Organic nitrates have been reported to have significant effects on bone mineral density (BMD) and bone turnover in previous clinical trials. However, results are inconsistent and some trials with strikingly positive results have been retracted because of scientific misconduct. As preparation for a potential fracture prevention study, we set out to determine the lowest effective dose and the most effective and acceptable nitrate preparation. We undertook a 1-year, double-blind, randomized, placebo-controlled trial of three different nitrate preparations and two different doses in osteopenic postmenopausal women, with a planned 1-year observational extension. The primary endpoint was change in BMD at the lumbar spine, and secondary endpoints included BMD changes at other sites, changes in bone turnover markers, and adverse events. A total of 240 eligible women who tolerated low-dose oral nitrate treatment in a 2-week run-in period were randomized to five different treatment groups or placebo. Over 12 months, there were no statistically significant between-group differences in changes in BMD at any site and no consistent differences in bone turnover markers. When the active treatment groups were pooled, there were also no differences in changes in BMD or bone turnover markers between nitrate treatment and placebo. Eighty-eight (27%) women withdrew during the run-in phase, with the majority because of nitrate-induced headache, and 41 of 200 (21%) women randomized to nitrate treatment withdrew or stopped study medication during the 1-year study compared with 1 of 40 (2.5%) in the placebo group. In summary, organic nitrates do not have clinically relevant effects on BMD or bone turnover in postmenopausal women and were poorly tolerated. These results call into question the validity of previous clinical research reporting large positive effects of nitrates on BMD and bone turnover. © 2020 American Society for Bone and Mineral Research.

BACKGROUND:Fructose consumption has been linked with insulin resistance, obesity and diabetes, which are more prevalent in those of Māori or Pacific ethnicity compared to New Zealand European.AIM:To determine whether the acute effects of fructose consumption on serum glucose, insulin, lipids and C-reactive protein differs according to body mass index (BMI) and/or ethnicity.METHODS:Participants of Māori (n = 25), Pacific (n = 26) or New Zealand European (n = 25) ethnicity consumed a 64 g fructose/16 g glucose solution. Changes in lipids, glucose, insulin and C-reactive protein were analysed using mixed models for repeated measures.RESULTS:After adjustment for age and gender, those with higher BMI had a higher glucose (P = 0.0064) and insulin (P = 0.0007) response than those with lower BMI. Those of Māori or Pacific ethnicity had similar glucose levels (P = 0.077) to those of New Zealand European ethnicity but higher insulin responses (P = 0.0005), which remained after additional adjustment for BMI (P = 0.001). Reported sugar-sweetened beverages (SSB) intake was higher among Māori and Pacific than New Zealand European (median 1.0 vs 0.0 SSB/day P = 0.002).CONCLUSION:Even after adjustment for BMI, those of Māori and Pacific ethnicity have a significantly higher insulin response to fructose than New Zealand Europeans. Higher habitual SSB intake may be a contributing factor.

The objective of the study was to determine clinical factors associated with activity limitation and predictors of a change in activity limitation after 1 year in people with gout. Two hundred ninety-five participants with gout (disease duration < 10 years) attended a baseline assessment which included medical and disease-specific history, pain visual analog score and plain radiographs scored for erosion and narrowing. Activity limitation was assessed using the Health Assessment Questionnaire-II (HAQ-II). After 1 year, participants were invited to complete a further HAQ-II; follow-up questionnaires were available for 182 participants. Fully saturated and stepwise regression analyses were used to determine associations between baseline characteristics and HAQ-II at baseline and 1 year, and to determine predictors of worsening HAQ-II in those with normal baseline scores. Median (range) baseline HAQ-II was 0.20 (0–2.50) and 0.20 (0–2.80) after 1 year of follow-up. Pain score was the strongest independent predictor of baseline HAQ-II, followed by radiographic narrowing score, type 2 diabetes, swollen joint count, BMI, age and urate (model R2 = 0.51, P < 0.001). Baseline HAQ-II was the strongest predictor of change in HAQ-II at 1 year, followed by tender joint count (model R2 = 0.19, P < 0.001). Of those with HAQ-II scores of 0 at baseline (n = 59, 32% of those with follow-up data), most did not progress (n = 52, 88%); however, baseline pain score, type 2 diabetes and flare frequency were significant predictors of worsening HAQ-II in this group (R2 = 0.34, P < 0.001). People with gout experience a wide range of activity limitation, and levels of activity limitation are, on average, stable over a 1-year period. Baseline pain scores are strongly associated with activity limitation and predict development of activity limitation in those with normal HAQ-II scores at baseline.

IMPORTANCE The minimal important difference (MID) on patient-reported outcome measures can indicate how much of a change on that scale is meaningful. OBJECTIVE To use an anchor-based approach to estimate MID in the Voice Handicap Index-10 (VHI-10) total score. DESIGN, SETTING, AND PARTICIPANTS In this cohort study, a volunteer sample of adult patients visiting the voice clinic at the University of Minnesota from April 7, 2013, through July 3, 2016, completed the VHI-10 (range, 0-40, with higher scores indicating greater voice-related handicap) at baseline and 2 weeks later in conjunction with a global rating of change. An anchor-based approach was used to identify an MID. The association between the global change score and change in VHI-10 score was analyzed using Pearson rank correlation. A distribution-based method was used to corroborate the findings. MAIN OUTCOME AND MEASURES Global rating of change on the VHI-10. RESULTS Of the 273 participants, 183 (67.0%) were women and 90 (33.0%) were men (mean [SD] age, 54.3 [15.6] years); 259 (94.9%) were white. Participants had a variety of voice disorders, most commonly muscle tension dysphonia, irritable larynx, benign vocal fold lesions, and motion abnormalities. Among patients reporting no change on the global change score, the mean (SD) change in VHI-10 score was 1 (5). Among those reporting a small change, the mean (SD) change in VHI-10 was also 1 (5). Among those reporting a moderate change in voice symptoms, the mean (SD) change in VHI-10 score was 6 (8). Among those with a large change, the mean (SD) change in VHI-10 score was 9 (13). The correlation between the global change score and the change in VHI-10 score was 0.32 (95% CI, 0.12-0.49). Distribution-based analyses identified effect sizes comparable to those of the anchor-based categories. CONCLUSIONS AND RELEVANCE These findings suggest that a difference of 6 on the VHI-10 may represent an MID. This difference was associated with a moderate change on the global rating scale, and the small-change and no-change categories were indistinguishable. Given the lack of differentiation between small and no change and the modest correlation between the global change score and change in the VHI-10 score, additional studies are needed.

ObjectiveTo examine whether illness perceptions independently predict mortality in early-onset gout. MethodsBetween December 2006 and January 2014, a total of 295 participants with early-onset gout (<10 years) were recruited in Auckland and Wellington, New Zealand. The participants were followed up until February 2015, and mortality information was collected. Participants with complete data were included in the current study (n=242). Cox proportional hazards models were used to examine the association between illness perceptions and mortality risk, after adjustment for covariates associated with disease severity and mortality in gout. ResultsIn a Cox proportional hazards model adjusted for predictors of disease severity and mortality in gout (number of tophi, serum urate level, and frequency of flares), consequence beliefs, identity beliefs, concern beliefs, and emotional response to gout were associated with all-cause mortality (hazard ratios [HRs] 1.29, 1.15, 1.18, and 1.19, respectively; P<0.05 for all). In the fully saturated model, the association between consequence beliefs and mortality remained robust after additional adjustment for ethnicity, disease duration, diuretic use, serum creatinine, and pain score (HR 1.18 [95% confidence interval 1.02-1.37]; P=0.029). ConclusionNegative beliefs about the impact of gout and severity of symptoms, as well as concerns about gout and the emotional response to gout, were independently associated with all-cause mortality. Illness perceptions are important and potentially modifiable risk factors to target in future interventions.

Background/aims Radiographic damage is frequently observed in patients with longstanding gout. The aim of this prospective observational study was to determine factors associated with change in radiographic damage scores in gout.Methods People with gout and disease duration <10 years were recruited into this prospective observational study. At the baseline visit, structured assessment was undertaken in 290 participants including detailed clinical examination and plain radiographs (XR) of the hands and feet. Participants were invited to attend a further study visit with repeat XR 3 years after the baseline visit. XR were scored for erosion and joint space narrowing according to the gout-modified Sharp/van der Heijde XR damage score.Results Age, subcutaneous tophus count and tender joint count were independently associated with XR damage score at the baseline visit. Paired serial XR were available for 140 participants. In stepwise linear regression analysis, change in total damage score over 3 years was positively associated with change in subcutaneous tophus count and baseline XR damage score, and inversely associated with baseline subcutaneous tophus count (model R-2=0.39, p<0.001). Change in subcutaneous tophus count contributed most to the change in erosion score (partial R-2 change=0.31, p<0.001), and baseline XR damage score contributed most to the change in narrowing score (partial R-2 change=0.31, p<0.001).Conclusions Development of new subcutaneous tophi and baseline radiographic damage are associated with progressive joint damage scores in people with gout. These data provide further evidence that the tophus plays a central role in bone erosion in gout.

Objective. To determine mortality rates and predictors of death at baseline in people with a recent onset of gout. Methods. People with gout disease duration < 10 years were recruited from primary and secondary care settings. Comprehensive clinical assessment was completed at baseline. Participants were prospectively followed for at least 1 year. Information about death was systematically collected from primary and secondary health records. Standardized mortality ratios (SMR) were calculated and risk factors for mortality were analyzed using Cox proportional hazard regression models. Results. The mean (SD) followup duration was 5.1 (1.6) years (a total 1511 patient-yrs accrued). Of the 295 participants, 43 (14.6%) had died at the time of censorship (SMR 1.96, 95% CI 1.44–2.62). In the reduced Cox proportional hazards model, these factors were independently associated with an increased risk of death from all causes: older age (70–80 yrs: HR 9.96, 95% CI 3.30–30.03; 80–91 yrs: HR 9.39, 95% CI 2.68–32.89), Māori or Pacific ethnicity (HR 2.48, 95% CI 1.17–5.29), loop diuretic use (HR 3.99, 95% CI 2.15–7.40), serum creatinine (per 10 µmol/l change; HR 1.04, 95% CI 1.00–1.07), and the presence of subcutaneous tophi (HR 2.85, 95% CI 1.49–5.44). The presence of subcutaneous tophi was the only baseline variable independently associated with both cardiovascular (CV) cause of death (HR 3.13, 95% CI 1.38–7.10) and non-CV cause of death (HR 3.48, 95% CI 1.25–9.63). Conclusion. People with gout disease duration < 10 years have an increased risk of death. The presence of subcutaneous tophi at baseline is an independent predictor of mortality, from both CV and non-CV causes.

Both sugar-sweetened beverage (SSB) intake and body mass index (BMI) are associated with elevated serum urate concentrations and gout risk. The aim of this study was to determine whether the associations of SSB intake with serum urate and gout are moderated by BMI.

BACKGROUND:The aim of this study was to compare the frequency and volume of dual energy CT (DECT) urate deposits in people with asymptomatic hyperuricaemia and symptomatic gout. METHODS:We analysed DECT scans of the feet from asymptomatic individuals with serum urate ≥540 µmol/L (n=25) and those with crystal proven gout without clinically apparent tophi (n=33). RESULTS:DECT urate deposits were observed in 6/25 (24%) participants with asymptomatic hyperuricaemia, 11/14 (79%) with early gout (predefined as disease duration ≤3 years) and 16/19 (84%) with late gout (p<0.001). DECT urate deposition was observed in both joints and tendons in the asymptomatic hyperuricaemia group, but significantly less frequently than in those with gout (p≤0.001 for both joint and tendon sites). The volume of urate deposition was also significantly lower in those with asymptomatic hyperuricaemia, compared with the early and the late gout groups (p<0.01 for both comparisons). Similar urate volumes were observed in the early and late gout groups. CONCLUSIONS:Although subclinical urate deposition can occur in people with asymptomatic hyperuricaemia, these deposits occur more frequently and at higher volumes in those with symptomatic gout. These data suggest that a threshold of urate crystal volume may be required before symptomatic disease occurs.

Objectives MicroRNAs (miRNA) are small non-coding RNAs that function as post-transcriptional repressors of gene expression. We hypothesised that miRNA regulate gene expression of proinflammatory cytokines in response to monosodium urate (MSU) crystals. Methods We stimulated human monocytic THP-1 cells with MSU crystals and examined miRNA and proinflammatory cytokine gene expression. The effects of miR-146a overexpression were examined by transfecting THP-1 cells with miR-146a precursor. miR-146a expression was examined in the urate peritonitis model, in peripheral blood mononuclear cells from people with gout and control participants, and in gouty tophus samples. Results MSU crystals increased miR-146a expression in THP-1 cells, but not other miRNA implicated in interleukin (IL)-1β regulation. Overexpression of miR-146a expression reduced MSU crystal-induced IL-1β, tumour necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and IL-8 gene expression. In the urate peritonitis model, reduced miR-146a expression was observed during the acute inflammatory response to MSU crystal injection. In people with intercritical gout, peripheral blood mononuclear cells expressed significantly higher levels of miR-146a, compared with normouricaemic and hyperuricaemic control participants and those with acute gout flares. Expression of miR-146a was also observed in all tophus samples. Conclusions Collectively, these data suggest that miR-146a is a transcriptional brake that is lost during the acute inflammatory response to MSU crystals.

Both genetic variation in ATP-binding cassette sub-family G member 2 (ABCG2) and intake of fructose-containing beverages are major risk factors for hyperuricemia and gout. This study aimed to test the hypothesis that the ABCG2 gout risk allele 141 K promotes the hyperuricaemic response to fructose loading.

BackgroundTophus burden is currently measured using physical examination and imaging methods. The aim of this study was to develop a patient-reported outcome (PRO) tool to assess tophus burden in people with gout.MethodsThe responses from interviews with 25 people with tophaceous gout were used to generate items for a preliminary PRO tool. Following cognitive testing of each item, a preliminary 34-item questionnaire was administered to 103 people with tophaceous gout. Rasch analysis generated a 20-item Tophus Impact Questionnaire (TIQ-20). Test-retest reproducibility and construct validity of the TIQ-20 were assessed.ResultsThe TIQ-20 responses fit the Rasch model and demonstrated unidimensionality, adequate precision, absence of differential item functioning and adequate person separation index. The TIQ-20 included items related to pain, activity limitation, footwear modification, participation, psychological impact and healthcare use due to tophi. In the 103 patients with tophaceous gout, floor effects were observed in 4.9% and ceiling effects in 1%. The TIQ-20 test-retest intraclass correlation coefficient was 0.76 (95% CI 0.61 to 0.85). All predicted correlations for construct validity testing were observed, including weak correlation with serum urate concentrations (r<0.30), moderate correlation with subcutaneous tophus count and dual energy CT urate volume (r=0.30–0.50), and stronger correlation with Health Assessment Questionnaire scores (r>0.50).ConclusionsWe have developed a tophus-specific PRO in patients with tophaceous gout. The TIQ-20 demonstrates acceptable psychometric properties. Initial results show internal, face and construct validity, reproducibility and feasibility. Further research is required to determine responsiveness to change.

OBJECTIVES:The osteoclast has been implicated in development of bone erosion in gout. The aim of this study was to determine whether zoledronate, a potent antiosteoclast drug, influences bone erosion in people with tophaceous gout. METHODS:This was a 2-year, randomised, double-blind, placebo-controlled trial of 100 people with tophaceous gout. Participants were randomised to annual administration of 5 mg intravenous zoledronate or placebo. The primary endpoint was change in the foot CT bone erosion score from baseline. Secondary endpoint was change in plain radiographic damage scores. Other endpoints were change in bone mineral density (BMD), bone turnover markers and the OMERACT-endorsed core domains for chronic gout studies. RESULTS:There was no change in CT erosion scores over 2 years, and no difference between the two treatment groups at Year 1 or 2 (p(treat)=0.10, p(time)=0.47, p(treat*time)=0.23). Similarly, there was no change in plain radiographic scores over 2 years, and no difference between the two groups at Year 1 or 2. By contrast, zoledronate increased spine, neck of femur, total hip and total body BMD. Zoledronate therapy also reduced the bone turnover markers P1NP and β-CTX compared with placebo. There was no difference between treatment groups in OMERACT-endorsed core domains. CONCLUSIONS:Despite improvements in BMD and suppression of bone turnover markers, antiosteoclast therapy with zoledronate did not influence bone erosion in people with tophaceous gout. These findings suggest a disconnect between responses in the healthy skeleton and at sites of focal bone erosion in tophaceous gout.

Background Complementary and alternative medicine (CAM) is frequently used by patients with arthritis. Objectives The objectives of this study were to determine the frequency and type of CAM used for gout, to understand the clinical and psychological factors associated with CAM use in people with gout, and to determine whether patients using CAM have different clinical outcomes over 1 year. Methods A total of 276 patients with gout for less than 10 years’ duration were recruited into a longitudinal observational study. Complementary and alternative medicine information including frequency, type, and cost of therapies were recorded at baseline. Gout disease activity (including flare frequency, tophus count, Health Assessment Questionnaire II, and serum urate) was assessed at baseline and after 1 year. Results Complementary and alternative medicine use was reported by 23.9% of patients. A diverse range of CAM was used, most commonly dietary supplements and vitamins. Patients using CAM reported higher levels of concern about their gout but did not differ from those not taking CAM with respect to age, sex, years of formal education, ethnicity, illness perceptions, or gout disease activity measures at baseline or after 1 year. Total costs at baseline related to gout therapy were higher in the CAM users compared with those not using CAM (mean [SD] cost per month NZ $35.7 [NZ $69.0] vs NZ $7.1 [NZ $22.8]; P = 0.001). Conclusions Complementary and alternative medicine use is not uncommon in patients with gout, albeit less than is reported in other rheumatic diseases. Inquiry about CAM use should be incorporated into the clinical assessment of patients with gout, to develop treatment plans that best suit the individual patient’s health beliefs.

Ca supplements are used for bone health; however, they have been associated with increased cardiovascular risk, which may relate to their acute effects on serum Ca concentrations. Microcrystalline hydroxyapatite (MCH) could affect serum Ca concentrations less than conventional Ca supplements, but its effects on bone turnover are unclear. In the present study, we compared the acute and 3-month effects of MCH with conventional Ca supplements on concentrations of serum Ca, phosphate, parathyroid hormone and bone turnover markers. We randomised 100 women (mean age 71 years) to 1 g/d of Ca as citrate or carbonate (citrate-carbonate), one of two MCH preparations, or a placebo. Blood was sampled for 8 h after the first dose, and after 3 months of daily supplementation. To determine whether the acute effects changed over time, eight participants assigned to the citrate dose repeated 8 h of blood sampling at 3 months. There were no differences between the citrate and carbonate groups, or between the two MCH groups, so their results were pooled. The citrate-carbonate dose increased ionised and total Ca concentrations for up to 8 h, and this was not diminished after 3 months. MCH increased ionised Ca concentrations less than the citrate-carbonate dose; however, it raised the concentrations of phosphate and the Ca-phosphate product. The citrate-carbonate and MCH doses produced comparable decreases in bone resorption (measured as serum C-telopeptide (CTX)) over 8 h and bone turnover (CTX and procollagen type-I N-terminal propeptide) at 3 months. These findings suggest that Ca preparations, in general, produce repeated sustained increases in serum Ca concentrations after ingestion of each dose and that Ca supplements with smaller effects on serum Ca concentrations may have equivalent efficacy in suppressing bone turnover.

BACKGROUND:Although typically a late feature of gout, tophi may present early in the course of disease. The aim of this study was to identify factors associated with the presence of early tophaceous disease.METHODS:People with gout for <10 years were prospectively recruited, and had a comprehensive clinical assessment including examination for subcutaneous tophi. The clinical factors independently associated with the presence and number of tophi were analyzed using regression models.RESULTS:Of the 290 participants, there were 47 (16.2%) with clinically apparent tophi. In univariate analysis, those with tophi were older, were more frequently taking diuretics and colchicine prophylaxis, and had lower creatinine clearance. The association between the presence of tophi and creatinine clearance was strongest in those with creatinine clearance ≤30 ml/min. In logistic regression analysis, creatinine clearance ≤30 ml/min was associated with the presence of tophi, even after adjusting for ethnicity, corticosteroid use, colchicine use and diuretic use (multivariate adjusted odds ratio 7.0, p = 0.005). Participants with tophi reported higher frequency of gout flares, pain scores, patient global assessment scores, and HAQ scores.CONCLUSIONS:The presence of tophi is associated with more symptomatic disease in people with gout for <10 years. Creatinine clearance is independently associated with early presentation of subcutaneous tophi.