Genetic risk for the polycystic ovary syndrome, bone mineral density and fractures in women and men: A UK Biobank Mendelian randomisation study.

INTRODUCTION: There is conflicting data on the effect of polycystic ovary syndrome (PCOS) on bone mineral density (BMD) and fracture risk. Recent genetic data suggest that men may also carry genetic risk factors for PCOS; the associations of these factors with parameters of bone health remains unknown. We aimed to investigate if the genetic risk of PCOS is associated with BMD and fracture risk in women and men in the UK Biobank dataset. METHODS: We used Mendelian randomisation (MR) analysis to test the association of genetic risk of excess testosterone in PCOS with BMD and fractures in the UK biobank study. The MR analysis was performed using linear regression analysis with the weighted genetic risk score (wGRS) as an independent variable adjusting for age, BMI and population eigenvectors. The horizontal pleiotropy in the MR analysis was tested using MR-Egger regression analysis. RESULTS: The study consisted of 221,086 Caucasian women (mean age ± SD: 56.7 ± 7.9 years, mean body mass index [BMI] ± SD: 27.0 ± 5.1 kg/m2, mean BMD ± SD: 0.50 ± 0.11 g/cm2) and 187,816 Caucasian men (mean age ± SD: 57.1 ± 8.1 years, mean BMI ± SD: 27.7 ± 4.1 kg/m2 and mean BMD ± SD: 0.56 ± 0.12 g/cm2). Women and men self-reported 24,797 (11%) and 17,076 (10%) fractures over the last 5 years, respectively. The MR analysis showed that one SD increase in the wGRS for clinical or biochemical hyperandrogenism in PCOS was associated with significantly higher heel BMD (Beta = 0.0007 [±0.0002], P-value = 0.001) and a significantly reduced risk of fractures (OR = 0.97, P-value = 0.003) in women. A similar wGRS in men was not associated with BMD or risk of fractures. CONCLUSION: In this study, we showed that the excess genetic risk for hyperandrogenism in women with PCOS is associated with a higher BMD and reduced risk of fractures.

Increased development of radiographic hip osteoarthritis in individuals with high bone mass: a prospective cohort study.

BACKGROUND: Individuals with high bone mass (HBM) have a greater odds of prevalent radiographic hip osteoarthritis (OA), reflecting an association with bone-forming OA sub-phenotypes (e.g. osteophytosis, subchondral sclerosis). As the role of bone mineral density (BMD) in hip OA progression is unclear, we aimed to determine if individuals with HBM have increased incidence and/or progression of bone-forming OA sub-phenotypes. METHODS: We analysed an adult cohort with and without HBM (L1 and/or total hip BMD Z-score > + 3.2) with pelvic radiographs collected at baseline and 8-year follow-up. Sub-phenotypes were graded using the OARSI atlas. Superior/inferior acetabular/femoral osteophyte and medial/superior joint space narrowing (JSN) grades were summed and Δosteophyte and ΔJSN derived. Pain and functional limitations were quantified using the WOMAC questionnaire. Associations between HBM status and change in OA sub-phenotypes were determined using multivariable linear/logistic regression, adjusting for age, sex, height, total body fat mass, follow-up time and baseline sub-phenotype grade. Generalised estimating equations accounted for individual-level clustering. RESULTS: Of 136 individuals, 62% had HBM at baseline, 72% were female and mean (SD) age was 59 (10) years. HBM was positively associated with both Δosteophytes and ΔJSN (adjusted mean grade differences between individuals with and without HBM ßosteophyte = 0.30 [0.01, 0.58], p = 0.019 and ßJSN = 0.10 [0.01, 0.18], p = 0.019). Incident subchondral sclerosis was rare. HBM individuals had higher WOMAC hip functional limitation scores (ß = 8.3 [0.7, 15.98], p = 0.032). CONCLUSIONS: HBM is associated with the worsening of hip osteophytes and JSN over an average of 8 years, as well as increased hip pain and functional limitation.

Hyperthyroidism and bone mineral density: Dissecting the causal association with Mendelian randomization analysis.

INTRODUCTION: Untreated hyperthyroidism is associated with accelerated bone turnover, low bone mineral density (BMD) and increased susceptibility to fragility fractures. Although treatment appears to improve or even reverse some of these adverse skeletal effects, there is limited guidance on routine BMD assessment in hyperthyroid patients following treatment. By using Mendelian randomization (MR) analysis, we aimed to assess the causal association of hyperthyroid thyroid states with BMD and fractures using the UK Biobank. METHODS: This MR analysis included data from 473 818 participants (women: 54% of the total sample, the median age of 58.0 years (IQR = 50-63 years), median body mass index (BMI) of 26.70 (IQR + 24.11-29.82 kg/m2 ) as part of the UK Biobank study. The study outcomes were heel BMD assessed by quantitative ultrasound of the heel and self-reported fractures. Beta-weighted genetic risk score analysis was performed using 19 single nucleotide polymorphisms (SNPs) for Graves' disease, 9 SNPs for hyperthyroidism and 11 SNPs for autoimmune thyroiditis. Since the unadjusted risk score MR is equivalent to the inverse-variance weighted method, the genetic risk score analysis was adjusted for age, gender and BMI. Sensitivity analyses were conducted using the Mendelian randomization-Egger (MR-Egger) and the inverse-variance weighted estimate methods. Replication analysis was performed using the GEnetic Factors for Osteoporosis (GEFOS) consortium data. RESULTS: MR analysis using beta-weighted genetic risk score showed no association of genetic risk for Graves' disease (Beta = -0.01, P-value = .10), autoimmune thyroiditis (Beta = -0.006 P-value = .25) and hyperthyroidism (Beta = -0.009, P-value = .18) with heel ultrasound BMD. MR-Egger and inverse-variance MR methods in UK Biobank and GEFOS consortium confirmed these findings. The genetic risk for these hyperthyroid conditions was not associated with an increased risk of fractures. CONCLUSION: Our study shows that excess genetic risk for Graves' autoimmune thyroiditis and hyperthyroidism does not increase the risk for low BMD and is not associated fractures in the Caucasian population. Our findings do not support routine screening for osteoporosis following definitive treatment of hyperthyroid states.

A 12-month continuous and intermittent high-impact exercise intervention and its effects on bone mineral density in early postmenopausal women: a feasibility randomized controlled trial.

BACKGROUND: Intermittent mechanical loading generates greater bone adaptations than continuous mechanical loading in rodents but has never been evaluated in humans. This study aimed to evaluate the feasibility of a continuous and intermittent countermovement jump (CMJ) intervention for attenuating early postmenopausal BMD loss. METHODS: 41 healthy early postmenopausal women (age=54.6±3.4 years) were randomly assigned to a continuous countermovement jumping group, an intermittent countermovement jumping group or a control group for 12 months. Adherence and dropout rates were recorded along with bone mineral density (BMD) at lumbar spine, femoral neck and trochanter sites at baseline, 6 months and 12 months. RESULTS: 28 participants completed the study. Dropout rate during the intervention (from the initiation of exercise) was 36% from continuous and 38% from intermittent countermovement jumping groups. For the participants that completed the intervention, adherence was 60.0±46.8% for continuous and 68.5±32.3% for intermittent countermovement jumping. The control group lost significant lumbar spine BMD (% difference=-2.7 [95%CI: -3.9 to -1.4]) and femoral neck BMD (% difference=-3.0% [95%CI: -5.1 to -0.8]). There was no statistically significant change in BMD for either countermovement jumping group. There was no statistically significant difference in BMD change between continuous or intermittent countermovement jumping groups when compared with the control group. CONCLUSIONS: Adherence and dropout rates were in line with previous similar interventions. To evaluate the effect of continuous and intermittent exercise on BMD, future studies should focus on maintaining participant engagement and adherence to the exercise intervention.

Soy Reduces Bone Turnover Markers in Women During Early Menopause: A Randomized Controlled Trial.

Menopausal estrogen loss leads to an increased bone loss. Soy isoflavones can act as selective estrogen receptor modulators, their role in bone turnover is unclear. The primary outcome was assessing changes in plasma bone turnover markers. The secondary outcomes were assessing changes in cardiovascular risk markers including insulin resistance, blood pressure, and lipid profile. We performed a double-blind randomized parallel study in which 200 women within 2 years after the onset of their menopause were randomized to 15 g soy protein with 66 mg isoflavone (SPI) or 15 g soy protein alone (SP), daily for 6 months. There was a significant reduction in type I collagen crosslinked beta C-telopeptide (ßCTX) (bone-resorption marker) with SPI supplementation (0.40 ± 0.17 versus 0.15 ± 0.09 µg/L; p < 0.01) compared to SP supplementation (0.35 ± 0.12 versus 0.35 ± 0.13 µg/L; p = 0.92) after 6 months. There was also a significant reduction in type I procollagen-N-propeptide (P1NP) (bone formation marker) with SPI supplementation (50.5 ± 25.0 versus 34.3 ± 17.6 µg/L; p < 0.01), more marked between 3 and 6 months. Following SPI there was a significant reduction in fasting glucose, fasting insulin, insulin resistance, and systolic blood pressure whereas no significant changes in these parameters was observed with SP. There were no significant changes in fasting lipid profile and diastolic blood pressure with either preparation. There was a significant increase in TSH and reduction in free thyroxine (p < 0.01) with SPI supplementation though free tri-iodothyronine was unchanged. In conclusion, soy protein with isoflavones may confer a beneficial effect on bone health, analogous to the mode of action of antiresorptive agents, albeit to a less magnitude. There was a significant improvement of cardiovascular risk markers, but a significant increase in TSH and reduction in free thyroxine after SPI supplementation indicating a detrimental effect on thyroid function. © 2016 American Society for Bone and Mineral Research.

Management of severe in-patient hyponatraemia: an audit in two teaching hospitals in Yorkshire, UK.

BACKGROUND: Hyponatraemia, the commonest electrolyte abnormality amongst in-patients, is associated with increased mortality. Until recently, there has been a lack of international consensus management of patients with severe hyponatraemia. AIM: We performed a retrospective study in two teaching hospitals in Yorkshire, UK, to evaluate the management of patients with severe hyponatraemia (serum Na ≤ 110 mmol/L) and to assess the frequency of complications observed in this group, in particular central pontine myelinolysis (CPM) and death. METHODS: Retrospective data collection was performed on all of patients admitted with severe hyponatraemia in a calendar year in two teaching hospitals in Yorkshire. A detailed case note evaluation was conducted to determine the patient clinical characteristics, aetiology, investigations performed, treatment, complications and outcome of patients. RESULTS: We identified 39 patients in total at both sites over a calendar year. There was a notable female predominance (n = 27), with the median (range) age being 65 (45-92) years and median sodium concentration 107 (94-110) mmol/L. Hyponatraemia was classified as acute (onset < 48 h) in six patients, chronic (onset > 48 h) in 20 patients and of unknown duration in 13 patients. Iatrogenic hyponatraemia secondary to drugs, especially thiazides was the most commonly observed aetiology. The mortality rate was 48.7% (n = 19) at the end of one year after admission episode and CPM was seen in 7.6% (n = 3) of patients. CONCLUSIONS: Severe hyponatraemia is associated with significant morbidity and mortality. Drug-induced hyponatraemia was the most common aetiology observed in our group of patients.

Glucocorticoid replacement therapy and fibrinolysis in patients with hypopituitarism.

BACKGROUND: Hypopituitarism is associated with increased cardiovascular mortality, and it has been suggested that unphysiological glucocorticoid replacement regimens might contribute to this risk. Traditional glucocorticoid replacement regimens have often led to excessive serum cortisol levels. The hypercortisolaemia of Cushing's syndrome is associated with an increased risk of thromboembolism. OBJECTIVE: To examine whether short-term higher-dose hydrocortisone replacement regimens adversely affect the fibrinolytic system. DESIGN: Crossover study comparing tailored low-dose (LD) glucocorticoid regimen (mean, 17·5 mg hydrocortisone daily), with a traditional high-dose (HD, 30-mg hydrocortisone daily) regimen for 2 weeks. PATIENTS: Ten patients with hypopituitarism and ACTH deficiency - median (range) age, 59 (41-75) years - and 10 age- and sex-matched controls. Nine patients had growth hormone deficiency (five replaced), nine patients had TSH deficiency (nine replaced), eight had gonadotrophin deficiency (five replaced). During the study, other pituitary hormone replacement therapy remained unchanged. Patients with acromegaly and Cushing's syndrome were excluded. MEASUREMENTS: Hourly serum cortisol for 11 h, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and fibrinogen levels after 2 weeks of treatment with both LD and HD regimens. RESULTS: No overall significant differences were found between the three groups using the Kruskal-Wallis test: PAI-1: [median (range)] HD, 25 (5-53) ng/ml; LD, 21 (4-56) ng/ml; controls, 27 (8-51); P = 0·3; tPA: HD, 10 (5-15) ng/ml; LD, 10 (4-13) ng/ml; controls 10 (3-13); P = 0·46; and fibrinogen: HD, 2·5 (1·8-3·5) g/l; LD, 3·0 (2·3-4·4) g/l; controls, 2·6 (1·6-3·2): P = 0·97 In addition, no significant differences between HD and LD using Wilcoxon's paired test; PAI-1 (P = 0·91), tPAag (P = 0·47) and fibrinogen (P = 0·09). CONCLUSIONS: An increased dose of hydrocortisone for 2 weeks creates excessive glucocorticoid exposure, but does not significantly affect fibrinolytic-coagulation parameters.

The effect of parathyroidectomy on neuropsychological symptoms and biochemical parameters in patients with asymptomatic primary hyperparathyroidism.

BACKGROUND: With increased biochemical screening, primary hyperparathyroidism (pHPT) is often discovered incidentally whilst patients are asymptomatic. OBJECTIVE: To assess the impact of parathyroidectomy on neuropsychological symptoms and biochemical parameters in people with asymptomatic pHPT, whilst controlling for the surgical procedure. PATIENTS/DESIGN/MEASUREMENTS: Twenty-four patients with asymptomatic pHPT requiring parathyroidectomy, in accordance with National Institutes for Health recommendations, were recruited prospectively. A control group of 23 subjects was recruited simultaneously from consecutive patients undergoing diagnostic hemithyroidectomy (HT) for benign thyroid nodules. Operations were performed by a single surgeon. Biochemical investigations and neuropsychological symptoms were measured preoperatively and 3 months after surgery. Neuropsychological symptoms were measured using the Hospital Anxiety (HAD-A) and Depression (HAD-D) scales and the Mood Rating Scale (MRS). RESULTS: Postoperatively, calcium and parathyroid hormone normalized in all patients in the pHPT group. Patients with pHPT showed a significant improvement in neuropsychological symptoms with a pre- and postoperative mean change of 2·45 ± 2·57 (P < 0·05) on HAD-A, 2·79 ± 3·85 (P < 0·05) on HAD-D, and 3·2 ± 4·57 (P < 0·05) on MRS, parameters that were unaltered in the HT group. The differences between the two groups remained statistically significant after adjustment for age and sex for HAD-D (mean change 2·8, 95% CI = 0·3, 5·3, P = 0·025) and MRS (mean difference 3·5, 95% CI = 0·4, 6·7, P = 0·027) but not for HAD-A (mean difference 1·5, 95% CI = -0·8, 3·8, P = 0·20). For all three mental health scores, there were no significant associations with either age or sex. CONCLUSIONS: Asymptomatic pHPT is associated with neuropsychological symptoms that improve after parathyroidectomy.

The effect of prior bisphosphonate therapy on the subsequent BMD and bone turnover response to strontium ranelate.

Strontium ranelate is an effective treatment for osteoporosis in treatment-naive women. In the United Kingdom, bisphosphonates are often used first line. Prior bisphosphonate use may blunt the bone mineral density (BMD) response to strontium ranelate by reducing strontium uptake into the bone. Sixty bisphosphonate-naive women and 60 women discontinuing bisphosphonates were recruited. All women commenced strontium ranelate and calcium/vitamin D. BMD and bone turnover markers were recorded for 12 months. After 12 months, the bisphosphonate-naive group's BMD increased by 5.6% (p < .001) at the spine, 3.4% (p < .001) at the total hip, and 4.0% (p < .001) at the heel. By comparison, the prior bisphosphonate group had a 2.1% (p = .002) increase at the spine but no change at the hip or heel. At all time points, BMD was significantly greater in the bisphosphonate-naive group. In the prior bisphosphonate group, there was no significant change in BMD during the first 6 months at the spine, but between months 6 and 12 there was a parallel gain in BMD (0.027 versus 0.020 g/cm(2), p = .40). The baseline difference in bone markers was no longer significant by 3 months for bone-specific alkaline phosphatase (BSAP) and 6 months for procollagen type 1 amino-terminal propeptide (P1NP) and carboxy-terminal cross-linking telopeptide of type I collagen (CTX). More women in the prior bisphosphonate group suffered a vertebral fracture (2 versus 8 women, p = .047). After bisphosphonates, bone turnover remains suppressed for up to 6 months, with blunting of the BMD response to strontium ranelate during this time. After 6 months, BMD increases in the spine but not at the hip or heel.

Interpretation of the short Synacthen test in the presence of low cortisol-binding globulin: two case reports.

CONTEXT: Ten percent of serum total cortisol (TC) is unbound; the remainder is bound to cortisol-binding globulin (CBG) and, to a lesser extent, albumin. CBG concentrations can drop significantly, particularly in critical illness, resulting in a low TC although the free, active, cortisol may be normal or increased. In the context of a low CBG, the diagnosis of pituitary-adrenal insufficiency with measurements of TC is difficult. OBJECTIVE: To remind clinicians of the difficulty in interpreting TC when the CBG is low, the circumstances when CBG concentrations may decrease and that measurement of CBG and calculation of the free cortisol index can help in the assessment of pituitary-adrenal reserve. CASE: We present two patients at risk of primary and secondary adrenal insufficiency with a poor response to 250 microg Synacthen. In both cases we confirmed low CBG concentrations but a normal free cortisol index (FCI), confirming normal pituitary-adrenal reserve. INTERVENTION: In case one, we have been able to avoid long-term steroid replacement therapy. We continue to reduce the steroid dose in case 2 but have been limited by the need for high-dose steroid treatment for exacerbations of the patient's airways disease. CONCLUSION: The use of TC in the assessment of the hypothalamic-pituitary-adrenal (HPA) axis may give rise to misleading results if the CBG concentration is low. The FCI may be a better marker of pituitary-adrenal reserve in these subjects. Clinicians should be cautious when interpreting abnormal cortisol results and we emphasize the importance of good clinical assessment.

Smell perception during early pregnancy: no evidence of an adaptive mechanism.

OBJECTIVE: It has been suggested that nausea and vomiting in pregnancy is an evolutionary adaptive mechanism to avoid the ingestion of potentially harmful foods. It has also been suggested that the mechanism that triggers nausea and vomiting in pregnancy may be olfaction and that olfactory senses are invoked to provide this protection. This study aimed to test this theory in a systematic design. DESIGN: Cross sectional study. SETTING: The antenatal department of a maternity hospital in the north of England. SAMPLE: Three groups of participants: pregnant women (n= 55), non-pregnant women (n= 42) and men (n= 48). METHODS: Sensitivity was tested towards the odours of six standard stimuli (half safe and half associated with potentially harmful compounds). MAIN OUTCOME MEASURES: Odour rating of likeness, strength and pleasantness. RESULTS: Pregnant women rated safe and odours with potentially harmful compounds differently but not more so than men or non-pregnant women. There was no evidence that pregnancy changed the olfactory processes from the non-pregnant state and only slight differences between pregnant women and men were recorded. CONCLUSIONS: There was no evidence that olfactory processes had undergone any adaptation during pregnancy. The ability to differentiate safe from potentially harmful compounds was common to all three groups studied.

Dermatological care of the diabetic foot.

Approximately 30% of patients with diabetes mellitus will have disease-related dermatological problems. Dry skin can be associated with autonomic neuropathy and may be fragile, promoting bacterial invasion. Any potentially infected 'diabetic foot' must be taken seriously, and non-painful deep sepsis suspected if there is evidence of sensory loss. Consideration should be given to eliminating nasal carriage of staphylococci if recurrent superficial sepsis occurs in the presence of poor diabetic control. Fungal infections, both of skin and nails, are common but usually not serious in the absence of immunosuppression. Treatment with topical antifungals may need to be combined with systemic therapy for successful eradication. Systemic antifungal therapy should be carefully considered as treatment needs to be prolonged and is potentially toxic, particularly in individuals with diabetes mellitus who often have co-morbidities. Varicose eczema should be treated by physical therapies intended to improve venous return and prevent peripheral edema and tissue injury. Allergic dermatitis is commonly associated with topical treatments and other sensitizers. Many reactions are not apparent from history, and patch testing for sensitivity is recommended. There are several diabetes mellitus-specific conditions that dermatologists must be aware of, including, necrobiosis lipoidica diabeticorum, granuloma annulare, diabetic dermopathy (spotted leg syndrome or shin spots), diabetic bullae (bullosis diabeticorum), and limited joint mobility and waxy skin syndrome. Ulceration, due to varying combinations of peripheral vascular disease and sensory neuropathy, is the province of the specialist team dealing with the diabetic foot and should ideally be referred to an appropriate multidisciplinary team.