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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.

Adequate sleep is critically important for a number of biological functions. Osteoporosis, a condition marked by bone fragility and fracture, has been increasingly linked to disturbances of sleep and circadian rhythm. Our review examines the links between disordered sleep, circadian disruption, and bone health and the ‘dual epidemic’ of poor sleep and osteoporosis. We explore the effect of disruptions in sleep and the circadian rhythm on bone mineral density and the development of osteoporosis and fractures.

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.

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 width37 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

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.

To develop evidence-based recommendations to guide the surgical management and postoperative follow-up of adults with primary hyperparathyroidism.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.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.This position statement provides up-to-date guidance on evidence-based best practice surgical and postoperative management of adults with primary hyperparathyroidism.

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.

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.

Proton pump inhibitor (PPI) induced hypomagnesaemia is an increasingly recognised side effect of these commonly used medications. We present a case series highlighting the delay in diagnosis of PPI induced hypomagnesaemia, in three patients who presented with symptomatic electrolyte abnormalities. Our first case depicts that, despite multiple presentations to an emergency department in a tertiary hospital, PPIs were not recognised as the underlying cause of hypomagnesaemia and hypocalcaemia. Our second case highlights the difficulty faced by primary case physicians in recognising this side effect. Similarly, our third case demonstrates these challenges in a patient that presented to hospital twice, before the offending agent was ceased. Given the widespread use of PPIs and the simplicity in treating this side effect, we aim to shed light on the incidence of PPI induced hypomagnesaemia. We suggest that a high index of suspicion must be maintained for patients on PPIs, who can present with potentially life threatening electrolyte derangement. Keywords: Proton pump inhibitor, Hypomagnesaemia, Hypocalcaemia, Hypoparathyroidism, PPI, Side effect

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

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.

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.

Denosumab is a highly effective treatment for postmenopausal osteoporosis, significantly improving BMD and reducing risk of fracture. However, denosumab's effect is transient with the risk of a rebound increase in bone turnover following withdrawal of this potent RANKL inhibitor. This poses challenges, particularly in individuals seeking to discontinue denosumab, such as those experiencing a direct complication of prolonged antiresorptive therapy or those in whom an antiresorptive drug holiday would be ordinarily considered. Bisphosphonate strategies to mitigate postdenosumab bone loss are being actively studied. We describe the case of a 73‐year‐old woman who developed a spontaneous vertebral fracture following denosumab discontinuation, despite prolonged treatment with bisphosphonate therapy both before her course of denosumab (20 years of use) and following denosumab discontinuation (1 year of use). This is a cautionary case seeking to highlight uncertainties around the safe withdrawal of denosumab therapy despite intervening treatment with bisphosphonates. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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.

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.

A 63-year-old woman with a smoking history of 20 pack-years presented with 3 months of weight loss. A right lung mass and uniformly enlarged adrenal glands were noted on computed tomography ([figure 1A][1]). A week later she developed severe hypokalemia (K 2.3 mEq/L, 3.5–5.5), hypertension and

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.

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., Highlights • Low vitamin D is associated with an increased risk of falls and proximal weakness. • Therapy is cheap, safe and effective, but larger doses may be needed and willingness to pay for over the counter medications can be an issue. • We present an overview of molecular mechanisms that explain vitamin D’s biological effects on muscle.

The major circulating metabolite of vitamin D3, 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 10-10M 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.

Purpose: Sacral stress fractures are rare complications which can arise during pregnancy or in the early postpartum period. We report a case and discuss the findings of a confirmed postpartum sacral stress fracture in a 39-year-old multiparous woman and review previous case reports in the literature of sacral stress fracture related to pregnancy. Methods: A review of the literature was conducted to examine the main characteristics of sacral stress fractures related to pregnancy. The Ovid/Medline, Embase and Google Scholar databases were searched with the inclusion criteria: human studies, English language, intrapartum, postpartum (within 6 months of parturition), sacrum and stress fracture. Our exclusion criteria included pubic fractures, vertebral fractures and non-English articles. The search terms included “stress fracture”, “postpartum”, “pregnancy”, “atraumatic” and the wildcard “sacr*”. 34 cases were found and summarised in Table 2. Results: 65% of patients had onset of symptoms postpartum. Most patients did not have risk factors for sacral stress fractures including macrosomia, excessive pregnancy weight gain, heparin exposure, rapid vaginal delivery or predisposition to accelerated osteoporosis. Lumbar radiculopathy can be a feature of sacral stress fracture and it is more common (17.6%) than reported in the literature (2%). MRI is the preferred imaging modality for its safety profile in pregnancy and high sensitivity. 70% of reported normal bone mineral density (BMD). The mainstay treatment for sacral stress fractures includes relative bedrest, analgesia and modified weight bearing exercises. Most patients have favourable outcome with complete symptom resolution. Conclusion: Sacral stress fractures in the absence of osteoporosis are rare complications of pregnancy that can present with lumbar radiculopathy. Conservative management often produces good clinical outcomes.

Sex steroids exert diverse, divergent and dynamic effects on muscle and bone. Beyond their essential role in sexual dimorphism, sex steroids contribute to the accrual, maintenance and age-related involution of the musculoskeletal system. Falls and fractures occur, dire consequences of musculoskeletal attrition and functional decline, in association with a critical reduction in sex steroids in older individuals. Conversely, the reversal of sex steroid deficiency and therapies that specifically target sex steroid receptor signalling (e.g. SARMs) mitigate aspects of musculoskeletal aging. This chapter will discuss key principles in sex steroid biology, evidence from preclinical and clinical studies on their anabolic and anti-catabolic effects on muscle and bone, and therapeutic possibilities for osteosarcopenia.

The association between vitamin D deficiency, myalgia, and muscle weakness is well known. However, the molecular basis of vitamin D’s effects on skeletal muscle is incompletely understood and evolving. Case reports in humans describe profound muscle weakness, muscle pain, and type II fiber atrophy in subjects with severe vitamin D deficiency. Animal studies employing models of vitamin D deficiency and aberrant vitamin D signaling have helped to characterize this association. In vitro studies have identified specific pathways by which vitamin D modulates myocytes and influences contraction and anabolism. This chapter discusses clinical aspects of the association between vitamin D deficiency and myopathy, its effects on muscle weakness, muscle pain, physical performance, and falls.

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.

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.

Beyond its established effects on bone and mineral homeostasis, vitamin D plays an emerging role in the regulation of skeletal muscle. Muscle weakness and myalgia have been described in humans with vitamin D deficiency for many years. Specific defects in muscle strength and morphology have been reported in animals with vitamin D deficiency and aberrant vitamin D signaling since the 1970's. However, molecular pathways underpinning functional effects of vitamin D on muscle have only recently come to light. This chapter discusses these effects with a focus on intramuscular calcium and phosphate signaling; insulin sensitivity; regulation of muscle mass and strength; and muscle development, aging, and regeneration. A central question in this field, namely whether the vitamin D receptor is expressed in skeletal muscle, has been a subject of intense debate and receives special mention. Cross-talk between muscle and bone is also a topic of emerging interest; putative mechanisms by vitamin D alters interactions between these tissues will be covered. Firstly, basic concepts in skeletal muscle physiology will be reviewed.