2015-pedroza.pdf: “Performance of informative priors skeptical of large treatment effects in clinical trials: A simulation study”, (2015-12-13; ):
One of the main advantages of Bayesian analyses of clinical trials is their ability to formally incorporate skepticism about large treatment effects through the use of informative priors. We conducted a simulation study to assess the performance of informative normal, Student-t, and beta distributions in estimating relative risk (RR) or odds ratio (OR) for binary outcomes. Simulation scenarios varied the prior standard deviation (SD; level of skepticism of large treatment effects), outcome rate in the control group, true treatment effect, and sample size. We compared the priors with regards to bias, mean squared error (MSE), and coverage of 95% credible intervals. Simulation results show that the SD influenced the posterior to a greater degree than the particular distributional form of the . For RR, priors with a 95% interval of 0.50–2.0 performed well in terms of bias, MSE, and coverage under most scenarios. For OR, priors with a wider 95% interval of 0.23–4.35 had good performance. We recommend the use of informative priors that exclude implausibly large treatment effects in analyses of clinical trials, particularly for major outcomes such as mortality.
[Keywords: Bayesian analysis, informative priors, large treatment effects, binary data, clinical trial, robust priors]
Context: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.
Objective: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.
Design, Setting, and Participants: Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.
Main Outcome Measure: Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.
Results: Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% , 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% , 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.
Conclusion: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.
2010-barnard.pdf: “Extraskeletal effects of vitamin D in older adults: Cardiovascular disease, mortality, mood, and cognition”, Karen Barnard MBBCh MPH, Cathleen Colón-Emeric MHS
2011-elamin.pdf: “Vitamin D and Cardiovascular Outcomes: A Systematic Review and Meta–Analysis”, (2011-07-01; ):
Context: Several studies found association between vitamin D levels and hypertension, coronary artery calcification, and heart disease.
Objective: The aim of this study was to summarize the evidence on the effect of vitamin D on cardiovascular outcomes.
Design and Methods: We searched electronic databases from inception through August 2010 for randomized trials. Reviewers working in duplicate and independently extracted study characteristics, quality, and the outcomes of interest. Random-effectswas used to pool the relative risks (RR) and the weighted mean differences across trials.
Results: We found 51 eligible trials with moderate quality. Vitamin D was associated with nonsignificant effects on the patient-important outcomes of death [RR, 0.96; 95% confidence interval (), 0.93, 1.00; p = 0.08], myocardial infarction (RR, 1.02; 95% , 0.93, 1.13; p = 0.64), and stroke (RR, 1.05; 95% , 0.88, 1.25; p = 0.59). These analyses were associated with minimal heterogeneity. There were no statistically-significant changes in the surrogate outcomes of lipid fractions, glucose, or diastolic or systolic blood pressure. The latter analyses were associated with statistically-significant heterogeneity, and the pooled estimates were trivial in absolute terms.
Conclusions: Trial data available to date are unable to demonstrate a statistically-significant reduction in mortality and cardiovascular risk associated with vitamin D. The quality of the available evidence is low to moderate at best.
Objectives: To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.
Design: Reanalysis of WHI CaD Study limited access dataset and incorporation in with eight other studies. Data source WHI CaD Study, a seven year, randomised, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36,282 community dwelling postmenopausal women. Main outcome measures Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data.
Results: In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16,718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (p = 0.05 for clinical myocardial infarction or stroke, p = 0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), p = 0.04), stroke (1.20 (1.00 to 1.43), p = 0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), p = 0.02). In meta-analyses of placebo of calcium or calcium and vitamin D, complete trial-level data were available for 28,072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), p = 0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), p = 0.009).
Conclusions: Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.
Introduction: Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from data (IPD) and trial level meta-analyses to assess mortality among participants randomized to either vitamin D alone or vitamin D with calcium., we performed individual patient
Subjects and Methods: Through a systematic literature search, we identified 24 participants each, eight trials were included in our IPD analysis. Using a stratified Cox regression model, we calculated risk of death during 3 yr of treatment in an intention-to-treat analysis. Also, we performed a trial level including data from all studies.reporting data on mortality in which vitamin D was given either alone or with calcium. From a total of 13 trials with more than 1000
Results: The IPD analysis yielded data on 70,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62–77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval ( ), 0.88-0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin D was given with calcium (hazard ratio, 0.91; 95% , 0.84-0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% , 0.88-0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91-1.06).
Conclusion: Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone.
Introduction: It has been suggested that vitamin D is effective to prevent mortality. However, there is no consistent conclusion that the effects of vitamin D supplementation on all-cause mortality are associated with duration of treatment. We conducted aregarding this issue in an effort to provide a more robust answer.
Methods: A comprehensive search in a number of databases, including MEDLINE, Embase and The Cochrane Central Register of Controlled Trials, was conducted for collecting randomized controlled trials ( ) on vitamin D supplementation preventing mortality. Two investigators independently screened the literature according to the inclusive and exclusive criteria and the relative data were extracted. Data analysis was performed by using Review Manager 5.0 software.
Results: Data from forty-twos were included. Vitamin D therapy significantly decreased all-cause mortality with a duration of follow-up longer than 3 years with a RR (95% ) of 0.94 (0.90-0.98). No benefit was seen in a shorter follow-up periods with a RR (95% ) of 1.04 (0.97-1.12). Results remain robust after sensitivity analysis. The following subgroups of long-term follow-up had significantly fewer deaths: female only, participants with a mean age younger than 80, daily dose of 800 IU or less, participants with vitamin D insufficiency (baseline 25-hydroxyvitamin D level less than 50 nmol/L) and cholecalciferol therapy. In addition, the combination of vitamin D and calcium significantly reduced mortality and vitamin D alone also had a trend to decrease mortality in a longer time follow up.
Conclusions: The data suggest that supplementation of vitamin D is effective in preventing overall mortality in a long-term treatment, whereas it is not significantly effective in a treatment duration shorter than 3 years. Future studies are needed to identify the efficacy of vitamin D on specific mortality, such as cancer and cardiovascular disease mortality in a long-term treatment duration.
2014-bjelakovic.pdf: “Vitamin D supplementation for prevention of cancer in adults (Review)”, Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Krstic G, Wetterslev J, Gluud C
2014-bjelakovic-2.pdf: “Vitamin D supplementation for prevention of mortality in adults”, Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C.
2014-autier.pdf: “Vitamin D status and ill health: a systematic review”, Philippe Autier, Mathieu Boniol, CÃ©cile Pizot, Patrick Mullie
2014-avenell.pdf: “Vitamin D and vitamin D analogues for preventing fractures in post‐menopausal women and older men”, (2014-04-14; ):
Background: Vitamin D and related compounds have been used to prevent osteoporotic fractures in older people. This is the third update of a Cochrane review first published in 1996.
Objectives: To determine the effects of vitamin D or related compounds, with or without calcium, for preventing fractures in post-menopausal women and older men.
Search methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (to December 2012), the Cochrane Central Register of MEDLINE (1966 to November Week 3 2012), EMBASE (1980 to 2012 Week 50), CINAHL (1982 to December 2012), BIOSIS (1985 to 2013-01-03), Current (December 2012) and reference lists of articles.(2012, Issue 12),
Selection criteria: Randomised or quasi-randomised trials that compared vitamin D or related compounds, alone or with calcium, against placebo, no intervention or calcium alone, and that reported fracture outcomes in older people. The primary outcome was hip fracture. Data collection and analysis
Two authors independently assessed trial risk of selection bias and aspects of methodological quality, and extracted data. Data were pooled, where possible, using the fixed-effect model, or the random-effects model when heterogeneity between studies appeared substantial. Main results
We included 53 trials with a total of 91,791 participants. Thirty-one trials, with sample sizes ranging from 70 to 36,282 participants, examined vitamin D (including 25-hydroxy vitamin D) with or without calcium in the prevention of fractures in community, nursing home or hospital inpatient populations. Twelve of these 31 trials had participants with a mean or median age of 80 years or over.
Another group of 22 smaller trials examined calcitriol or alfacalcidol (1-alphahydroxyvitamin D3), mostly with participants who had established osteoporosis. These trials were carried out in the setting of institutional referral clinics or hospitals.
In the assessment of risk of bias for random sequence generation, 21 trials (40%) were deemed to be at low risk, 28 trials (53%) at unclear risk and four trials at high risk (8%). For allocation concealment, 22 trials were at low risk (42%), 29 trials were at unclear risk (55%) and two trials were at high risk (4%).
There is high quality evidence that vitamin D alone, in the formats and doses tested, is unlikely to be effective in preventing hip fracture (11 trials, 27,693 participants; risk ratio (RR) 1.12, 95%( ) 0.98 to 1.29) or any new fracture (15 trials, 28,271 participants; RR 1.03, 95% CI 0.96 to 1.11).
There is high quality evidence that vitamin D plus calcium results in a small reduction in hip fracture risk (nine trials, 49,853 participants; RR 0.84, 95%(CI) 0.74 to 0.96; P value 0.01). In low-risk populations (residents in the community: with an estimated eight hip fractures per 1000 per year), this equates to one fewer hip fracture per 1000 older adults per year (95% 0 to 2). In high risk populations (residents in institutions: with an estimated 54 hip fractures per 1000 per year), this equates to nine fewer hip fractures per 1000 older adults per year (95% 2 to 14).
There is high quality evidence that vitamin D plus calcium is associated with areduction in incidence of new non-vertebral fractures. However, there is only moderate quality evidence of an absence of a statistically-significant preventive effect on clinical vertebral fractures. There is high quality evidence that vitamin D plus calcium reduces the risk of any type of fracture (10 trials, 49,976 participants; RR 0.95, 95% CI 0.90 to 0.99).
In terms of the results for adverse effects: mortality was not adversely affected by either vitamin D or vitamin D plus calcium supplementation (29 trials, 71,032 participants, RR 0.97, 95% CI 0.93 to 1.01). Hypercalcaemia, which was usually mild (2.6 to 2.8 mmol/L), was more common in people receiving vitamin D or an analogue, with or without calcium (21 trials, 17,124 participants, RR 2.28, 95%1.57 to 3.31), especially for calcitriol (four trials, 988 participants, RR 4.41, 95% 2.14 to 9.09), than in people receiving placebo or control. There was also a small increased risk of gastrointestinal symptoms (15 trials, 47,761 participants, RR 1.04, 95% 1.00 to 1.08), especially for calcium plus vitamin D (four trials, 40,524 participants, RR 1.05, 95% 1.01 to 1.09), and a increase in renal disease (11 trials, 46,548 participants, RR 1.16, 95% CI 1.02 to 1.33). Other systematic reviews have found an increased association of myocardial infarction with supplemental calcium; and evidence of increased myocardial infarction and stroke, but decreased cancer, with supplemental calcium plus vitamin D, without an overall effect on mortality.
Authors’ conclusions: Vitamin D alone is unlikely to prevent fractures in the doses and formulations tested so far in older people. Supplements of vitamin D and calcium may prevent hip or any type of fracture. There was a small but statistically-significant increase in gastrointestinal symptoms and renal disease associated with vitamin D and calcium. This review found that there was no increased risk of death from taking calcium and vitamin D.
Background: The effects of intermittent, high dose vitamin D treatment in older adults have not been documented. We conducted a meta-analysis to provide a quantitative assessment of the efficiency of intermittent, high dose vitamin D treatment on falls, fractures, and mortality among older adults.
Methods: Electronic databases were searched for randomized controlled trials () on high dose, intermittent vitamin D supplementation among older adults. Two researchers independently screened the literature according to specified inclusive and exclusive criteria to extract the data. was performed by using Review Manager 5.1.0 software.
Results: Nine trials were included in this. High dose, intermittent vitamin D therapy did not decrease all-cause mortality among older adults. The risk ratio (95% ) was 1.04 (0.91-1.17). No benefit was seen in fracture or fall prevention. The risk ratio for hip fractures (95% ) was 1.17 (0.97-1.41) while for non-vertebral fractures (95% ) it was 1.06 (0.91-1.22), and the risk ratio for falls (95% ) was 1.02 (0.96-1.08). Results remained robust after sensitivity analysis.
Conclusion: Supplementation of intermittent, high dose vitamin D may not be effective in preventing overall mortality, fractures, or falls among older adults. The route of administration of vitamin D supplements may well change the physiological effects.
1999-komulainen.pdf: “Prevention of Femoral and Lumbar Bone Loss with Hormone Replacement Therapy and Vitamin D3 in Early Postmenopausal Women: A Population–Based 5–Year Randomized Trial”, (1999-02-01; ):
The long term effects of hormone replacement therapy (HRT) and vitamin D3 (Vit D) on bone mineral density (BMD) were studied. A total of 464 nonosteoporotic early postmenopausal women from the Kuopio Osteoporosis Study (n = 13100) were randomized to 4 groups: (1) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate), (2) Vit D3 (300 and 100 IU/day during the fifth year), (3) HRT and Vit D combined, and (4) placebo. Lumbar (L2–L4) and femoral neck BMD were determined by dual x-ray absorptiometry (DXA) at baseline and after 2.5 and 5 yr of treatment.
Intention to treat analysis (n = 464) showed that after 5 yr, lumbar BMD remained unchanged in the HRT and HRT plus Vit D groups[+ 0.2% (p = 0.658) and +0.9% (p = 0.117), respectively], whereas lumbar BMD decreased by 4.6% in the Vit D group and by 4.5% in the placebo group (p < 0.001 in both). The loss of femoral neck BMD was less in the HRT (−1.4%; p = 0.005) and HRT plus Vit D (−1.3%; p = 0.003) groups than in the Vit D and placebo groups (−4.3%; p < 0.001 in both). Among those 370 women who complied with the 5-yr treatment, the effect was more pronounced: lumbar BMD had increased by 1.5% in the HRT (p = 0.009) and by 1.8% in the HRT plus Vit D group (p = 0.005), with a plateau after 2.5 yr, whereas lumbar BMD had decreased in both the Vit D and placebo groups (4.6% and 4.7%; p < 0.001, respectively). Femoral neck BMD decreased again less in the HRT (−0.4%) and HRT plus Vit D (−0.6%) groups than in the Vit D and placebo groups (−4.4% in both).
This study confirms the positive long term effect of HRT on BMD also seen in intention to treat analysis. The data suggest that low dose vitamin D3 supplementation does not prevent bone loss in healthy, nonosteoporotic, early postmenopausal women, and it confers no benefit additional to that of HRT alone.
2003-latham.pdf: “A Randomized, Controlled Trial of Quadriceps Resistance Exercise and Vitamin D in Frail Older People: The Frailty Interventions Trial in Elderly Subjects (FITNESS)”, (2003-02-20; ):
Objectives: To determine the effectiveness of vitamin D and home-based quadriceps resistance exercise on reducing falls and improving the physical health of frail older people after hospital discharge.
Design: Multicenter, randomized,with a factorial design.
Setting: Five hospitals in Auckland, New Zealand, and Sydney, Australia.
Participants: Two hundred forty-three frail older people.
Interventions: Patients were randomized to receive a single dose of vitamin D (calciferol, 300,000 IU) or placebo tablets and 10 weeks of high-intensity home-based quadriceps resistance exercise or frequency-matched visits.
Measurements: The primary endpoints were physical health according to the short-form health survey at 3 months and falls over 6 months. Physical performance and self-rated function were secondary endpoints. Assessments took place in the participants’ homes at 3 and 6 months after randomization and were performed by blinded assessors.
Results: There was no effect of either intervention on physical health or falls, but patients in the exercise group were at increased risk of musculoskeletal injury (risk ratio = 3.6, 95% confidence interval = 1.5–8.0). Vitamin D supplementation did not improve physical performance, even in those who were vitamin D deficient (<12 ng/mL) at baseline.
Conclusion: Neither vitamin D supplementation nor a home-based program of high-intensity quadriceps resistance exercise improved rehabilitation outcomes in frail older people after hospitalization. There was no effect of vitamin D on physical performance, and the exercises increased the risk of musculoskeletal injury. These findings do not support the routine use of these interventions at these dosages in the rehabilitation of frail older people.
Objective: To determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.
Design: Randomised double blindof 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.
Setting and Participants: 2686 people (2037 men and 649 women) aged 65–85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.
Main Outcome Measures: Fracture incidence and total mortality by cause.
Results: After five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, p = 0.04) for any first fracture and 0.67 (0.48 to 0.93, p = 0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, p = 0.18). Findings were consistent in men and women and in doctors and the general practice population.
Conclusion: Four monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.
2008-zhu.pdf: “Effects of Calcium and Vitamin D Supplementation on Hip Bone Mineral Density and Calcium–Related Analytes in Elderly Ambulatory Australian Women: A Five–Year Randomized Controlled Trial”, (2008-03-01; ):
Context: Effects of long-term calcium, with or without vitamin D, on hip bone mineral density (BMD) and bone turnover in sunny climates have not been reported.
Objective: The aim was to evaluate the effect of vitamin D added to calcium supplementation on hip dual-energy x-ray absorptiometry BMD and calcium-related analytes.
Design, Setting, and Participants: The study was a 5-yr randomized, controlled, double-blind trial of 120 community-dwelling women aged 70–80 yr.
Intervention: The interventions were 1200 mg/d calcium with placebo vitamin D (Ca group) or with 1000 IU/d vitamin D2 (CaD group), or double placebo (control).
Main Outcome Measures: Hip BMD, plasma 25-hydroxyvitamin D, biomarkers of bone turnover, PTH, and intestinal calcium absorption were measured.
Results: Hip BMD was preserved in CaD (−0.17%) and Ca (0.19%) groups but not controls (−1.27%) at yr 1 and maintained in the CaD group only at yr 3 and 5. The beneficial effects were mainly in those with baseline 25-hydroxyvitamin D levels below the median (68 nmol/liter). At yr 1, compared with controls, the Ca and CaD groups had 6.8 and 11.3% lower plasma alkaline phosphatase, respectively (p ≤ 0.02), and 28.7 and 34.5% lower urinary deoxypyridinoline to creatinine ratio, respectively (p ≤ 0.05). At 5 yr, this suppression was maintained only in the CaD group. CaD reduced PTH at 3 and 5 yr cf. controls (27.8 and 31.3%, p ≤ 0.005) in those with baseline PTH levels above the median (3.6 pmol/liter). Therapy did not affect intestinal calcium absorption at high carrier loads.
Conclusions: Addition of vitamin D to calcium has long-term beneficial effects on bone density in elderly women living in a sunny climate, probably mediated by a long-term reduction in bone turnover rate.
Objective: To assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.
Design: Pragmatic open.
Setting: Practice nurse led clinics in primary care.
Participants: 3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.
Intervention: Daily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).
Main Outcome Measures: Primary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).
Results: 69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95%0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.
Conclusion: We found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, registry.
2016-barzilai.pdf: “Metformin as a Tool to Target Aging”, Nir Barzilai, Jill P. Crandall, Stephen B. Kritchevsky, Mark A. Espeland
2017-campbell.pdf: “Metformin reduces all–cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta–analysis”, (2017-11-01; ):
- Diabetics on metformin have lower morality than non-diabetics and other diabetics.
- Diabetics on metformin have less cancer than non-diabetics and other diabetics.
- Diabetics on metformin have less cardiovascular disease than other diabetics.
- Metformin appears to extend health and life spans independent of its effect on diabetes.
- Metformin may be able to extend health and lifespans in the general population.
This systematic review investigated whether the insulin sensitizer metformin has a geroprotective effect in humans.
Pubmed and Embase were searched along with databases of unpublished studies. Eligible research investigated the effect of metformin on all-cause mortality or diseases of ageing relative to non-diabetic populations or diabetics receiving other therapies with adjustment for disease control achieved. Overall, 260 full-texts were reviewed and 53 met the inclusion criteria.
Diabetics taking metformin had statistically-significantly lower all-cause mortality than non-diabetics (hazard ratio (HR) = 0.93, 95% 0.92–0.97) and cardiovascular disease (CVD) compared to diabetics receiving non-metformin therapies (HR = 0.76, 95% 0.66–0.87) or insulin (HR = 0.78, 95% CI 0.73–0.83).0.88–0.99), as did diabetics taking metformin compared to diabetics receiving non-metformin therapies (HR = 0.72, 95% CI 0.65–0.80), insulin (HR = 0.68, 95% 0.63–0.75) or sulphonylurea (HR = 0.80, 95% 0.66–0.97). Metformin users also had reduced cancer compared to non-diabetics (rate ratio = 0.94, 95%
Differences in baseline characteristics were observed which had the potential to bias findings, although statistical adjustments were made.
The apparent reductions in all-cause mortality and diseases of ageing associated with metformin use suggest that metformin could be extending life and healthspans by acting as a geroprotective agent.
[Keywords: metformin, ageing, insulin sensitizer, lifespan, longevity, geroprotection]
2011-bulterijs.pdf: “Metformin As a Geroprotector”, Sven Bulterijs
Studies in mammals have demonstrated that hyperglycemia and hyperinsulinemia are important factors in aging and cancer. Inactivation of insulin/insulin-like signaling increases lifespan in nematodes, fruit flies, and mice. Life-prolonging effects of caloric restriction are in part due to reduction in IGF-1, insulin, and glucose levels. Antidiabetic biguanides such as metformin, which reduce hyperglycemia and hyperinsulinemia by decreasing insulin resistance, extend lifespan, and inhibit carcinogenesis in rodents. Will antidiabetic biguanides increase lifespan in humans?
“Metformin and Aging: A Review”, (2019-09-13):
Metformin is sometimes proposed to be an “anti-aging” drug, based on preclinical experiments with lower-order organisms and numerous retrospective data on beneficial health outcomes for type 2 diabetics. Large prospective, placebo-controlled trials are planned, in pilot stage or running, to find a new use (or indication) for an aging population. As one of the metformin trials has “frailty” as its endpoint, similar to a trial with a plant-derived senolytic, the latter class of novel anti-aging drugs is briefly discussed. Concerns exist not only for vitamin B12 and B6 deficiencies, but also about whether there are adverse effects of metformin on individuals who try to remain healthy by maintaining cardiovascular fitness via exercise.
…Conclusions, Recommendations, and Perspectives: The rationale for the ongoing or planned metformin trials is almost exclusively based on observations (associations) of potential benefits in a diabetic (or prediabetic) population. Its efficacy even in an at-risk cohort of aged people has not yet been proven. Metformin is associated with a higher risk of vitamin B12 and vitamin B6 deficiency, which may result in an increased risk of cognitive dysfunction . Supplementation is strongly recommended to metformin users.
Of greater concern are the results of small trials in which the effects of metformin on metabolic responses to exercise or on cardiorespiratory fitness were tested. In a placebo-controlled, double-blind, crossover trial with healthy young subjects, metformin caused a small but (repurposing) MASTERS trial (NCT02308228; Metformin to Augment Strength Training Effective Response in Seniors)  will be instructive. MASTERS is testing the hypothesis that older individuals’ long-term treatment with metformin augments the effects of resistance exercise, especially in the “nonresponder” aging population.decline in maximal aerobic capacity . A double-blind, placebo-controlled landmark trial with older adults with one risk factor for T2D investigated the effects of metformin and 12 weeks of aerobic exercise . Contrary to expectations—namely, that the effects of exercise and the drug would be additive–“metformin attenuated the increase in whole-body insulin sensitivity and abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration.” The results of the
“Epigenetic clocks: A review”, (2020-06-16):
It has recently been found possible to estimate age, mortality risk, or general health by looking merely at the epigenome. The models used to do so are referred to as epigenetic (or methylation) clocks.
Epigenetic clocks are increasingly becoming a popular choice for scientists in the field of aging research to measure the putative efficacy of anti-aging interventions. They may make it possible to get results before full Kaplan-Meier curves are available, and they could serve, at least seemingly, as a replacement for a host of other biomarkers. I recommend reading the introductory sections of “The Longevity FAQ” as well as those about epigenetics before reading this post as it gives some more context.
Even with a small number of the CpGs of the epigenome measured, it has been possible to construct clocks that accurately track age and health. We still don’t know exactly why the clocks work, just that they do. There is some interesting evidence pointing out to at least part of the pattern seem in the aged epigenome being causal, not just a reflection of the overall condition of the tissue or organism, so we may soon see the epigenome becoming a target for novel drugs. If you want to continue reading about this, Bell et. al 2019’s review (from where I extract the table below) and Raj & Horvath 2020 are the best starting points.
2019-fahy.pdf: “TRIIM: Reversal of epigenetic aging and immunosenescent trends in humans”, (2019-09-08; ):
Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age-related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (−2.5-year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from −1.6 year/year from 0–9 month to −6.5 year/year from 9–12 month. The GrimAge predictor of human morbidity and mortality showed a 2-year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.
Manipulations to set back biological age and extend lifespan in animal models are well established, and translation to humans has begun. The length of human life makes it impractical to evaluate results by plotting mortality curves, so surrogate markers of age have been suggested and, at present, the best established surrogates are DNA methylation clocks. Herein we report on a randomized, designed to be a first step in evaluating the effect of a diet and lifestyle intervention on biological age. Compared to participants in the control group (n = 20), participants in the treatment group tested an average 3.23 years younger at the end of the eight-week program according to the Horvath DNAmAge clock (p = 0.018). Those in the treatment group (n = 18) tested an average 1.96 years younger at the end of the program compared to the same individuals at the beginning with a strong trend towards statistical-significance (p = 0.066 for within group change). This is the first such trial to demonstrate a potential reversal of biological age. In this study, the intervention was confined to diet and lifestyle changes previously identified as safe to use. The prescribed program included multiple components with documented mechanistic activity on epigenetic pathways, including moderate exercise, breathing exercises for stress, and a diet rich in methyl donor nutrients and polyphenols.
“The economic value of targeting aging”, (2021-07-05):
Developments in life expectancy and the growing emphasis on biological and ‘healthy’ aging raise a number of important questions for health scientists and economists alike. Is it preferable to make lives healthier by compressing morbidity, or longer by extending life? What are the gains from targeting aging itself compared to efforts to eradicate specific diseases? Here we analyze existing data to evaluate the economic value of increases in life expectancy, improvements in health and treatments that target aging.
We show that a compression of morbidity that improves health is more valuable than further increases in life expectancy, and that targeting aging offers potentially larger economic gains than eradicating individual diseases. We show that a slowdown in aging that increases life expectancy by 1 year is worth US$38 trillion, and by 10 years, US$367 trillion.
Ultimately, the more progress that is made in improving how we age, the greater the value of further improvements.
…The economic value of gains from targeting aging are large because delaying aging produces complementarities between health and longevity, affect a large number of diseases due to the rising prevalence of age-related comorbidities, and create synergies arising from competing risks. Crucially, delaying aging leads to a virtuous circle in which slowing aging begets demand for further slowing in aging. This virtuous circle arises because society’s gains from delaying aging rise with the average age of society, increase with the quality of life in old age, and depend on the number of older people. This provides a distinctive dynamic to targeting aging compared to treatments aimed at specific diseases, in which gains diminish once successful treatments are discovered.
“Who By Very Slow Decay”, (2013-07-17):
[Essay by psychiatrist about care of the dying in American healthcare: people die agonizing, slow, expensive deaths, prolonged by modern healthcare, deprived of all dignity and joy by disease and decay. There is little noble about it.]
You will become bedridden, unable to walk or even to turn yourself over. You will become completely dependent on nurse assistants to intermittently shift your position to avoid pressure ulcers. When they inevitably slip up, your skin develops huge incurable sores that can sometimes erode all the way to the bone, and which are perpetually infected with foul-smelling bacteria. Your limbs will become practically vestigial organs, like the appendix, and when your vascular disease gets too bad, one or more will be amputated, sacrifices to save the host. Urinary and fecal continence disappear somewhere in the process, so you’re either connected to catheters or else spend a while every day lying in a puddle of your own wastes until the nurses can help you out…
Somewhere in the process your mind very quietly and without fanfare gives up the ghost. It starts with forgetting a couple of little things, and progresses…They don’t remember their own names, they don’t know where they are or what they’re doing there, and they think it’s the 1930s or the 1950s or don’t even have a concept of years at all. When you’re alert and oriented “x0”, the world becomes this terrifying place where you are stuck in some kind of bed and can’t move and people are sticking you with very large needles and forcing tubes down your throat and you have no idea why or what’s going on.
So of course you start screaming and trying to attack people and trying to pull the tubes and IV lines out. Every morning when I come in to work I have to check the nurses’ notes for what happened the previous night, and every morning a couple of my patients have tried to pull all of their tubes and lines out. If it’s especially bad they try to attack the staff, and although the extremely elderly are really bad at attacking people this is nevertheless Unacceptable Behavior and they have to be restrained ie tied down to the bed. A presumably more humane alternative sometimes used instead or in addition is to just drug you up on all of those old-timey psychiatric medications that actual psychiatrists don’t use anymore because of their bad reputation…Nevertheless, this is the way many of my patients die. Old, limbless, bedridden, ulcerated, in a puddle of waste, gasping for breath, loopy on morphine, hopelessly demented, in a sterile hospital room with someone from a volunteer program who just met them sitting by their bed.
…I work in a Catholic hospital. People here say the phrase “culture of life” a lot, as in “we need to cultivate a culture of life.” They say it almost as often as they say “patient-centered”. At my hospital orientation, a whole bunch of nuns and executives and people like that got up and told us how we had to do our part to “cultivate a culture of life.”
And now every time I hear that phrase I want to scream. 21st century American hospitals do not need to “cultivate a culture of life”. We have enough life. We have life up the wazoo. We have more life than we know what to do with. We have life far beyond the point where it becomes a sick caricature of itself. We prolong life until it becomes a sickness, an abomination, a miserable and pathetic flight from death that saps out and mocks everything that made life desirable in the first place. 21st century American hospitals need to cultivate a culture of life the same way that Newcastle needs to cultivate a culture of coal, the same way a man who is burning to death needs to cultivate a culture of fire.
And so every time I hear that phrase I want to scream, or if I cannot scream, to find some book of hospital poetry that really is a book of hospital poetry and shove it at them, make them read it until they understand. There is no such book, so I hope it will be acceptable if I just rip off of Wilfred Owen directly:
If in some smothering dreams you too could pace
Behind the gurney that we flung him in,
And watch the white eyes writhing in his face,
His hanging face, like a devil’s sack of sin;
If you could hear, at every jolt, the blood
Come gargling from the froth-corrupted lungs,
Obscene with cancer, bitter with the cud
Of vile, incurable sores on innocent tongues
My friend, you would not so pontificate
To reasoners beset by moral strife
The old lie: we must try to cultivate
A culture of life.