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Summary: Osteoporosis is more common than most feared non-communicable diseases in the Middle East. This justifies the need to place osteoporosis as a health priority in the region. Introduction: Osteoporosis is a common disease associated with severe debilitating consequences. The objective of this study is To evaluate and compare disease burden from osteoporosis and other non-communicable diseases (NCDs) in Lebanon. Methods: We assessed the prevalence of osteoporosis and other NCDs, such as obesity, diabetes, hypertension, dyslipidemia, and cardiovascular diseases, based on a published population-based study of Lebanese ≥ 65 years. We compared incidence rates of hip fractures and major osteoporotic fractures (MOF) (spine, hip, humerus, and forearm) to the five commonest cancers in women ≥ 50 years. Rates were based on the national hip fracture and cancer registry data, provided by the Lebanese Ministry of Public Health. MOF incidence rates were derived from national hip fracture incidence rates and MOF/hip fractures incidence rate ratios from the literature. Results: Over 70% of elderly Lebanese had osteoporosis defined by densitometric criteria or prevalent morphometric vertebral fractures. This by far exceeded the prevalence of other NCDs, such as hypertension (53%), diabetes (21%), dyslipidemia (31%), and cardiovascular diseases (30%). Morphometric vertebral fractures (grades 2 and 3) were present in 19% of women and 12% of men. The incidence rates for MOF were 1.6 times greater than those for breast cancer, and 7.4–9.9 folds higher than those for the next commonest cancers of the lungs, colon, and ovaries. Hip fracture incidence rates were lower than those of breast cancer but were 2.1–2.8 folds higher than those of the above-mentioned cancers. Conclusion: This first of its kind study in the Middle East demonstrates that osteoporosis is a common disease, more common than most feared NCDs. Our findings are comparable to those in western populations and justify placing osteoporosis on the top of NCDs' priority list in our country and possibly the region. [ABSTRACT FROM AUTHOR]

Introduction: The vitamin D recommended doses during pregnancy differ between societies. The WHO guidelines do not recommend routine prenatal supplementation, but they underscore the fact that women with the lowest levels may benefit most. The effects of routine supplementation during pregnancy on maternal and neonatal clinical outcomes have not been investigated in the Middle East, where hypovitaminosis D is prevalent. Our hypothesis is that in Middle Eastern pregnant women, a vitamin D dose of 3000 IU/day is required to reach a desirable maternal 25-hydroxyvitamin D [25(OH)D] level, and to positively impact infant bone mineral content (BMC). Methods and analysis: This is a multicentre blinded randomised controlled trial. Pregnant women presenting to the Obstetrics and Gynaecology clinics will be approached. Eligible women will be randomised to daily equivalent doses of cholecalciferol, 600 IU or 3000 IU, from 15 to 18 weeks gestation until delivery. Maternal 25(OH)D and chemistries will be assessed at study entry, during the third trimester and at delivery. Neonatal anthropometric variables and 25(OH)D level will be measured at birth, and bone and fat mass assessment by dual-energy X-ray absorptiometry scan at 1 month. A sample size of 280 pregnant women is needed to demonstrate a statistically significant difference in the proportion of women reaching a 25 (OH)D level ≥50 nmol/L at delivery, and a difference in infant BMC of 6 (10)g, for a 90% power and a 2.5% level of significance. The proportions of women achieving a target 25(OH)D level will be compared between the two arms, using χ². An independent t test will be used to compare mean infant BMC between the two arms. The primary analysis is an intention-to-treat analysis of unadjusted results. Ethics and dissemination: The protocol has been approved by the Institutional Review Board at the American University of Beirut-Lebanon (IM.GEHF.22). The trial results will be published in peer-reviewed medical journals and presented at scientific conferences. [ABSTRACT FROM AUTHOR]

Abstract: A large body of data demonstrates a high prevalence worldwide of hypovitaminosis D in children and adolescents, at a critical time of bone mass accrual. Increasing evidence supports a deleterious effect of vitamin D insufficiency on musculoskeletal health in this age group based on cross-sectional studies, studies relating vitamin D to biochemical variables in the homeostatic pathway for vitamin D physiology (PTH, calcitriol, bone remodeling). Two recent randomized interventional trials show that vitamin D supplementation increases accrual of bone mass in girls, and this is partly explained by enhanced calcium absorption and bone mineralization. However, recent data also suggest beneficial effects on lean mass and bone geometry. It remains uncertain whether the beneficial effects of vitamin D in girls are reflected in the peak bone mass they eventually attain. A desirable 25(OH) D level to optimize musculoskeletal health in girls seems to be between 30 and 40 ng/ml (70–100 nmol/L). Future investigations are needed to shed light on mechanisms for the beneficial effect of vitamin D on musculoskeletal health, on optimal timing and dosing for vitamin D supplementation, on the biological basis for sexual dimorphism in the response to vitamin D supplementation in the young, and on the key clinical outcomes, such as lifetime reduction in fracture risk. [Copyright &y& Elsevier]

Background: Preventing bone loss associated with menopause and aging and maintaining the normal micro-architecture of bone provide important opportunities for the prevention of osteoporosis and fractures.Objective: To determine the safety and efficacy of alendronate, an aminobisphosphonate, for preventing postmenopausal bone loss.Design: 3-year double-blind, randomized, placebo-controlled trial.Setting: 15 osteoporosis centers throughout the world.Participants: 447 women who had recently experienced menopause (6 to 36 months before study entry).Intervention: Participants were randomly assigned to one of five regimens: oral placebo; oral alendronate, 1, 5, or 10 mg/d; or oral alendronate, 20 mg/d for 2 years followed by placebo during the third year (20/0 mg/d).Measurements: Bone mineral density was measured by dual-energy x-ray absorptiometry. Bone turnover and bone quality were assessed with biochemical markers and bone histomorphometry.Results: Alendronate at 5, 10, and 20/0 mg/d increased bone mineral density from baseline at the lumbar spine, femoral neck, and trochanter by 1% to 4% and in the total body by 0.3% to 1.0%; placebo led to losses of 2% to 4% at these sites. Alendronate, 1 mg/d, attenuated losses relative to those seen with placebo. Alendronate decreased markers of bone resorption to a new steady state by 3 months and decreased markers of bone formation by 6 to 12 months. Bone quality remained normal. At all dosages studied, alendronate had a safety and tolerability profile similar to that of placebo.Conclusions: In early postmenopausal women, alendronate given for 3 years at dosages of 5 mg/d or greater prevented the loss of bone mineral density at the spine and hip and in the total body. Alendronate seems to be a safe and effective nonhormonal option for prevention of postmenopausal bone loss. [ABSTRACT FROM AUTHOR]

Context: Evidence for a beneficial role of vitamin D on blood pressure (BP) outcomes is inconclusive., Objective: This work aimed to investigate the effect of 2 doses of cholecalciferol (vitamin D 3 ) supplementation coadministered with calcium on systolic blood pressure (SBP) and diastolic blood pressure (DBP)., Methods: Exploratory analyses were conducted from a 1-year, multicenter, double-blind, randomized controlled trial (RCT). Total of 221 ambulatory older overweight individuals received calcium dose and oral vitamin D 3 , at the equivalent of 600 IU/day or 3750 IU/day., Results: SBP and DBP decreased significantly in the overall group, and in the high-dose group at 6 and 12 months. Similar trends were observed in the low-dose group, but did not achieve statistical significance. In participants with a body mass index (BMI) greater than 30, SBP decreased significantly in both treatment groups whereas DBP significantly decreased in the high-dose group only. In the subgroups of hypertensive participants (N = 143), there was a decrease in SBP and DBP at 6 and 12 months, with both vitamin D doses and independently of BMI levels. Using multivariate linear mixed models with random effects in the overall group of participants, SBP at 6 and 12 months was significantly predicted by BMI (β = .29; P = .05) and by baseline SBP (β = .16; P < .001), but not by vitamin D treatment dose., Conclusion: Vitamin D and calcium decrease SBP and DBP in overweight older individuals, but more is not necessarily better. This effect is seen in individuals with BMI greater than 30, in hypertensive patients, and seems to be largely independent of dose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Vitamin D deficiency following bariatric surgery is common and is expected to be associated with a deleterious impact on the skeleton. However, the benefits of vitamin D supplementation and the optimal dose in this population is currently unknown. The available guidelines on the topic are derived from experts' opinions, and are not evidence based., Objectives: To compare the effects of different doses of vitamin D supplementation (low dose (less than 600 international units (IU)/day), moderate dose (600 IU/day to 3500 IU/day), high dose (greater than 3500 IU/day)) to each other or to placebo in adults living with obesity undergoing bariatric surgery., Search Methods: We searched CENTRAL, MEDLINE, Embase, LILACS, two trial registries, and the reference lists of systematic reviews, articles, and health technology assessment reports without language restrictions. The last search of all databases was 27 June 2023, except Embase, which we searched on 14 August 2015., Selection Criteria: We included randomised controlled trials or controlled clinical trials on vitamin D supplementation comparing different doses or comparing vitamin D to placebo in people undergoing bariatric surgery., Data Collection and Analysis: We used standard Cochrane methods. Primary outcomes were fractures and adverse events. Secondary outcomes were vitamin D status, all-cause mortality, bone mineral change, secondary hyperparathyroidism, health-related quality of life, and muscle strength. We used GRADE to assess the certainty of the evidence for each outcome in each comparison., Main Results: We identified five trials with 314 participants. We included three trials in the quantitative analysis. Moderate-dose vitamin D compared to placebo One trial compared moderate-dose vitamin D (3200 IU/day) to placebo. Moderate-dose vitamin D, compared to placebo, may improve vitamin D status and may result in little to no difference in the achieved parathyroid hormone level (achieved 25-hydroxyvitamin D level: mean difference (MD) 13.60 ng/mL, 95% confidence interval (CI) 7.94 to 19.26; achieved parathyroid hormone level: -6.60 pg/mL, 95% CI -17.12 to 3.92; 1 study, 79 participants; low-certainty evidence). The trial reported no adverse events in the moderate-dose vitamin D arm, but did not provide any information on adverse events in the placebo arm. There were no data on fractures, all-cause mortality, bone density change, health-related quality of life, and muscle strength. High-dose vitamin D compared to moderate-dose vitamin D Two trials in Roux-en-Y gastric bypass compared moderate-dose (equivalent dose 800 IU/day to 2000 IU/day) to high-dose (equivalent dose 5000 IU/day to 7943 IU/day) vitamin D. The evidence of high-dose vitamin D on adverse events is very uncertain (risk ratio (RR) 5.18, 95% CI 0.23 to 116.56; 2 studies, 81 participants; very low-certainty evidence). High-dose vitamin D may increase 25-hydroxyvitamin D levels compared to a moderate dose at 12 months, but the evidence is very uncertain (MD 15.55 ng/mL, 95% CI 3.50 to 27.61; I 2 = 62%; 2 studies, 73 participants; very low-certainty evidence). High-dose vitamin D may have little to no effect on parathyroid hormone levels compared to a moderate dose at 12 months, but the evidence is very uncertain (MD 2.15 pg/mL, 95% CI -21.31 to 17.01; I 2 = 0%; 2 studies, 72 participants; very low-certainty evidence). High-dose vitamin D may have little to no effect on mortality and bone mineral density at the lumbar spine, hip, and forearm, but the evidence is very uncertain. There were no data on fractures, health-related quality of life, or muscle strength., Authors' Conclusions: No trials reported on fractures and the evidence available on adverse events is scarce. Moderate-dose vitamin D may improve vitamin D status and may result in little to no improvement in parathyroid hormone levels compared with placebo. High-dose vitamin D supplementation (greater than 3500 IU/day) may increase 25-hydroxyvitamin D levels, and may have little to no effect on parathyroid hormone levels, compared to a moderate dose, but the evidence for both is very uncertain. The currently available limited evidence may not have a significant impact on practice. Further studies are needed to explore the impact of vitamin D supplementation on fractures, adverse events, and musculoskeletal parameters in people undergoing bariatric surgery., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

The Mediterranean Region registers an increasing prevalence of obesity. The region lacks a diet screener to assess obesogenic nutrients. This study aimed to evaluate the reproducibility and validity of the Modified Mediterranean Prime Screen (MMPS) in estimating obesogenic nutrients' intake among women of reproductive age, as compared with a culturally validated Food Frequency Questionnaire (FFQ), in Lebanon. We developed the MMPS consisting of thirty-two food/beverage items specific to the Lebanese Mediterranean culture. The MMPS and FFQ were administered in two visits (2 weeks-6 months apart), face to face and via telephone during the coronavirus disease 2019 pandemic. The reproducibility and validity of the MMPS were assessed using intraclass correlation coefficients (ICC) and Pearson's correlations, respectively. The study included 143 women, aged 31·5 (sd 4·6) years, BMI 24·2 (sd 4·0) kg/m 2 , 87 % with university education and 91 % food secure. The reproducibility of the MMPS was moderate for energy and all assessed nutrients except for SFA (ICC = 0·428). The agreement of the MMPS with the reference FFQ was adequate for energy and obesogenic nutrients. Yet, the Pearson correlations for energy-adjusted nutrient intake were low for trans-fatty acids (0·294) and PUFA (0·377). The MMPS can be a time-efficient tool for dietary assessment of energy and many obesogenic nutrients. Future studies should validate the MMPS across the lifespan and re-evaluate it after updating the fatty acid profiles in the culturally specific food composition tables.

This retrospective study investigates the prevalence of atypical femoral fractures (AFFs) among patients admitted with hip and shaft fractures at a tertiary referral center in Beirut, Lebanon. We analyzed electronic medical records and radiology studies of patients aged above 40 admitted with hip and shaft fractures between January 2006 and December 2019. Fractures were confirmed by ICD9 or ICD10 codes. All cases were reviewed by radiologists, and AFFs were identified according to the 2013 revised ASBMR criteria. We identified 1366 hip and shaft fracture patients, of which 14 female patients had 19 AFFs. This represents a prevalence of 1.0% among all hip and shaft fractures patients and 1.7% among all female hip and shaft fracture patients. Bilateral AFFs were found in 5 of the 14 patients. Patients with AFF tended to be younger, with a mean age of 74.3 (±8.6) yr compared to 78.0 (±10.6) for patients with non-AFF fractures. A total of 36% of AFF patients had a prior history of non-traumatic fracture at first admission. A high percentage of patients with AFFs reported intake of proton pump inhibitors (42.9%) and glucocorticoids (21.4%). Bisphosphonate exposure was noted in 64.3% of AFF patients. None of the AFF patients were active smokers or consumed alcohol regularly. BMD assessments were available for 7 AFF patients, indicating osteoporosis in 4 and osteopenia in 3 cases. Hip axis length measurements showed no significant difference between AFF patients ( N  = 7) and sex and age-matched controls ( N  = 21). The study underlines the prevalence and characteristics of AFFs in Lebanon, which is consistent with the numbers reported in the literature (0.32%-5%). A larger prospective study that includes hospitals across the nation is needed to gain a more comprehensive view of the prevalence of AFFs in the Lebanese population., Competing Interests: All authors declare having no conflict of interest with regard to the submitted work., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background: Developing countries have a significantly higher incidence of breast cancer in patients younger than 40 years as compared to developed countries. This study aimed to examine if young age at diagnosis is an independent prognostic factor for worse survival outcomes in breast cancer as well as the effect of age on Disease-free survival (DFS) and local recurrence free survival (LRFS) after adjusting for various tumor characteristics, local and systemic treatments., Methods: This is a secondary analysis of prospective cohort of patients from two existing databases. We identified patients with breast cancer aged 40 years or less and we matched them to those older than 40 years. We also matched based on stage and molecular subtypes. In cohort 1, we matched at a ratio of 1:1, while in cohort 2 we matched at a ratio of 1:3., Results: In cohort 1, Disease-free survival (DFS) at 5 years was significantly shorter for those younger than 40 years (75.6% and 92.7% respectively; p < 0.03). On multivariate analysis, only chemotherapy was found to be significant, while age was not found to be an independent predictor of prognosis. Local recurrence free survival at 5 years was similar between both age categories. Only hormonal therapy is a significant predictor for LRFS at 5 years. In the second cohort, DFS and LRFS at 3 years were similar between those younger and those older than 40 years. On multivariate analysis, no factor including age was found to be an independent predictor of prognosis., Conclusion: Data in the literature is controversial on the effect of young age on breast cancer prognosis. Our findings could not demonstrate that age is an independent prognostic factor in our population. There is a need for outcomes from larger, prospective series that have longer follow-ups and more data from our region., (© 2024. The Author(s).)

Multiple changes occur across various endocrine systems as an individual ages. The understanding of the factors that cause age-related changes and how they should be managed clinically is evolving. This statement reviews the current state of research in the growth hormone, adrenal, ovarian, testicular, and thyroid axes, as well as in osteoporosis, vitamin D deficiency, type 2 diabetes, and water metabolism, with a specific focus on older individuals. Each section describes the natural history and observational data in older individuals, available therapies, clinical trial data on efficacy and safety in older individuals, key points, and scientific gaps. The goal of this statement is to inform future research that refines prevention and treatment strategies in age-associated endocrine conditions, with the goal of improving the health of older individuals., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This work aims to review and discuss controversial topics in the field of vitamin D, SARS-CoV-2 infection, and COVID-19., Methods: The International Conferences "Controversies in Vitamin D" are a series of workshops that started in 2017 featuring international experts and leaders in vitamin D research and clinical practice. The fifth annual conference was held in Stresa, Italy, September 15 to 18, 2021., Evidence: Before the event, participants reviewed available studies on their assigned topic, drafted a related abstract, and presented their findings at the time of the conference. Relevant literature that became available since was also discussed within the panel and updated accordingly., Consensus: Before the event, the drafted abstracts had been merged to prepare a preliminary document. After the conference presentations, in-depth discussions in open sessions led to consensus. The document was subsequently modified according to discussions and up-to-date literature inclusion., Conclusions: There is quite consistent evidence for an association between low 25 OH vitamin D (25(OH)D) levels and poor COVID-19 outcomes, despite heterogeneous publications of variable quality. However, the low vitamin D status in COVID-19 patients might also reflect reverse causality. Vitamin D supplementation might have a positive role in COVID-19 prevention. The evidence supporting a beneficial effect of vitamin D treatment in decreasing the risk of COVID-19 complications is conflicting. Conclusive statements regarding the beneficial effect of vitamin D in this context await high-quality, randomized controlled trials., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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)., (© 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).)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)