Publications by authors named "Ian R Reid"

285 Publications

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.

J Bone Miner Res 2021 Sep 29. Epub 2021 Sep 29.

Department of Medicine, University of Auckland, Auckland, New Zealand.

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 β-C-terminal telopeptide of type I collagen (β-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, β-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).
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http://dx.doi.org/10.1002/jbmr.4453DOI Listing
September 2021

The Interaction of Acute-Phase Reaction and Efficacy for Osteoporosis After Zoledronic Acid: HORIZON Pivotal Fracture Trial.

J Bone Miner Res 2021 Sep 28. Epub 2021 Sep 28.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Zoledronic acid (ZOL) as a yearly infusion is effective in reducing fracture risk. An acute-phase reaction (APR), consisting of flu-like symptoms within 3 days after infusion, is commonly seen. The objective of this analysis was to investigate whether APR occurrence influences drug efficacy. This analysis uses data from the 3-year randomized clinical trial, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT). APRs were identified as adverse events within 3 days of first infusion with higher frequency in ZOL than placebo. To compare mean 3-year change in bone mineral density (BMD) in ZOL versus placebo, among women with and without APR, t tests were used. Logistic regression was used to examine the relationship between APR occurrence and odds of incident morphometric vertebral fracture. Cox regression was used to determine the risk of nonvertebral and hip fractures for women with versus without APR. Logistic and Cox models were used to determine the risk of incident fracture in ZOL versus placebo for women with and without an APR. The analysis included 3862 women in the ZOL group and 3852 in placebo, with 42.4% in ZOL versus 11.8% in placebo experiencing an APR. The difference in BMD mean change for ZOL versus placebo was similar for women with and without an APR (all p interaction >0.10). Among ZOL women, those with APR had 51% lower vertebral fracture risk than those without (odds ratio [OR] = 0.49, p < 0.001). A similar but nonsignificant trend was observed for nonvertebral and hip fracture (relative hazard [RH] = 0.82, p = 0.10; RH = 0.70, p = 0.22, respectively). There was a greater treatment-related reduction in vertebral fracture risk among women with APR (OR = 0.19) than those without (OR = 0.38) (p interaction = 0.01). Our results suggest that women starting ZOL who experience an APR will have a larger reduction in vertebral fracture risk with ZOL. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4434DOI Listing
September 2021

Stopping osteoporosis medications.

Authors:
Ian R Reid

J Intern Med 2021 Sep 28. Epub 2021 Sep 28.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

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http://dx.doi.org/10.1111/joim.13369DOI Listing
September 2021

Monitoring Osteoporosis Therapy.

Authors:
Ian R Reid

J Bone Miner Res 2021 08 24;36(8):1423-1424. Epub 2021 Jun 24.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

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http://dx.doi.org/10.1002/jbmr.4393DOI Listing
August 2021

Dietary calcium intake and change in bone mineral density in older adults: a systematic review of longitudinal cohort studies.

Eur J Clin Nutr 2021 Jun 15. Epub 2021 Jun 15.

Department of Medicine, University of Auckland, Auckland, New Zealand.

Many older adults do not achieve recommended intakes of calcium and there is some concern over the potential impact of this on bone health. The objective of this review was to examine evidence from cohort studies on the relationship between calcium intake and change in bone mineral density (BMD) in older adults, something not undertaken in the last two decades. Data sources included Ovid Medline, Embase, and PubMed and references from retrieved reviews and articles. The final search was performed in February 2021. We included cohort studies of calcium intake in participants aged >50 years with change in BMD over ≥1 year as an outcome. We identified 23 studies of women and 7 of men. Most studies found no association between calcium intake and change in BMD in women (71%) or men (71%). Among women, five studies reported high rates (>30% of participants) of hormone treatment or osteoporosis therapy (HT/OT) use; 80% of these studies reported a positive association between calcium intake and change in BMD, compared with 10% of studies in which HT/OT use was low. No study in women in which the mean age was >60 years reported a positive association between calcium intake and change in BMD. We conclude that calcium intake across the ranges consumed in these studies (mean intake in all but one study >500 mg/day) is not an important determinant of bone loss, particularly among women >60 years. The positive findings in studies with high rates of HT/OT use are likely to arise from confounding as a result of co-administration of calcium supplements with these medications.
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http://dx.doi.org/10.1038/s41430-021-00957-8DOI Listing
June 2021

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

Calcif Tissue Int 2021 07 12;109(1):12-16. Epub 2021 Mar 12.

Faculty of Medical and Health Sciences, Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand.

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.
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http://dx.doi.org/10.1007/s00223-021-00830-7DOI Listing
July 2021

Bisphosphonate holidays.

Authors:
Ian R Reid

Drug Ther Bull 2021 Mar;59(3):35-36

Department of Medicine, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

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http://dx.doi.org/10.1136/dtb.2020.000057DOI Listing
March 2021

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

Arthritis Rheumatol 2021 09 16;73(9):1758-1764. Epub 2021 Jul 16.

University of Auckland, Auckland, New Zealand.

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 β-C-telopeptide of type I collagen (β-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 β-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.
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http://dx.doi.org/10.1002/art.41691DOI Listing
September 2021

Molecular characterisation of osteoblasts from bone obtained from people of Polynesian and European ancestry undergoing joint replacement surgery.

Sci Rep 2021 01 28;11(1):2428. Epub 2021 Jan 28.

Department of Medicine, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.

Population studies in Aotearoa New Zealand found higher bone mineral density and lower rate of hip fracture in people of Polynesian ancestry compared to Europeans. We hypothesised that differences in osteoblast proliferation and differentiation contribute to the differences in bone properties between the two groups. Osteoblasts were cultured from bone samples obtained from 30 people of Polynesian ancestry and 25 Europeans who had joint replacement surgeries for osteoarthritis. The fraction of cells in S-phase was determined by flow cytometry, and gene expression was analysed by microarray and real-time PCR. We found no differences in the fraction of osteoblasts in S-phase between the groups. Global gene expression analysis identified 79 differentially expressed genes (fold change > 2, FDR P < 0.1). Analysis of selected genes by real-time PCR found higher expression of COL1A1 and KRT34 in Polynesians, whereas BGLAP, DKK1, NOV, CDH13, EFHD1 and EFNB2 were higher in Europeans (P ≤ 0.01). Osteoblasts from European donors had higher levels of late differentiation markers and genes encoding proteins that inhibit the Wnt signalling pathway. This variability may contribute to the differences in bone properties between people of Polynesian and European ancestry that had been determined in previous studies.
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http://dx.doi.org/10.1038/s41598-021-81731-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844412PMC
January 2021

A prediction tool for vitamin D deficiency in New Zealand adults.

Arch Osteoporos 2020 10 31;15(1):172. Epub 2020 Oct 31.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Purpose: This study aims to develop a model for predicting vitamin D deficiency in New Zealand adults using easily accessible clinical characteristics.

Methods: Data were derived from the Vitamin D Assessment (ViDA) study dataset. Included participants in the main analysis were aged 50-84 years and resided in Auckland, New Zealand. The dataset was split into a discovery dataset in which the prediction model was developed (n = 2036) and a validation dataset in which it was tested (n = 2037). The prediction model was developed using clinical characteristics in a logistic regression analysis with deseasonalised serum 25OHD (DS-25OHD) as the dependent variable.

Results: DS-25OHD < 40 nmol/L was found in 8.2% of European participants, 18.8% of Māori participants, 23.1% of Pacific participants and 52.2% of South Asian participants. Predictors for DS-25OHD < 40 nmol/L in the European sub-cohort included increasing age, female sex, higher body mass index, current smoking, no alcohol intake, lower self-reported general health status, lower physical activity hours, lower outdoor hours and no use of vitamin D-containing supplementation. The area under the curve in the discovery dataset was 0.73, and in the validation dataset was 0.71. Of those with a prediction score ≥ 10 (total risk score range 0-21.5), the sensitivity and specificity for predicting vitamin D deficiency was 0.90 and 0.41, respectively.

Conclusion: Non-European ethnicity is an important risk factor for vitamin D deficiency. Our vitamin D deficiency prediction model performed well and demonstrates its potential as a tool that can be integrated into clinical practice for the prediction of vitamin D deficiency.
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http://dx.doi.org/10.1007/s11657-020-00844-yDOI Listing
October 2020

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

J Bone Miner Res 2021 01 2;36(1):61-66. Epub 2020 Sep 2.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

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).
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http://dx.doi.org/10.1002/jbmr.4167DOI Listing
January 2021

Benefits of Bisphosphonate Therapy: Beyond the Skeleton.

Curr Osteoporos Rep 2020 10;18(5):587-596

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Purpose Of Review: Recent evidence from clinical trials and observational studies raises the possibility that bisphosphonate use might confer a lower risk of cardiovascular disease and cancer, resulting in a mortality benefit. This review summarizes clinical and preclinical studies examining the non-skeletal effects of bisphosphonates.

Recent Findings: Data from clinical trials are conflicting regarding whether or not bisphosphonates have beneficial effects on mortality, cardiovascular events, or cancer incidence. No clinical trials have assessed these outcomes as primary endpoints, and most trials were shorter than 4 years. Observational data suggest that bisphosphonate users may have lower mortality, delayed progression of vascular calcification and atherosclerotic burden, and reduced incidence of breast and colorectal cancer compared to non-users. Preclinical studies confirm that bisphosphonates can be taken up by macrophages and monocytes, and nitrogen-containing bisphosphonates have the ability to disrupt the mevalonate pathway within these cells. In this manner, bisphosphonates exert anti-atherogenic and anti-cancer effects. Bisphosphonates also appear to exert protective effects on vascular smooth muscle cells and endothelial cells and may have direct cytotoxic effects on cancer cells. The balance of evidence does not support bisphosphonate treatment for the primary purpose of improving non-skeletal outcomes, although appropriately designed controlled trials that further explore this possibility are both justified and required. Patients with skeletal indications for bisphosphonate therapy can be reassured that these agents are not associated with increased mortality, cardiovascular disease, or cancer incidence.
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http://dx.doi.org/10.1007/s11914-020-00612-4DOI Listing
October 2020

No more fracture trials in osteoporosis?

Authors:
Ian R Reid

Lancet Diabetes Endocrinol 2020 08;8(8):650-651

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Auckland District Health Board, Auckland, New Zealand. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(20)30232-1DOI Listing
August 2020

Osteoporosis: evidence for vitamin D and calcium in older people.

Authors:
Ian R Reid

Drug Ther Bull 2020 Aug 25;58(8):122-125. Epub 2020 Jun 25.

Department of Medicine, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

Topics for DTB review articles are selected by DTB's editorial board to provide concise overviews of medicines and other treatments to help patients get the best care. Articles include a summary of key points and a brief overview for patients. Articles may also have a series of multiple choice CME questions.
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http://dx.doi.org/10.1136/dtb.2019.000063DOI Listing
August 2020

The effect of age on the microarchitecture and profile of gene expression in femoral head and neck bone from patients with osteoarthritis.

Bone Rep 2020 Dec 5;13:100287. Epub 2020 Jun 5.

Department of Medicine, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

Ageing of the skeleton is characterised by decreased bone mineral density, reduced strength, and increased risk of fracture. Although it is known that these changes are determined by the activities of bone cells through the processes of bone modelling and remodelling, details of the molecular mechanisms that underlie age-related changes in bone are still missing. Here, we analysed age-related changes in bone microarchitecture along with global gene expression in samples obtained from patients with osteoarthritis (OA). We hypothesised that changes would be evident in both microarchitecture and gene expression and aimed to identify novel molecular mechanisms that underlie ageing processes in bone. Samples of femoral head and neck were obtained from patients undergoing hip arthroplasty for OA, who were either ≤60 years or ≥70 years of age. Bone microarchitecture was analysed in cores of trabecular bone from the femoral head (17 from the younger group and 18 from the older), and cortical bone from the femoral neck (25 younger/22 older), using a Skyscan 1172 microCT scanner (Bruker). Gene expression was compared between the two age groups in 20 trabecular samples from each group, and 10 cortical samples from each group, using Clariom S Human microarrays (ThermoFisher Scientific). We found no significant changes between the two age groups in indices of trabecular or cortical bone microarchitecture. Gene expression analysis identified seven genes that had higher expression in the older group, including the transcription factor and the glucose transporter (), and 21 differentially expressed genes in cortical bone samples (<0.05, fold change>2). However, none of the comparisons of gene expression had false discovery rate-adjusted <0.1. In contrast to our working hypothesis, we found only minor differences in gene expression and no differences in bone microarchitecture between the two age-groups. It is possible that pathological processes related to OA provide protection against age-related changes in bone. Our study suggests that in patients with OA, the bone properties measured here in femoral head and neck do not deteriorate significantly from the sixth to the eighth decade of life.
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http://dx.doi.org/10.1016/j.bonr.2020.100287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292911PMC
December 2020

The vitamin D testing rate is again rising, despite new MBS testing criteria.

Med J Aust 2020 08 20;213(4):155-155.e1. Epub 2020 May 20.

QIMR Berghofer Medical Research Institute, Brisbane, QLD.

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http://dx.doi.org/10.5694/mja2.50619DOI Listing
August 2020

Nitrates Do Not Affect Bone Density or Bone Turnover in Postmenopausal Women: A Randomized Controlled Trial.

J Bone Miner Res 2020 06 5;35(6):1040-1047. Epub 2020 May 5.

Department of Medicine, University of Auckland, Auckland, New Zealand.

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.
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http://dx.doi.org/10.1002/jbmr.3982DOI Listing
June 2020

What factors modify the effect of monthly bolus dose vitamin D supplementation on 25-hydroxyvitamin D concentrations?

J Steroid Biochem Mol Biol 2020 07 30;201:105687. Epub 2020 Apr 30.

School of Population Health, The University of Auckland, Auckland, New Zealand. Electronic address:

The increasing use of vitamin D supplements has stimulated interest in identifying factors that may modify the effect of supplementation on circulating 25-hydroxyvitamin D (25(OH)D) concentrations. Such information is of potential interest to researchers, clinicians and patients when deciding on bolus dose of vitamin D supplementation. We carried out a large randomized controlled trial of 5110 adults aged 50-84 years, of European/Other (84%), Polynesian (11%) and Asian (5%) ethnicity, to whom we gave a standard dose of vitamin D supplements (200,000 IU initially, then 100,000 IU monthly) which was taken with high adherence. All participants provided a baseline blood sample, and follow-up blood samples were collected at 6 months and annually for 3 years in a random sample of 441 participants, and also at 2 years in 413 participants enrolled in a bone density sub-study. Serum 25(OH)D was measured by LC/MSMS. Mixed model analyses were carried out on all 854 participants providing follow-up blood samples in multivariable models that included age, sex, ethnicity, body mass index (kg/m), tobacco smoking, alcohol intake, physical activity, sun exposure, season, medical prescription of high-dose vitamin D (Cal.D.Forte tablets), asthma/COPD and the study treatment (vitamin D or placebo). The adjusted mean difference in 25(OH)D in the follow-up points between vitamin D supplementation and placebo groups was inversely related (all p for interaction <0.05) to baseline 25(OH)D, BMI, and hours of sun exposure, and higher in females, elders, and those with high frequency of alcohol, medical prescription of vitamin D, and asthma/COPD. The mean difference was not significantly related to ethnicity (p = 0.12), tobacco (p = 0.34), and vigorous activity (p = 0.33). In summary, these data show that vitamin D status, BMI, sun exposure hours, sex and asthma/COPD modify the 25(OH)D response to vitamin D supplementation. By contrast, ethnicity, tobacco smoking, and vigorous activity do not.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105687DOI Listing
July 2020

Zoledronate.

Bone 2020 08 27;137:115390. Epub 2020 Apr 27.

Department of Clinical Medicine, University of Oslo, Oslo, Norway.

Zoledronate is the most potent and most long-acting bisphosphonate in clinical use, and is administered as an intravenous infusion. Its major uses are in osteoporosis, Paget's disease, and in myeloma and cancers to reduce adverse skeletal related events (SREs). In benign disease, it is a first- or second-line treatment for osteoporosis, achieving anti-fracture efficacy comparable to that of the RANKL blocker, denosumab, over 3 years, and it reduces fracture risk in osteopenic older women. It is the preferred treatment for Paget's disease, achieving higher rates of remissions which are much more prolonged than with any other agent. Some trials have suggested that it reduces mortality, cardiovascular disease and cancer, but these findings are not consistent across all studies. It is nephrotoxic, so should not be given to those with significant renal impairment, and, like other potent anti-resorptive agents, can cause hypocalcemia in patients with severe vitamin D deficiency, which should be corrected before administration. Its most common adverse effect is the acute phase response, seen in 30-40% of patients after their first dose, and much less commonly subsequently. Clinical trials in osteoporosis have not demonstrated increases in osteonecrosis of the jaw or in atypical femoral fractures. Observational databases are currently inadequate to determine whether these problems are increased in zoledronate users. Now available as a generic, zoledronate is a cost-effective agent for fracture prevention and for management of Paget's disease, but wider provision of infusion facilities is important to increase patient access. There is a need to further explore its potential for reducing cancer, cardiovascular disease and mortality, since these effects could be substantially more important than its skeletal actions.
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http://dx.doi.org/10.1016/j.bone.2020.115390DOI Listing
August 2020

Reply to Serious Adverse Events With Romosozumab Use in Japanese Patients: Need for Clear Formulation of Contraindications Worldwide.

J Bone Miner Res 2020 05 16;35(5):996-997. Epub 2020 Apr 16.

Department of Medicine, University of Auckland, Auckland, New Zealand.

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http://dx.doi.org/10.1002/jbmr.4000DOI Listing
May 2020

Calcium and/or Vitamin D Supplementation for the Prevention of Fragility Fractures: Who Needs It?

Nutrients 2020 Apr 7;12(4). Epub 2020 Apr 7.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand.

Vitamin D and calcium have different biological functions, so the need for supplementation, and its safety and efficacy, need to be evaluated for each separately. Vitamin D deficiency is usually the result of low sunlight exposure (e.g., in frail older people, those who are veiled, those with dark-skin living at higher latitudes) and is reversible with calciferol 400-800 IU/day. Calcium supplements produce a 1% increase in bone density in the first year of use, without further increases subsequently. Vitamin D supplements do not improve bone density in clinical trials except in analyses of subgroups with baseline levels of 25-hydroxyvitamin D <30 nmol/L. Supplementation with calcium, vitamin D, or their combination does not prevent fractures in community-dwelling adults, but a large study in vitamin D-deficient nursing home residents did demonstrate fracture prevention. When treating osteoporosis, co-administration of calcium with anti-resorptive drugs has not been shown to impact on treatment efficacy. Correction of severe vitamin D deficiency (<25 nmol/L) is necessary before use of potent anti-resorptive drugs to avoid hypocalcemia. Calcium supplements cause gastrointestinal side effects, particularly constipation, and increase the risk of kidney stones and, probably, heart attacks by about 20%. Low-dose vitamin D is safe, but doses >4000 IU/day have been associated with more falls and fractures. Current evidence does not support use of either calcium or vitamin D supplements in healthy community-dwelling adults.
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http://dx.doi.org/10.3390/nu12041011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231370PMC
April 2020

A broader strategy for osteoporosis interventions.

Authors:
Ian R Reid

Nat Rev Endocrinol 2020 06 17;16(6):333-339. Epub 2020 Mar 17.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Approximately 50% of women experience at least one bone fracture postmenopause. Current screening approaches target anti-fracture interventions to women aged >60 years who satisfy clinical risk and bone mineral density criteria for osteoporosis. Intervention is only recommended in 7-25% of those women screened currently, well short of the 50% who experience fractures. Large screening trials have not shown clinically significant decreases in the total fracture numbers. By contrast, six large clinical trials of anti-resorptive therapies (for example, bisphosphonates) have demonstrated substantial decreases in the number of fractures in women not identified as being at high risk of fracture. This finding suggests that broader use of generic bisphosphonates in women selected by age or fracture risk would result in a reduction in total fracture numbers, a strategy likely to be cost-effective. The utility of the current bone density definition of osteoporosis, which neither corresponds with who suffers fractures nor defines who should be treated, requires reappraisal.
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http://dx.doi.org/10.1038/s41574-020-0339-7DOI Listing
June 2020

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

J Clin Endocrinol Metab 2020 04;105(4)

Department of Medicine, University of Auckland, Private Bag, Auckland, New Zealand.

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.
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http://dx.doi.org/10.1210/clinem/dgaa062DOI Listing
April 2020

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

Calcif Tissue Int 2020 04 2;106(4):386-391. Epub 2020 Jan 2.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.

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.
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http://dx.doi.org/10.1007/s00223-019-00653-7DOI Listing
April 2020

Calcium and Bone.

Handb Exp Pharmacol 2020 ;262:259-280

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

The maintenance of extracellular calcium levels within a narrow range is necessary for normal function of the nervous system, muscle, and coagulation, to maintain mineralization of the skeleton but to avoid calcification of soft tissues. Accordingly, absorption and excretion of calcium is closely regulated, and adult humans can adapt to a wide range of calcium intakes from 300 to 2,000 mg/day. The evidence that low calcium intakes contribute to osteoporosis development is weak, as is evidence that increasing these intakes significantly changes fracture risk. Consistent with this view, the United States Preventive Services Task Force does not support the use of calcium supplements in healthy community-dwelling adults. While some groups continue to recommend that supplements of calcium and vitamin D are given with drug treatments for osteoporosis, this view is not supported by clinical trials which demonstrate anti-fracture efficacy of estrogens and bisphosphonates in the absence of such supplementation. Thus, calcium supplements have only a minor place in contemporary medical practice.
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http://dx.doi.org/10.1007/164_2019_324DOI Listing
December 2020

Controversies in medicine: the role of calcium and vitamin D supplements in adults.

Med J Aust 2019 11 3;211(10):468-473. Epub 2019 Nov 3.

University of Auckland, Auckland, New Zealand.

Vitamin D is made in the skin when exposed to sunlight, so deficiency is usually the result of low sunlight exposure (eg, in frail older people and in individuals who are veiled). Calcium and/or vitamin D supplements have been used for the prevention and treatment of osteoporosis. The major trials in community-dwelling individuals have not demonstrated fracture prevention with either calcium, vitamin D, or their combination, but the results of a large study in vitamin D-deficient nursing home residents indicated a reduced fracture incidence. Trials show that vitamin D increases bone density when winter 25-hydroxyvitamin D levels are below 25-30 nmol/L. However, assay expense and variability suggest that supplements are better targeted based on clinical status to frail older people and possibly to people with dark skin living at higher latitudes. A daily dose of 400-800 units (10-20 μg) is usually adequate. Parenteral antiresorptive drugs can cause hypocalcaemia in severe vitamin D deficiency (< 25 nmol/L), which should therefore be corrected before treatment. Clinical trials have not demonstrated benefits of vitamin D on non-skeletal endpoints. Calcium supplements in healthy individuals are not needed, nor are they required in most people receiving treatment for osteoporosis, where they have not been shown to affect treatment efficacy. Calcium supplements cause constipation, bloating and kidney stones, and some evidence suggests they may cause a small increase in the risk of myocardial infarction. Low dose vitamin D is safe, but high doses result in more falls and fractures. Current evidence does not support the use of these supplements in healthy community-dwelling adults.
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http://dx.doi.org/10.5694/mja2.50393DOI Listing
November 2019

Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study.

Lancet Diabetes Endocrinol 2019 12 31;7(12):899-911. Epub 2019 Oct 31.

Merck & Co, Inc, Kenilworth, NJ, USA.

Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis.

Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between -2·5 and -4·0 if no previous radiographic vertebral fracture, or between -1·5 and -4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than -4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66).

Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43-40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45-60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40-0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39-0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68-0·87; all p<0·0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4·9% (341/6909) versus 9·6% (675/7011), HR 0·48, 95% CI 0·42-0·55; hip fractures 1·1% (86/8043) versus 2·0% (162/8028), 0·52, 0·40-0·67; non-vertebral fractures 6·4% (512/8043) versus 8·4% (675/8028), 0·74, 0·66-0·83; all p<0·0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3·4%) of 8043 patients in the odanacatib group versus 245 (3·1%) of 8028 in the placebo group (HR 1·12, 95% CI 0·95-1·34; p=0·18). New-onset atrial fibrillation or flutter occurred in 112 (1·4%) of 8043 patients in the odanacatib group versus 96 (1·2%) of 8028 in the placebo group (HR 1·18, 0·90-1·55; p=0·24). Odanacatib was associated with an increased risk of stroke (1·7% [136/8043] vs 1·3% [104/8028], HR 1·32, 1·02-1·70; p=0·034), but not myocardial infarction (0·7% [60/8043] vs 0·9% [74/8028], HR 0·82, 0·58-1·15; p=0·26). The HR for all-cause mortality was 1·13 (5·0% [401/8043] vs 4·4% [356/8028], 0·98-1·30; p=0·10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5·0%] of 8043 vs 343 [4·3%] of 8028, HR 1·17, 1·02-1·36; p=0·029, as did stroke (2·3% [187/8043] vs 1·7% [137/8028], HR 1·37, 1·10-1·71; p=0·0051).

Interpretation: Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis.

Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.
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http://dx.doi.org/10.1016/S2213-8587(19)30346-8DOI Listing
December 2019

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

J Bone Miner Res 2020 01 11;35(1):20-27. Epub 2019 Oct 11.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

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.
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http://dx.doi.org/10.1002/jbmr.3860DOI Listing
January 2020

Recent advances in understanding and managing Paget's disease.

Authors:
Ian R Reid

F1000Res 2019 22;8. Epub 2019 Aug 22.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand.

Paget's disease is a condition which continues to challenge and surprise. The dramatic fall in its incidence over the last three decades has been an enormous surprise, as is the capacity of a single infusion of the potent bisphosphonate, zoledronate, to produce biochemical remission in 90% of patients, remissions which usually persist for many years and raise the possibility of a cure in some patients. However, challenges in its management remain. The trials carried out in Paget's disease have almost always had biochemical indices as their primary endpoints. From these studies, we also know that bone pain is relieved, quality of life improved, bone histology normalised, and radiological lesions healed. Thus, disease progression is halted. Studies have not been powered to assess whether clinically important endpoints such as fracture and the need for joint replacement surgery are diminished, although these complications are well established as part of the natural history of the condition. Since disease progression is prevented by potent bisphosphonates, it is likely that disease complications will also be prevented. Zoledronate also reduces the frequency of follow-up needed and therefore provides a very cost-effective intervention in those who have symptomatic disease or are at risk of complications.
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http://dx.doi.org/10.12688/f1000research.19676.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707397PMC
May 2020

Bisphosphonates for Prevention of Bone Loss in Glucocorticoid-Treated Young People.

Authors:
Ian R Reid

EClinicalMedicine 2019 Jul 12;12:8-9. Epub 2019 Jul 12.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

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http://dx.doi.org/10.1016/j.eclinm.2019.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686132PMC
July 2019
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