No effect of monthly supplementation with 12000 IU, 24000 IU or 48000 IU vitamin D3 for one year on muscle function: The vitamin D in older people study

Vitamin D plays a role in muscle function through genomic and non-genomic processes. The objective of this RCT was to determine the effect of monthly supplemental vitamin D3 onmuscle function in 70+ years old adults. Participants (n = 379) were randomized to receive, 12000 IU, 24000 IU or 48000 IU of vitamin D3 monthly for 12 months. Standardized Hand Grip Strength (GS) and Timed-Up and Go (TUG) were measured before and after vitamin D3 supplementation. Fasting total plasma 25 hydroxyvitamin D (25OHD) and Parathyroid Hormone (PTH) concentrations were measured by Liquid Chromatography Tandem Mass Spectrometry (LC-MSMS) and immunoassay, respectively. Baseline plasma 25OHD concentrations were 41.3 (SD 19.9), 39.5 (SD 20.6), 38.9 (SD 19.7) nmol/L; GS values were 28.5 (SD 13.4), 28.8 (SD 13.0) and 28.1 (SD 12.1) kg and TUG test values were 10.8 (SD 2.5), 11.6 (SD 2.9) and 11.9 (SD 3.6) s for the 12000 IU, 24000 IU and 48000 IU dose groups, respectively. Baseline plasma 25OHD concentration < 25 nmol/L was associated with lower GS (P = 0.003). Post-interventional plasma 25OHD concentrations increased to 55.9 (SD 15.6), 64.6 (SD15.3) and 79.0 (SD 15.1) nmol/L in the 12000 IU, 24000 IU and 48000 IU dose groups, respectively and there was a significant dose-related response in post-interventional plasma 25OHD concentration (p<0.0001). Post-interventional GS values were 24.1 (SD 10.1), 26.2 (SD10.6) and 25.7 (SD 9.4) kg and TUG test values were 11.5 (SD 2.6), 12.0 (SD 3.7) and 11.9 (SD 3.2) s for 12000 IU, 24000 IU and 48000 IU dose groups, respectively. The change (Δ) in GS and TUG from pre to post-intervention was not different between treatment groups before and after the adjustment for confounders, suggesting no effect of the intervention. Plasma 25OHD concentration was not associated with GS and TUG test after supplementation. In conclusion, plasma 25OHD concentration < 25 nmol/L was associated with lower GS at baseline. However, monthly vitamin D3 supplementation with 12000 IU, 24000 IU and 48000 IU, for 12 months had no effect on muscle function in older adults aged 70+ years

Recruitment strategies for sarcopenia trials – lessons from the LACE randomised controlled trial

Background: Sarcopenia is rarely diagnosed and is not recorded electronically in routine clinical care, posing challenges to trial recruitment. We describe the performance of four components of a strategy to efficiently recruit participants with sarcopenia to a trial of perindopril and/or leucine for sarcopenia: primary care vs. hospital recruitment, a comparison of central vs. local telephone pre-screening, performance of a questionnaire on physical function conducted as part of the pre-screening telephone call, and performance of bioimpedance measurement to identify low muscle mass. Methods: Hospital-based recruitment took place through inpatient and outpatient geriatric medicine services. Local research nurses reviewed medical notes and approached potentially eligible patients. Primary care recruitment reviewed primary care lists from collaborating practices, sending mailshots to patients aged 70 and over who were not taking angiotensin-converting enzyme inhibitors. Telephone pre-screening was conducted either by research nurses at each site or centrally by Tayside Clinical Trials Unit. The 10-point SARC-F questionnaire was used for pre-screening. De-identified recruitment information was held on a central electronic tracking system and analysed using SPSS. Bioimpedance was measured using the Akern BIA 101 system, with the Sergi equation used to estimate lean mass. Results: Fourteen UK sites recruited to the trial. The 1202 sets of notes in hospital-based care were reviewed at these sites; 7 participants (0.6% of total notes screened) were randomized. From primary care, 13 808 invitations were sent; 138 (1.0% of total invited) were randomized. 633/2987 primary care respondents were pre-screened centrally; the mean number of calls per respondent was 2.3. For 10 sites where central and local pre-screening could be compared, the conversion rate from pre-screening to randomization was 18/588 (3.1%) for centralized calls, compared with 73/1814 (4.0%) for local pre-screening calls (P = 0.29). A weak relationship was seen between higher (worse) SARC-F score at screening and lower likelihood of progression to randomization (r = −0.08, P = 0.03). Muscle mass estimates generated using the Sergi equation were systematically biased, and a recalibrated equation for bioimpedance-estimated muscle mass was derived. Conclusions: Primary care recruitment led to higher response rates and overall numbers randomized than hospital-based recruitment. Centralized pre-screening saved local research nurses' time but did not improve conversion to randomization. SARC-F did not help to target screening activity in this sarcopenia trial, and a recalibration of the equation for estimating muscle mass from bioimpedance measures may improve accuracy of the screening process

Randomized controlled trial of Vitamin D supplementation in older people to optimize bone health

Background: Vitamin D insufficiency is common in older people and may lead to increased bone resorption, bone loss, and increased falls and fractures. However, clinical trials assessing the effect of vitamin D supplementation on bone mineral density (BMD) have yielded conflicting results. Objectives This study examined the effect of vitamin D supplementation on BMD at the hip, using dual-energy X-ray absorptiometry. Methods: A total of 379 adults aged ≥70 y (48% women; mean age: 75 y) from the northeast of England were randomly allocated to 1 of 3 doses of vitamin D 3 [12,000 international units (IU), 24,000 IU, or 48,000 IU] given once a month. The primary outcome was change in BMD (δBMD) at the hip. Secondary endpoints comprised the dose effects on femoral neck BMD, falls, circulating calciotropic hormones, bone turnover markers, and adverse events. Results: The mean ± SD baseline plasma 25-hydroxyvitamin D [25(OH)D] concentration was 40.0 ± 20.1 nmol/L, which increased after 12 mo to a mean 25(OH)D of 55.9, 64.6, or 79.0 nmol/L for participants receiving a monthly dose of 12,000, 24,000, or 48,000 IU, respectively (P < 0.01 for difference). There was no between-group difference in δBMD. However, parathyroid hormone concentrations decreased in all 3 groups, with a significantly greater decrease in the 48,000-IU group compared with the 12,000-IU group (P < 0.01). There were no differences in any adverse events between groups, with 3 cases of hypercalcemia, none of nephrolithiasis, and 249 falls observed. Conclusions: There was no difference in change in BMD over 12 mo between the 3 doses of vitamin D, suggesting no effect of the intervention or a similar attenuation of the anticipated decrease in BMD over 12 mo. The treatment was safe and effective in increasing plasma 25(OH)D concentrations, with no dose-related adverse events. This trial was registered at the EU Clinical Trials Register (EudraCT 2011-004890-10) and the ISRCTN Registry (ISRCTN35648481)

Randomized controlled trial of Vitamin D supplementation in older people to optimize bone health

Background: Vitamin D insufficiency is common in older people and may lead to increased bone resorption, bone loss, and increased falls and fractures. However, clinical trials assessing the effect of vitamin D supplementation on bone mineral density (BMD) have yielded conflicting results. Objectives This study examined the effect of vitamin D supplementation on BMD at the hip, using dual-energy X-ray absorptiometry. Methods: A total of 379 adults aged ≥70 y (48% women; mean age: 75 y) from the northeast of England were randomly allocated to 1 of 3 doses of vitamin D 3 [12,000 international units (IU), 24,000 IU, or 48,000 IU] given once a month. The primary outcome was change in BMD (δBMD) at the hip. Secondary endpoints comprised the dose effects on femoral neck BMD, falls, circulating calciotropic hormones, bone turnover markers, and adverse events. Results: The mean ± SD baseline plasma 25-hydroxyvitamin D [25(OH)D] concentration was 40.0 ± 20.1 nmol/L, which increased after 12 mo to a mean 25(OH)D of 55.9, 64.6, or 79.0 nmol/L for participants receiving a monthly dose of 12,000, 24,000, or 48,000 IU, respectively (P < 0.01 for difference). There was no between-group difference in δBMD. However, parathyroid hormone concentrations decreased in all 3 groups, with a significantly greater decrease in the 48,000-IU group compared with the 12,000-IU group (P < 0.01). There were no differences in any adverse events between groups, with 3 cases of hypercalcemia, none of nephrolithiasis, and 249 falls observed. Conclusions: There was no difference in change in BMD over 12 mo between the 3 doses of vitamin D, suggesting no effect of the intervention or a similar attenuation of the anticipated decrease in BMD over 12 mo. The treatment was safe and effective in increasing plasma 25(OH)D concentrations, with no dose-related adverse events. This trial was registered at the EU Clinical Trials Register (EudraCT 2011-004890-10) and the ISRCTN Registry (ISRCTN35648481)

Activin type I receptor polymorphisms and body composition in older individuals with sarcopenia—Analyses from the LACE randomised controlled trial

Background: Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia.Methods: We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) =0.26 and rs2854464, MAF =0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial.Results: Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p=0.023) and had higher arm fat mass, (median higher by 15%, p=0.008), and leg fat mass (median higher by 14%, p=0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj=0.024). No associations (adjusted or unadjusted) were seen in females.Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p=0.017) and greater arm fat mass (median higher by 16%, p=0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone.Conclusion: These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals

Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial

Acknowledgements: AAS, TA and MDW acknowledge support from the NIHR Newcastle Biomedical Research Centre. AA acknowledges support from the Health Services Research Unit which is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorate. The authors acknowledge support from the NIHR Ageing Clinical Research Network and the NHS Scotland Support for Science programme, The authors would also thank the efforts of all the research nurses and other ants to the trial, all the participants, and all the staff of the Tayside Clinical Trials Unit for their support of the trial. Funding: The LACE trial (project reference 13/53/03) is funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership. The views expressed in this publication are those of the authors and not necessarily those of the MRC, NIHR or the Department of Health and Social Care.Peer reviewedPublisher PD

Odanacatib: the best osteoporosis treatment we never had?

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Food for thought: the efficiency of glucose metabolism predicts the self-generation of temporally distant cognition

The generation of thought independent of environmental input occupies almost half of mental life and is important for skills such as creativity and planning. To understand how this ubiquitous cognitive process relates to the brain's 'energy budget', a cross-sectional study is carried out to examine how the capacity for mental time travel relates to the efficiency with which adults metabolize glucose, the brain's primary source of fuel. On day 1 the ability of a group of 36 younger and 36 older individuals to metabolize glucose was assessed using the gold standard two-hour glucose tolerance test. Twenty-four hours later, the same group of participants returned to the laboratory to perform a non-demanding choice reaction time task during which experience sampling was used to assess the frequency with which they generated thoughts that were unrelated to the here and now. Analysis indicated that younger individuals who were the most efficient at metabolizing glucose exhibited mental time travel that spanned longer time periods. Given the importance of self-generated thought in daily life these results suggest that the capacity to mentally simulate events not present in the immediate environment is highly dependent on efficient glucose metabolism

National osteoporosis society vitamin D guideline summary

The National Osteoporosis Society (NOS) published its document, Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management, in 2013 as a practical clinical guideline on the management of vitamin D deficiency in adult patients with, or at risk of developing, bone disease. There has been no clear consensus in the UK on vitamin D deficiency its assessment and treatment, and clinical practice is inconsistent. This guideline is aimed at clinicians, including doctors, nurses and dieticians. It recommends the measurement of serum 25 (OH) vitamin D (25OHD) to estimate vitamin D status in the following clinical scenarios: bone diseases that may be improved with vitamin D treatment; bone diseases, prior to specific treatment where correcting vitamin D deficiency is appropriate; musculoskeletal symptoms that could be attributed to vitamin D deficiency. The guideline also states that routine vitamin D testing is unnecessary where vitamin D supplementation with an oral antiresorptive treatment is already planned and sets the following serum 25OHD thresholds: 50 nmol/l is sufficient for almost the whole population. For treatment, oral vitamin D3 is recommended with fixed loading doses of oral vitamin D3 followed by regular maintenance therapy when rapid correction of vitamin D deficiency is required, although loading doses are not necessary where correction of deficiency is less urgent or when co-prescribing with an oral antiresorptive agent. For monitoring, serum calcium (adjusted for albumin) should be checked 1 month after completing a loading regimen, or after starting vitamin D supplementation, in case primary hyperparathyroidism has been unmasked. However, routine monitoring of serum 25OHD is generally unnecessary but may be appropriate in patients with symptomatic vitamin D deficiency or malabsorption and where poor compliance with medication is suspected. The guideline focuses on bone health as, although there are numerous putative effects of vitamin D on immunity modulation, cancer prevention and the risks of cardiovascular disease and multiple sclerosis, there remains considerable debate about the evaluation of extraskeletal factors and optimal vitamin D status in these circumstances