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Darshika J Christie-David,1,2 Christian M Girgis,2–4 Jenny E Gunton1–4 1Department of Endocrinology and Diabetes, Westmead Hospital, 2Faculty of Medicine, University of Sydney, 3Westmead Millennium Institute, 4Garvan Institute of Medical Research, Sydney, NSW, Australia Abstract: Scurvy and rickets are largely considered historical diseases in developed countries. However, deficiencies in vitamins C and D are re-emerging due to increased consumption of processed foods and reduced fresh foods in the Western diet, as well as to an indoor sedentary lifestyle away from sun exposure. These dietary and lifestyle factors also predispose one to diabetes and metabolic syndrome. Our understanding of the potential roles of vitamin C (an antioxidant) and vitamin D (a biologically active hormone) in disease is increasing. In this review, we present observational, interventional, and mechanistic studies that examine the potential links between vitamins C and D in reversing defects in glucose homeostasis and the prevention of type 2 diabetes. Studies suggest an association between vitamin C deficiency and diabetes. An association between vitamin D and insulin resistance has been well described; however, the role of vitamin C and D supplementation in diabetes and its prevention requires further controlled trials. Keywords: glucose homeostasis, diabetes, insulin resistance, vitamin C, vitamin D

Several small genetic association studies have been conducted for atypical femur fracture (AFF) without replication of results. We assessed previously implicated and novel genes associated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES). We performed gene-based association analysis on 139 European AFF cases and 196 controls matched for bisphosphonate use. We tested all rare, protein-altering variants using both candidate gene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs (uncorrected p-values <.01) were investigated in a Swedish whole-genome sequencing replication study and assessed in 46 non-European cases. In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-free approach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likely candidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in the replication analysis, albeit not statistically significant. Three SNPs associated with SORD expression according to the GTEx portal were in linkage disequilibrium (R2 ≥ 0.2) with an SNP previously reported in a genome-wide association study of AFF. The prevalence of carriers of variants for both PLOD2 and SORD was higher in Asian versus European cases. While we did not identify genes enriched for damaging variants, we found suggestive evidence of a role for XRN2, PLOD2, and SORD, which requires further investigation. Our findings indicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The study provides a stepping-stone for future larger genetic studies of AFF., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

In severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab is unclear. We utilised a novel overlapping strategy in three patients with very-high fracture risk despite long-term denosumab which led to greater bone density improvements than previously reported with standard approaches. Larger confirmatory prospective studies are needed., Purpose/introduction: In patients with severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab has not been established. The ideal strategy would maximise gains in bone mineral density (BMD) with romosozumab and effectively mitigate the risk of rebound increased bone turnover when sequencing from denosumab. Limited studies exploring the sequence from denosumab to romosozumab report only modest-to-no improvement in BMD and inadequate suppression of rebound bone turnover., Methods: We describe three patients with severe osteoporosis and multiple fragility fractures despite long-term denosumab. A novel overlapping sequential treatment approach was utilised to maximise therapeutic benefit given these patients had a very high fracture risk. Romosozumab was commenced 3 months after the last denosumab dose. Instead of waiting until completion of romosozumab, denosumab was recommenced 6 months after commencing romosozumab in response to rising bone turnover markers., Results: Patients experienced a ~ 5-22% increase in lumbar spine BMD, and one patient had an 8% increase in total hip BMD after 12 months romosozumab. Serum bone turnover markers demonstrated an anabolic effect of romosozumab occurred despite overlapping treatment with denosumab. Recommencement of denosumab suppressed an increase in bone resorption in all cases. No new vertebral fractures occurred during this treatment., Conclusions: A novel overlapping sequential treatment approach between denosumab and romosozumab produced greater improvements in lumbar spine and hip BMD than previously reported with standard approaches. Larger prospective controlled studies are needed to confirm these findings and establish the optimal use of romosozumab in patients pre-treated with denosumab to maximise BMD gains and minimise fracture risk., (© 2024. The Author(s).)

Introduction: Novel strategies are needed to address the rising burden of osteoporosis and fragility fractures. High-intensity resistance and impact (HiRIT) exercise has shown benefit in improving bone density in postmenopausal women with osteoporosis/osteopenia. Whether HiRIT can enhance the therapeutic effects of osteoporosis pharmacotherapy has not been established. ROLEX-DUO is a randomised controlled trial designed to assess the efficacy of romosozumab on various bone and muscle outcomes in combination with different exercise interventions in women with postmenopausal osteoporosis/osteopenia., Methods and Analysis: ROLEX-DUO is an 8-month randomised placebo-controlled trial conducted at two tertiary referral centres for patients with osteoporosis/osteopenia in Sydney, New South Wales, Australia. The study is implementing the combination of romosozumab or placebo with different forms of exercise in postmenopausal women with osteoporosis/osteopenia without recent fragility fracture (n=102). Eligible women will be randomised 1:1:1 into one of three groups: (1) romosozumab with supervised HiRIT, (2) romosozumab with unsupervised low-intensity exercise or (3) placebo with unsupervised low-intensity exercise. Co-primary outcomes are the mean percentage change in lumbar spine bone mineral density (BMD), and mean change in five times sit-to-stand test performance (seconds) at 8 months. Secondary/exploratory outcomes include BMD changes at the femoral neck, total hip and distal radius, three-dimensional dual-energy X-ray absorptiometry (DXA) hip outcomes, DXA-derived lean and fat mass, serum markers of bone turnover (procollagen type 1 peptide, C-telopeptide of type 1 collagen) and bone biomarkers (dickkopf-1), serum extracellular vesicle analyses, 36-Item Short Form Survey (SF-36) quality-of-life scores, Menopause-Specific Quality Of Life (MENQOL) Questionnaire menopause symptom burden scores, number of falls and fractures. Mixed-effects models will be performed to compare longitudinal outcome results between groups using intention-to-treat analysis., Ethics and Dissemination: The trial was approved by the Northern Sydney Local Health District Human Research Ethics Committee (2022/ETH01794, protocol V.8, dated 03 July 2024). Participants will provide written informed consent prior to inclusion. Findings will be disseminated via peer-reviewed journals, scientific conferences and summary reports to funding bodies., Trial Registration Number: ACTRN12623000867695., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare: all authors had financial support from Healthy Bones Australia, Australian New Zealand Bone and Mineral Society, Avant Mutual and NORTH Foundation for grant funding for the submitted work. Belinda R Beck is owner and director of The Bone Clinic (TBC) which is the licensee of the HiRIT programme being used in this study. All other authors declare no financial relationships with any organisations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite well-defined criteria for radiographic diagnosis of atypical femur fractures (AFFs), missed and delayed diagnosis is common. An AFF diagnostic software could provide timely AFF detection to prevent progression of incomplete or development of contralateral AFFs. In this study, we investigated the ability for an artificial intelligence (AI)-based application, using deep learning models (DLMs), particularly convolutional neural networks (CNNs), to detect AFFs from femoral radiographs. A labelled Australian dataset of pre-operative complete AFF (cAFF), incomplete AFF (iAFF), typical femoral shaft fracture (TFF), and non-fractured femoral (NFF) X-ray images in anterior-posterior view were used for training (N = 213, 49, 394, 1359, respectively). An AFFnet model was developed using a pretrained (ImageNet dataset) ResNet-50 backbone, and a novel Box Attention Guide (BAG) module to guide the model's scanning patterns to enhance its learning. All images were used to train and internally test the model using a 5-fold cross validation approach, and further validated by an external dataset. External validation of the model's performance was conducted on a Sweden dataset comprising 733 TFF and 290 AFF images. Precision, sensitivity, specificity, F1-score and AUC were measured and compared between AFFnet and a global approach with ResNet-50. Excellent diagnostic performance was recorded in both models (all AUC >0.97), however AFFnet recorded lower number of prediction errors, and improved sensitivity, F1-score and precision compared to ResNet-50 in both internal and external testing. Sensitivity in the detection of iAFF was higher for AFFnet than ResNet-50 (82 % vs 56 %). In conclusion, AFFnet achieved excellent diagnostic performance on internal and external validation, which was superior to a pre-existing model. Accurate AI-based AFF diagnostic software has the potential to improve AFF diagnosis, reduce radiologist error, and allow urgent intervention, thus improving patient outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Peter R Ebeling reports financial support was provided by National Health & Medical Research Council. Peter R Ebeling reports a relationship with Amgen Inc., Sanofi, Alexion, Kyowa-Kirin that includes: funding grants. Senior author Peter R Ebeling is the Editor in Chief of Bone If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: International osteoporosis guidelines have recommended treatment approaches based on fracture risk stratification, in particular, anabolic therapy for patients with very high risk (VHR) of fragility fracture., Aim: To summarise Australian clinicians' perceptions of patients at VHR of fracture., Methods: Australian clinicians invited to educational webinars on anabolic treatments for osteoporosis were surveyed in March and April 2021 about a typical patient they had most recently seen and identified as at VHR of fracture., Results: Of the 268 clinician attendees who were invited to complete the post-webinar surveys, 67 (25%) responded and permitted the publication of aggregated data. A typical patient perceived to have a VHR of fracture was a woman in her 80's, living at home, who had been diagnosed with osteoporosis between 5 and 10 years ago, and received treatment for 1-5 years' duration, most commonly denosumab. The patient frequently had a T-score below -3.0 SD (standard deviation), multiple fragility fractures and most commonly suffered a vertebral fracture in the past 12 months, whereas on an adequate regimen of osteoporosis medication. There was a mismatch between the patient being eligible for anabolic therapy (64.2%) and actually having been prescribed an anabolic treatment in the past (20.9%)., Conclusions: Australian clinicians' perceptions of patients with a VHR of fracture and the use of anabolic agents appear to be heavily influenced by local reimbursement criteria. The mismatch between patients deemed eligible for reimbursed anabolic therapy and those prescribed an anabolic agent suggests treatment inertia., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of denosumab treatment and discontinuation to show the temporal changes in osteoclast formation and activity during RANKL inhibition and withdrawal. We show that the cellular processes that drive the formation of osteoclasts and subsequent bone resorption following withdrawal of RANKL inhibition precede the rebound bone loss. Furthermore, a rise in serum TRAP and RANKL levels is detected before markers of bone turnover used in current clinical practice. These mechanistic advances may provide insight into a more defined window of opportunity to intervene with sequential therapy following denosumab discontinuation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Objective: To describe the development of a new position statement regarding balancing the risks and benefits of sun exposure for Australian adults., Methods: We conducted a Sun Exposure Summit in March 2021, with presentations from invited experts and a workshop including representation from academic, clinical, policy, and patient stakeholder organisations. The group considered advice about balancing the risks and benefits of sun exposure for Australian adults and developed a revised consensus position statement., Results: The balance of risks and benefits of sun exposure is not the same for everybody. For people at very high risk of skin cancer, the risks of exposure likely outweigh the benefits; sun protection is essential. Conversely, people with deeply pigmented skin are at low risk of skin cancer but at high risk of vitamin D deficiency; routine sun protection is not recommended. For those at intermediate risk of skin cancer, sun protection remains a priority, but individuals may obtain sufficient sun exposure to maintain adequate vitamin D status., Conclusions: The new position statement provides sun exposure advice that explicitly recognises the differing needs of Australia's diverse population., Implications for Public Health: Mass communication campaigns should retain the focus on skin cancer prevention. The new position statement will support the delivery of personalised advice., Competing Interests: Conflicts of interest David Whiteman reports a relationship with Pierre Fabre Australia that includes speaking and lecture fees. Peter Ebeling reports a relationship with Healthy Bones Australia that includes board membership. Peter Ebeling reports a relationship with the American Society for Bone and Mineral Research that includes board membership. Peter Ebeling reports a relationship with International Osteoporosis Foundation that includes: board membership. Peter Ebeling reports a relationship with the Asian Pacific Consortium on Osteoporosis that includes board membership. Craig Sinclair reports a relationship with Cancer Council Victoria that includes employment. Christian Girgis reports a relationship with the Australian and New Zealand Bone and Mineral Society that includes board membership. Christian Girgis reports a relationship with the University of Sydney that includes employment. Stephen Shumack reports a relationship with the Australasian College of Dermatologists that includes non-financial support., (Copyright © 2024. Published by Elsevier B.V.)

Patients with cancer and diabetes face unique challenges. Limited data are available on diabetes management in patients undergoing concurrent chemoradiotherapy (CCRT), a curative intent anticancer therapy commonly associated with glucocorticoid administration, weight fluctuations and enteral feeds. This retrospective case-control study examined the real-world incidence of acute diabetes-related complications in patients with head and neck cancer receiving CCRT, along with the impact of diabetes on CCRT tolerance and outcomes., Methods: Consecutive patients with head and neck squamous cell or nasopharyngeal cancer who underwent definitive or adjuvant CCRT between 2010 and 2019 at two large cancer centers in Australia were included. Clinicopathological characteristics, treatment complications and outcomes were collected from medical records., Results: Of 282 patients who received CCRT, 29 (10.3%) had pre-existing type 2 diabetes. None had type 1 diabetes. The majority (74.5%) required enteral feeding. A higher proportion of patients with diabetes required admission to a high-dependency or intensive care unit (17.2 versus 4.0%, p = 0.003). This difference was driven by the group who required insulin at baseline ( n = 5), of which four (80.0%) were admitted to a high-dependency unit with diabetes-related complications, and three (60.0%) required omission of at least one cycle of chemotherapy., Conclusions: Patients with diabetes requiring insulin have a high risk of acute life-threatening diabetes-related complications while receiving CCRT. We recommend multidisciplinary management involving a diabetes specialist, educator, dietitian, and pharmacist, in collaboration with the cancer care team, to better avoid these complications.

Objective: To formulate clinical consensus recommendations on the presentation, assessment, and management of primary hyperparathyroidism (PHPT) in adults., Methods: Representatives from relevant Australian and New Zealand Societies used a systematic approach for adaptation of guidelines (ADAPTE) to derive an evidence-informed position statement addressing nine key questions., Results: PHPT is a biochemical diagnosis. Serum calcium should be measured in patients with suggestive symptoms, reduced bone mineral density or minimal trauma fractures, and in those with renal stones. Other indications are detailed in the manuscript. In patients with hypercalcaemia, intact parathyroid hormone, 25-hydroxy vitamin D, phosphate, and renal function should be measured. In established PHPT, assessment of bone mineral density, vertebral fractures, urinary tract calculi/nephrocalcinosis and quantification of urinary calcium excretion is warranted. Parathyroidectomy is the only definitive treatment and is warranted for all symptomatic patients and should be considered for asymptomatic patients without contraindications to surgery and with >10 years life expectancy. In patients who do not undergo surgery, we recommend annual evaluation for disease progression. Where the diagnosis is not clear or the risk-benefit ratio is not obvious, multidisciplinary discussion and formulation of a consensus management plan is appropriate. Genetic testing for familial hyperparathyroidism is recommended in selected patients., Conclusions: These clinical consensus recommendations were developed to provide clinicians with contemporary guidance on the assessment and management of PHPT in adults. It is anticipated that improved health outcomes for individuals and the population will be achieved at a decreased cost to the community., (© 2021 John Wiley & Sons Ltd.)

Objective: Older people are more prone to vitamin D deficiency than younger populations. Individual lifestyle factors have been associated with vitamin D status. We examined the influence of a combination of lifestyle factors on vitamin D status in older men., Participants and Measurements: In a population-based cohort study of older men (age ≥65 years), a lifestyle score was calculated from eight prudent health-related behaviours (smoking, exercise, alcohol, fish and meat consumption, adding salt, milk choices and obesity) collected via questionnaire at baseline. Blood samples were collected 5 years afterwards to measure plasma 25-hydroxyvitamin D (25OHD) levels. Associations between lifestyles and the likelihood of having plasma 25OHD levels of ≥75 versus <75 nmol/L and ≥50 versus <50 nmol/L were tested using logistic regression models., Results: Of the 2717 men analysed, mean plasma 25OHD was 69.0 ± 23.5 nmol/L, with 20.7% having plasma 25OHD <50 nmol/L. Men engaging in ≥4 healthy lifestyle behaviours had 20% higher odds of plasma 25OHD ≥75 nmol/L (adjusted OR = 1.20, 95% CI: 1.01-1.45) compared to those with <4 healthy behaviours. No association was found for 25OHD ≥50 nmol/L. Higher physical activity was the only individual component significantly associated with vitamin D sufficiency (highest vs. lowest quintiles of physical activity, adjusted OR = 2.01, 95% CI: 1.47-2.74 for 25OHD ≥50 nmol/L, adjusted OR = 2.35, 95% CI: 1.81-3.06 for 25OHD ≥75 nmol/L)., Conclusion: Multiple healthy lifestyle behaviours are associated with better vitamin D status in older men. Further work is needed to determine the effects of promoting healthy lifestyle behaviours, including physical activity, on vitamin D sufficiency., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Introduction: The aim of this study was to determine the prevalence of diabetic retinopathy (DR) in a low socioeconomic region of a high-income country, as well as determine the diagnostic utility of point-of-care screening for high-risk populations in tertiary care settings., Research Design and Methods: This was a cross-sectional study of patients with diabetes attending foot ulcer or integrated care diabetes clinics at two Western Sydney hospitals (n=273). DR was assessed using portable, two-field, non-mydriatic fundus photography and combined electroretinogram/ pupillometry (ERG). With mydriatic photographs used as the reference standard, sensitivity and specificity of the devices were determined. Prevalence of DR and vision-threatening diabetic retinopathy (VTDR) were reported, with multivariate logistic regression used to identify predictors of DR., Results: Among 273 patients, 39.6% had any DR, while 15.8% had VTDR, of whom 59.3% and 62.8% were previously undiagnosed, respectively. Non-mydriatic photography demonstrated 20.2% sensitivity and 99.5% specificity for any DR, with a 56.7% screening failure rate. Meanwhile, mydriatic photography produced high-quality images with a 7.6% failure rate. ERG demonstrated 72.5% sensitivity and 70.1% specificity, with a 15.0% failure rate. The RETeval ERG was noted to have an optimal DR cut-off score at 22. Multivariate logistic regression identified an eGFR of ≤29 mL/min/1.73 m 2 , HbA1c of ≥7.0%, pupil size of <4 mm diameter, diabetes duration of 5-24 years and RETeval score of ≥22 as strong predictors of DR., Conclusion: There is a high prevalence of vision-threatening and undiagnosed DR among patients attending high-risk tertiary clinics in Western Sydney. Point-of-care DR screening using portable, mydriatic photography demonstrates potential as a model of care which is easily accessible, targeted for high-risk populations and substantially enhances DR detection., Competing Interests: Competing interests: Similarly, Welch Allyn loaned equipment for data collection, with no involvement in study design, data analysis, interpretation, manuscript preparation, nor the decision to submit the report for publication. Duality of Interest: Welch Allyn provided financial support for another clinical study run in the Department of Ophthalmology, Westmead Hospital. The authors received no personal financial support., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aneurysmal bone cysts (ABC) are rare osteolytic, benign but often locally aggressive tumours of the long bones or vertebrae. For spinal ABC, surgical management, embolisation or sclerotherapy alone often carry high morbidity and/or high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. We aimed to review the approach to surgical management and evaluate the efficacy and safety of denosumab for ABC of the spine in children. Retrospective review of 7 patients treated with denosumab using a standardised protocol for ABC of the spine in a tertiary paediatric centre. Surgical intervention was only conducted if there was spinal instability or significant neurological impairment. Denosumab 70 mg/m 2 was given 4-weekly for at least 6 months, followed by 2 doses of zoledronate 0.025 mg/kg, aiming to prevent rebound hypercalcaemia. All patients achieved stability of the spine and resolution of neurological impairment, if present. Six patients achieved metabolic remission and have ceased denosumab without recurrence to date; the other showed clinical and radiological improvement without complete metabolic remission. Three patients developed symptomatic hypercalcaemia 5-7 months after cessation of denosumab, requiring additional bisphosphonate treatment. We present our algorithm for the surgical and medical management of paediatric spinal ABC. Denosumab produced a radiological and metabolic response in all patients, with complete remission in most. Follow-up time was not long enough to evaluate the endurance of response after cessation in some patients. Incidence of rebound hypercalcaemia in this paediatric cohort was high, prompting a change to our protocol., (© 2023. Crown.)

Background: Low bone density leads to fragility fracture, with significant impact on morbidity and mortality. While ethnic differences in bone density have been observed in healthy subjects, this has not yet been explored in fragility fracture patients., Aims: To assess if ethnicity is associated with bone mineral density and serum markers of bone health in female patients who experience fragility fractures., Methods: 219 female patients presenting with at least one fragility fracture at a major tertiary hospital in Western Sydney Australia were studied. Western Sydney is a region with great cultural diversity, comprising people from over 170 ethnicities. Within this cohort, the three largest broad ethnic groups were Caucasians (62.1 %), Asians (22.8 %), and Middle Eastern patients (15.1 %). Location and nature of the presenting fracture and other relevant past medical history were obtained. Bone mineral density, measured by dual-energy X-ray absorptiometry, and bone-related serum markers were compared between ethnicities. Covariates (age, height, weight, diabetes, smoking, and at-risk drinking) were adjusted in multiple linear regression model., Results: Although Asian ethnicity was associated with lower bone mineral density at the lumbar spine in fragility fracture patients, this association was no longer significant after adjustment for weight. Ethnicity (Asian or Middle Eastern) was not a determinant of bone mineral density at any other skeletal site. Caucasians had lower estimated glomerular filtration rate compared to Asian and Middle Eastern subjects. Serum parathyroid hormone concentrations were significantly lower in Asians compared to other ethnicities., Conclusion: Asian ethnicity and Middle Eastern ethnicity were not major determinants of bone mineral density at the lumbar spine, femoral neck, or total hip., Competing Interests: All authors declare no conflict of interests., (© 2023 The Authors.)

Patients with type 2 diabetes mellitus (T2DM) experience a higher risk of fractures despite paradoxically exhibiting normal to high bone mineral density (BMD). This has drawn into question the applicability to T2DM of conventional fracture reduction treatments that aim to retain BMD. In a primary human osteoblast culture system, high glucose levels (25 mM) impaired cell proliferation and matrix mineralization compared to physiological glucose levels (5 mM). Treatment with parathyroid hormone (PTH, 10 nM), a bone anabolic agent, and cinacalcet (CN, 1 µM), a calcimimetic able to target the Ca 2+ -sensing receptor (CaSR), were tested for their effects on proliferation and differentiation. Strikingly, CN+PTH co-treatment was shown to promote cell growth and matrix mineralization under both physiological and high glucose conditions. CN+PTH reduced apoptosis by 0.9-fold/0.4-fold as measured by Caspase-3 activity assay, increased alkaline phosphatase (ALP) expression by 1.5-fold/twofold, increased the ratio of nuclear factor κ-B ligand (RANKL) to osteoprotegerin (OPG) by 2.1-fold/1.6-fold, and increased CaSR expression by 1.7-fold/4.6-fold (physiological glucose/high glucose). Collectively, these findings indicate a potential for CN+PTH combination therapy as a method to ameliorate the negative impact of chronic high blood glucose on bone remodeling., (© 2023. The Author(s).)

Objectives: To develop guidelines, informed by health-care consumer values and preferences, for sarcopenia prevention, assessment and management for use by clinicians and researchers in Australia and New Zealand., Methods: A three-phase Consumer Expert Delphi process was undertaken between July 2020 and August 2021. Consumer experts included adults with lived experience of sarcopenia or health-care utilisation. Phase 1 involved a structured meeting of the Australian and New Zealand Society for Sarcopenia and Frailty Research (ANZSSFR) Sarcopenia Diagnosis and Management Task Force and consumer representatives from which the Phase 2 survey was developed. In Phase 2, consumers from Australia and New Zealand were surveyed online with opinions sought on sarcopenia outcome priorities, consultation preferences and interventions. Findings were confirmed and disseminated in Phase 3. Descriptive statistical analyses were performed., Results: Twenty-four consumers (mean ± standard deviation age 67.5 ± 12.8 years, 18 women) participated in Phase 2. Ten (42%) identified as being interested in sarcopenia, 7 (29%) were health-care consumers and 6 (25%) self-reported having/believing they have sarcopenia. Consumers identified physical performance, living circumstances, morale, quality of life and social connectedness as the most important outcomes related to sarcopenia. Consumers either had no preference (46%) or preferred their doctor (40%) to diagnose sarcopenia and preferred to undergo assessments at least yearly (54%). For prevention and treatment, 46% of consumers preferred resistance exercise, 2-3 times per week (54%)., Conclusions: Consumer preferences reported in this study can inform the implementation of sarcopenia guidelines into clinical practice at local, state and national levels across Australia and New Zealand., (© 2022 The Authors. Australasian Journal on Ageing published by John Wiley & Sons Australia, Ltd on behalf of AJA Inc’.)

Background: Sarcopenia is an age-associated skeletal muscle condition characterized by low muscle mass, strength, and physical performance. There is no international consensus on a sarcopenia definition and no contemporaneous clinical and research guidelines specific to Australia and New Zealand. The Australian and New Zealand Society for Sarcopenia and Frailty Research (ANZSSFR) Sarcopenia Diagnosis and Management Task Force aimed to develop consensus guidelines for sarcopenia prevention, assessment, management and research, informed by evidence, consumer opinion, and expert consensus, for use by health professionals and researchers in Australia and New Zealand., Methods: A four-phase modified Delphi process involving topic experts and informed by consumers, was undertaken between July 2020 and August 2021. Phase 1 involved a structured meeting of 29 Task Force members and a systematic literature search from which the Phase 2 online survey was developed (Qualtrics). Topic experts responded to 18 statements, using 11-point Likert scales with agreement threshold set a priori at >80%, and five multiple-choice questions. Statements with moderate agreement (70%-80%) were revised and re-introduced in Phase 3, and statements with low agreement (<70%) were rejected. In Phase 3, topic experts responded to six revised statements and three additional questions, incorporating results from a parallel Consumer Expert Delphi study. Phase 4 involved finalization of consensus statements., Results: Topic experts from Australia (n = 62, 92.5%) and New Zealand (n = 5, 7.5%) with a mean ± SD age of 45.7 ± 11.8 years participated in Phase 2; 38 (56.7%) were women, 38 (56.7%) were health professionals and 27 (40.3%) were researchers/academics. In Phase 2, 15 of 18 (83.3%) statements on sarcopenia prevention, screening, assessment, management and future research were accepted with strong agreement. The strongest agreement related to encouraging a healthy lifestyle (100%) and offering tailored resistance training to people with sarcopenia (92.5%). Forty-seven experts participated in Phase 3; 5/6 (83.3%) revised statements on prevention, assessment and management were accepted with strong agreement. A majority of experts (87.9%) preferred the revised European Working Group for Sarcopenia in Older Persons (EWGSOP2) definition. Seventeen statements with strong agreement (>80%) were confirmed by the Task Force in Phase 4., Conclusions: The ANZSSFR Task Force present 17 sarcopenia management and research recommendations for use by health professionals and researchers which includes the recommendation to adopt the EWGSOP2 sarcopenia definition in Australia and New Zealand. This rigorous Delphi process that combined evidence, consumer expert opinion and topic expert consensus can inform similar initiatives in countries/regions lacking consensus on sarcopenia., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Purpose of Review: Inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) with denosumab is an effective treatment in a number of conditions including osteoporosis where suppression of bone resorption is desired. However, denosumab discontinuation is associated with rebound increase in bone resorption and subsequent loss in bone mass and a rapid return to baseline fracture risk. We review recent data on the rebound increase in bone resorption following denosumab discontinuation and the potential mechanisms behind this phenomenon., Recent Findings: Osteoclasts have been considered to be highly specialised cells that undergo apoptosis after fulfilling their function of bone resorption. However, recent studies suggest that osteoclasts are longer lived cells which migrate through vasculature and are capable of undergoing fission into a novel cell type (the osteomorph) and re-fusion in a process termed osteoclast recycling. The life cycle of the osteoclast is more complex than previously appreciated. Osteoclast recycling provides a novel mechanistic framework to examine changes in osteoclast biology in response to treatment of bone diseases and provides an exciting new avenue towards personalised medicine., (© 2022. Crown.)

The prevalence of type 1 diabetes (T1D) is rising steadily. A potential contributor to the rise is vitamin D. In this systematic review, we examined the literature around vitamin D and T1D. We identified 22 papers examining the role of vitamin D in cultured β-cell lines, islets, or perfused pancreas, and 28 papers examining vitamin D in humans or human islets. The literature reports strong associations between T1D and low circulating vitamin D. There is also high-level (systematic reviews, meta-analyses) evidence that adequate vitamin D status in early life reduces T1D risk. Several animal studies, particularly in NOD mice, show harm from D-deficiency and benefit in most studies from vitamin D treatment/supplementation. Short-term streptozotocin studies show a β-cell survival effect with supplementation. Human studies report associations between VDR polymorphisms and T1D risk and β-cell function, as assessed by C-peptide. In view of those outcomes, the variable results in human trials are generally disappointing. Most studies using 1,25D, the active form of vitamin D were ineffective. Similarly, studies using other forms of vitamin D were predominantly ineffective. However, it is interesting to note that all but one of the studies testing 25D reported benefit. Together, this suggests that maintenance of optimal circulating 25D levels may reduce the risk of T1D and that it may have potential for benefits in delaying the development of absolute or near-absolute C-peptide deficiency. Given the near-complete loss of β-cells by the time of clinical diagnosis, vitamin D is much less likely to be useful after disease-onset. However, given the very low toxicity of 25D, and the known benefits of preservation of C-peptide positivity for long-term complications risk, we recommend considering daily cholecalciferol supplementation in people with T1D and people at high risk of T1D, especially if they have vitamin D insufficiency.

Bisphosphonates (BPs) are commonly used in the treatment of osteoporosis and are effective in the prevention of fragility fracture. Long-term use has been associated with the development of atypical femur fractures (AFFs) and osteonecrosis of the jaw (ONJ). Drug holidays seek to reduce the risk of insufficiency fractures (AFFs) while maintaining durable effects of long-term treatment in the prevention of fragility fracture. Guidelines suggest that BP drug holidays be considered after 3 to 5 years. However individual factors impacting this decision and outcomes are unclear. This review examines key factors in the planning of a safe BP drug holiday and surrogate markers of fracture risk in patients discontinuing treatment. Fifteen randomized control trials and 19 real-world studies were included, including nationwide prospective studies from several countries. Increases in bone turnover markers (BTMs) and reductions in bone mineral density (BMD) were generally observed during BP drug holidays. Resurgent bone turnover was problematic in high-risk patients in whom fractures recurred as early as 12 months following a drug holiday. Risk factors for holiday-related fractures included older age, low hip BMD, underweight, low medication adherence, and prevalent/incident fractures. Zoledronic acid conferred the most durable reduction in fractures, particularly after six annual infusions. Five years of alendronate was insufficient in preventing vertebral fractures in high-risk patients embarking on a drug holiday. Relatively faster offset of antiresorptive effect was seen in risedronate users with more frequent fractures than alendronate during a drug holiday. Studies directly counterbalancing effects of long-term treatment on AFF risk versus drug holiday outcomes in the same population were lacking. In the absence of persistently high fracture risk and following a specific treatment duration dependent on the BP used, drug holidays are safe and mitigate the risk of AFF. However, anti-resorptive effects diminish over time; ongoing monitoring and careful planning of BP resumption is necessary. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: The authors have no conflicts of interest to report., (© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Central giant cell granuloma (CGCG) is a rare lesion of the jaw occurring in young adults and adolescents. Surgery, the traditional mainstay of therapy, is associated with significant morbidity. Denosumab, a humanised monoclonal antibody to RANKL, is effective in a related entity, giant cell tumour of bone (GCTB), but experience in the more indolent CGCG is limited. This prospective observational study of all denosumab-treated CGCG at a tertiary referral centre (2015-2021) aimed to evaluate the safety, efficacy and recurrence risk using denosumab in CGCG at lower-frequency dosing than used for GCTB. All received standardised, time-limited courses of denosumab 120 mg with stepwise increase in dosing interval based on response. They were followed for up to 75 months using a radiation-minimising protocol: 3-monthly clinical, biochemical and radiological assessment (orthopantomograms, cone beam CT). Eight patients, median age 20.5 years [IQR 6], received 13 initial doses [IQR 10] of denosumab 120 mg. Radiologic response was seen after 5.5 doses [IQR 4.5]: ossification in all and size reduction in three. Recurrence occurred in four of seven completing therapy, observed 12 months post-cessation [IQR 6.5]. Larger baseline size, aggressive subtype and fewer than 12 initial doses were more common in the recurrence group. There was no osteonecrosis of the jaw. Hypocalcaemia occurred in one receiving modified dosing. This study represents the largest, most diverse cohort of denosumab-treated CGCG with the longest follow-up in literature. It demonstrates the efficacy of lower-frequency, time-restricted course of denosumab but highlights the risk of recurrence. Long-term follow-up is critical., (© 2021. Crown.)

Chronic Kidney Disease Stage 5 (CKD-5) imparts a 4-fold increase in minimal trauma fracture with a substantial increase in mortality following hip fracture. Bone disease in CKD is complex, characterised by abnormal levels of PTH, calcium, phosphate, ALP, and vitamin D, manifesting as a condition known as CKD-Mineral and Bone Disorder (CKD-MBD). While bisphosphonates (BPs) are widely used in the management of osteoporosis, their therapeutic role when end-stage renal function and bone disease co-exist remains unclear. This 15-year retrospective cohort study examines the long-term use of BPs in CKD-4 and -5 patients receiving no renal replacement therapy, haemodialysis and renal transplant in a tertiary centre in Sydney, Australia. In multivariate regression adjusting for age, baseline bone mineral density (BMD) and history of fracture, BP use was associated with net gain in lumbar spine bone density in renal transplant recipients over a mean treatment period of 3.5 years (net annual BMD gain of 0.039 g/cm 2 , p  = 0.005). No such benefit was seen in hip BMD in CKD subjects. Regardless of transplant status, CKD patients treated with BPs had no improvement in hip BMD with a general decline in hip BMD across both groups during the study period (hip BMD: transplant recipients decline 0.024 ± 0.81 g/cm 2 , non-transplant CKD patients decline 0.055 ± 0.84 g/cm 2 ). BP therapy did not result in significant changes in biochemical parameters (ALP, PTH, and phosphate) and no serious adverse effects were detected in association with BP use. In particular, kidney function was not affected by BPs post-transplant (eGFR = 43 ± 29 ml/min/1.73 m 2 , p  = 0.80). BPs preserved lumbar spine bone density in kidney transplant recipients but did not prevent declines in hip bone mineral density in either transplant patients or those with CKD-4 and -5., Summary: There remains a lack of clarity of the risks vs. benefits of bone-sparing pharmacotherapy in chronic kidney disease Stages 4 and 5. This single-centre 15-year retrospective data analysis showed that bisphosphonates are not associated with any detectable serious adverse effects in CKD-4 and -5 and effective at mitigating lumbar spine bone loss in kidney transplant patients., Competing Interests: Dominic Hauck, Liza Nery, Rachel O'Connell, Roderick Clifton-Bligh, Amanda Mather, and Christian Girgis declare that they have no conflict of interest., (© 2022 The Authors.)

The earliest reports of atypical femur fractures (AFF) emerged from Asia. In the West, epidemiologic studies report a greater incidence of AFFs among subjects of Asian background. Asian ethnicity is an established risk factor for AFF, but clear mechanisms to explain this risk and implications for the general development of AFF are open questions. Ethno-specific differences in bisphosphonate action and femoral geometry have been proposed as hypotheses. In a retrospective cohort of 163 female patients presenting with AFFs or typical femur fractures (TFF), relative contributions of Asian ethnicity, proximal femoral geometry, and bisphosphonate use in AFF status were examined. There was a fourfold higher proportion of Asian subjects in the AFF compared with TFF groups (31.6%, 30/95 versus 7.4%, 5/68). Asian subjects had smaller femurs in femoral head, neck, and axial dimensions. A multiple logistic regression model for AFF status was fitted adding Asian ethnicity to three previously reported independent predictors of AFF including femoral geometry, which together comprise the Sydney AFF Score (age ≤80 years, femoral neck width <37 mm than non-Asian, lateral cortical width at lesser trochanter ≥5 mm). Asian ethnicity was a robust independent predictor of AFF, imparting sevenfold increase in the odds of AFF after adjusting for all three variables (95% confidence interval [CI] 2.2-23.2, p  = 0.001) or for overall AFF score (95% CI 2.2-22.3 p  = 0.001). Overall Asian subjects had higher rates of bisphosphonate use than non-Asian subjects (67.6% versus 47.2%, p  = 0.034). Among AFF bisphosphonate users, Asian subjects had lower AFF scores than non-Asians (Sydney AFF Score ≤1, 45.5% Asian subjects versus 22.2% non-Asian subjects, p  = 0.05). Asian ethnicity is a strong independent risk factor for AFF, unaccounted for by ethno-specific differences in proximal femoral geometry. Bisphosphonate use may be associated with a greater predisposition for AFF in Asian subjects compared with non-Asian subjects. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Objective: To develop evidence-based recommendations to guide the surgical management and postoperative follow-up of adults with primary hyperparathyroidism., Methods: Representatives from relevant Australian and New Zealand Societies used a systematic approach for adaptation of guidelines (ADAPTE) to derive an evidence-informed position statement addressing eight key questions., Results: Diagnostic imaging does not determine suitability for surgery but can guide the planning of surgery in suitable candidates. First-line imaging includes ultrasound and either parathyroid 4DCT or scintigraphy, depending on local availability and expertise. Minimally invasive parathyroidectomy is appropriate in most patients with concordant imaging. Bilateral neck exploration should be considered in those with discordant/negative imaging findings, multi-gland disease and genetic/familial risk factors. Parathyroid surgery, especially re-operative surgery, has better outcomes in the hands of higher volume surgeons. Neuromonitoring is generally not required for initial surgery but should be considered for re-operative surgery. Following parathyroidectomy, calcium and parathyroid hormone levels should be re-checked in the first 24 h and repeated early if there are risk factors for hypocalcaemia. Eucalcaemia at 6 months is consistent with surgical cure; parathyroid hormone levels do not need to be re-checked in the absence of other clinical indications. Longer-term surveillance of skeletal health is recommended., Conclusions: This position statement provides up-to-date guidance on evidence-based best practice surgical and postoperative management of adults with primary hyperparathyroidism., (© 2021 John Wiley & Sons Ltd.)

Chronic foot ulcers are associated with a high risk of osteomyelitis, poor quality of life, amputations and disability. Few strategies improve their healing, and amputation rates in high-risk foot services are usually over 30 %. We conducted a randomised, inactive-placebo controlled, double-blind trial of 500 mg of slow-release vitamin C in sixteen people with foot ulcers in the Foot Wound Clinic at Westmead Hospital. Nine were randomised to control and seven to vitamin C. When serum vitamin C results become available at 4 weeks, all people with deficiency were offered both vitamin C and glucosamine tablets for the next 4 weeks. Patients without baseline deficiency continued their original assigned treatment. The primary outcome was percentage ulcer healing (reduction in ulcer size) at 8 weeks. Fifty percentage of subjects had baseline vitamin C deficiency, half having undetectable levels. Healing at 8 weeks was significantly better in the vitamin C group (median 100 v. -14 %, P = 0·041). Healing without amputation occurred in all patients in the vitamin C group. In contrast, 44 % of controls had not healed their ulcer at the end of the study period. Vitamin C improved healing of foot ulcers. Further studies are needed to determine whether there is a threshold effect for serum vitamin C above which therapy is ineffective and whether there are better or lesser responding subgroups. Because of its low cost and ease of access and administration, we recommend offering vitamin C therapy to all people who have chronic foot ulcers and potentially suboptimal vitamin C intake. Trial registration number: ACTRN12617001142325.

Muscle weakness has been recognized as a hallmark feature of vitamin D deficiency for many years. Until recently, the direct biomolecular effects of vitamin D on skeletal muscle have been unclear. Although in the past, some reservations have been raised regarding the expression of the vitamin D receptor in muscle tissue, this special issue review article outlines the clear evidence from preclinical studies for not only the expression of the receptor in muscle but also the roles of vitamin D activity in muscle development, mass, and strength. Additionally, muscle may also serve as a dynamic storage site for vitamin D, and play a central role in the maintenance of circulating 25-hydroxy vitamin D levels during periods of low sun exposure. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: The authors have no conflict of interest to report., (© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Background: Diabetes is a major risk factor for foot ulceration and leg amputation, but the effect of intensive glycaemic control on wound healing is unknown. While an interdisciplinary approach has been shown to be important in the management of diabetic foot ulcer (DFU), there is no standardised definition of such an interdisciplinary team., Objective: To investigate the role of an opportunistic, rapid-access, inter-disciplinary model of diabetes care at a foot wound clinic., Methods: A retrospective case-control study of patients with DFUs attending a diabetes foot wound clinic over a 6-month period. Outcomes in patients who were seen by a rapid-access interdisciplinary team (RAIT) consisting of an endocrinologist, diabetes educator and dietician during the standard wound care those who were not seen by this team were compared., Results: Fifty-five patients were seen by the RAIT and 64 control patients were not seen by this team during their attendance of a diabetes foot wound clinic. Patients in the intervention group had non-significantly higher baseline HbA1c and a significantly larger proportion were active cigarette smokers. Both groups achieved comparable reduction in the total number of DFUs per patient (p=0.971). Patients in the intervention group had a 60.1% reduction in wound size compared to 52.4% reduction in control group (p=0.526)., Conclusion: Our study shows that the use of a rapid-access interdisciplinary team to assess and manage patients' diabetes in a foot wound clinic is feasible. Patients with higher-risk diabetes foot wounds exposed to RAIT had comparable wound healing outcomes to lower risk patients., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Increased risks of skeletal fractures are common in patients with impaired glucose handling and type 2 diabetes mellitus (T2DM). The pathogenesis of skeletal fragility in these patients remains ill-defined as patients present with normal to high bone mineral density. With increasing cases of glucose intolerance and T2DM it is imperative that we develop an accurate rodent model for further investigation. We hypothesized that a high fat diet (60%) administered to developing male C57BL/6J mice that had not reached skeletal maturity would over represent bone microarchitectural implications, and that skeletally mature mice would better represent adult-onset glucose intolerance and the pre-diabetes phenotype. Two groups of developing (8 week) and mature (12 week) male C57BL/6J mice were placed onto either a normal chow (NC) or high fat diet (HFD) for 10 weeks. Oral glucose tolerance tests were performed throughout the study period. Long bones were excised and analysed for ex vivo biomechanical testing, micro-computed tomography, 2D histomorphometry and gene/protein expression analyses. The HFD increased fasting blood glucose and significantly reduced glucose tolerance in both age groups by week 7 of the diets. The HFD reduced biomechanical strength, both cortical and trabecular indices in the developing mice, but only affected cortical outcomes in the mature mice. Similar results were reflected in the 2D histomorphometry. Tibial gene expression revealed decreased bone formation in the HFD mice of both age groups, i.e., decreased osteocalcin expression and increased sclerostin RNA expression. In the mature mice only, while the HFD led to a non-significant reduction in runt-related transcription factor 2 (Runx2) RNA expression, this decrease became significant at the protein level in the femora. Our mature HFD mouse model more accurately represents late-onset impaired glucose tolerance/pre-T2DM cases in humans and can be used to uncover potential insights into reduced bone formation as a mechanism of skeletal fragility in these patients.

Atypical femur fractures (AFF) are a rare but serious complication of long-term bisphosphonate use. Although clearly defined by ASBMR criteria, a proportion of patients with AFFs may go unrecognized and the use of qualitative fracture criteria may lead to uncertainty in AFF diagnosis, with significant therapeutic implications. A score that rapidly and accurately identifies AFFs among subtrochanteric femur fractures using quantitative, measurable parameters is needed. In a retrospective cohort of 110 female patients presenting with AFFs or typical femur fractures (TFFs), multiple logistic regression and decision tree analysis were used to develop the Sydney AFF score. This score, based on demographic and femoral geometry variables, uses three dichotomized independent predictors and adds one point for each: (age ≤80 years) + (femoral neck width <37 mm) + (lateral cortical width at lesser trochanter ≥5 mm), (score, 0 to 3). In an independent validation set of 53 female patients at a different centre in Sydney, a score ≥2 demonstrated 73.3% sensitivity and 69.6% specificity for AFF (area under the receiver-operating characteristic curve [AUC] 0.775, SE 0.063) and remained independently associated with AFF after adjustment for bisphosphonate use. The Sydney AFF score provides a quantitative means of flagging female patients with atraumatic femur fractures who have sustained an AFF as opposed to a TFF. This distinction has clear management implications and may augment current ASBMR diagnostic criteria. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Background: In Australia and other developed countries, chronic illness prevalence is increasing, as are costs of healthcare, particularly hospital-based care. Integrating healthcare and supporting illness management in the community can be a means of preventing illness, improving outcomes and reducing unnecessary hospitalisation. Western Sydney has high rates of diabetes, heart and respiratory diseases and the NSW State Ministry of Health funded a range of key strategies through the Western Sydney Integrated Care Program (WSICP) to integrate care across hospital and community settings for patients with these illnesses. Complementing our previously reported analysis related to specific WSICP strategies, this research provided information concerning overall experiences and perspectives of WSICP implementation and integrated care generally., Methods: We administered 125 in-depth interviews in two rounds over 12 months with 83 participants including patients and their carers, care facilitators, hospital specialists and nurses, allied health professionals, general practitioners and primary care nurses, and program managers. Half of the participants (n = 42) were interviewed twice. We conducted an inductive, thematic analysis on the interview transcripts., Results: Key themes related to the set-up and operationalising of WSICP; challenges encountered; and the added value of the program. Implementing WSICP was a large and time consuming undertaking but challenges including those with staffing and information technology were being addressed. The WSICP was considered valuable in reducing hospital admissions due to improved patient self-management and a focus on prevention, greater communication and collaboration between healthcare providers across health sectors and an increased capacity to manage chronic illness in the primary care setting., Conclusions: Patients, carers and health providers experienced the WSICP as an innovative integrated care model and valued its patient-centred approach which was perceived to improve access to care, increase patient self-management and illness prevention, and reduce hospital admissions. Long-term sustainability of the WSICP will depend on retaining key staff, more effectively sharing information including across health sectors to support enhanced collaboration, and expanding the suite of activities into other illness areas and locations. Enhanced support for general practices to manage chronic illness in the community, in collaboration with hospital specialists is critical. Timely evaluation informs ongoing program implementation.

Objective: In the light of increased adverse outcomes for people with diabetes affected by COVID-19, we have described the clinical course of a cohort of critically ill patients with COVID-19 and diabetes., Methods: We retrospectively analysed characteristics, glucometrics and inflammatory markers of patients with diabetes mellitus admitted to intensive care unit (ICU) with COVID-19., Results: Eight patients with diabetes were admitted to ICU with COVID-19. All had type 2 diabetes, with three being newly diagnosed that admission. Mean HbA1c was 9.2%. Glucometric analysis indicated that extremely high insulin doses were required during peak inflammatory response to maintain glycaemic control with a mean peak insulin requirement of 201 units per day (2.2 units/kg/day)., Conclusions: Critically unwell patients with diabetes mellitus and COVID-19 had high insulin requirements and poorer time in target range at the time of peak inflammatory response, and this improved as their illness resolved., (© 2020 John Wiley & Sons Ltd.)

As the world grapples with the crisis of COVID-19, established economies and healthcare systems have been brought to their knees. Tough decisions regarding redirection of resources away from the management of conditions deemed "nonessential" are being made. How can we balance urgent resourcing of our acute crisis while not abandoning the real need of patients with osteoporosis? This article offers a few practical solutions.

Competing Interests: Competing interests: None declared.

Summary: A 19-year-old female presented at 25-weeks gestation with pancreatitis. She was found to have significant hypertriglyceridaemia in context of an unconfirmed history of familial hypertriglyceridaemia. This was initially managed with fasting and insulin infusion and she was commenced on conventional interventions to lower triglycerides, including a fat-restricted diet, heparin, marine oil and gemfibrozil. Despite these measures, the triglyceride levels continued to increase as she progressed through the pregnancy, and it was postulated that she had an underlying lipoprotein lipase defect. Therefore, a multidisciplinary decision was made to commence therapeutic plasma exchange to prevent further episodes of pancreatitis. She underwent a total of 13 sessions of plasma exchange, and labour was induced at 37-weeks gestation in which a healthy female infant was delivered. There was a rapid and significant reduction in triglycerides in the 48 h post-delivery. Subsequent genetic testing of hypertriglyceridaemia genes revealed a missense mutation of the LPL gene. Fenofibrate and rosuvastatin was commenced to manage her hypertriglyceridaemia postpartum and the importance of preconception counselling for future pregnancies was discussed. Hormonal changes in pregnancy lead to an overall increase in plasma lipids to ensure adequate nutrient delivery to the fetus. These physiological changes become problematic, where a genetic abnormality in lipid metabolism exists and severe complications such as pancreatitis can arise. Available therapies for gestational hypertriglyceridaemia rely on augmentation of LPL activity. Where there is an underlying LPL defect, these therapies are ineffective and removal of triglyceride-rich lipoproteins via plasma exchange should be considered., Learning Points: Hormonal changes in pregnancy, mediated by progesterone,oestrogen and human placental lactogen, lead to a two- to three-fold increase in serum triglyceride levels. Pharmacological intervention for management of gestational hypertriglyceridaemia rely on the augmentation of lipoprotein lipase (LPL) activity to enhance catabolism of triglyceride-rich lipoproteins. Genetic mutations affecting the LPL gene can lead to severe hypertriglyceridaemia. Therapeutic plasma exchange (TPE) is an effective intervention for the management of severe gestational hypertriglyceridaemia and should be considered in cases where there is an underlying LPL defect. Preconception counselling and discussion regarding contraception is of paramount importance in women with familial hypertriglyceridaemia.

This special issue article will focus on morphologic and functional roles of vitamin D in muscle, from strength to contraction to development and ageing and will characterise the controversy of VDR's expression in skeletal muscle, central to our understanding of vitamin D's effects on this tissue.

Background: With aging populations, a growing prevalence of chronic illnesses, higher expectations for quality care and rising costs within limited health budgets, integration of healthcare is seen as a solution to these challenges. Integrated healthcare aims to overcome barriers between primary and secondary care and other disconnected patient services to improve access, continuity and quality of care. Many people in Australia are admitted to hospital for chronic illnesses that could be prevented or managed in the community. Western Sydney has high rates of diabetes, heart and respiratory diseases and the NSW State Ministry of Health has implemented key strategies through the Western Sydney Integrated Care Program (WSICP) to enhance primary care and the outcomes and experiences of patients with these illnesses., Methods: We aimed to investigate the WSICP's effectiveness through a qualitative evaluation focused on the 10 WSICP strategies using a framework analysis. We administered 125 in-depth interviews in two rounds over 12 months with 83 participants including patients and their carers, care facilitators, hospital specialists and nurses, allied health professionals, general practitioners (GPs) and primary care nurses, and program managers. Most participants (71%) were interviewed twice. We analysed data within a framework describing how strategies were implemented and used, the experiences around these, their perceived value, facilitators and barriers, and participant-identified suggestions for improvement., Results: Care facilitators helped patients access services within the hospital and in primary care and connected general practices with hospital specialists and services. Rapid access and stabilisation clinics with their patient hotlines assisted patients and carers to self-manage chronic illness while connecting GPs to specialists through the GP support-line. Action plans from the hospital informed GPs and their shared care plans which could be accessed by other community health professionals and patients. HealthPathways provided GPs with local, evidence-based guidelines for managing patients. Difficulties persisted in effective widespread access to shared records and electronic communication across sectors., Conclusions: The combined WSICP strategies improved patient and carer experience of healthcare and capacity of GPs to provide care in the community. Information sharing required longer-term investment and support, though benefits were evident by the end of our research.

Background: It has long been recognized that vitamin D deficiency is associated with muscle weakness and falls. Vitamin D receptor (VDR) is present at very low levels in normal muscle. Whether vitamin D plays a direct role in muscle function is unknown and is a subject of hot debate. Myocyte-specific deletion of VDR would provide a strategy to answer this question., Methods: Myocyte-specific vitamin D receptor (mVDR) null mice were generated by crossing human skeletal actin-Cre mice with floxed VDR mice. The effects of gene deletion on the muscle phenotype were studied in terms of body tissue composition, muscle tissue histology, and gene expression by real-time PCR., Results: Unlike whole-body VDR knockout mice, mVDR mice showed a normal body size. The mVDR showed a distinct muscle phenotype featuring reduced proportional lean mass (70% vs. 78% of lean mass), reduced voluntary wheel-running distance (22% decrease, P = 0.009), reduced average running speed, and reduced grip strength (7-16% reduction depending on age at testing). With their decreased voluntary exercise, and decreased lean mass, mVDR have increased proportional fat mass at 20% compared with 13%. Surprisingly, their muscle fibres showed slightly increased diameter, as well as the presence of angular fibres and central nuclei suggesting ongoing remodelling. There were, however, no clear changes in fibre type and there was no increase in muscle fibrosis. VDR is a transcriptional regulator, and changes in the expression of candidate genes was examined in RNA extracted from skeletal muscle. Alterations were seen in myogenic gene expression, and there was decreased expression of cell cycle genes cyclin D1, D2, and D3 and cyclin-dependent kinases Cdk-2 and Cdk-4. Expression of calcium handling genes sarcoplasmic/endoplasmic reticulum calcium ATPases (SERCA) Serca2b and Serca3 was decreased and Calbindin mRNA was lower in mVDR muscle., Conclusions: This study demonstrates that vitamin D signalling is needed for myocyte function. Despite the low level of VDR protein normally found muscle, deleting myocyte VDR had important effects on muscle size and strength. Maintenance of normal vitamin D signalling is a useful strategy to prevent loss of muscle function and size., (© 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Globally there are several operational definitions for sarcopenia, complicating clinical and research applications., Objective: The objective of the Australian and New Zealand Society for Sarcopenia and Frailty Research (ANZSSFR) Task Force on Diagnostic Criteria for Sarcopenia was to reach consensus on the operational definition of sarcopenia for regional use by clinicians and researchers., Method: A four-Phase modified Delphi process was undertaken in which 24 individuals with expertise or a recognised interest in sarcopenia from different fields across Australia and New Zealand were invited to be Task Force members. An initial face-to-face meeting was held in Adelaide, South Australia, in November 2017, followed by two subsequent online Phases conducted by electronic surveys. A final Phase was used to approve the final statements. Responses were analysed using a pre-specified strategy. The level of agreement required for consensus was 80%., Results: In Phase 2, 94.1% of Task Force respondents voted in favour of adopting an existing operational definition of sarcopenia. In Phase 3, 94.4% of respondents voted in favour of adopting the European Working Group on Sarcopenia in Older People (EWGSOP) definition as the operational definition for sarcopenia in Australia and New Zealand., Conclusion: With consensus achieved, the ANZSSFR will adopt, promote and validate the EWGSOP operational definition of sarcopenia for use by clinicians and researchers in Australia and New Zealand., Competing Interests: There are no conflicts of interests to declare.

Vitamin D is increasingly recognised to play an important role in normal muscle function. Low vitamin D status is associated with an increased risk of falls and proximal weakness. Since vitamin D deficiency is very common, and the signs are non-specific, it is important to maintain a high index of suspicion of vitamin D deficiency in patients with muscle pain and weakness, and it is simple to measure serum 25(OH) vitamin D. Therapy is cheap, safe and effective, but sometimes a larger dose may be needed, and, as shown in our case report, willingness of people to pay for an over the counter medication can be an issue. Following a striking case report that demonstrates muscle defects in severe vitamin D deficiency, we discuss clinical studies examining specific effects of vitamin D on physical performance, muscle strength and falls. Finally, we present an overview of molecular mechanisms that explain vitamin D's biological effects on muscle.

The major circulating metabolite of vitamin D 3 , 25-hydroxycholecalciferol [25(OH)D], has a remarkably long half-life in blood for a (seco)steroid. Data from our studies and others are consistent with the hypothesis that there is a role for skeletal muscle in the maintenance of vitamin D status. Muscle cells internalise vitamin D-binding protein (DBP) from the circulation by means of a megalin/cubilin plasma membrane transport mechanism. The internalised DBP molecules then bind to actin and thus provide an intracellular array of high affinity binding sites for its specific ligand, 25(OH)D. There is evidence that the residence time for DBP in muscle cells is short and that it undergoes proteolytic degradation, releasing bound 25(OH)D. The processes of internalisation of DBP and its intracellular residence time, bound to actin, appear to be regulated. To explore whether 1,25-dihydroxycholecalciferol (calcitriol) has any effect on this process, cell cultures of myotubes and primary skeletal muscle fibers were incubated in a medium containing 10 -10 M calcitriol but with no added DBP. After 3h pre-incubation with calcitriol, the net uptake of 25(OH)D by these calcitriol-treated cells over a further 4h was significantly greater than that in vehicle-treated control cells. This was accompanied by a significant increase in intracellular DBP protein. However, after 16h of pre-incubation with calcitriol, the muscle cells showed a significantly depressed ability to accumulate 25(OH)D compared to control cells over a further 4 or 16hours. These effects of pre-incubation with calcitriol were abolished in fibers from VDR-knockout mice. The effect was also abolished by the addition of 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), which inhibits chloride channel opening. Incubation of C2 myotubes with calcitriol also significantly reduced retention of previously accumulated 25(OH)D after 4 or 8h. It is concluded from these in vitro studies that calcitriol can modify the DBP-dependent uptake and release of 25(OH)D by skeletal muscle cells in a manner that suggests some inducible change in the function of these cells., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Vitamin D deficiency is associated with muscle weakness, pain, and atrophy. Serum vitamin D predicts muscle strength and age-related muscle changes. However, precise mechanisms by which vitamin D affects skeletal muscle are unclear. To address this question, this study characterizes the muscle phenotype and gene expression of mice with deletion of vitamin D receptor (VDRKO) or diet-induced vitamin D deficiency. VDRKO and vitamin D-deficient mice had significantly weaker grip strength than their controls. Weakness progressed with age and duration of vitamin D deficiency, respectively. Histological assessment showed that VDRKO mice had muscle fibers that were significantly smaller in size and displayed hyper-nuclearity. Real-time PCR also indicated muscle developmental changes in VDRKO mice with dysregulation of myogenic regulatory factors (MRFs) and increased myostatin in quadriceps muscle (>2-fold). Vitamin D-deficient mice also showed increases in myostatin and the atrophy marker E3-ubiqutin ligase MuRF1. As a potential explanation for grip strength weakness, both groups of mice had down-regulation of genes encoding calcium-handling and sarco-endoplasmic reticulum calcium transport ATPase (Serca) channels. This is the first report of reduced strength, morphological, and gene expression changes in VDRKO and vitamin D-deficient mice where confounding by calcium, magnesium, and phosphate have been excluded by direct testing. Although suggested in earlier in vitro work, this study is the first to report an in vivo association between vitamin D, myostatin, and the regulation of muscle mass. These findings support a direct role for vitamin D in muscle function and corroborate earlier work on the presence of VDR in this tissue.

Beyond the established roles of vitamin D in bone and mineral homeostasis, we are becoming increasingly aware of its diverse effects in skeletal muscle. Subjects with severe vitamin D deficiency or mutations of the vitamin D receptor develop generalized atrophy of muscle and bone, suggesting coordinated effects of vitamin D in musculoskeletal physiology. At a mechanistic level, vitamin D exerts wide-ranging effects in muscle and bone calcium handling, differentiation and development. Vitamin D also modulates muscle and bone-derived hormones, facilitating cross-talk between these tissues. In this review, we discuss emerging evidence that vitamin D regulates bone and muscle in a direct, integrated fashion, positioning the vitamin D pathway as a potential therapeutic target for musculoskeletal diseases. This article is part of a Special Issue entitled "Muscle Bone Interactions"., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Beyond the established effects of muscle loading on bone, a complex network of hormones and growth factors integrates these adjacent tissues. One such hormone, vitamin D, exerts broad-ranging effects in muscle and bone calcium handling, differentiation and development. Vitamin D also modulates muscle and bone-derived hormones, potentially facilitating cross-talk between these tissues. In the clinical setting, vitamin D deficiency or mutations of the vitamin D receptor result in generalized atrophy of muscle and bone, suggesting coordinated effects of vitamin D at these sites. In this review, we discuss emerging evidence that vitamin D exerts specific effects throughout the life of the musculoskeletal system - in development, aging and injury. From this holistic viewpoint, we offer new insights into an old debate: whether vitamin D's effects in the musculoskeletal system are direct via local VDR signals or indirect via its systemic effects in calcium and phosphate homeostasis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)