Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines from the Second International Workshop.

This clinical practice guideline addresses the prevention, diagnosis, and management of hypoparathyroidism (HypoPT) and provides evidence-based recommendations. The HypoPT task forces included four teams with a total of 50 international experts including representatives from the sponsoring societies. A methodologist (GG) and his team supported the taskforces and conducted the systematic reviews. A formal process following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology and the systematic reviews provided the structure for seven of the guideline recommendations. The task force used a less structured approach based on narrative reviews for 20 non-GRADEd recommendations. Clinicians may consider postsurgical HypoPT permanent if it persists for >12 months after surgery. To predict which patients will not develop permanent postsurgical HypoPT, we recommend evaluating serum PTH within 12 to 24 hours post total thyroidectomy (strong recommendation, moderate quality evidence). PTH > 10 pg/mL (1.05 pmol/L) virtually excludes long-term HypoPT. In individuals with nonsurgical HypoPT, genetic testing may be helpful in the presence of a positive family history of nonsurgical HypoPT, in the presence of syndromic features, or in individuals younger than 40 years. HypoPT can be associated with complications, including nephrocalcinosis, nephrolithiasis, renal insufficiency, cataracts, seizures, cardiac arrhythmias, ischemic heart disease, depression, and an increased risk of infection. Minimizing complications of HypoPT requires careful evaluation and close monitoring of laboratory indices. In patients with chronic HypoPT, the panel suggests conventional therapy with calcium and active vitamin D metabolites as first-line therapy (weak recommendation, low-quality evidence). When conventional therapy is deemed unsatisfactory, the panel considers the use of PTH. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training.

Normocalcaemic primary hyperparathyroidism: what is the role of parathyroid surgery?

Primary hyperparathyroidism (PHPT) is classically associated with both an elevated or 'inappropriately normal' parathyroid hormone (PTH) level and raised serum calcium. However, in clinical practice, increasing numbers of patients present with raised PTH but normal serum calcium, renal function and vitamin D; this is known as normocalcaemic PHPT (nPHPT). Studies investigating the clinical presentation of this condition have shown that patients may present with hypertension, nephrolithiasis, impaired glucose tolerance, osteoporosis and fragility fractures. The prevalence of such complications in nPHPT is similar to that in classical hypercalcaemic PHPT (hPHPT). Although the National Institute for Health and Care Excellence (NICE) have developed guidelines for the management of PHPT generally, a consensus is yet to be reached on the optimal management of nPHPT specifically. A review of the literature on parathyroidectomy in the treatment of nPHPT revealed that nPHPT patients were more likely to present with multi-glandular disease and significantly less nPHPT patients had an intra-operative PTH fall of >50% compared with those with hPHPT. These findings demonstrate that patients with nPHPT are more likely to receive bilateral neck explorations and require remedial surgery compared with hPHPT patients. Following surgery, improvements in bone mineral density (BMD) and renal stones are generally observed in those with nPHPT. Where surgery is not possible, medical management with alendronate has been shown to be effective in nPHPT patients. Given the higher incidence of multi-gland disease and greater possibility of remedial surgery in nPHPT, careful consideration of risks and benefits should be made on an individualised basis and surgery should be performed by surgeons experienced in four gland exploration.

Management of Parathyroid Disease during the COVID-19 Pandemic.

The coronavirus disease, COVID-19, has caused widespread and sustained disruption to healthcare, not only in the delivery of emergency care, but knock-on consequences have resulted in major delays to the delivery of elective care, including surgery. COVID-19 has accelerated novel pathways for delivering clinical services, many of which have an increased reliance on technology. COVID-19 has impacted care for patients with both hypoparathyroidism and hyperparathyroidism. The role of vitamin D in the prevention of severe COVID-19 infection has also been widely debated. Severe hypocalcemia can be precipitated by infection in patients with hypoparathyroidism. With this in mind, compliance with medical management, including calcium and vitamin D supplementation, is crucial. Technology in the form of text message reminders and smartphone apps may have a key role in ensuring this. Furthermore, clinicians should ensure that patients are educated on the symptoms of hypocalcemia and the steps needing to be taken should these symptoms be experienced. Patients with primary hyperparathyroidism (PHPT) should be educated on the symptoms of hypercalcemia, as well as the importance of remaining adequately hydrated. In addition, patients should be reassured that the postponement of parathyroidectomy is likely to have negligible impact on their condition; for those with symptomatic hypercalcemia, cinacalcet can be considered as an interim measure.

Management of endocrine conditions at the end of life.

An important facet to end-of-life care is deprescribing. This can be challenging when reviewing life-sustaining endocrine medications but, unlike for diabetes, there is no national guidance to support patients and clinicians faced with care planning. This article reviews the limited current evidence to highlight areas for further discussion and research with the aim of moving towards consensus opinion. Discontinuation of certain endocrine medications, including corticosteroids, desmopressin and levothyroxine, is likely to precipitate an 'endocrine-driven mechanism of death', while it may be reasonable to discontinue other endocrine medications without the risk of hastening death or causing unnecessary symptoms. However, the over-arching theme should be that early discussion with patients regarding conversion or discontinuation of endocrine medications or monitoring is central to care planning.

Diagnosis and management of vitamin D deficiency in the Gulf Cooperative Council (GCC) countries: an expert consensus summary statement from the GCC vitamin D advisory board.

OBJECTIVE: A summary of recommendations is given within the Gulf Cooperation Council (GCC) setting on the assessment and management of vitamin D deficiency in the region. METHODS: An assembly of 11 regional experts gathered to formulate an all-inclusive approach to vitamin D deficiency within GCC. RESULTS AND CONCLUSION: Several gaps were identified before regional guidelines could be developed. These include adequacy and standardization of vitamin D testing, frequency of repeated testing and reference ranges, distinguishing prevention from the treatment of vitamin D deficiency, quality assurance of vitamin D products sold within GCC including contents and origins of products, and cut-points for vitamin D levels in local populations. A platform is created that can be further developed for overall regional implementation.

Mild primary hyperparathyroidism-to treat or not to treat?

INTRODUCTION: The presentation of primary hyperparathyroidism (PHPT) has shifted from a disease characterized by renal and skeletal complications to a mild or asymptomatic condition. Modern imaging allows localization of a surgical target in the majority of cases. SOURCES OF DATA: Data were collected from literature searches of online databases including PUBMED, MEDLINE and Cochrane. A narrative review was performed. AREAS OF AGREEMENT: Parathyroidectomy is the only therapy with curative potential with good outcomes and low risk of complications in experienced hands. Current guidelines advocate that surgery is offered in all symptomatic cases and in those who meet criteria depending on age, serum calcium concentration, skeletal and renal parameters. A structured monitoring approach should be offered to those who do not undergo surgery. AREAS OF CONTROVERSY: Thresholds for intervention to improve skeletal and renal outcomes are debatable. In addition, controversy persists over the benefit of surgery for non-skeletal/renal outcomes. GROWING POINTS: The role of medical management of PHPT using agents such as bisphosphonates, denosumab and cinacalcet are discussed. AREAS TIMELY FOR DEVELOPING RESEARCH: In summary, further data on the natural history and effects of treatment of mild and asymptomatic PHPT are required to determine thresholds for surgery. In particular, further investigations of non-skeletal and non-renal parameters, such as neurocognitive quality of life and cardiovascular disease are required. Data on normocalcaemic PHPT are lacking. Large-scale randomized controlled trials would be welcome in these areas, however in view of the cost implications a more pragmatic approach may be to develop collaborative multi-centre registries.

Lesson of the month 2: Blunt abdominal trauma: atypical presentation of phaeochromocytoma.

A 26-year-old man presented following blunt abdominal trauma to a regional major trauma centre for emergency embolisation of a retroperitoneal bleed from a presumed renal laceration. Imaging had also revealed a large right suprarenal mass. Embolisation resulted in a hypertensive crisis raising the suspicion of a metabolically active adrenal tumour. The course was further complicated by the development of ischaemic bowel requiring emergency laparotomy. Intraoperatively he became haemodynamically unstable from an actively haemorrhaging lesion. Emergency laparotomy and adrenalectomy was performed as a life-saving procedure. Histology confirmed a phaeochromocytoma. The patient made a gradual recovery and was discharged home with no sequelae. Definitive management of phaeochromocytoma is surgical resection which requires prolonged preoperative optimisation with alpha receptor blockers to adequately control blood pressure and prevent hypertensive crises. Parenteral alpha receptor blockers, such as phentolamine, are optimal treatment for intraoperative hypertensive emergencies, yet they are currently not available in the UK.

Impact of menopause on outcomes in prolactinomas after dopamine agonist treatment withdrawal.

OBJECTIVE: Discontinuation of dopamine agonist (DA) treatment in women with prolactinoma after menopause is a potential approach; studies systematically assessing long-term outcomes are lacking. Our aim was to investigate the natural history of prolactinoma in this group. DESIGN/PATIENTS: Retrospective cohort study of women with prolactinoma diagnosed before menopause and who after menopause were not on DA. RESULTS: Thirty women were included. Twenty-eight received DA (median duration 18 years, median age at DA withdrawal 52 years). At last assessment (median follow-up 3 years) and compared with values 6-12 months after stopping DA, Prolactin (PRL) increased in 15%, decreased but not normalized in 33% and was normal in 52%; PRL levels or visible adenoma on imaging before DA withdrawal, treatment duration and presence of macro-/microadenoma at diagnosis were not predictors of normoprolactinaemia at last review, whereas PRL values 6-12 months after stopping DA were. Adenoma regrowth was detected in 2/27 patients (7%), who showed gradual increase in PRL. Comparison with 28 women who had DA withdrawal before their menopause revealed lower risk of hyperprolactinaemia recurrence in the postmenopausal group (HR:0.316, 95% CI: 0.101-0.985, P < .05). Two women with microprolactinoma diagnosed in perimenopausal period had not been offered DA; PRL decreased (but not normalized) during observation of 1 and 8 years. CONCLUSIONS: Prolactin normalized over time in nearly half of the women and serum PRL 6-12 months after DA withdrawal is useful predictor. Nonetheless, 7% of the patients demonstrated adenoma regrowth which, given the life expectancy postmenopause, necessitate regular monitoring of the cases with persistent hyperprolactinaemia.

A rare challenging case of co-existent craniopharyngioma, acromegaly and squamous cell lung cancer.

Co-existence of craniopharyngioma and acromegaly has been very rarely reported. A 65-year-old man presented with visual deterioration, fatigue and frontal headaches. Magnetic resonance imaging revealed a suprasellar heterogeneous, mainly cystic, 1.9 × 2 × 1.9 cm mass compressing the optic chiasm and expanding to the third ventricle; the findings were consistent with a craniopharyngioma. Pituitary hormone profile showed hypogonadotropic hypogonadism, mildly elevated prolactin, increased insulin-like growth factor 1 (IGF-1) and normal thyroid function and cortisol reserve. The patient had transsphenoidal surgery and pathology of the specimen was diagnostic of adamantinomatous craniopharyngioma. Post-operatively, he had diabetes insipidus, hypogonadotropic hypogonadism and adrenocorticotropic hormone and thyroid-stimulating hormone deficiency. Despite the hypopituitarism, his IGF-1 levels remained elevated and subsequent oral glucose tolerance test did not show complete growth hormone (GH) suppression. Further review of the pre-operative imaging revealed a 12 × 4 mm pituitary adenoma close to the right carotid artery and no signs of pituitary hyperplasia. At that time, he was also diagnosed with squamous cell carcinoma of the left upper lung lobe finally managed with radical radiotherapy. Treatment with long-acting somatostatin analogue was initiated leading to biochemical control of the acromegaly. Latest imaging has shown no evidence of craniopharyngioma regrowth and stable adenoma. This is a unique case report of co-existence of craniopharyngioma, acromegaly and squamous lung cell carcinoma that highlights diagnostic and management challenges. Potential effects of the GH hypersecretion on the co-existent tumours of this patient are also briefly discussed. LEARNING POINTS: Although an extremely rare clinical scenario, craniopharyngioma and acromegaly can co-exist; aetiopathogenic link between these two conditions is unlikely.Meticulous review of unexpected biochemical findings is vital for correct diagnosis of dual pituitary pathology.The potential adverse impact of GH excess due to acromegaly in a patient with craniopharyngioma (and other neoplasm) mandates adequate biochemical control of the GH hypersecretion.

The Cost-Effectiveness of Screening in the Community to Reduce Osteoporotic Fractures in Older Women in the UK: Economic Evaluation of the SCOOP Study.

The SCOOP study was a two-arm randomized controlled trial conducted in the UK in 12,483 eligible women aged 70 to 85 years. It compared a screening program using the FRAX® risk assessment tool in addition to bone mineral density (BMD) measures versus usual management. The SCOOP study found a reduction in the incidence of hip fractures in the screening arm, but there was no evidence of a reduction in the incidence of all osteoporosis-related fractures. To make decisions about whether to implement any screening program, we should also consider whether the program is likely to be a good use of health care resources, ie, is it cost-effective? The cost per gained quality adjusted life year of screening for fracture risk has not previously been demonstrated in an economic evaluation alongside a clinical trial. We conducted a "within trial" economic analysis alongside the SCOOP study from the perspective of a national health payer, the UK National Health Service (NHS). The main outcome measure in the economic analysis was the cost per quality adjusted life year (QALY) gained over a 5-year time period. We also estimated cost per osteoporosis-related fracture prevented and the cost per hip fracture prevented. The screening arm had an average incremental QALY gain of 0.0237 (95% confidence interval -0.0034 to 0.0508) for the 5-year follow-up. The incremental cost per QALY gained was £2772 compared with the control arm. Cost-effectiveness acceptability curves indicated a 93% probability of the intervention being cost-effective at values of a QALY greater than £20,000. The intervention arm prevented fractures at a cost of £4478 and £7694 per fracture for osteoporosis-related and hip fractures, respectively. The current study demonstrates that a systematic, community-based screening program of fracture risk in older women in the UK represents a highly cost-effective intervention. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Management of Patients With High Baseline Hip Fracture Risk by FRAX Reduces Hip Fractures-A Post Hoc Analysis of the SCOOP Study.

The Screening for Osteoporosis in Older Women for the Prevention of Fracture (SCOOP) study was a community-based screening intervention in women aged 70 to 85 years in the United Kingdom. In the screening arm, licensed osteoporosis treatments were recommended in women identified to be at high risk of hip fracture using the FRAX risk assessment tool (including bone mineral density measurement). In the control arm, standard care was provided. Screening led to a 28% reduction in hip fractures over 5 years. In this planned post hoc analysis, we wished to examine for interactions between screening effectiveness on fracture outcome (any, osteoporotic, and hip fractures) on the one hand and baseline FRAX 10-year probability of hip fracture on the other. All analyses were conducted on an intention-to-treat basis, based on the group to which women were randomized, irrespective of whether screening was completed. Of 12,483 eligible participants, 6233 women were randomized to screening, with treatment recommended in 898 (14.4%). No evidence of an effect or interaction was observed for the outcomes of any fracture or osteoporotic fracture. In the screening arm, 54 fewer hip fractures were observed than in the control arm (164 versus 218, 2.6% versus 3.5%), and commensurate with treatment being targeted to those at highest hip fracture risk, the effect on hip fracture increased with baseline FRAX hip fracture probability (p = 0.021 for interaction); for example, at the 10th percentile of baseline FRAX hip probability (2.6%), there was no evidence that hip fractures were reduced (hazard ratio [HR] = 0.93; 95% confidence interval [CI] 0.71 to 1.23), but at the 90th percentile (16.6%), there was a 33% reduction (HR = 0.67; 95% CI 0.53 to 0.84). Prior fracture and parental history of hip fracture positively influenced screening effectiveness on hip fracture risk. We conclude that women at high risk of hip fracture based on FRAX probability are responsive to appropriate osteoporosis management. © 2018 American Society for Bone and Mineral Research.

Screening in the community to reduce fractures in older women (SCOOP): a randomised controlled trial.

BACKGROUND: Despite effective assessment methods and medications targeting osteoporosis and related fractures, screening for fracture risk is not currently advocated in the UK. We tested whether a community-based screening intervention could reduce fractures in older women. METHODS: We did a two-arm randomised controlled trial in women aged 70-85 years to compare a screening programme using the Fracture Risk Assessment Tool (FRAX) with usual management. Women were recruited from 100 general practitioner (GP) practices in seven regions of the UK: Birmingham, Bristol, Manchester, Norwich, Sheffield, Southampton, and York. We excluded women who were currently on prescription anti-osteoporotic drugs and any individuals deemed to be unsuitable to enter a research study (eg, known dementia, terminally ill, or recently bereaved). The primary outcome was the proportion of individuals who had one or more osteoporosis-related fractures over a 5-year period. In the screening group, treatment was recommended in women identified to be at high risk of hip fracture, according to the FRAX 10-year hip fracture probability. Prespecified secondary outcomes were the proportions of participants who had at least one hip fracture, any clinical fracture, or mortality; and the effect of screening on anxiety and health-related quality of life. This trial is registered with the International Standard Randomised Controlled Trial registry, number ISRCTN 55814835. FINDINGS: 12 483 eligible women were identified and participated in the trial, and 6233 women randomly assigned to the screening group between April 15, 2008, and July 2, 2009. Treatment was recommended in 898 (14%) of 6233 women. Use of osteoporosis medication was higher at the end of year 1 in the screening group compared with controls (15% vs 4%), with uptake particularly high (78% at 6 months) in the screening high-risk subgroup. Screening did not reduce the primary outcome of incidence of all osteoporosis-related fractures (hazard ratio [HR] 0·94, 95% CI 0·85-1·03, p=0·178), nor the overall incidence of all clinical fractures (0·94, 0·86-1·03, p=0·183), but screening reduced the incidence of hip fractures (0·72, 0·59-0·89, p=0·002). There was no evidence of differences in mortality, anxiety levels, or quality of life. INTERPRETATION: Systematic, community-based screening programme of fracture risk in older women in the UK is feasible, and could be effective in reducing hip fractures. FUNDING: Arthritis Research UK and Medical Research Council.

Prolactinomas diagnosed in the postmenopausal period: Clinical phenotype and outcomes.

OBJECTIVE: Most prolactinomas in females are diagnosed during the reproductive age, and the majority are microadenomas. Prolactinomas detected in the postmenopausal period are less common with limited published data on their presentation and prognosis. Our objective was to assess the presenting clinical, biochemical and imaging findings, as well as the outcomes of women diagnosed with a prolactinoma in the postmenopausal period. DESIGN AND METHODS: We undertook a retrospective cohort study of women diagnosed with prolactinoma after menopause and followed up in a large UK pituitary centre. Information on presentation, management and outcomes was collected. RESULTS: Seventeen women with a median age at diagnosis of 63 years (range 52-78) were identified. Headaches and/or visual deterioration were the most commonly reported complaints at detection of the adenoma (47%). Acute pituitary apoplexy was diagnosed at presentation or during follow-up in 18% of the cases. The median serum prolactin was 12 364 mU/L (range 2533-238 479). Macroprolactinomas comprised 94% of the tumours, and 88% of them had supra/parasellar extension. All patients with macroprolactinoma were offered dopamine agonist, and normal prolactin was achieved in 94% of them (median follow-up 91.5 months). Adenoma shrinkage was observed in all women. Improvement or resolution of visual disturbances documented at presentation was observed in 86% of cases. CONCLUSIONS: The clinical phenotype of prolactinomas diagnosed in the postmenopausal period is characterized by dominance of macroadenomas, with frequent supra/parasellar extension and a relative high rate of acute pituitary apoplexy. In this group of patients, the response of the macroadenomas to dopamine agonists is good.

Effect of vitamin D deficiency in developed countries.

Introduction: Vitamin D deficiency is common worldwide with adverse effects on skeletal health. In recent years, there has been great interest in non-classical actions of vitamin D. Basic research has uncovered actions in a range of non-skeletal tissues, and observational studies have identified inverse relationships with risk of a number of disease states including sarcopenia, obesity, the metabolic syndrome, cardiovascular disease, cancer and autoimmune diseases. Sources of data: PubMed, Medline and Cochrane Systematic Reviews. Areas of agreement: Current evidence supports the use of vitamin D supplementation in deficiency to improve skeletal outcomes such as falls/fracture risk and bone mineral density. Areas of controversy: There is debate reflected in guidelines on optimal thresholds for circulating levels of vitamin D. Further studies are required to refine dosing regimens and treatment target levels of vitamin D. Growing points: A number of studies have investigated the extra-skeletal effects of vitamin D deficiency but causality in humans has yet to be confirmed. Areas timely for developing research: Large-scale randomized controlled trials incorporating data on vitamin D status at baseline and follow up, adverse events, and comparison of dosing regimens are required. It is imperative that studies are carried out with a diverse range of participants (age, gender and ethnicity), and settings to allow for a more individualized approach. In addition, we would advocate incorporating cutting-edge research tools into human studies to advance our understanding of the mechanisms of vitamin D action in extra-skeletal disease. This may involve multi-metabolite analysis of vitamin D metabolites, or unbiased approaches to assess regulation of gene/protein expression in tissues of interest.

Outcome of Nonfunctioning Pituitary Adenomas That Regrow After Primary Treatment: A Study From Two Large UK Centers.

Context: Despite the major risk of regrowth of clinically nonfunctioning pituitary adenomas (CNFAs) after primary treatment, systematic data on the probability of further tumor progression and the effectiveness of management approaches are lacking. Objective: To assess the probability of further regrowth(s), predictive factors, and outcomes of management approaches in patients with CNFA diagnosed with adenoma regrowth after primary treatment. Patients, Design, and Setting: Retrospective cohort study of 237 patients with regrown CNFA managed in two UK centers. Results: Median follow-up was 5.9 years (range, 0.4 to 37.7 years). The 5-year second regrowth rate was 35.3% (36.2% after surgery; 12.5% after radiotherapy; 12.7% after surgery combined with radiotherapy; 63.4% with monitoring). Of those managed with monitoring, 34.8% eventually were offered intervention. Type of management and sex were risk factors for second regrowth. Among those with second adenoma regrowth, the 5-year third regrowth rate was 26.4% (24.4% after surgery; 0% after radiotherapy; 0% after surgery combined with radiotherapy; 48.3% with monitoring). Overall, patients with a CNFA regrowth had a 4.4% probability of a third regrowth at 5 years and a 10.0% probability at 10 years; type of management of the first regrowth was the only risk factor. Malignant transformation was diagnosed in two patients. Conclusions: Patients with regrown CNFA after primary treatment continue to carry considerable risk of tumor progression, necessitating long-term follow-up. Management approach to the regrowth was the major factor determining this risk; monitoring had >60% risk of progression at 5 years, and a substantial number of patients ultimately required intervention.

25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 exert distinct effects on human skeletal muscle function and gene expression.

Age-associated decline in muscle function represents a significant public health burden. Vitamin D-deficiency is also prevalent in aging subjects, and has been linked to loss of muscle mass and strength (sarcopenia), but the precise role of specific vitamin D metabolites in determining muscle phenotype and function is still unclear. To address this we quantified serum concentrations of multiple vitamin D metabolites, and assessed the impact of these metabolites on body composition/muscle function parameters, and muscle biopsy gene expression in a retrospective study of a cohort of healthy volunteers. Active serum 1,25-dihydroxyvitamin D3 (1α,25(OH)2D3), but not inactive 25-hydroxyvitamin D3 (25OHD3), correlated positively with measures of lower limb strength including power (rho = 0.42, p = 0.02), velocity (Vmax, rho = 0.40, p = 0.02) and jump height (rho = 0.36, p = 0.04). Lean mass correlated positively with 1α,25(OH)2D3 (rho = 0.47, p = 0.02), in women. Serum 25OHD3 and inactive 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) had an inverse relationship with body fat (rho = -0.30, p = 0.02 and rho = -0.33, p = 0.01, respectively). Serum 25OHD3 and 24,25(OH)2D3 were also correlated with urinary steroid metabolites, suggesting a link with glucocorticoid metabolism. PCR array analysis of 92 muscle genes identified vitamin D receptor (VDR) mRNA in all muscle biopsies, with this expression being negatively correlated with serum 25OHD3, and Vmax, and positively correlated with fat mass. Of the other 91 muscle genes analysed by PCR array, 24 were positively correlated with 25OHD3, but only 4 were correlated with active 1α,25(OH)2D3. These data show that although 25OHD3 has potent actions on muscle gene expression, the circulating concentrations of this metabolite are more closely linked to body fat mass, suggesting that 25OHD3 can influence muscle function via indirect effects on adipose tissue. By contrast, serum 1α,25(OH)2D3 has limited effects on muscle gene expression, but is associated with increased muscle strength and lean mass in women. These pleiotropic effects of the vitamin D 'metabolome' on muscle function indicate that future supplementation studies should not be restricted to conventional analysis of the major circulating form of vitamin D, 25OHD3.

A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures.

BACKGROUND: Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. OBJECTIVES: To evaluate the clinical effectiveness and safety of bisphosphonates [alendronic acid (Fosamax® and Fosamax® Once Weekly, Merck Sharp & Dohme Ltd), risedronic acid (Actonel® and Actonel Once a Week®, Warner Chilcott UK Ltd), ibandronic acid (Bonviva®, Roche Products Ltd) and zoledronic acid (Aclasta®, Novartis Pharmaceuticals UK Ltd)] for the prevention of fragility fracture and to assess their cost-effectiveness at varying levels of fracture risk. DATA SOURCES: For the clinical effectiveness review, six electronic databases and two trial registries were searched: MEDLINE, EMBASE, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science and BIOSIS Previews, Clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform. Searches were limited by date from 2008 until September 2014. REVIEW METHODS: A systematic review and network meta-analysis (NMA) of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years (QALYs) for each bisphosphonate treatment strategy and a strategy of no treatment for a simulated cohort of patients with heterogeneous characteristics. The model was populated with effectiveness evidence from the systematic review and NMA. All other parameters were estimated from published sources. A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net benefit (INB) was estimated using non-parametric regression. Probabilistic sensitivity analysis (PSA) and scenario analyses were used to assess uncertainty. RESULTS: Forty-six randomised controlled trials (RCTs) were included in the clinical effectiveness systematic review, with 27 RCTs providing data for the fracture NMA and 35 RCTs providing data for the femoral neck bone mineral density (BMD) NMA. All treatments had beneficial effects on fractures versus placebo, with hazard ratios varying from 0.41 to 0.92 depending on treatment and fracture type. The effects on vertebral fractures and percentage change in BMD were statistically significant for all treatments. There was no evidence of a difference in effect on fractures between bisphosphonates. A statistically significant difference in the incidence of influenza-like symptoms was identified from the RCTs for zoledronic acid compared with placebo. Reviews of observational studies suggest that upper gastrointestinal symptoms are frequently reported in the first month of oral bisphosphonate treatment, but pooled analyses of placebo-controlled trials found no statistically significant difference. A strategy of no treatment was estimated to have the maximum INB for patients with a 10-year QFracture risk under 1.5%, whereas oral bisphosphonates provided maximum INB at higher levels of risk. However, the PSA suggested that there is considerable uncertainty regarding whether or not no treatment is the optimal strategy until the QFracture score is around 5.5%. In the model using FRAX, the mean INBs were positive for all oral bisphosphonate treatments across all risk categories. Intravenous bisphosphonates were estimated to have lower INBs than oral bisphosphonates across all levels of fracture risk when estimated using either QFracture or FRAX. LIMITATIONS: We assumed that all treatment strategies are viable alternatives across the whole population. CONCLUSIONS: Bisphosphonates are effective in preventing fragility fractures. However, the benefit-to-risk ratio in the lowest-risk patients may be debatable given the low absolute QALY gains and the potential for adverse events. We plan to extend the analysis to include non-bisphosphonate therapies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013006883. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Successful treatment of recurrent renal stones with Cinacalcet in a patient with primary hyperparathyroidism.

A man aged 72 years with long-standing primary hyperparathyroidism (HPT), a background of recurrent bilateral renal stones and failed parathyroid surgery is described. During the 27 months preceding treatment, episodes of renal colic became increasingly frequent and he required multiple surgical interventions. Given the lack of medical therapies to definitively treat his symptoms, he was started on a trial of the calcimimetic, Cinacalcet. Cinacalcet has previously been shown to reduce hypercalcaemia in patients with primary HPT. Despite this, there is a paucity of evidence to suggest that its use is associated with a long-term reduction in urinary calcium excretion and renal stone recurrence. In our case, within 4 months of starting treatment, serum and urinary calcium had normalised and parathyroid hormone concentrations were within reference ranges. To date, over a 50-month treatment period, there has been a complete cessation in stone formation, and no further urological intervention has been required.