Comparative Effectiveness of Supine Avoidance versus Continuous Positive Airway Pressure for Treating Supine-isolated Sleep Apnea: A Clinical Trial.

Rationale: About 20-35% of patients with obstructive sleep apnea (OSA) have supine-isolated OSA, for which supine sleep avoidance could be an effective therapy. However, traditional supine discomfort-based methods show poor tolerance and compliance to treatment and so cannot be recommended. Supine alarm devices show promise, but evidence to support favorable adherence to treatment and effectiveness at reducing excessive daytime sleepiness compared with continuous positive airway pressure (CPAP) remains limited. Objectives: To establish if alarm-based supine-avoidance treatment in patients with supine-isolated OSA is noninferior to CPAP in reducing daytime sleepiness. Methods: After baseline questionnaire administration and in-home supine-time and polysomnography assessments, patients with supine-isolated OSA and Epworth Sleepiness Scale scores ⩾8 were randomized to ⩾6 weeks of supine-avoidance or CPAP treatment, followed by crossover to the remaining treatment with repeat assessments. Noninferiority was assessed from change in Epworth Sleepiness Scale with supine avoidance compared with CPAP using a prespecified noninferiority margin of 1.5. Average nightly treatment use over all nights and treatment efficacy and effectiveness at reducing respiratory disturbances were also compared between treatments. Results: The reduction in sleepiness score with supine avoidance (mean [95% confidence interval], -1.9 [-2.8 to -1.0]) was noninferior to that with CPAP (-2.4 [-3.3 to -1.4]) (supine avoidance-CPAP difference, -0.4 [-1.3 to 0.6]), and the lower confidence limit did not cross the noninferiority margin of 1.5 (P = 0.021). Average treatment use was higher with supine avoidance compared with CPAP (mean ± standard deviation, 5.7 ± 2.4 vs. 3.9 ± 2.7 h/night; P < 0.001). Conclusions: In patients with supine-isolated OSA, vibrotactile supine alarm device therapy is noninferior to CPAP for reducing sleepiness and shows superior treatment adherence. Clinical trial registered with www.anzctr.org.au (ACTRN 12613001242718).

Blood Pressure, Aortic Stiffness, Hemodynamics, and Cognition in Twin Pairs Discordant for Type 2 Diabetes.

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of cognitive impairment and dementia with poorly understood underlying mechanisms. OBJECTIVE: We examined the role of blood pressure (BP), aortic stiffness, and hemodynamics in this association. METHODS: Cross-sectional sample of late middle-aged twins discordant for T2D from the Australian Twin Registry. Measurements included neuropsychological battery and brain MRI including arterial spin labelling (ASL) to measure cerebral perfusion. Mobil-o-Graph devices were used to non-invasively obtain 24-hour BP, aortic stiffness, and hemodynamic measures. Using mixed modelling, we studied associations of T2D with cognition, MRI measures, BP, aortic stiffness, and hemodynamics. RESULTS: There were 23 twin pairs with mean age 63.7 (SD = 6.1) years. T2D (ß=-0.45, p < 0.001) and age (ß=-0.05, p = 0.022) were independently associated with poorer attention but not with memory or perceptual speed. T2D was associated with reduced nocturnal central systolic BP dipping (ß=-3.79, p = 0.027), but not with BP, aortic stiffness, cerebral perfusion, or other hemodynamic measures. There was a statistically significant interaction between T2D and central systolic BP dipping in predicting attention scores (both p < 0.05 for the interaction term) whereby there was a positive association between BP dipping and attention scores in those with T2D, but not in those without T2D. CONCLUSION: We found an association between T2D and reduced nocturnal central systolic dipping, but not with any other measures of BP, stiffness or hemodynamic measures. Further study of the role of nocturnal central BP dipping in the association between T2D and cognitive impairment may help identify potential mechanisms.

Fat mass, but not fat-free mass, predicts increased foot pain with obesity, independent of bariatric surgery.

BACKGROUND: Foot pain is a common manifestation of obesity. OBJECTIVE: To determine if bariatric surgery is associated with a reduction in foot pain and if body mass index (BMI) or body composition predict a change in foot pain. SETTING: University hospital. METHODS: Participants with foot pain awaiting bariatric surgery were recruited for this prospective study. Multivariable linear regression was used to determine predictors of change in foot pain between baseline and 6-month follow-up using body composition (fat mass index and fat-free mass index) or BMI, adjusting for, depression, age, sex, and group (surgery versus control). RESULTS: Forty-five participants (38 female), mean ± standard deviation age of 45.7 ± 9.4 years, were recruited for this study. Twenty-nine participants mean ± standard deviation BMI of 44.8 ± 7.0 kg underwent bariatric surgery, while 16 participants mean ± standard deviation BMI of 47.9 ± 5.2 kg were on the waiting list (control). One participant was lost to follow-up. The treatment group lost a mean of 24.3 kg (95% confidence interval [CI] 21.1-27.5), while the control group gained 1.2 kg (95% CI -2.5 to 4.9), respectively. In multivariable analysis, bariatric surgery was significantly associated with reduced foot pain at 6-month follow-up -32.6 points (95% CI -43.8 to -21.4, P < .001), while fat mass index was significantly associated with increased pain at follow-up 1.5 points (95% CI .2 to 2.8, P = .027), after controlling for fat-free mass index, age, sex, and depression. CONCLUSIONS: Bariatric surgery was significantly associated with reduced foot pain. Higher baseline fat mass index, but not fat-free mass index or BMI, was predictive of increased foot pain at follow-up. Foot pain may be mediated by metabolic, rather than mechanical, factors in bariatric surgery candidates.

Mid-term migration of a cementless, porous acetabular cup: A 5 year Radiostereometric analysis.

PURPOSE: The aim of the study was to determine the 5 year migratory and wear patterns, adverse events and clinical outcomes of a cementless, porous acetabular cup. METHODS: RSA imaging of a cohort of 11 patients was retrospective analysed at 5 years post Total Hip Arthroplasty (THA). Changes in pain, function and symptoms of the hip at 5 years post-THA were compared to preoperative and 2 year postoperative assessments on the Harris Hip Score (HHS) and Hip dysfunction and Osteoarthritis Outcome Score (HOOS). RESULTS: The majority of cup migration occurred up to 6 months and stabilised thereafter (6 months to 5 years, p = 0.091-0.866, Wilcoxon Signed Rank test). The direction of rotation around the 3 axes was evenly distributed among the cups between anterior-posterior rotation, internal-external rotation and increased-decreased inclination. The majority of the cups translated proximally, at an average migration of 0.36 mm (±95%CI 0.17) at 5-years post-THA. Following initial bedding in, up to 6 months, there was no detectable polyethylene wear between 6 months and 5 years. At 5 years postoperatively, a statistically significant difference was observed across all HOOS subscales in comparison to preoperative values, with higher means reported at 5 years (p < 0.001). The total mean HHS displayed a statistically significant improvement, increasing from 'poor' preoperatively to 'good' at 5 years post-THA. CONCLUSION: Following initial migration between discharge and 6 months, the cementless porous acetabular cup demonstrated a tendency for stabilisation from 6 months up to 5 years post-THA, suggesting good mid-term fixation. Additionally, improvements in clinical outcome measures of pain, function and quality-of-life remained high following THA at 5 years post-surgery.

Predictors of Mortality for Delirium in Palliative Care.

INTRODUCTION: Delirium has a high mortality rate. Understanding predictors of prognosis in patients with delirium will aid treatment decisions and communication. This study aimed to explore variables associated with death during an established episode of delirium in palliative care when haloperidol treatment had been commenced. METHODS: A consecutive cohort of palliative care patients, from 14 centers across four countries, is reported. The outcome of interest was death within 14 days from commencement of haloperidol treatment for delirium. Clinicodemographic variables explored were delirium severity, age, gender, primary life limiting illness, body mass index (BMI), total daily haloperidol dose at baseline (mg), functional status, and comorbidities. RESULTS: One hundred and sixteen palliative care patients where vital status was known were included in the analysis; 45% (n = 52) died within 10 days, and 56% (n = 65) died within 14 days. In multivariate analyses no clinical or demographic variables predicted death, apart from lower BMI in noncancer patients. CONCLUSION: This study has shown a very high mortality rate within two weeks of commencing haloperidol for delirium in palliative care, with no clear clinical predictors for those with a higher chance of dying. Having a higher BMI offered some benefit in survival, but only in noncancer patients. When delirium occurs in advanced illness, discussion should be initiated about the gravity of the clinical situation.

Supports for medical students during rural clinical placements: factors associated with intention to practise in rural locations.

INTRODUCTION: Through rural clinical schools (RCSs), medical students may undertake an extended block of clinical training in rural Australia. The premise of these placements is that meaningful rural exposure will facilitate rural career uptake. RCSs offer a range of supports to facilitate student engagement in the program. This study aims to analyse RCS students' perceptions of these supports and impact on intentions to work rurally. METHODS: Between September 2012 and January 2013 RCS students were invited to complete questions regarding perceptions of student support, as a part of the annual Federation of Australian Medical Educators survey. Multivariable logistic regression was used to identify associations between supports and intentions for rural internship or career. RESULTS: There were 454 participants. A majority of students (n=349, 79.1%) felt well supported by their RCS. Students from a rural background (odds ratio (OR)=1.64 (95% confidence interval (CI):1.13-2.38)), or who indicated that their placement had a positive impact on their wellbeing (OR=1.38 (95%CI:1.07-1.80)), were more likely to intend to complete a rural internship. Those who felt socially isolated were less likely to elect this (OR=0.82 (0.70-0.97)). Outcomes were similar for those indicating a preference for rural or remote practice after completing training. CONCLUSIONS: Student perceptions of supports offered by RCSs were generally very positive. Perceptions of financial support were not predictive of rural career intent. Although this does not negate the importance of providing appropriate financial supports, it does demonstrate that student wellbeing is a more important recruitment factor for rural practice.

Pharmacovigilance in hospice/palliative care: net effect of pregabalin for neuropathic pain.

INTRODUCTION: Real-world effectiveness of many medications has been poorly researched, including in hospice/palliative care. Directly extrapolating findings from other clinical settings may not yield robust clinical advice. Pharmacovigilance studies provide an opportunity to understand better the net impact of medications. The study aimed to examine immediate and short-term benefits and harms of pregabalin in routine practice for neuropathic pain in hospice/palliative care. METHODS: A consecutive cohort of 155 patients from 62 centres in 5 countries was started on pregabalin and studied prospectively. Data were collected at three time points: baseline; day 7 (immediate, short-term harms); ad hoc reports of any harms ≤21 days; and day 21 (short-term benefits). RESULTS: Median dose for 155 patients at day 21 was 150 mg/24 h. Benefits were reported by 61 patients (39%), of whom 11 (7%) experienced complete pain resolution. Harms were reported by 51 (35%) patients at or before 7 days, the most frequent of which were somnolence, fatigue, cognitive disturbance and dizziness. 10 patients (6%) ceased pregabalin due to harms, but 82 patients (53%) were being treated at 21 days. In regression modelling, people with worse baseline pain derived more benefit (OR=8.5 (95% CI 2.5 to 28.68). CONCLUSIONS: Pregabalin delivered benefit to many patients, with 4 of 10 experiencing pain reductions by 21 days. Harms, occurring in 1 in 3 patients, may be difficult to detect in clinical practice, as they mostly involve worsening of symptoms prevalent at baseline.

Summary goodness-of-fit statistics for binary generalized linear models with noncanonical link functions.

Generalized linear models (GLM) with a canonical logit link function are the primary modeling technique used to relate a binary outcome to predictor variables. However, noncanonical links can offer more flexibility, producing convenient analytical quantities (e.g., probit GLMs in toxicology) and desired measures of effect (e.g., relative risk from log GLMs). Many summary goodness-of-fit (GOF) statistics exist for logistic GLM. Their properties make the development of GOF statistics relatively straightforward, but it can be more difficult under noncanonical links. Although GOF tests for logistic GLM with continuous covariates (GLMCC) have been applied to GLMCCs with log links, we know of no GOF tests in the literature specifically developed for GLMCCs that can be applied regardless of link function chosen. We generalize the Tsiatis GOF statistic originally developed for logistic GLMCCs, (TG), so that it can be applied under any link function. Further, we show that the algebraically related Hosmer-Lemeshow (HL) and Pigeon-Heyse (J(2) ) statistics can be applied directly. In a simulation study, TG, HL, and J(2) were used to evaluate the fit of probit, log-log, complementary log-log, and log models, all calculated with a common grouping method. The TG statistic consistently maintained Type I error rates, while those of HL and J(2) were often lower than expected if terms with little influence were included. Generally, the statistics had similar power to detect an incorrect model. An exception occurred when a log GLMCC was incorrectly fit to data generated from a logistic GLMCC. In this case, TG had more power than HL or J(2) .

Relative Hyperglycemia, a Marker of Critical Illness: Introducing the Stress Hyperglycemia Ratio.

CONTEXT: Hyperglycemia in hospitalized patients is associated with increased morbidity and mortality. OBJECTIVE: We examined whether critical illness is more strongly associated with relative or absolute hyperglycemia. DESIGN: The study was an observational cohort study. PATIENTS AND SETTING: A total of 2290 patients acutely admitted to a tertiary hospital. MAIN OUTCOME MEASURE: The relative hyperglycemia (stress hyperglycemia ratio [SHR]) was defined as admission glucose divided by estimated average glucose derived from glycosylated hemoglobin. The relationships between glucose and SHR with critical illness (in-hospital death or critical care) were examined. RESULTS: In univariable analyses, SHR (odds ratio, 1.23 per 0.1 increment [95% confidence interval, 1.18-1.28]; P < .001) and glucose (odds ratio, 1.18 per mmol/L [1.13-1.23]; P < .001) were associated with critical illness. In multivariable analysis, the association was maintained for SHR (odds ratio, 1.20 per 0.1 increment [1.13-1.28]; P < .001), but not glucose (odds ratio, 1.03 per mmol/L [0.97-1.11]; P = .31). Background hyperglycemia affected the relationship between glucose (P = .002) and critical illness, but not SHR (P = .35) and critical illness. In patients with admission glucose ≤ 10 mmol/L, the odds ratio for critical illness was higher in the fourth (2.4 [1.4-4.2]; P = .001) and fifth (3.9 [2.3-6.8]; P < .001) SHR quintiles than in the lowest SHR quintile. CONCLUSIONS: SHR controls for background glycemia and is a better biomarker of critical illness than absolute hyperglycemia. SHR identifies patients with relative hyperglycemia at risk of critical illness. Future studies should explore whether basing glucose-lowering therapy on relative, rather than absolute, hyperglycemia improves outcomes in hospitalized patients.

Routine prescribing of gabapentin or pregabalin in supportive and palliative care: what are the comparative performances of the medications in a palliative care population?

Neuropathic pain is a prevalent and distressing problem faced by people with life-limiting illness that is often difficult to palliate. Gabapentin and pregabalin are widely prescribed as part of the routine approach to palliating neuropathic pain. Although they are often viewed as interchangeable agents, very little comparative data of their benefits and harms exists in clinical practice. Two previously reported pharmacovigilance studies that had used the same methodology for gabapentin and pregabalin were compared. These studies examined the benefits and harms of gabapentin and pregabalin after the medications had been routinely prescribed by clinicians working in a network of palliative care services using the same data collection tools with the same definitions and the same time points. Data were collected over 21 days from 282 patients prescribed either gabapentin or pregabalin for pain. Items included medication doses, pain scores, and adverse effects. In order to compare the medication responses, the final doses of pregabalin were converted to gabapentin does equivalents using previously published recommendations. The final pain scores were similar for both groups, and the reduction in pain were similar (OR = 11.2; 95 % CI 3.9, 32.7, p < 0.001). However, this was achieved at lower doses of gabapentin compared to pregabalin. Those receiving gabapentin were more likely to experience harms (OR = 3.5; 95 % CI 1.4, 9.1, p = 0.009) with the reported harms including somnolence, ataxia, nausea, tremor and nystagmus This hypothesis-generating work strongly supports the need for further trials to best delineate clinical differences in the GABA analogues.

Caregiver Expectations: Predictors of a Worse Than Expected Caregiving Experience at the End of Life.

CONTEXT: The gap between informal caregivers' expectations of caregiving at the end of life and their actual caregiving experience has important affective and behavioral consequences. OBJECTIVES: This study analyzes for the first time the characteristics of those caregivers who report a worse or much worse than expected caregiving experience, providing a potential for future targeted intervention into the caregiving experience. METHODS: The South Australian Health Omnibus is an annual, random, face-to-face, and cross-sectional survey. From 2000 to 2007, respondents were asked a range of questions about end-of-life care, including in several years a question about how the caregiving experience compared with caregivers' expectation(s). Family members and friends who reported a worse or much worse than expected caregiving experience were the focus of this analysis. Univariable and multivariable logistic regression models were created to better define this group. RESULTS: Of the 1628 active caregivers for people at the end of life, almost half (48.3%) reported a worse or much worse than expected caregiving experience. A worse or much worse than expected caregiving experience was significantly associated with gender and with level of care provided. Women who provided daily hands-on care were significantly more likely to have a worse than expected experience compared with women who provided intermittent care (odds ratio [OR] 0.65; 95% CI 0.48-0.88; P = 0.005) or rare care (OR 0.39; 95% CI 0.27-0.56; P < 0.001). Of all those providing rare care, women were significantly less likely than men to report a worse than expected caregiving experience (OR 0.61; 95% CI 0.41-0.93; P = 0.020). CONCLUSION: Caregiver expectations represent a novel and important focus for investigation into the caregiver experience. Explicitly eliciting expectations may in future lead to ways of better supporting caregivers.

Pharmacovigilance in hospice/palliative care: net effect of gabapentin for neuropathic pain.

OBJECTIVE: Hospice/palliative care patients may differ from better studied populations, and data from other populations cannot necessarily be extrapolated into hospice/palliative care clinical practice. Pharmacovigilance studies provide opportunities to understand the harms and benefits of medications in routine practice. Gabapentin, a γ-amino butyric acid analogue antiepileptic drug, is commonly prescribed for neuropathic pain in hospice/palliative care. Most of the evidence however relates to non-malignant, chronic pain syndromes (diabetic neuropathy, postherpetic neuralgia, central pain syndromes, fibromyalgia). The aim of this study was to quantify the immediate and short-term clinical benefits and harms of gabapentin in routine hospice/palliative care practice. DESIGN: Multisite, prospective, consecutive cohort. POPULATION: 127 patients, 114 of whom had cancer, who started gabapentin for neuropathic pain as part of routine clinical care. SETTINGS: 42 centres from seven countries. Data were collected at three time points-at baseline, at day 7 (and at any time; immediate and short-term harms) and at day 21 (clinical benefits). RESULTS: At day 21, the average dose of gabapentin for those still using it (n=68) was 653 mg/24 h (range 0-1800 mg) and 54 (42%) reported benefits, of whom 7 (6%) experienced complete pain resolution. Harms were reported in 39/127 (30%) patients at day 7, the most frequent of which were cognitive disturbance, somnolence, nausea and dizziness. Ten patients had their medication ceased due to harms. The presence of significant comorbidities, higher dose and increasing age increased the likelihood of harm. CONCLUSIONS: Overall, 42% of people experienced benefit at a level that resulted in continued use at 21 days.

High sensitivity-troponin elevation secondary to non-coronary diagnoses and death and recurrent myocardial infarction: An examination against criteria of causality.

BACKGROUND: Myonecrosis provoked by illness unrelated to unstable coronary plaque is common, but uncertainty about a cause-effect relationship with future events challenges the appropriateness of initiating therapies known to be effective in cardiac conditions. We examined the causal relationship between troponin elevation in non-coronary diagnoses and late cardiac events using the Bradford Hills criteria for causality. METHODS AND RESULTS: Patients presenting acutely to South Australian public hospitals receiving at least one troponin between September 2011-September 2012 were included. Diagnoses were classified as coronary, non-coronary cardiac and non-cardiac using the International Classification of Diseases, version 10 Australian Modified, codes. The relationship between peak in-hospital troponin, using a high-sensitivity troponin T assay and adjudicated cardiac and non-cardiac mortality, and subsequent myocardial infarction (MI) was assessed using competing-risk flexible parametric survival models. Troponin results were available for 38,161 patients of whom, 12,645 (33.6%), 3237 (8.5%), and 22,079 (57.9%) patients were discharged with coronary, non-coronary cardiac and non-cardiac diagnoses, respectively. Troponin >14 ng/l was observed in 43.6%. The relationship between troponin and cardiac mortality was stronger among the non-coronary diagnosis group (troponin 1000 ng/l: coronary hazard ratio: 5.1 (95% confidence interval (CI) 4.0-6.6) vs non-coronary hazard ratio: 16.3 (95% CI 12.6-22.4)). The temporal hazard for cardiac death was marked within 30 days in both groups. Among non-coronary diagnoses, the hazard for recurrent MI was higher but did not vary with time. CONCLUSIONS: Consistency with causal criteria between secondary myonecrosis and cardiac events suggest the potential benefit for extending cardiac specific interventions to this population if supported in trials appropriately designed to address competing risks. Troponin elevation precipitated by non-coronary events is common and demonstrates an associations with late mortality that are analogous to spontaneous MI resulting from unstable coronary plaque. These observations help inform the design of randomized clinical trials exploring the benefits and risk of therapies with established benefits in other cardiac conditions. Such studies will need to appropriately account for competing risks in this population of patients.

Pharmacovigilance in hospice/palliative care: net effect of haloperidol for delirium.

INTRODUCTION: Prescribing practice in hospice/palliative care is largely extrapolated from other areas of clinical practice, with few studies of net medication effects (benefits and harms) in hospice/palliative care to guide prescribing decisions. Hospice/palliative care patients differ in multiple ways from better studied participant groups, hence the applicability of studies in other participant groups is uncertain. Haloperidol, a butyrophenone derivative and dopamine antagonist, is commonly prescribed for nausea, vomiting, and delirium in hospice/palliative care. Its frequent use in delirium occurs despite little evidence of the effect of antipsychotics on the untreated course of delirium. The aim of this study was to examine the immediate and short-term clinical benefits and harms of haloperidol for delirium in hospice/palliative care patients. METHOD: A consecutive cohort of participants from 14 centers across four countries who had haloperidol commenced for delirium were recruited. Data were collected at three time points: baseline, 48 hours (clinical benefits), and day 10 (clinical harms). Investigators were also able to report clinical harms at any time up to 14 days after it was commenced. RESULTS: Of the 119 participants included, the average dose was 2.1 mg per 24 hours; 42 of 106 (35.2%) reported benefit at 48 hours. Harm was reported in 14 of 119 (12%) at 10 days, the most frequent being somnolence (n=11) and urinary retention (n=6). Seven participants had their medication ceased due to harms (2 for somnolence and 2 for rigidity). Approximately half (55/119) were still being treated with haloperidol after 10 days. CONCLUSION: Overall, 1 in 3 participants gained net clinical benefit at 10 days.

CaSR-mediated interactions between calcium and magnesium homeostasis in mice.

Calcium (Ca) and magnesium (Mg) homeostasis are interrelated and share common regulatory hormones, including parathyroid hormone (PTH) and vitamin D. However, the role of the calcium-sensing receptor (CaSR) in Mg homeostasis in vivo is not well understood. We sought to investigate the interactions between Mg and Ca homeostasis using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR) (double knockout, DKO). Serum Mg is lower in PTH KO and DKO mice than in WT mice on standard chow, whereas supplemental dietary Ca leads to equivalent Mg levels for all three genotypes. Mg loading increases serum Mg in all genotypes; however, the increase in serum Mg is most pronounced in the DKO mice. Serum Ca is increased with Mg loading in the PTH KO and DKO mice but not in the WT mice. Here, too, the hypercalcemia is much greater in the DKO mice. Serum and especially urinary phosphate are reduced during Mg loading, which is likely due to intestinal chelation of phosphate by Mg. Mg loading decreases serum PTH in WT mice and increases serum calcitonin in both WT and PTH KO mice but not DKO mice. Furthermore, Mg loading elevates serum 1,25-dihydroxyvitamin D in all genotypes, with greater effects in PTH KO and DKO mice, possibly due to reduced levels of serum phosphorus and FGF23. These hormonal responses to Mg loading and the CaSR's role in regulating renal function may help to explain changes in serum Mg and Ca found during Mg loading.

Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo.

Calcium and phosphorus homeostasis are highly interrelated and share common regulatory hormones, including FGF23. However, little is known about calcium's role in the regulation of FGF23. We sought to investigate the regulatory roles of calcium and phosphorus in FGF23 production using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR; PTH-CaSR DKO). In wild-type, PTH KO, and PTH-CaSR DKO mice, elevation of either serum calcium or phosphorus by intraperitoneal injection increased serum FGF23 levels. In PTH KO and PTH-CaSR DKO mice, however, increases in serum phosphorus by dietary manipulation were accompanied by severe hypocalcemia, which appeared to blunt stimulation of FGF23 release. Increases in dietary phosphorus in PTH-CaSR DKO mice markedly decreased serum 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] despite no change in FGF23, suggesting direct regulation of 1,25(OH)(2)D(3) synthesis by serum phosphorus. Calcium-mediated increases in serum FGF23 required a threshold level of serum phosphorus of about 5 mg/dl. Analogously, phosphorus-elicited increases in FGF23 were markedly blunted if serum calcium was less than 8 mg/dl. The best correlation between calcium and phosphorus and serum FGF23 was found between FGF23 and the calcium × phosphorus product. Since calcium stimulated FGF23 production in the PTH-CaSR DKO mice, this effect cannot be mediated by the full-length CaSR. Thus the regulation of FGF23 by both calcium and phosphorus appears to be fundamentally important in coordinating the serum levels of both mineral ions and ensuring that the calcium × phosphorus product remains within a physiological range.

Deficiency of the calcium-sensing receptor in the kidney causes parathyroid hormone-independent hypocalciuria.

Rare loss-of-function mutations in the calcium-sensing receptor (Casr) gene lead to decreased urinary calcium excretion in the context of parathyroid hormone (PTH)-dependent hypercalcemia, but the role of Casr in the kidney is unknown. Using animals expressing Cre recombinase driven by the Six2 promoter, we generated mice that appeared grossly normal but had undetectable levels of Casr mRNA and protein in the kidney. Baseline serum calcium, phosphorus, magnesium, and PTH levels were similar to control mice. When challenged with dietary calcium supplementation, however, these mice had significantly lower urinary calcium excretion than controls (urinary calcium to creatinine, 0.31±0.03 versus 0.63±0.14; P=0.001). Western blot analysis on whole-kidney lysates suggested an approximately four-fold increase in activated Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). In addition, experimental animals exhibited significant downregulation of Claudin14, a negative regulator of paracellular cation permeability in the thick ascending limb, and small but significant upregulation of Claudin16, a positive regulator of paracellular cation permeability. Taken together, these data suggest that renal Casr regulates calcium reabsorption in the thick ascending limb, independent of any change in PTH, by increasing the lumen-positive driving force for paracellular Ca(2+) transport.

A prospective study of the impact of musculoskeletal pain and radiographic osteoarthritis on health related quality of life in community dwelling older people.

BACKGROUND: Pain and radiographic changes are common in persons with osteoarthritis, but their relative contributions to quality of life are unknown. METHODS: Prospective cohort study of 1098 men and women aged 50-80 years, randomly selected from the electoral roll. Participants were interviewed at baseline and approximately 2.6 and five years later. Participants self-reported prior diagnosis of arthritis and presence of joint pain. Joint space narrowing (JSN) and osteophytes at the hip and knee were assessed by X-ray. Quality of life (QoL) was assessed using the Assessment of QoL (AQoL) instrument. Data was analysed using linear regression and mixed modelling. RESULTS: The median AQoL score at baseline was 7.0, indicating very good QoL. Prevalence of pain ranged from 38-62%. Over five years of observation, pain in the neck, shoulders, back, hips, hands, knees and feet were all independently and negatively associated with QoL, in a dose-response relationship. Diagnosed osteoarthritis at all sites was associated with poorer QoL but after adjustment for pain, this only remained significant at the back. Radiographic OA was not associated with QoL. While AQoL scores declined over five years, there was no evidence of an interaction between pain and time. CONCLUSIONS: Pain is common in older adults, is stable over time, and the strongest musculoskeletal correlate of QoL. It also mediates the association between diagnosed OA and QoL. Since the same factors were associated with quality of life over time as at baseline, this suggests that quality of life tracks over a five year period.

Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial.

OBJECTIVES: To compare the effect of a single infusion of zoledronic acid (ZA) with placebo on knee pain and bone marrow lesions (BMLs). METHODS: Adults aged 50-80 years (n=59) with clinical knee osteoarthritis and knee BMLs were randomised to receive either ZA (5 mg/100 ml) or placebo. BMLs were determined using proton density-weighted fat saturation MR images at baseline, 6 and 12 months. Pain and function were measured using a visual analogue scale (VAS) and the knee injury and osteoarthritis outcome score (KOOS) scale. RESULTS: At baseline, mean VAS score was 54 mm and mean total BML area was 468 mm(2). VAS pain scores were significantly reduced in the ZA group compared with placebo after 6 months (-14.5 mm, 95% CI -28.1 to -0.9) but not after 3 or 12 months. Changes on the KOOS scales were not significant at any time point. Reduction in total BML area was greater in the ZA group compared with placebo after 6 months (-175.7 mm(2), 95% CI -327.2 to -24.3) with a trend after 12 months (-146.5 mm(2), 95% CI -307.5 to +14.5). A greater proportion of those in the ZA group achieved a clinically significant reduction in BML size at 6 months (39% vs 18%, p=0.044). Toxicity was as expected apart from a high rate of acute phase reactions in treatment and placebo arms. CONCLUSIONS: ZA reduces knee pain and areal BML size and increases the proportion improving over 6 months. Treatment of osteoarthritis may benefit from a lesion specific therapeutic approach. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN 12609000399291.