Predicting Gout Flares in People Starting Allopurinol Using the Start-Low Go-Slow Dose Escalation Strategy.

OBJECTIVE: The study objective was to determine predictors of gout flare when commencing allopurinol using the "start-low go-slow" dose escalation strategy. METHODS: A post hoc analysis of a 12-month double-blind placebo-controlled noninferiority trial with participants randomized 1:1 to colchicine 0.5 mg daily or placebo for the first six months was undertaken. Multivariate logistic regression models were used to identify independent predictors of gout flares in the first and last six months of the trial. RESULTS: Multivariable analysis revealed a significant association between risk of a gout flare in the first six months and flare in the month before starting allopurinol (odds ratio [OR] 2.65, 95% confidence interval [CI] 1.36-5.17) and allopurinol 100 mg starting dose (OR 3.21, 95% CI 1.41-7.27). The predictors of any gout flares in the last six months of the trial, after stopping colchicine or placebo, were having received colchicine (OR 2.95, 95% CI 1.48-5.86), at least one flare in the month before stopping study drug (OR 5.39, 95% CI 2.21-13.15), and serum urate ≥0.36 mmol/L at month 6 (OR 2.85, 95% CI 1.14-7.12). CONCLUSION: Anti-inflammatory prophylaxis when starting allopurinol using the "start-low go-slow" dose escalation strategy may be best targeted at those who have had a gout flare in the month before starting allopurinol and are commencing allopurinol 100 mg daily. For those with ongoing gout flares during the first six months of starting allopurinol who have not yet achieved serum urate target, a longer period of prophylaxis may be required.

Duration of fracture prevention after zoledronate treatment in women with osteopenia: observational follow-up of a 6-year randomised controlled trial to 10 years.

BACKGROUND: We previously identified that zoledronate administered at 18-month intervals reduced fragility fractures by a third in a 6-year trial of women older than 65 years with osteopenia. This extension aims to identify the persistence of these effects. METHODS: Of the 2000 ambulant, community dwelling, postmenopausal women older than 65 years recruited in Auckland, New Zealand, with T-scores at the total hip or femoral neck in the range -1·0 to -2·5, we invited participants who received four doses of intravenous zoledronate, completed follow-up to year 6 of the core trial, did not have metabolic bone disease (other than osteoporosis), and were not using bone-active drugs into this 4-year observational study extension, during which further treatment was at the discretion of their own doctors. Participants were asked to notify study staff of any new fractures and were telephoned at 7·5 years and 9·0 years to update their health status. Participants were then invited to an onsite visit at 10·0 years. Fractures and other health events were documented at each contact and analysed in all women who entered the extension, and bone mineral density (BMD; analysed in participants without notable use of bone-active medications who attended an onsite visit at 10 years) and turnover markers (measured from fasting morning blood in a random subset of 50 participants) were measured at year 10. FINDINGS: Of the 1000 women randomly assigned to receive zoledronate in the core trial, 796 participants were eligible for the extension, of whom 762 (96%) entered the extension between Sept 24, 2015, and Dec 13, 2017. Mean follow-up duration was 4·24 years (SD 0·57, range 0·61-6·55; final follow-up on May 25, 2022). 727 (91%) of participants were assessed at 10 years. 25 women died during the extension, six withdrew for medical reasons, and four were lost to follow-up. 92 women suffered 114 non-vertebral fractures during the extension. Non-vertebral fracture rates increased from a nadir of 15 fractures per 1000 woman-years (95% CI 10-21) in the last 2 years of the core trial to 24 fractures (17-33) in years 6-8 and 42 fractures (32-53) in years 8-10, similar to that in the placebo group in the last 2 years of the core trial. Total hip BMD (relative risk per 0·1 g/cm2 0·73, 95% CI 0·57-0·93; p=0·011) and a previous history of non-vertebral fracture (1·74, 1·12-2·69; p=0·013) at year 6 predicted incident fractures but change in total hip BMD did not. Total hip BMD decreased from 4·2% above study baseline to 0·8% above baseline (p<0·0001) during the extension. Turnover markers were not useful for predicting BMD loss in individuals. Osteonecrosis of the jaw or atypical femoral fractures did not occur in any participants. INTERPRETATION: The reduced fracture rates following zoledronate in the core trial were substantially maintained for 1·5-3·5 years after the last zoledronate infusion, but not thereafter. FUNDING: Health Research Council of New Zealand.

Is colchicine prophylaxis required with start-low go-slow allopurinol dose escalation in gout? A non-inferiority randomised double-blind placebo-controlled trial.

OBJECTIVES: To determine whether placebo is non-inferior to low-dose colchicine for reducing gout flares during the first 6 months of allopurinol using the 'start-low go-slow' dose approach. METHODS: A 12-month double-blind, placebo-controlled non-inferiority trial was undertaken. Adults with at least one gout flare in the preceding 6 months, fulfilling the American College of Rheumatology (ACR) recommendations for starting urate-lowering therapy and serum urate ≥0.36 mmol/L were recruited. Participants were randomised 1:1 to colchicine 0.5 mg daily or placebo for the first 6 months. All participants commenced allopurinol, increasing monthly to achieve target urate <0.36 mmol/L. The primary efficacy outcome was the mean number of gout flares/month between 0 and 6 months, with a prespecified non-inferiority margin of 0.12 gout flares/month. The primary safety outcome was adverse events over the first 6 months. RESULTS: Two hundred participants were randomised. The mean (95% CI) number of gout flares/month between baseline and month 6 was 0.61 (0.47 to 0.74) in the placebo group compared with 0.35 (0.22 to 0.49) in the colchicine group, mean difference 0.25 (0.07 to 0.44), non-inferiority p=0.92. There was no difference in the mean number of gout flares/month between randomised groups over the 12-month period (p=0.68). There were 11 serious adverse events in 7 participants receiving colchicine and 3 in 2 receiving placebo. CONCLUSIONS: Placebo is not non-inferior to colchicine in prevention of gout flares in the first 6 months of starting allopurinol using the 'start-low go-slow' strategy. After stopping colchicine, gout flares rise with no difference in the mean number of gout flares/month between groups over a 12-month period. TRIAL REGISTRATION NUMBER: ACTRN 12618001179224.

No Effect of NSAID Use on Efficacy of Zoledronate: A Post Hoc Analysis of a Randomized Trial in Osteopenic Older Women.

Bisphosphonates are widely used for the prevention and treatment of osteoporosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are also widely used among the older population group at high risk of fractures. NSAIDs have been shown to impact on bone turnover, and a recent reanalysis of a clinical trial of clodronate found that NSAID use at baseline abrogated any effect of clodronate on either bone density (BMD) or fracture risk. To determine whether NSAIDs influence the efficacy of other bisphosphonates, we have reanalyzed our 6-year randomized controlled trial of zoledronate in 2000 osteopenic postmenopausal women. NSAID use was reported at baseline in 38% of the cohort and anytime use was reported by 65%. The evolution of the zoledronate effects on BMD were almost identical whether or not women were using NSAIDs at baseline and were significant in both subgroups at all BMD sites (p < 0.0001). The significant reduction in the risk of fracture in those allocated to zoledronate (p < 0.0001) showed no interaction with baseline use of NSAIDs (p = 0.33) nor with NSAID use at any time during the study (p = 0.28). The odds of fracture were significantly reduced in both NSAID users and nonusers. We conclude that the present analysis provides no support for the suggestion that NSAIDs interfere with the efficacy of potent bisphosphonates in terms of their effects on bone density or fracture. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Impact of Television Depictions of Gout on Perceptions of Illness: A Randomized Controlled Trial.

OBJECTIVE: Gout is a chronic disease that can be effectively managed with long-term urate-lowering therapy. However, it is frequently portrayed on screen as an acute disease caused by a poor diet that should be managed with lifestyle changes. This study was undertaken to investigate the impact of a fictional television depiction of gout on perceptions of the disease and its management. METHODS: In a randomized controlled single-blind study, 200 members of the public watched either a 19-minute commercial television comedy episode that depicted gout as an acute disease caused by poor diet and managed with lifestyle changes, or a control episode from the same television series that did not mention gout or other diseases. Participants completed a survey regarding their perceptions of gout, its likely causes, and management strategies. RESULTS: Participants randomized to watch the gout-related episode believed gout had greater consequences (mean score of 7.1 versus 6.2 on an 11-point Likert scale; P < 0.001) and were more likely to rank the most important cause as poor eating habits compared to the control group (70% versus 38%; P < 0.001). They were also less likely to believe it is caused by genetic factors or chance. Participants watching the gout-related episode believed a change in diet would be a more effective management strategy (9.0 versus 8.4; P = 0.004) and long-term medication use would be less effective (6.9 versus 7.6; P = 0.007) compared to participants in the control group. CONCLUSION: Television depictions of gout can perpetuate inaccurate beliefs regarding causes of the disease and underemphasize effective medical strategies required in chronic disease management.

Zoledronate Reduces Height Loss Independently of Vertebral Fracture Occurrence in a Randomized Trial in Osteopenic Older Women.

Vertebral fractures are associated with height loss, reduced quality of life, and increased mortality and are an important endpoint for osteoporosis trials. However, height loss is associated with quality of life and mortality independent of associations with fracture. We have used data from a recent 6-year trial of zoledronate in 2000 osteopenic women aged >65 years to assess the impact of the semiquantitative and quantitative components of the definition of vertebral fracture on the outcome of that trial, to determine what factors impacted on height loss and to test whether height loss can be used as a surrogate for vertebral fracture incidence. In the trial protocol, an incident vertebral fracture was defined as a change in Genant grade plus both a 20% and 4 mm decrease in a vertebral height. The addition of the quantitative criteria reduced the number of fractures detected but did not change the size of the anti-fracture effect (odds ratios of 0.49 versus 0.45) nor the width of the confidence intervals for the odds ratios. Multivariate analysis of baseline predictors of height change showed that age accelerated height loss (p < 0.0001) and zoledronate reduced it (p = 0.0001). Incident vertebral fracture increased height loss (p = 0.0005) but accounted for only 0.7% of the variance in height change, so fracture could not be reliably inferred from height loss. In women without incident vertebral fractures, height loss was still reduced by zoledronate (height change: zoledronate, -1.23; placebo -1.51 mm/yr, p < 0.0001). This likely indicates that zoledronate prevents a subtle but widespread loss of vertebral body heights not detected by vertebral morphometry. Because height loss is associated with quality of life and mortality independent of associations with fracture, it is possible that zoledronate impacts on these endpoints via its effects on vertebral body integrity. © 2022 American Society for Bone and Mineral Research (ASBMR).

Effects of elevated serum urate on cardiometabolic and kidney function markers in a randomised clinical trial of inosine supplementation.

In observational studies, serum urate positively associates with cardiometabolic and kidney diseases. We analyzed data from a randomised placebo-controlled trial to determine whether moderate hyperuricemia induced by inosine affects cardiometabolic and kidney function markers. One hundred and twenty post-menopausal women were recruited into a 6-month randomised, double-blind, placebo-controlled trial of inosine for bone health. Change from baseline in the following pre-specified endpoints was analyzed: body mass index; blood pressure; lipid profile; C-reactive protein; fasting glucose; insulin; HbA1c; serum creatinine; and estimated glomerular filtration rate (eGFR). Despite increases in serum urate levels (+ 0.17 mmol/L at week 6, P < 0.0001), no significant between-group differences were observed in cardiometabolic markers, with the exception of lower fasting glucose concentrations with inosine at week 19. In the inosine group, change in serum urate correlated with change in serum creatinine (r = 0.41, P = 0.0012). However, there was no between-group difference in serum creatinine values. Over the entire study period, there was no significant difference in eGFR (ANCOVA P = 0.13). Reduction in eGFR was greater in the inosine group at Week 13 (mean difference - 4.6 mL/min/1.73 m2, false detection rate P = 0.025), with no between-group difference in eGFR at other time points. These data indicate that increased serum urate does not negatively influence body mass index, blood pressure, lipid profile, or glycaemic control. Serum urate changes associated with inosine intake correlate with changes in serum creatinine, but this does not lead to clinically important reduction in kidney function over 6 months.Clinical trial registration number: Australia and New Zealand Clinical Trials Registry (ACTRN12617000940370), registered 30/06/2017.

Bone Mineral Density and Bone Turnover 10 Years After a Single 5 mg Dose or Two 5-Yearly Lower Doses of Zoledronate in Osteopenic Older Women: An Open-Label Extension of a Randomized Controlled Trial.

Intravenous zoledronate reduces fracture risk (5 mg at 18-month intervals) and prevents bone loss (doses of 1 to 5 mg for 3 to >5 years), but the duration of action of a single 5 mg dose and the effects of lower doses beyond 5 years are unknown. We report the second open-label extension (years 5 to 10) of a 2-year randomized, multidose, placebo-controlled, double-blinded trial. A total of 116 older women who completed 5 years of participation either continued observation without further treatment (zoledronate 5 mg and placebo at baseline) or received repeat doses of 1 or 2.5 mg zoledronate (zoledronate 1 mg and zoledronate 2.5 mg at baseline, respectively). Outcomes were spine, hip, and total body bone mineral density (BMD) and serum markers of bone turnover. After a single 5 mg dose of zoledronate, mean BMD at the lumbar spine and total hip was maintained at or above baseline levels for 9 and 10 years, respectively. The mean level of the bone resorption marker ß-C-terminal telopeptide of type I collagen (ß-CTX) was at least 25% lower than that in the placebo group for 9 years. In women administered 5-yearly doses of 2.5 mg zoledronate, mean BMD at the total hip and lumbar spine was maintained at or above baseline levels for 9 and 10 years, respectively. Redosing with 1 or 2.5 mg zoledronate at 5 years reduced bone turnover markers for 3 to 4 years. BMD increased for 3 to 4 years after redosing with 1 mg zoledronate. In the group given 5-yearly 2.5 mg zoledronate, ß-CTX was at least 20% lower than that in the placebo group for 10 years. Both a single baseline 5 mg dose of zoledronate and 5-yearly doses of 1 and 2.5 mg zoledronate prevented bone loss at hip and spine for 8 to 10 years in older postmenopausal women. Clinical trials to evaluate the effects on fracture risk of these very infrequent and lower doses of zoledronate are justified. © 2021 American Society for Bone and Mineral Research (ASBMR).

Which Attributes Are Most and Least Important to Patients When Considering Gout Flare Burden Over Time? A Best-worst Scaling Choice Study.

OBJECTIVE: Several factors contribute to the patient experience of gout flares, including pain intensity, duration, frequency, and disability. It is unknown which of these factors are most important to patients when considering flare burden over time, including those related to the cumulative experience of all flares, or the experience of a single worst flare. This study aimed to determine which flare attributes are the most and least important to the patient experience of flare burden over time. METHODS: Participants with gout completed an anonymous online survey. Questions were aimed at identifying which attributes of gout flares, representing both individual and cumulative flare burden, were the most and least important over a hypothetical 6-month period. A best-worst scaling method was used to determine the importance hierarchy of the included attributes. RESULTS: Fifty participants were included. Difficulty doing usual activities during the worst flare and pain of the worst flare were ranked as the most important, whereas average pain of all flares was considered the least important. Overall, attributes related to the single worst gout flare were considered more important than attributes related to the cumulative impact of all flares. CONCLUSION: When thinking about the burden of gout flares over time, patients rank activity limitation and pain experienced during their worst gout flare as the most important contributing factors, whereas factors related to the cumulative impact of all flares over time are relatively less important.

Intensive Serum Urate Lowering With Oral Urate-Lowering Therapy for Erosive Gout: A Randomized Double-Blind Controlled Trial.

OBJECTIVE: To determine whether a therapeutic approach of intensive serum urate lowering results in improved bone erosion scores in patients with erosive gout. METHODS: We undertook a 2-year, double-blind randomized controlled trial of 104 participants with erosive gout who were receiving serum urate-lowering therapy orally and who had serum urate levels of ≥0.30 mmoles/liter at baseline. Participants were randomly assigned to either an intensive serum urate target of <0.20 mmoles/liter or a standard target of <0.30 mmoles/liter (considered the standard according to rheumatology guidelines). Oral serum urate-lowering therapy was titrated to target using a standardized protocol (with the maximum approved doses of allopurinol, probenecid, febuxostat, and benzbromarone). The primary end point was the total computed tomography (CT) bone erosion score. Outcome Measures in Rheumatology (OMERACT) gout core outcome domains were secondary end points. RESULTS: Although the serum urate levels were significantly lower in the intensive target group compared to the standard target group over the study period (P = 0.002), fewer participants in the intensive target group achieved the randomized serum urate target level by year 2 (62% versus 83% of patients in the standard target group; P < 0.05). The intensive target group required higher doses of allopurinol (mean ± SD 746 ± 210 mg/day versus 497 ± 186 mg/day; P < 0.001) and received more combination therapy (P = 0.0004) compared to the standard target group. We observed small increases in CT bone erosion scores in both serum urate target groups over 2 years, with no between-group difference (P = 0.20). OMERACT core outcome domains (gout flares, tophi, pain, patient's global assessment of disease activity, health-related quality of life, and activity limitation) improved in both groups over 2 years, with no between-group differences. Adverse event and serious adverse event rates were similar between the groups. CONCLUSION: Compared to a serum urate target of <0.30 mmoles/liter, more intensive serum urate lowering is difficult to achieve with an oral urate-lowering therapy. Intensive serum urate lowering leads to a high medication burden and does not improve bone erosion scores in patients with erosive gout.

Global patterns of treat-to-serum urate target care for gout: Systematic review and meta-analysis.

BACKGROUND: International rheumatology guidelines advocate a treat to serum urate target (T2T) approach for gout management. While individual studies have reported regional and national-level gout management, global patterns in gout care have not been synthesized. This study aimed to systematically review and meta-analyze global T2T care for patients with gout. METHODS: Electronic databases were searched for studies reporting medication and serum urate testing in patients with gout. Meta-analyses were conducted to determine the pooled proportion of patients with gout achieving pre-specified T2T indicators. RESULTS: Sixty-seven papers were included from North America (n = 31 studies), Europe (n = 22), Oceania (n = 7), Asia (n = 6), and reporting data from multiple continents (n = 1). The global pooled percentages (95% confidence interval (CI)) of patients with gout achieving T2T indicators were: 52% (45%, 59%) on urate lowering therapy (ULT), 50% (40%, 61%) on ULT receiving regular uninterrupted ULT, 53% (40%, 65%) on ULT having any serum urate testing, and 34% (28%, 41%) on ULT achieving a serum urate target. CONCLUSION: Outside North America and Europe, there are relatively few studies about T2T care for gout management. However, available data demonstrate that a minority of people with gout receive T2T care worldwide. For those prescribed ULT, there are low rates of continuous therapy, serum urate testing, and achievement of serum urate target.

Effect of Zoledronate on Lower Respiratory Infections in Older Women: Secondary Analysis of a Randomized Controlled Trial.

A recent observational study of the incidence of pneumonia in patients with previous hip fractures found that bisphosphonate use reduced pneumonia risk by about one-quarter, in comparisons with those either not receiving osteoporosis treatment or receiving treatment with non-bisphosphonate drugs. Mortality from pneumonia was similarly reduced. It was hypothesized that effects of these drugs on immune or inflammatory function might mediate this effect. We have used the adverse event database from our recent 6-year randomized controlled trial of zoledronate in 2000 women over the age of 65 years, to determine whether a similar effect is observed using this more rigorous study design. Seventy-five women had at least one episode of pneumonia (32 [3.2%] zoledronate, 43 [4.3%] placebo) and 119 women had at least one episode of either pneumonia or a lower respiratory tract infection (57 [5.7%] zoledronate, 62 [6.2%] placebo). There were 93 pneumonia events and 167 pneumonia/lower respiratory infection events. For pneumonia, the hazard ratio associated with randomization to zoledronate was 0.73 (95% confidence interval, 0.46-1.16; P = 0.18) and the rate ratio was 0.69 (0.45, 1.04; P = 0.073). For the composite endpoint of pneumonia or lower respiratory infection, the hazard ratio was 0.90 (0.61, 1.30; P = 0.58) and the rate ratio 0.74 (0.54, 0.997; P = 0.048). The proportion of people with events changed approximately linearly over time in both groups, suggesting a progressive divergence in cumulative incidence during the study. In conclusion, these findings lend support to the hypothesis that bisphosphonate use reduces the number of lower respiratory tract infections in older women, though the present study is under-powered for this endpoint and the findings are of borderline statistical significance. Further analysis of other trials of bisphosphonates is necessary to test this possibility further, and exploration of the possible underlying mechanisms is needed.

Elevated Urate Levels Do Not Alter Bone Turnover Markers: Randomized Controlled Trial of Inosine Supplementation in Postmenopausal Women.

OBJECTIVE: Observational studies have consistently demonstrated that serum urate level positively correlates with bone mineral density (BMD). We undertook this study to determine whether moderate hyperuricemia induced by inosine supplements influences bone turnover markers in postmenopausal women over a 6-month period. METHODS: One hundred twenty postmenopausal women were recruited for a 6-month randomized, double-blind, placebo-controlled trial. Key exclusion criteria were osteoporosis, previous fragility fracture, bisphosphonate therapy, gout, kidney stones, and a urine pH level of ≤5.0. Participants were randomized in a 1:1 ratio to receive placebo or inosine. The coprimary end points were change in levels of N-propeptide of type I procollagen (PINP) and change in levels of ß-C-telopeptide of type I collagen (ß-CTX). Change in BMD, as measured by dual x-ray absorptiometry, was an exploratory end point. RESULTS: Administration of inosine led to a significant increase in serum urate concentration over the study period (P < 0.0001 for all follow-up time points). At week 26, the mean change in serum urate concentration was +0.13 mmoles/liter (+2.2 mg/dl) in the inosine group and 0.00 mmoles/liter (0 mg/dl) in the placebo group. There was no difference in PINP or ß-CTX levels between groups over the 6 months. There were no significant changes in bone density between groups over the 6 months. Adverse events and serious adverse events were similar between the 2 groups. CONCLUSION: This clinical trial shows that although inosine supplementation leads to sustained increases in serum urate levels over a 6-month period, it does not alter markers of bone turnover in postmenopausal women. These findings do not support the concept that urate has direct biologic effects on bone turnover.

Predictors of Fracture in Older Women With Osteopenic Hip Bone Mineral Density Treated With Zoledronate.

A recent analysis has found that during treatment with denosumab, women attaining higher bone densities (BMD) are less likely to have incident fractures. We have reexamined this important question using data from our recent trial of zoledronate in osteopenic women. One thousand women randomized to treatment with zoledronate were followed for 6 years. Of those, 122 sustained fragility fractures during follow-up. Baseline age, nonvertebral fracture history, total hip BMD, and calculated fracture risk were all significantly different between those who had fractures during the study and those who did not. BMDs achieved during the study were higher in those without incident fractures. However, achieved BMDs were very closely related to baseline values (r = 0.93, p < 0.0001). The increase in BMD during zoledronate treatment was not different between those who had incident fractures and those who did not (0.15 < p < 0.78), and change in BMD was not predictive of fracture (univariate logistic regression analysis). Stepwise regression analysis of all baseline variables showed the best independent predictors of fracture to be age (odds ratio [OR] = 1.08, 95% confidence interval [CI] 1.04-1.13, p = 0.0003), baseline spine BMD (OR = 0.81, 95% CI 0.67-0.96, p = 0.016), and history of nonvertebral fracture (OR = 1.69, 95% CI 1.06-2.69, p = 0.028). Addition of change in BMD to this model did not improve its predictive power. If changes in BMD were included in the stepwise regression analysis of baseline variables, they did not emerge as significant predictors of fracture. It is concluded that age, fracture history, and baseline BMD determine the risk of new fractures. Differences in achieved BMD between those who do or do not fracture arise from the close relationship between baseline and achieved BMDs. These findings suggest that targeting any particular BMD during treatment is unlikely to be a useful or valid strategy. © 2020 American Society for Bone and Mineral Research (ASBMR).

Ten Years of Very Infrequent Zoledronate Therapy in Older Women: An Open-Label Extension of a Randomized Trial.

CONTEXT: Intravenous zoledronate prevents bone loss and reduces fracture risk in older adults but the optimal dosing strategy required to achieve each outcome is not known. OBJECTIVE: To assess the effect of very infrequent zoledronate therapy on bone mineral density (BMD) and markers of bone turnover. DESIGN AND PARTICIPANTS: An average of 5.5 years after randomization to either a single dose of 5 mg of zoledronateor placebo, 33 of the original cohort of 50 older women with osteopenia entered a 5-year open-label extension study. SETTING: Academic research center. INTERVENTION: A 5-mg dose of intravenous zoledronate was administered to all participants. MAIN OUTCOME MEASURES: BMD and bone turnover were measured annually, generating data over almost 11 years in women who received 5 mg of zoledronate at 0 and 5.5 years (ZZ, n = 16), or placebo at baseline and 5 mg of zoledronate at 5.5 years (PZ, n = 17). RESULTS: After redosing, BMD in ZZ remained stable, while BMD in PZ increased. At 11 years, changes from baseline BMD in ZZ and PZ were 3.8% (95% confidence interval (CI) 1.1,6.5) and 2.9% (0.3,5.5) at the lumbar spine (P = .61), 0.9% (-1.7,3.5) and -2.8% (-5.3,-0.3) at the total hip (P = .006), and 0.4% (-0.8,1.6) and -0.4% (-1.3,0.5) at the total body (P = .14). Bone turnover markers were similar in the PZ and ZZ groups throughout the 5 years after redosing. CONCLUSIONS: These results suggest that zoledronate 5 mg administered at a 5.5-year interval prevents bone loss over almost 11 years. Clinical trials to investigate whether very infrequent treatment with zoledronate reduces fracture risk are justified.

Zoledronate Slows Weight Loss and Maintains Fat Mass in Osteopenic Older Women: Secondary Analysis of a Randomized Controlled Trial.

Studies in mice have suggested that osteocalcin plays an important role in glucose and fat metabolism. Since anti-resorptive drugs reduce circulating levels of osteocalcin they might be associated with increased fat mass and an increased risk of diabetes. Positive changes in body weight have been found in trials of alendronate and denosumab, but no significant effect in a previous trial of zoledronate. Whether those weight differences were in fat or lean mass is unknown. There were no effects of anti-resorptive treatments on fasting glucose concentrations or incidence of diabetes in those three studies. We have used our recent trial comparing zoledronate and placebo over 6 years in 2000 older osteopenic women to re-examine these questions. Both treatment groups lost body weight during the study (placebo 1.65 kg, zoledronate 1.05 kg), and this was significantly greater in the placebo group (P = 0.01). Both groups lost lean mass, and this loss was marginally (0.17 kg) but significantly (P = 0.02) greater in those receiving zoledronate. The placebo group had a mean loss of fat mass of 0.63 kg but there was no change in fat mass in the zoledronate group (between-groups comparison, P = 0.007). In the placebo group, there were 20 new diagnoses of diabetes, and in the zoledronate group, 19 (P = 0.87). Zoledronate prevented age-related loss of fat mass in these late postmenopausal women. The present study is the first to document a significant effect of zoledronate treatment on body weight, confirming results previously found with alendronate and denosumab. It also demonstrates that this is principally an effect to maintain fat mass rather than influencing lean mass, raising an important physiological question as to how anti-resorptive drugs have this effect on intermediary metabolism. It is possible that this anti-catabolic action contributes to the beneficial effects of anti-resorptive drugs on bone and longevity.

Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women.

We recently showed that zoledronate prevented fractures in older women with osteopenia (hip T-scores between -1.0 and -2.5). In addition to fewer fractures, this study also suggested that women randomized to zoledronate had fewer vascular events, a lower incidence of cancer, and a trend to lower mortality. The present analysis provides a more detailed presentation of the adverse event data from that study, a 6-year, double-blind trial of 2000 women aged >65 years recruited using electoral rolls. They were randomly assigned to receive four infusions of either zoledronate 5 mg or normal saline at 18-month intervals. Supplements of vitamin D, but not calcium, were provided. There were 1017 serious adverse events in 443 participants in the placebo group, and 820 events in 400 participants in those randomized to zoledronate (relative risk = 0.90; 95% CI, 0.81 to 1.00). These events included fractures resulting in hospital admission. Myocardial infarction occurred in 39 women (43 events) in the placebo group and in 24 women (25 events) in the zoledronate group (hazard ratio 0.60 [95% CI, 0.36 to 1.00]; rate ratio 0.58 [95% CI, 0.35 to 0.94]). For a prespecified composite cardiovascular endpoint (sudden death, myocardial infarction, coronary artery revascularization, or stroke) 69 women had 98 events in the placebo group, and 53 women had 71 events in the zoledronate group (hazard ratio 0.76 [95% CI, 0.53 to 1.08]; rate ratio 0.72 [95% CI, 0.53 to 0.98]). Total cancers were significantly reduced with zoledronate (hazard ratio 0.67 [95% CI, 0.51 to 0.89]; rate ratio 0.68 [95% CI, 0.52 to 0.89]), and this was significant for both breast cancers and for non-breast cancers. Eleven women had recurrent or second breast cancers during the study, all in the placebo group. The hazard ratio for death was 0.65 (95% CI, 0.40 to 1.06; p = 0.08), and 0.51 (95% CI, 0.30 to 0.87) in those without incident fragility fracture. These apparent beneficial effects justify further appropriately powered trials of zoledronate with these nonskeletal conditions as primary endpoints. © 2019 American Society for Bone and Mineral Research.

Dietary Calcium Intake and Bone Loss Over 6 Years in Osteopenic Postmenopausal Women.

CONTEXT: Calcium intakes are commonly lower than the recommended levels, and increasing calcium intake is often recommended for bone health. OBJECTIVE: To determine the relationship between dietary calcium intake and rate of bone loss in older postmenopausal women. PARTICIPANTS: Analysis of observational data collected from a randomized controlled trial. Participants were osteopenic (hip T-scores between -1.0 and -2.5) women, aged >65 years, not receiving therapy for osteoporosis nor taking calcium supplements. Women from the total cohort (n = 1994) contributed data to the analysis of calcium intake and bone mineral density (BMD) at baseline, and women from the placebo group (n = 698) contributed data to the analysis of calcium intake and change in BMD. BMD and bone mineral content (BMC) of the spine, total hip, femoral neck, and total body were measured three times over 6 years. RESULTS: Mean calcium intake was 886 mg/day. Baseline BMDs were not related to quintile of calcium intake at any site, before or after adjustment for baseline age, height, weight, physical activity, alcohol intake, smoking status, and past hormone replacement use. There was no relationship between bone loss and quintile of calcium intake at any site, with or without adjustment for covariables. Total body bone balance (i.e., change in BMC) was unrelated to an individuals' calcium intake (P = 0.99). CONCLUSIONS: Postmenopausal bone loss is unrelated to dietary calcium intake. This suggests that strategies to increase calcium intake are unlikely to impact the prevalence of and morbidity from postmenopausal osteoporosis.