Secondary fracture prevention in primary care: a narrative review.

The global burden of osteoporosis continues to rise with an ageing population. Untreated osteoporotic fractures not only heighten the risk of subsequent fractures but are associated with excess mortality. Although primary care guidelines consistently stress the importance of secondary fracture prevention, fewer than 20% of patients are appropriately treated for osteoporosis following an initial osteoporotic fracture. This worldwide phenomenon is known as the osteoporosis care gap. This literature review examines the barriers to secondary fracture prevention in primary care and evaluates the effectiveness of targeted primary care interventions. Common themes emerged from the majority of qualitative studies, including a need for improved communication between the hospital team and primary care, better defined responsibilities and osteoporosis-directed education for the primary care physicians. Quantitative studies demonstrated that most targeted, intensive interventions aimed at educating patients and their primary care physician about osteoporosis treatment significantly increased rates of investigation and treatment. Greater uptake of models of secondary fracture prevention in primary care is urgently needed to address the osteoporosis care gap.

Causes of stillbirths in diabetic and gestational diabetes pregnancies at a NSW tertiary referral hospital.

BACKGROUND: Diabetes in pregnancy may result in stillbirth or neonatal death. AIM: This audit examined stillbirths of mothers with pre-existing diabetes in pregnancy (DIP) and gestational diabetes (GDM) to determine maternal and diabetic characteristics implicated in these deaths. MATERIALS AND METHODS: A retrospective cohort study was conducted to identify stillbirths occurring in diabetic pregnancies at Westmead Hospital during 2006-2017. Medical records were reviewed to obtain data relating to maternal factors, diabetes history, glycaemic control and cause of death. RESULTS: There were 37 women (seven with type 1 diabetes [T1DM], 11 with type 2 diabetes [T2DM] and 19 with GDM) who had 38 stillbirths. The leading cause of stillbirth was lethal congenital malformations in nine cases, followed by placental and umbilical abnormalities in six, intra-uterine growth restriction (IUGR) in six, and obstetric factors in four cases. Malformations were predominantly cardiovascular (n = 7), musculoskeletal (n = 5) and gastrointestinal (n = 4). There was no difference in the proportion of stillbirths related to malformations between the DIP and GDM groups (P = 0.22). In the pre-conception period or first trimester, all T1DM subjects and all but two T2DM subjects had HbA1c >7% or there was no measurement. HbA1c was >7% in 6/7 T1DM subjects and 7/11 T2DM subjects at some stage during the pregnancy. CONCLUSION: Stillbirth remains a problem in diabetic pregnancy in the 21st century. Lethal malformations, placental abnormalities and IUGR were the leading causes of stillbirth related to diabetes. Pre-conception counselling and planning to achieve better glycaemic control in pregnancy needs to be improved.

Approach to the Patient With Bone Fracture: Making the First Fracture the Last.

The global burden of osteoporosis and osteoporotic fractures will increase significantly as we enter a rapidly aging population. Osteoporotic fractures lead to increased morbidity, mortality, and risk of subsequent fractures if left untreated. However, studies have shown that the majority of patients who suffer an osteoporotic fracture are not investigated or treated for osteoporosis, leading to an inexcusable "osteoporosis care gap." Systematic and coordinated models of care in secondary fracture prevention known as fracture liaison services (FLS) have been established to streamline and improve the care of patients with osteoporotic fractures, and employ core principles of identification, investigation, and initiation of treatment. Our approach to the multifaceted care of secondary fracture prevention at a hospital-based FLS is illustrated through several case vignettes.

Skin and bones: systemic mastocytosis and bone.

Summary: We report the case of a 69-year-old female with systemic mastocytosis, diagnosed based on widespread pigmented papules and macules, elevated serum tryptase levels and confirmatory skin and bone marrow biopsy, on a background of osteoporosis. A CT demonstrated multiple sclerotic lesions within lumbar vertebral bodies, sacrum and ileum, with surrounding osteolysis but no obvious compression fractures. She was treated with the RANK-L inhibitor denosumab, resulting in significant bone mineral density gain over the following 5 years. However, her serum tryptase levels gradually increased during this period despite treatment with the multikinase inhibitor, midostaurin. It is thus conceivable that her rapid increase in bone mineral density may be partly contributed by a predominance of pro-osteoblastic mediators released by abnormal mast cells, suggestive of more advanced disease. This case highlights the complexities of systemic mastocytosis-related bone disease and the interplay of numerous mediators contributing to a phenotype of both increased bone resorption and formation. Learning points: Systemic mastocytosis is a neoplastic disease of mast cells characterized by abnormal proliferation and accumulation in the skin and other organs. It is most frequently associated with the somatic gain-of-function KIT D816V mutation. Systemic mastocytosis should be suspected in patients presenting with not only cutaneous symptoms suggestive of mast cell degranulation such as anaphylaxis, flushing or urticaria but also unexplained osteoporosis and gastrointestinal and constitutional symptoms. The prevalence of osteoporosis in systemic mastocytosis is high. Mast cell activation leads to the secretion of numerous chemical mediators which either promote or inhibit osteoclastic and/or osteoblastic activity, with the balance usually in favour of increased bone resorption. However, in advanced diseases with high mast cell burden, mast-cell-derived cytokines and mediators may promote osteoblastic activity, leading to osteosclerosis and apparent increases in bone mineral density. Treatment of osteoporosis in systemic mastocytosis involves antiresorptive therapy with bisphosphonates and more recently, denosumab. There are limited data on the role of osteoanabolic agents.

Bisphosphonate Drug Holidays: Evidence From Clinical Trials and Real-World Studies.

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.

Metastatic papillary thyroid cancer to cerebellum with incidental medullary microcarcinoma.

Thyroid cancer is the most common endocrine cancer, with papillary thyroid carcinoma (PTC) accounting for the majority of these cases. Cerebellar metastasis is rarely the presenting feature and confers poor prognosis. Genetic mutations in this setting are most commonly TERTp, in contrast to BRAF V600E in the majority of PTC. We report the case of an 82 year-old male who presented with a symptomatic right cerebellar lesion and underwent surgical resection to demonstrate metastatic PTC. Extensive workup with computed tomography, neck ultrasound and FDG-PET was suggestive of a left thyroid primary lesion, with FNA confirming PTC. However, total thyroidectomy demonstrated incidental microMTC (medullary thyroid microcarcinoma, defined as tumour <10mm) without any evidence of PTC, whereas the left level VI neck dissection demonstrated a 30mm nodule of PTC without identifiable normal thyroid or lymph node tissue.

Dexamethasone-induced hyperglycaemia in COVID-19: Glycaemic profile in patients without diabetes and factors associated with hyperglycaemia.

AIMS: To evaluate glycaemic profiles of COVID-19 patients without diabetes receiving dexamethasone and determine factors associated with hyperglycaemia. METHODS: All subjects without pre-existing diabetes receiving dexamethasone 6 mg for COVID-19 in a non-critical care setting were identified. Glucose profiles were obtained from capillary blood glucose (BG). Univariate and multivariate analyses were performed to identify factors associated with dexamethasone-induced hyperglycaemia (BG ≥ 10 mmol/L). RESULTS: Of 254 subjects, 129 (50.8%) were male with age 51.1 ± 18.2 years and weight 89.7 ± 26.3 kg. Hyperglycaemia post-dexamethasone occurred in 121 (47.6%). Glucose excursions began within three hours (6.8 ± 1.4 mmol/L pre-dexamethasone vs 8.7 ± 2.4 mmol/L at ≤ 3 h, p < 0.001) and peaked at 7-9 h (10.5 ± 2.3 mmol/L, p < 0.001 vs pre-dexamethasone). BGs post-intravenous were higher than post-oral administration for the initial six hours. Hyperglycaemic subjects were older (57.8 ± 17.5 years vs 45.0 ± 16.6 years, p < 0.001), had higher initial glucose (6.3 ± 1.0 vs 5.9 ± 0.9 mmol/L, p = 0.004), higher HbA1c (5.8 ± 0.3% [40 ± 3.5 mmol/mol] vs 5.5 ± 0.4% [37 ± 4.1 mmol/mol], p < 0.001) higher C-reactive protein (CRP) (100 ± 68 vs 83 ± 58 mg/L, p = 0.026), and lower eGFR (79 ± 17 vs 84 ± 16 mL/min/1.73 m2, p = 0.045). Mortality was greater in the hyperglycaemia group (9/121 [7.4%] vs 2/133 [1.5%], p = 0.02). Age, HbA1c and CRP were independently associated with hyperglycaemia. CONCLUSIONS: Half of subjects without diabetes experienced hyperglycaemia post-dexamethasone for COVID-19, peak occurring after 7-9 h. Age, HbA1c and CRP were associated with hyperglycaemia.

Iron chelation increases beige fat differentiation and metabolic activity, preventing and treating obesity.

Beige and brown fat consume glucose and lipids to produce heat, using uncoupling protein 1 (UCP1). It is thought that full activation of brown adipose tissue (BAT) may increase total daily energy expenditure by 20%. Humans normally have more beige and potentially beige-able fat than brown fat. Strategies to increase beige fat differentiation and activation may be useful for the treatment of obesity and diabetes. Mice were fed chow or high-fat diet (HFD) with or without the iron chelator deferasirox. Animals fed HFD + deferasirox were markedly lighter than their HFD controls with increased energy expenditure (12% increase over 24 h, p < 0.001). Inguinal fat from HFD + deferasirox mice showed increased beige fat quantity with greater Ucp1 and Prdm16 expression. Inguinal adipose tissue explants were studied in a Seahorse bioanalyser and energy expenditure was significantly increased. Deferasirox was also effective in established obesity and in ob/ob mice, indicating that intact leptin signalling is not needed for efficacy. These studies identify iron chelation as a strategy to preferentially activate beige fat. Whether activating brown/beige fat is effective in humans is unproven. However, depleting iron to low-normal levels is a potential therapeutic strategy to improve obesity and related metabolic disorders, and human studies may be warranted.

HbA1c: More than just a number.

BACKGROUND: Glycated haemoglobin, or HbA1c, is the main biomarker used to assess long-term glycaemic control in individuals with diabetes, and it correlates with the development of complications. OBJECTIVE: The aim of this article is to provide an overview of HbA1c to understand its role in the treatment of individuals living with diabetes. Topics discussed include recommended treatment targets, methods of measurement, causes of measurement inaccuracy and alternative means available to assess glycaemic control. DISCUSSION: HbA1c should not be interpreted in isolation; the measurement accuracy and other parameters, including treatment goals and comorbidities, need to be considered.

Ectopic insulin secretion by a large-cell neuroendocrine carcinoma of the cervix.

In patients presenting with hyperinsulinemic hypoglycemia with a nonpancreatic neuroendocrine tumor, the diagnosis of an ectopic insulin-secreting tumor should be considered, and investigated further with confirmatory insulin staining.

Fatal high-grade skull osteosarcoma 30 years following radiotherapy for Cushing's disease.

SUMMARY: Cushing's disease is a rare disorder characterised by excessive cortisol production as a consequence of a corticotroph pituitary tumour. While the primary treatment is surgical resection, post-operative radiation therapy may be used in cases of ongoing inadequate hormonal control or residual or progressive structural disease. Despite improved outcomes, radiotherapy for pituitary tumours is associated with hypopituitarism, visual deficits and, rarely, secondary malignancies. We describe an unusual case of a 67-year-old female with presumed Cushing's disease diagnosed at the age of 37, treated with transsphenoidal resection of a pituitary tumour with post-operative external beam radiotherapy (EBRT), ketoconazole for steroidogenesis inhibition, and finally bilateral adrenalectomy for refractory disease. She presented 30 years after her treatment with a witnessed generalised tonic-clonic seizure. Radiological investigations confirmed an extracranial mass infiltrating through the temporal bone and into brain parenchyma. Due to recurrent generalised seizures, the patient was intubated and commenced on dexamethasone and anti-epileptic therapy. Resection of the tumour revealed a high-grade osteoblastic osteosarcoma. Unfortunately, the patient deteriorated in intensive care and suffered a fatal cardiac arrest following a likely aspiration event. We describe the risk factors, prevalence and treatment of radiation-induced osteosarcoma, an exceedingly rare and late complication of pituitary irradiation. To our knowledge, this is the longest reported latency period between pituitary irradiation and the development of an osteosarcoma of the skull. LEARNING POINTS: Cushing's disease is treated with transsphenoidal resection as first-line therapy, with radiotherapy used in cases of incomplete resection, disease recurrence or persistent hypercortisolism. The most common long-term adverse outcome of pituitary tumour irradiation is hypopituitarism occurring in 30-60% of patients at 10 years, and less commonly, vision loss and oculomotor nerve palsies, radiation-induced brain tumours and sarcomas. Currently proposed characteristics of radiation-induced osteosarcomas include: the finding of a different histological type to the primary tumour, has developed within or adjacent to the path of the radiation beam, and a latency period of at least 3 years. Treatment of osteosarcoma of the skull include complete surgical excision, followed by systemic chemotherapy and/or radiotherapy. Overall prognosis in radiation-induced sarcoma of bone is poor. Newer techniques such as stereotactic radiosurgery may reduce the incidence of radiation-induced malignancies.

Milk-alkali syndrome: a 'quick ease' or a 'long-lasting problem'.

SUMMARY: We report the case of a 65-year-old female who presented with symptomatic hypercalcaemia (corrected calcium of 4.57 mmol/L) with confusion, myalgias and abdominal discomfort. She had a concomitant metabolic alkalosis (pH 7.46, HCO3- 40 mmol/L, pCO2 54.6 mmHg). A history of significant Quick-Eze use (a calcium carbonate based antacid) for abdominal discomfort, for 2 weeks prior to presentation, suggested a diagnosis of milk-alkali syndrome (MAS). Further investigations did not demonstrate malignancy or primary hyperparathyroidism. Following management with i.v. fluid rehydration and a single dose of i.v. bisphosphonate, she developed symptomatic hypocalcaemia requiring oral and parenteral calcium replacement. She was discharged from the hospital with stable biochemistry on follow-up. This case demonstrates the importance of a detailed history in the diagnosis of severe hypercalcaemia, with MAS representing the third most common cause of hypercalcaemia. We discuss its pathophysiology and clinical importance, which can often present with severe hypercalcaemia that can respond precipitously to calcium-lowering therapy. LEARNING POINTS: Milk-alkali syndrome is an often unrecognised cause for hypercalcaemia, but is the third most common cause of admission for hypercalcaemia. Calcium ingestion leading to MAS can occur at intakes as low as 1.0-1.5 g per day in those with risk factors. Early recognition of this syndrome can avoid the use of calcium-lowering therapy such as bisphosphonates which can precipitate hypocalcaemia.