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.

Denosumab is a highly effective treatment for osteoporosis, and its long-term use is associated with incremental gains in BMD and sustained fracture risk reduction. Stopping denosumab, however, results in a rebound increase in bone turnover, loss of treatment-associated BMD gains, and in the worst case, spontaneous vertebral fractures (VFs). Insights into the risk factors, the underlying mechanisms for rebound-associated bone loss, and true incidence of rebound VFs are emerging. Conventional strategies using bisphosphonates to mitigate post-denosumab rebound display mixed success. Bisphosphonates may preserve bone density following short-term denosumab but the optimal sequential approach after longer-term denosumab remains elusive. Patients at particular risk of are those with prevalent VFs or greater on-treatment BMD gains. To greater understand these risks and strategies to preserve bone after denosumab, an emerging body of translational and preclinical work is shedding new light on the biology of RANKL inhibition and withdrawal. Discovering an effective “exit strategy” to control rebound bone turnover and avoid bone loss after denosumab will improve confidence among patients and clinicians in this highly effective and otherwise safe treatment for osteoporosis. This perspective characterizes the clinical problem of post-denosumab rebound, provides a comprehensive update on human studies examining the use of bisphosphonates following denosumab and explores mechanistic insights from preclinical studies that will be critical in the design of definitive human trials.

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. Summary: 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.

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.

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.