lebanese Middle Eastern Population: An Exome-Wide Association Study.

The Middle East region experiences a high prevalence of vitamin D deficiency, yet most genetic studies on vitamin D have focused on European populations. Furthermore, there is a lack of research on the genomic risk factors affecting elderly people, who are more susceptible to health burdens. We investigated the genetic determinants of 25-hydroxyvitamin D concentrations in elderly Lebanese individuals (n = 199) through a whole-exome-based genome-wide association study. Novel genomic loci displaying suggestive evidence of association with 25-hydroxyvitamin D levels were identified in our study, including rs141064014 in the MGAM (p-value of 4.40 × 10-6) and rs7036592 in PHF2 (p-value of 8.43 × 10-6). A meta-analysis of the Lebanese data and the largest European genome-wide association study confirmed consistency replication of numerous variants, including rs2725405 in SLC38A10 (p-value of 3.73 × 10-8). Although the polygenic risk score model derived from European populations exhibited lower performance than European estimations, it still effectively predicted vitamin D deficiency among our cohort. Our discoveries offer novel perspectives on the genetic mechanisms underlying vitamin D deficiency among elderly Middle Eastern populations, facilitating the development of personalized approaches for more effective management of vitamin D deficiency. Additionally, we demonstrated that whole-exome-based genome-wide association study is an effective method for identifying genetic components associated with phenotypes.

Biochemical Markers of Bone Fragility in Patients with Diabetes. A Narrative Review by the IOF and the ECTS.

CONTEXT: The risk of fragility fractures is increased in both type 1 and type 2 diabetes. Numerous biochemical markers reflecting bone and/or glucose metabolism have been evaluated in this context. This review summarizes current data on biochemical markers in relation to bone fragility and fracture risk in diabetes. METHODS: Literature review by a group of experts from the International Osteoporosis Foundation (IOF) and European Calcified Tissue Society (ECTS) focusing on biochemical markers, diabetes, diabetes treatments and bone in adults. RESULTS: Although bone resorption and bone formation markers are low and poorly predictive of fracture risk in diabetes, osteoporosis drugs seem to change bone turnover markers in diabetics similarly to non-diabetics, with similar reductions in fracture risk. Several other biochemical markers related to bone and glucose metabolism have been correlated with BMD and/or fracture risk in diabetes, including osteocyte-related markers such as sclerostin, HbA1c and advanced glycation end products (AGEs), inflammatory markers and adipokines, as well as IGF-1 and calciotropic hormones. CONCLUSION: Several biochemical markers and hormonal levels related to bone and/or glucose metabolism have been associated with skeletal parameters in diabetes. Currently, only HbA1c levels seem to provide a reliable estimate of fracture risk, while bone turnover markers could be used to monitor the effects of anti-osteoporosis therapy.

Biochemical Markers of Bone Fragility in Patients With Diabetes.

CONTEXT: The risk of fragility fractures is increased in both type 1 and type 2 diabetes. Numerous biochemical markers reflecting bone and/or glucose metabolism have been evaluated in this context. OBJECTIVE: This review summarizes current data on biochemical markers in relation to bone fragility and fracture risk in diabetes. METHODS: A group of experts from the International Osteoporosis Foundation and European Calcified Tissue Society reviewed the literature focusing on biochemical markers, diabetes, diabetes treatments, and bone in adults. RESULTS: Although bone resorption and bone formation markers are low and poorly predictive of fracture risk in diabetes, osteoporosis drugs seem to change bone turnover markers (BTMs) in diabetics similarly to nondiabetics, with similar reductions in fracture risk. Several other biochemical markers related to bone and glucose metabolism have been correlated with bone mineral density and/or fracture risk in diabetes, including osteocyte-related markers such as sclerostin, glycated hemoglobin A1c (HbA1c) and advanced glycation end products, inflammatory markers, and adipokines, as well as insulin-like growth factor-1 and calciotropic hormones. CONCLUSION: Several biochemical markers and hormonal levels related to bone and/or glucose metabolism have been associated with skeletal parameters in diabetes. Currently, only HbA1c levels seem to provide a reliable estimate of fracture risk, while BTMs could be used to monitor the effects of antiosteoporosis therapy.

A suggested protocol for the endocrine postoperative management of patients undergoing pituitary surgery.

PURPOSE: Endocrine disorders are the most frequent postoperative complications in patients undergoing pituitary surgery. Given the absence of recent guidelines on the postoperative care following pituitary surgery, this article summarizes the available evidence on the topic. METHOD: We conducted a systematic search of PubMed up to 2021 and updated the search in December 2022. We retrieved 119 articles and included 53 full-text papers. RESULTS: The early postoperative care consists of the assessment for cortisol deficiency and diabetes insipidus (DI). Experts suggest that all patients should receive a glucocorticoid (GC) stress dose followed by a rapid taper. The decision for GC replacement after discharge depends on the morning plasma cortisol level on day 3 after surgery. Experts suggest that patients with a morning plasma cortisol<10 mcg/dL should receive GC replacement at discharge, and those with 10-18 mcg/dL a morning dose only, with formal assessment of the hypothalamic-pituitary-adrenal axis at week 6 postoperatively. When the cortisol level is>18 mcg/dL, the patient can be discharged safely without GC, as suggested by observational studies. Postoperative care also includes a close monitoring of water balance. If DI develops, desmopressin is used only in case of uncomfortable polyuria or hypernatremia. The assessment of other hormones is indicated at 3 months postoperatively and beyond. CONCLUSION: The evaluation and treatment of patients following pituitary surgery are based on expert opinion and a few observational studies. Further research is needed to provide additional evidence on the most appropriate approach.

Pharmacotherapy of obesity: an update on the available medications and drugs under investigation.

Obesity is an epidemic and a public health threat. Medical weight management remains one of the options for the treatment of excess weight and recent advances have revolutionized how we treat, and more importantly how we will be treating obesity in the near future. Metreleptin and Setmelanotide are currently indicated for rare obesity syndromes, and 5 other medications (orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide) are approved for non-syndromic obesity. Tirzepatide is about to be approved, and other drugs, with exciting novel mechanisms of action primarily based on incretins, are currently being investigated in different phases of clinical trials. The majority of these compounds act centrally, to reduce appetite and increase satiety, and secondarily, in the gastrointestinal tract to slow gastric emptying. All anti-obesity medications improve weight and metabolic parameters, with variable potency and effects depending on the specific drug. The currently available data do not support a reduction in hard cardiovascular outcomes, but it is almost certain that such data are forthcoming in the very near future. The choice of the anti-obesity medication needs to take into consideration the patient's clinical and biochemical profile, co-morbidities, and drug contra-indications, as well as expected degree of weight loss and improvements in cardio-renal and metabolic risk. It also remains to be seen whether precision medicine may offer personalized solutions to individuals with obesity, and whether it may represent the future of medical weight management along with the development of novel, very potent, anti-obesity medications currently in the pipeline. Funding: None.

Research fellowship in a Lebanese academic medical center: What does it take to shift from an informal to a formal program?

Research fellowship programs help medical graduates acquire research skills for an academic career. While our institution employed a large number of research fellows, it did not offer them a formal training program. This study aimed to assess the views of fellows and their mentors regarding the current research fellowship program, and to seek their suggestions for a formal training program at our medical center. We conducted a qualitative descriptive study using both focus group discussions and individual interviews with research fellows, and individual interviews with their mentors. We recruited all eligible participants by email. We collected data in person and analyzed it thematically. We followed the consolidated criteria for reporting of qualitative research (COREQ) checklist. A total of 17 research fellows and 17 mentors participated in the study. Participants described the current non-formal program and proposed suggestions for a formal training program. The identification of available vacant positions and the recruitment process followed an unstructured approach, through networking with mentors and previous fellows. Although there is a formal contract, there is no job description, and no definition of roles, responsibilities and rights. Some fellows get the opportunity of being involved in all aspects of research and benefit from a favorable mentor-mentee relationship. Conversely, others struggle with authorship and with the projects allocated to them, some being "non-research" related. Not all fellows end up publishing their projects. Participants provided suggestions to shift into a formal training, including measures to improve on the recruitment process of fellows, defining roles and exposure to all aspects of research. Research fellows are eager to learn, but the currently available program is unstructured. They need a formal training program that meets their expectations, one that offers equitable learning opportunities and benefits to all.

Classical and Nonclassical Manifestations of Primary Hyperparathyroidism.

This narrative review summarizes data on classical and nonclassical manifestations of primary hyperparathyroidism (PHPT). It is based on a rigorous literature search, inclusive of a Medline search for systematic reviews from 1940 to December 2020, coupled with a targeted search for original publications, covering four databases, from January 2013-December 2020, and relevant articles from authors' libraries. We present the most recent information, identify knowledge gaps, and suggest a research agenda. The shift in the presentation of PHPT from a predominantly symptomatic to an asymptomatic disease, with its varied manifestations, has presented several challenges. Subclinical nephrolithiasis and vertebral fractures are common in patients with asymptomatic disease. The natural history of asymptomatic PHPT with no end organ damage at diagnosis is unclear. Some observational and cross-sectional studies continue to show associations between PHPT and cardiovascular and neuropsychological abnormalities, among the different disease phenotypes. Their causal relationship is uncertain. Limited new data are available on the natural history of skeletal, renal, cardiovascular, neuropsychological, and neuromuscular manifestations and quality of life. Normocalcemic PHPT (NPHPT) is often diagnosed without the fulfillment of rigorous criteria. Randomized clinical trials have not demonstrated a consistent long-term benefit of parathyroidectomy (PTX) versus observation on nonclassical manifestations. We propose further refining the definition of asymptomatic disease, into two phenotypes: one without and one with evidence of target organ involvement, upon the standard evaluation detailed in our recommendations. Each of these phenotypes can present with or without non-classical manifestations. We propose multiple albumin-adjusted serum calcium determinations (albumin-adjusted and ionized) and exclusion of all secondary causes of high parathyroid hormone (PTH) when establishing the diagnosis of NPHPT. Refining the definition of asymptomatic disease into the phenotypes proposed will afford insights into their natural history and response to interventions. This would also pave the way for the development of evidence-based guidance and recommendations. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Abdominal Visceral Adipose Tissue and All-Cause Mortality: A Systematic Review.

Introduction: Increased abdominal visceral adipose tissue (VAT) implies an adverse cardio-metabolic profile. We examined the association of abdominal VAT parameters and all-cause mortality risk. Methods: We systematically searched four databases. We performed citations/articles screening, data abstraction, and quality assessment in duplicate and independently (CRD42020205021). Results: We included 12 cohorts, the majority used computed tomography to assess abdominal VAT area. Six cohorts with a mean age ≤ 65 years, examining all-cause mortality risk per increment in VAT area (cm2) or volume (cm3), showed a 11-98% relative risk increase with higher VAT parameters. However, the association lost significance after adjusting for glycemic indices, body mass index, or other fat parameters. In 4 cohorts with a mean age >65 years, the findings on mortality were inconsistent. Conversely, in two cohorts (mean age 73-77 years), a higher VAT density, was inversely proportional to VAT area, and implied a higher mortality risk. Conclusion: A high abdominal VAT area seems to be associated with increased all-cause mortality in individuals ≤ 65 years, possibly mediated by metabolic complications, and not through an independent effect. This relationship is weaker and may reverse in older individuals, most likely secondary to confounding bias and reverse causality. An individual participant data meta-analysis is needed to confirm our findings, and to define an abdominal VAT area cutoff implying increased mortality risk. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=205021, identifier CRD42020205021.

Long Term Weight Loss Diets and Obesity Indices: Results of a Network Meta-Analysis.

Background: Scientists have been investigating efficient interventions to prevent and manage obesity. This network meta-analysis (NMA) compared the effect of different diets [moderate macronutrients (MMs), low fat/high carbohydrate (LFHC), high fat/low carbohydrate (HFLC), and usual diet (UD)] on weight, body mass index (BMI), and waist circumference (WC) changes at ≥12 months. Methods: We searched Medline, Embase, PubMed databases, and the Cochrane Library. We systematically assessed randomized controlled trials (RCTs) evaluating dietary interventions on adults (mean BMI ≥ 25 kg/m2) receiving active dietary counseling for ≥12 months. We pooled the data using a random-effect NMA. We assessed the quality of the included RCTs using the Cochrane risk of bias (ROB) tool. Results: We included 36 trials, 14 of which compared HFLC with MM diets. Compared with UD, all diets were associated with a significant weight loss (WL) at ≥12 months, HFLC [mean difference in kg (95% CI): -5.5 (-7.6; -3.4)], LFHC [-5.0 (-7.1; -2.9)] and MM [-4.7 (-6.8; -2.7)]. HFLC, compared with MM diet, was associated with a slightly higher WL (of -0.77 kg) and drop in BMI (of -0.36 kg/m2), while no significant difference was detected in other dietary comparisons. WC was lower with all diets compared to UD, with no significant difference across specific diets. There was no significant interaction of the results with the pre-specified sub-groups. The ROB was moderate to high, mostly related to unclear allocation concealment, high dropout rate and unclear or lack of blinding of participants, providers, and outcome assessors. Conclusion: Dietary interventions extending over ≥12 months are superior to UD in inducing weight, BMI and WC loss. HFLC might be associated with a slightly higher WL compared with MM diets. Systematic Trial Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=103116, PROSPERO (CRD42018103116).

Teaching critical appraisal to large classes of undergraduate medical students using team-based learning versus group discussions: a randomized controlled trial.

BACKGROUND: Evidence on the effectiveness of team-based learning in teaching critical appraisal to large classes of preclinical medical students is scarce. This study investigated whether team-based learning is effective in teaching critical appraisal to large classes of preclinical medical students. METHODS: Between April 2018 and May 2019, 107 first-year medical students were randomly allocated to receive instruction in critical appraisal using team-based learning or traditional group discussions as teaching methods. The primary outcome was students' performance on the Berlin Questionnaire administered at the end of second year. RESULTS: Students' mean (SD) age was 22.0 (0.7) years. Baseline characteristics of the two groups were similar (all p values > 0.05). The mean (SD) Berlin scores of both groups were 80.4 (11.6) and 80.1 (12.1) for team-based learning and group discussions, respectively. Multivariate stepwise linear regression analysis revealed that the student's academic achievement in medical school was the sole predictor of performance on the Berlin Questionnaire (ß = 1.079, p < 0.001), adjusting for gender, Medical College Admission Test score, student's self-reported preferred teaching method, rank upon admission to medical school, score on the Epidemiology and Biostatistics course, and teaching method (team-based learning versus group discussions). CONCLUSIONS: Team-based learning and group discussions were equally effective instructional strategies to teach critical appraisal to large classes of undergraduate medical students. Replication of our findings is needed in other educational settings. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15430424 , retrospectively registered on December 30, 2021.

Vitamin D Supplementation and Fractures in Adults: A Systematic Umbrella Review of Meta-Analyses of Controlled Trials.

CONTEXT: The growing number of systematic reviews/meta-analyses (SR/MAs) on vitamin D (±â€…calcium) for fracture prevention has led to contradictory guidelines. OBJECTIVE: This umbrella review aims to assess the quality and explore the reasons for the discrepancy of SR/MAs of trials on vitamin D supplementation for fracture risk reduction in adults. METHODS: We searched 4 databases (2010-2020), Epistemonikos, and references of included SRs/MAs, and we contacted experts in the field. We used A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR-2) for quality assessment. We compared results and investigated reasons for discordance using matrices and subgroup analyses (PROSPERO registration: CRD42019129540). We included 13 SR/MAs on vitamin D and calcium (Ca/D) and 19 SR/MAs on vitamin D alone, compared to placebo/control. RESULTS: Only 2 from 10 SRs/MAs on Ca/D were of moderate quality. Ca/D reduced the risk of hip fractures in 8 of 12 SRs/MAs (relative risk [RR] 0.61-0.84), and any fractures in 7 of 11 SR/MAs (RR 0.74-0.95). No fracture risk reduction was noted in SRs/MAs exclusively evaluating community-dwelling individuals or in those on vitamin D alone compared to placebo/control. Discordance in results between SRs/MAs stems from inclusion of different trials, related to search periods and eligibility criteria, and varying methodology (using intention to treat, per-protocol, or complete case analysis from individual trials). CONCLUSION: Ca/D reduces the risk of hip and any fractures, possibly driven by findings from institutionalized individuals. Individual participant data meta-analyses of patients on Ca/D with sufficient follow-up periods, and subgroup analyses, would unravel determinants for a beneficial response to supplementation.

Effect of antiresorptive therapy on aromatase inhibitor induced bone loss in postmenopausal women with early-stage breast cancer: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Aromatase inhibitors (AIs) are routinely used to treat postmenopausal women with early-stage breast cancer. Although AIs improve breast cancer outcomes, they increase the risk of osteoporosis and fractures. This systematic review and meta-analysis assesses the effect of antiresorptive drugs on AI induced bone loss in postmenopausal women with non-metastatic breast cancer. METHODS: We searched four databases until November 4th 2020. We included Randomized controlled trials (RCTs) of antiresorptive drugs in postmenopausal women with breast cancer treated with AI. Two authors screened studies, extracted data and assessed the risk of bias independently and in duplicate. RESULTS: We identified 14 RCTs: 7 on zoledronic acid, 6 on oral bisphosphonates and 1 on denosumab. The mean difference in bone mineral density (BMD) was 5% at the lumbar spine and 4% at the total hip, at 12 months, favoring zoledronic acid compared to control. The certainty of the evidence was low for lumbar spine and moderate for total hip BMD. Similarly, the mean difference was 3% at the lumbar spine and 2% at the total hip, favoring oral bisphosphonates with moderate certainty. The mean difference was 6% at the lumbar spine, and 4% at the total hip BMD favoring denosumab compared to placebo. In addition, zoledronic acid resulted in a mean difference in bone turnover marker levels of -35-41%, and the relarive risk for morphometric vertebral fractures was 0.7 [0.3-1.4], compared to control. Denosumab reduced fracture incidence by 50% compared to placebo. CONCLUSION: Evidence suggests a protective effect of antiresorptive drugs on BMD and bone turnover markers in postmenopausal women with non-metastatic breast cancer on AI. However, data on fracture risk reduction remains unclear.

Treatment of Hypercalcemia of Malignancy.

The treatment of hypercalcemia of malignancy (HCM) consists of enhancing renal calcium excretion, mostly through hydration with isotonic fluids and the use of antiresorptive therapies. Intravenous zoledronic acid is currently the first-line treatment. Subcutaneous denosumab is used for bisphosphonate-refractory hypercalcemia and in patients with renal failure. There is no evidence that bisphosphonates prevent the occurrence of HCM. Conversely, denosumab, compared with zoledronic acid, is associated with a lower risk of HCM, both first episode and recurrence, in patients with breast cancer and multiple myeloma.