Diagnosis and Management of Osteoporosis During COVID-19: Systematic Review and Practical Guidance.

It is acknowledged that the COVID-19 pandemic has caused profound disruption to the delivery of healthcare services globally. This has affected the management of many long-term conditions including osteoporosis as resources are diverted to cover urgent care. Osteoporosis is a public health concern worldwide and treatment is required for the prevention of further bone loss, deterioration of skeletal micro-architecture, and fragility fractures. This review provides information on how the COVID-19 pandemic has impacted the diagnosis and management of osteoporosis. We also provide clinical recommendations on the adaptation of care pathways based on experience from five referral centres to ensure that patients with osteoporosis are still treated and to reduce the risk of fractures both for the individual patient and on a societal basis. We address the use of the FRAX tool for risk stratification and initiation of osteoporosis treatment and discuss the potential adaptations to treatment pathways in view of limitations on the availability of DXA. We focus on the issues surrounding initiation and maintenance of treatment for patients on parenteral therapies such as zoledronate, denosumab, teriparatide, and romosozumab during the pandemic. The design of these innovative care pathways for the management of patients with osteoporosis may also provide a platform for future improvement to osteoporosis services when routine clinical care resumes.

Virtual fracture liaison clinics in the COVID era: an initiative to maintain fracture prevention services during the pandemic associated with positive patient experience.

We introduced virtual fracture liaison clinics during the COVID-19 pandemic in order to support clinical care while DXA services were down-turned. We observed that virtual FLS clinics are effective in delivering fracture risk assessment, health promotion, and clinical management and are well received by patients with positive patient experience. INTRODUCTION: We examined the impact of virtual FLS telephone clinics, as an alternative to face-to-face clinics during the COVID-19 lockdown. METHODS: Patients presenting with low trauma fracture were recruited according to standard criteria. A structured telephone clinic appointment was offered, which included fracture risk and health promotion assessment and a treatment plan. Risk factors, demographics, fracture type, FRAX scores, and outcomes were analysed. We assessed patient experience with an anonymised patient survey. RESULTS: Clinical outcomes from virtual clinics were assessed (77F/33M; mean age 65.7 years). The mean 10-year observed fracture risk for major osteoporotic fracture was 18.2% and 7.0% for hip fracture. We observed high 'attendance' rates at 79%; however, a significant number were still not available for telephone review (11%) or cancelled their appointment (10%). A recommendation for bisphosphonate treatment was made in 54% of the cohort based on National Osteoporosis Guidelines Group (NOGG) criteria. Follow-up DXA assessment is planned for 64%, according to fracture risk and NOGG guidance. We received 60 responses from the initial patient survey. Ninety percent rated their overall experience of service at 4 or 5 (very good to excellent). Ninety-eight indicated they would recommend the service to others. CONCLUSIONS: Virtual clinics are effective in delivery of fracture risk assessment and clinical management with positive patient experience. While a significant proportion will require DXA follow-up to complete the clinical assessment, virtual clinics have mitigated delays in fracture prevention interventions during the COVID-19 pandemic.

Real World Experience of Denosumab Treatment in the Belfast Osteoporosis Service.

Osteoporosis is a significant global health and economic burden associated with bone fracture, morbidity and mortality. Denosumab, a novel human monoclonal antibody second-line treatment, inhibits osteoclast-mediated bone resorption and increases bone mineral density (BMD). Treatment achieves reductions in vertebral, non-vertebral and hip fracture risk. We undertook a service evaluation to review clinical outcomes of patients treated with denosumab in an osteoporosis department that provides regional services. We identified 529 patients (95% female; mean age 72.8 years; 35-98 years), who had at least one dose of denosumab administered for the treatment of osteoporosis. The mean number of denosumab doses administered was 4.9 (range: 1 to 12). 330/529 patients had completed a baseline and post-treatment bone densitometry scan (DXA). The mean observed BMD change at around 18 months at the lumbar spine was +8.4% and at the hip was +3.5%. While the majority have transitioned to shared care administration of treatment within primary care (53%), 20% continue to attend hospital clinics to receive treatment. During follow-up, there were 66 deaths (12%). 15% switched to an alternative treatment or were discharged. This retrospective cohort study demonstrates the clinical effectiveness of denosumab in improving bone mineral density in a real life setting in an ageing, co-morbid population. There has been recent progress with adoption of shared care administration in primary care. As part of a quality improvement programme we have recently developed a dedicated denosumab database and day-case treatment clinic for those receiving treatment in secondary care.

Cerebral Nocardiosis: A Rare Cause of Hemiplegia in the Acute Medicine Unit.

Nocardiosis, a rare infection occurring mostly in immunosuppressed patients can present with neurological complications including cerebral abscess formation, and is associated with high morbidity and mortality. We describe the case of a 54-year-old immunocompetent man with cerebral nocardiosis, who presented with sudden onset hemiparesis in an acute medicine unit. He required three craniotomies with excision, following failure to respond to antimicrobial therapy, with subsequent clinical improvement and radiological resolution of multiple cerebral abscesses. Challenges in diagnosis and management of hemiparesis in the acute medical unit are discussed. Successful management of cerebral nocardiosis require early communication with a neurosurgical unit, neuropathology and microbiology services to optimise management with targeted antimicrobial therapy.

Insulin Autoimmune Syndrome: a rare case of hypoglycaemia resolving with immunosuppression.

We report a case of a 58-year-old male presenting with confusion and hypoglycaemia. There had been no prior exposure to oral hypoglycaemic agents or insulin. He was found to have inappropriate endogenous hyperinsulinaemia. Insulinoma was excluded by detailed endocrine assessment. Insulin antibodies were positive in keeping with a diagnosis of insulin autoimmune syndrome (IAS). He was treated with prednisolone 5mg once daily and nutritional supplements leading to resolution of acute confusion and hypoglycaemic episodes. The patient also had severe psoriasis and following discharge was treated with a variety of immunosuppressant therapies. This was associated with disappearance of insulin antibodies after twelve months of follow up. While it is possible that there was spontaneous resolution of insulin antibodies, we speculate that his prednisolone and immunosuppressant therapy may have suppressed insulin antibody production. There are several well recognised associations with IAS and autoimmune conditions, including Grave's disease, systemic lupus erythematous and rheumatoid arthritis. To our knowledge this is the first reported case of insulin autoimmune syndrome, resolving with immunosuppressant treatment of psoriasis.

HbA1c for Diabetes Screening in Acute Coronary Syndrome: time for a reappraisal of the guidelines?

OBJECTIVE: Diabetes is highly prevalent in individuals with acute coronary syndrome (ACS). Current NICE guidelines recommend diabetes screening of hyperglycaemic patients using a fasting plasma glucose after 4 days from admission. In 2012 the World Health Organisation (WHO) approved the use of HbA1c in the diagnosis and targeted screening for type 2 diabetes. We introduced a service improvement project using HbA1c for diabetes screening in patients with no previous diagnosis of diabetes admitted with ACS regardless of glycaemic state. METHOD: An initial retrospective audit utilised 21 months of data from the MINAP database to identify patients meeting current NICE criteria for diabetes screening. A prospective service improvement project was undertaken over a 4 month period using HbA1c as a universal screening test to categorise ACS patients based on WHO criteria. RESULTS: The retrospective audit identified 93 of 420 (22%) patients with pre-existing diabetes and 8 of the remaining 327 (2.4%) were hyperglycaemic, thus meeting NICE criteria for diabetes screening. In the service improvement project 2/49 patients (4%) met NICE criteria for diabetes screening. Twenty six of these 49 patients had a HbA1c test on admission and 17/26 (65.4%) were classified as probable diabetes or high risk. CONCLUSION: A significant proportion of ACS patients have diabetes, which may be undetected by current NICE criteria. Universal HbA1c testing offers utility as a simple and effective screening test for diabetes in the ACS population.

Challenges in management of primary hypoparathyroidism associated with autoimmune polyglandular syndrome type 1.

We report a case of autoimmune polyglandular syndrome type 1 (APS1) complicated by severe vascular insufficiency due to diffuse vascular calcification. APS1 is characterised clinically by multiple autoimmune conditions and development of at least two components of the triad of mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency. We highlight the problems in current serum calcium monitoring methods and suggest that fluctuations in serum calcium concentrations due to difficulties treating hypoparathyroidism may have contributed to the vascular calcification seen in this case.

Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement.

OBJECTIVE: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing's syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing's syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing's disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing's disease, and 5) management of ectopic ACTH syndrome, Nelson's syndrome, and special patient populations. EVIDENCE: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS: ACTH-dependent Cushing's syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing's syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing's disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing's syndrome, early diagnosis and prompt therapy are warranted.

Meal-dependent regulation of circulating glycated insulin in type 2 diabetic subjects.

There is mounting evidence that elevated circulating concentrations of glycated insulin play a role in insulin resistance in type 2 diabetes. This study evaluated the secretion of glycated insulin in response to enteral stimulation in type 2 diabetic subjects. Following a mixed meal (450 kcal; 44 % carbohydrate; 40 % fat; 16 % protein), glycated insulin rose 10-fold to peak (60 min) at 104.5 +/- 25.0 pmol/l (p < 0.001), representing 22 % total circulating insulin. The response paralleled early rises in insulin and C-peptide, which peaked at 90 min and were more protracted. Maximum glucose concentrations were observed at 50 min. These data indicate that type 2 diabetic subjects exhibit a rapid meal-induced release of glycated insulin from readily releasable pancreatic beta-cell stores, which might contribute to impaired glucose homeostasis following enteral nutrition.

A comparison of immunometric and radioimmunoassay measurement of ACTH for the differential diagnosis of Cushing's syndrome.

OBJECTIVE: Measurement of plasma ACTH levels by radioimmunoassay (RIA) is used to identify adrenal causes (AA) of Cushing's syndrome (CS) and to distinguish ectopic CS (EAS) from Cushing's disease (CD) using CRH stimulation testing and inferior petrosal sinus sampling (IPSS). We wished to determine whether diagnostic criteria developed with RIA would also be applicable for immunoradiometric (IRMA) or immunochemiluminescent (ICMA) assays. SUBJECTS AND METHODS: ACTH was measured by RIA, immunoradiometric and/or immunochemiluminescent assay on samples obtained during three types of diagnostic testing in a tertiary referral setting: a) basally (63 CD, 5 AA, 2 EAS and 37 non-CS patients); b) in 44 CD patients following CRH; c) in 6 ectopic CS and 17 CD patients during IPSS. The primary outcome was comparison of diagnostic utility. RESULTS: a) IRMA results, while lower, correlated highly with RIA (r=0.9, p<0.0001) and had similar sensitivity (100 vs 80%) and specificity (89 vs 94%) for the diagnosis of AA (p=0.3); b) the sensitivity for CD of CRH testing using IRMA was similar to that of RIA (85 vs 83%, p=1.0); c) during IPSS, IRMA had similar sensitivity (100%) and specificity (100 vs 83%) compared with ICMA or RIA (p=1.0). CONCLUSIONS: ACTH immunometric assays correlate closely to RIA and offer similar diagnostic utility.

Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes.

AIMS: Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are important insulinotropic hormones that enhance the insulin secretory response to feeding. Their potential for treating Type 2 diabetes is limited by short biological half-life owing to degradation by dipeptidyl peptidase IV (DPP IV). We investigated the acute effects of metformin on DPP IV activity in Type 2 diabetes to elucidate inhibition of DPP IV as a possible mechanism of action. METHODS: Eight fasting subjects with Type 2 diabetes (5M/3F, age 53.1+/-4.2 years, BMI 36.8+/-1.8 kg/m2, glucose 8.9+/-1.2 mmol/l, HbA1c 7.8+/-0.6%) received placebo or metformin 1 g orally 1 week apart in a random, crossover design. RESULTS: Following metformin, DPP IV activity was suppressed compared with placebo (AUC0-6 h 3230+/-373 vs. 5764+/-504 nmol ml/l, respectively, P=0.001). Circulating glucose, insulin and total GLP-1 were unchanged. Metformin also concentration-dependently inhibited endogenous DPP IV activity in vitro in plasma from Type 2 diabetic subjects. CONCLUSION: Oral metformin effectively inhibits DPP IV activity in Type 2 diabetic patients, suggesting that the drug may have potential for future combination therapy with incretin hormones.

Poor responses to a test dose of subcutaneous octreotide predict the need for adjuvant therapy to achieve 'safe' growth hormone levels.

OBJECTIVE: Somatostatin analogues are an established treatment in acromegaly. This study was designed to evaluate whether the acute serum growth hormone (GH) response to a test dose of octreotide in acromegaly predicts longer-term response to the drug at 3 years. DESIGN AND METHODS: In 23 patients, GH responses across 8 h to a subcutaneous test dose (50 microg) of octreotide were compared with GH levels after 3 years of therapy. The majority had pituitary surgery as primary therapy and at 3 years were receiving at least 600 microg octreotide daily subcutaneously or 20 mg LAR monthly intramuscularly. RESULTS: Seven had a test day GH Nadir of 5 mU/l or less of whom 4 achieved GH < 5 mU/l at 3 years. Sixteen had a test day nadir GH of 10 mU/l or less and of these 8 achieved GH < 5 mU/l at 3 years. Seven of the 23 had a GH Nadir >10 mU/l and of these 3 had achieved GH <5 mU/l at 3 years. However all of these 3 had received external pituitary irradiation within 4 years of the 3 year assessment, as compared with 3 of the <5 mU/l nadir group and 5 of the <10 mU/l nadir group. CONCLUSIONS: In patients on optimal long-term doses of octreotide for acromegaly, absence of a nadir GH <10 mU/l in the 8 h after a test dose was associated with failure to achieve GH levels associated with a normal life expectancy (5 mU/l or less) unless adjunctive external pituitary irradiation was given. As well as testing tolerability a test dose of octreotide may help in determining which patients should be offered early external pituitary irradiation or therapy with a GH receptor antagonist if surgery has failed to achieve 'safe' GH levels.

Effects of nateglinide on the secretion of glycated insulin and glucose tolerance in type 2 diabetes.

AIMS: Glycation of insulin has been demonstrated within pancreatic beta-cells and the resulting impaired bioactivity may contribute to insulin resistance in diabetes. We used a novel radioimmunoassay to evaluate the effect of nateglinide on plasma concentrations of glycated insulin and glucose tolerance in type 2 diabetes. METHODS: Ten patients (5 M/5 F, age 57.8+/-1.9 years, HbA(1c) 7.6+/-0.5%, fasting plasma glucose 9.4+/-1.2 mmol/l, creatinine 81.6+/-4.5 microM/l) received oral nateglinide 120 mg or placebo, 10 min prior to 75 g oral glucose in a random, single blind, crossover design, 1 week apart. Blood samples were taken for glycated insulin, glucose, insulin and C-peptide over 225 min. RESULTS: Plasma glucose and glycated insulin responses were reduced by 9% (P=0.005) and 38% (P=0.047), respectively, following nateglinide compared with placebo. Corresponding AUC measures for insulin and C-peptide were enhanced by 36% (P=0.005) and 25% (P=0.007) by nateglinide. CONCLUSIONS: Glycated insulin in type 2 diabetes is reduced in response to the insulin secretagogue nateglinide, resulting in preferential release of native insulin. Since glycated insulin exhibits impaired biological activity, reduced glycated insulin release may contribute to the antihyperglycaemic action of nateglinide.