Positive Studies
A study from the LASA population evaluated the relationship between Vitamin D and PTH on loss of muscle strength and sarcopenia (Visser et al., 2003). Sarcopenia was measured using grip-strength and was defined as 40% loss of grip strength over a 3 year follow up period and body mass was measured using appendicular skeletal mass, measured by DXA. Of the 1,008 participants with complete data included in this analysis, the mean age was 75.5 years and 9.2% of the population had serum Vitamin D level <25nmol/L. Those who lost grip strength were older, had lower weight, and had more chronic diseases and weaker grip strength at baseline. Regression models revealed a significant association between low serum 25(OH)D levels (<25nmol/L) and loss of grip strength, OR 2.57 (1.40-4.70, 95% CI) compared with Vitamin D levels >50nmol/L. 25(OH)D levels <50nmol/L were found to be associated with loss of appendicular skeletal muscle strength over time, OR 2.25 (1.11- 2.56, 95% CI).
The association between Vitamin D and lower limb extremity strength (assessed using the eight foot (2.4meters) walking speed test and five repetitions of the sit-to-stand test) in 4,100 ambulatory older US adults from NHANES III was investigated (Bischoff-Ferrari et al., 2004c). The mean age of participants was 71.4 years with mean 25(OH)D levels of 57.9nmol/L in the inactive participants versus 68.4nmol/L in those who are active. There was an association between 25(OH)D levels and lower limb extremity function in adjusted models, performance speed was lowest at lower 25(OH)D levels and speed increased with increasing Vitamin D levels.
Puts et al found increased risk of frailty associated with Vitamin D in the LASA study population (Puts et al., 2005). Cross-sectional analysis was performed on 1,271 participants. Prospective data was available for 885, which excluded those lost to follow- up, those who died, those who were frail at baseline (n=242), and those who were not contactable at 3-year follow-up. Nine frailty indicators were measured including: BMI, MMSE, PEFR, vision and hearing impairment, incontinence, low sense of mastery and depressive symptoms. At baseline those who were frail were older (79.2 years compared
(23.2% of frail versus 8.3% of non-frail had 25(OH)D levels <25nmol/L). At 3-year follow-up, 14.1% of participants had transitioned to frail from non-frail status at baseline. Logistic regression for cross-sectional data revealed that low 25(OH)D levels had greater odds of frailty, OR 2.55 (1.56-617, 95% CI) in fully adjusted models. In longitudinal regression models, there was increased odds of frailty in those participants with 25(OH)D kevels <25nmol/L, OR 1.90 (0.92-3.95, 95% CI).
In 2006, Carpintero et al assessed the relationship between 1,2-dihydroxycholcalciferol (1,25(OH)2D3) and older adults with hip fracture following low trauma injury (Carpintero et al., 2006). Participants were seen at three and twelve months post hip fracture. This study included 109 participants with a mean age 81.4 years and with mean 25(OH)D levels of 26.9nmol/L and mean 1,25(OH)2D3 of 23.9mcg/ml. Multivariate logistic regression showed an increased odds of dependence at year one, OR 6.97 (1.7-28.4, 95% CI) with 1,25(OH)2D3 levels but report no association based on 25(OH)D and functional outcome, although results were not reported.
Wicherts et al report a relationship between Vitamin D and decline in physical performance over a three-year period in an older Dutch population (n=1,234) from the LASA study (Wicherts et al., 2007). After three years, 979 participants completed a repeat assessment. The mean age of participants at baseline was 75.3 years, with a mean 25(OH)D level of 53.9nmol/L, 48% of the study population had Vitamin D levels <50nmol/L at baseline. In fully adjusted models, physical performance was found to be poorer at lowest Vitamin D levels and appeared to increase with increasing serum 25(OH)D levels up to approximately 50nmol/L. Multivariate regression models showed Vitamin D levels <50nmol/L were associated with poorer physical performance compared with the reference group, OR -1.65 (-2.24 - -1.07, 95% CI) p <0.001. Regression models showed greater risk of decline in physical performance after three years in those with lower 25(OH)D levels (<25nmol/L) at baseline, OR 2.21 (1.00-4.87, 95% CI).
A study from the Hawaiian Osteoporosis Study (HOS) found an association between serum 25(OH)D and quadriceps strength (Pramyothin et al., 2009). Participants were female, n=495, with a mean age of 74.5 years with a mean Vitamin D level of 79.9nmol/L. Among the performance based tests and three strength tests carried out, quadriceps strength was associated with Vitamin D levels, β 0.114, p=0.006. Vitamin D was not correlated with any Activates of Daily Living (ADLs). Longitudinal data over the follow up period (mean 2.7 years) showed there was increased risk of vertebral fractures with increasing 25- hydroxyitamin D3 levels, OR 1.55, p=0.040. There was no significant association between Vitamin D and falls, although there were small event numbers for multivariate analysis models.
Shardell et al evaluated the relationship between frailty and Vitamin D status in a longitudinal Italian study, the InChianti study (Shardell et al., 2009). Data was collected from residents randomly selected from a population registry and further data collected at three and six years. Frailty was defined using the five criteria proposed by Fried et al. 904 participants aged >65 years were included. The median 25(OH)D level was 40nmol/L and mean age was 74.4 years. At baseline, those with lower Vitamin D levels (<50nmol/L) tended to be older, lower MMSE scores and higher frailty prevalence. 295 participants died over the 6-year follow-up period. Standardised frailty state transition models based on 25(OH)D levels (</>50nmol/L) were provided. Pre-frail participants with low 25(OH)D levels were 8.9% more likely to die than those with levels >50nmol/L (2.5-152%, 95% CI). Pre-frail participants with low Vitamin D levels were more likely to become frail at three years, 7.7% (-3.5-18.7%, 95% CI) and were less likely to become robust after three years than those with high 25(OH)D levels. Using 25(OH)D as a continuous variable, each 7.5nmol/l decrease in 25(OH)D was associated with increased odds of death in those without exhaustion at baseline and increased odds of dying rather than recovery in those with exhaustion. It was also associated with greater odds of developing weakness (as a frailty category) in those without weakness, OR 1.11 (1.10-2.72, 95% CI) or dying, OR 2.63 (1.18-10.4, 95% CI).
were included if they had; full frailty data available (defined using modified Fried criteria), 25(OH)D measured, aged >60 years and 5,048 met inclusion criteria. The mean 25(OH)D in whites was 70.4nmol/L and in non-whites was 54.9nmol, which was a statistically significant difference (p<0.0001). 25(OH)D levels were associated with frailty in both whites, OR 3.7 (2.1-6.8, 95% CI) and non-whites, OR 4.0 (1.7-9.2, 95% CI).
Chang et al explored the relationship between Vitamin D and frailty in an older community dwelling Taiwanese population (Chang et al., 2010). Subjects had participated in a prior study regarding integrated care for frail older adults, those (n=548) who scored 3-6 on the Chinese Canadian Study of Health and Ageing Clinical Frailty Scale Telephone Version (CCSHA_CFS_TV) were invited to participate in the current study. Their mean age was 71.1 years, mean MMSE of 25.1 and mean 25(OH)D of 99.6nmol/L. Frailty was assessed using the Fried Frailty Index (FFI) and the Edmonton Frail Scale (EFS). Analysis found increased odds of frailty associated with low levels of Vitamin D (<50nmol/L), using the FFI, OR 2.67 (1.29-5.52, 95% CI) for pre-frail versus robust and OR 8.26 (2.82-24.24, 95% CI) for frail versus robust on basic regression models and findings remained significant on fully adjusted models. Using the EFS results are similar but the model lost significance with multivariate analysis.
An Italian study including 904 participants from the InChianti study investigated the relationship between 25(OH)D and frailty states (Shardell et al., 2012). Frailty was again defined using the Fried criteria. The mean age of participants was 74.4 years and the median Vitamin D level was 39.9nmol/L. Participants were followed at 3 and 6 years after recruitment. Robust participants with low Vitamin D levels (<50nmol/L) were 4.9% less likely to remain robust, 6.4% more likely to become pre-frail and 1.4% more likely to become frail than those with high Vitamin D levels. Pre-frail participants were 7.7% less likely to become robust, 4.3% less likely to stay pre-frail and 3% more likely to become frail and 8.9% more likely to die than those with high Vitamin D levels. Findings for frail participants were less consistent, as those with low Vitamin D levels were 0.5% more
likely to die and 13.5% more likely to become frail than those with high Vitamin D levels over the follow-up period.
A population study of European men from the EMAS study reported an association between Vitamin D, Parathyroid Hormone (PTH) and frailty (Tajar et al., 2013). Frailty in this study was defined using the Fried criteria to calculate their own frailty measures including the EMAS FP (Frailty Phenotype) and EMAS FI (Frailty Index). This study included 1,504 men with a mean age of 69.5 years and mean Vitamin D of 62.9nmol/L. Using the FP with lower Vitamin D levels there was increased risk of being pre-frail, OR 1.45 (1.26-1.67, 95% CI) or frail, OR 1.89 (1.30-2.76, 95% CI) compared with being robust in fully adjusted models. Analysis for individual frailty factors showed that lower levels of Vitamin D were associated with increased risk of weakness, slower walking speed, lower activity levels and exhaustion.
A prospective study from the HIMS population was performed assessing the link between Vitamin D and frailty (measured using the FRAIL scale which has five domains; fatigue, resistance, ambulation, illness and weight loss (Wong et al., 2013). The mean age of the 4,203 men was 76.6 years with a mean 25(OH)D of 68.3nmol/L. At baseline, 16.1% were frail. After a mean follow-up period of 5.3years, 1,817 men responded and of these, 25.3% were frail. On cross-sectional analysis, low Vitamin D levels were associated with increased odds of frailty, OR 1.96 (1.52-2.52, 95%CI). In longitudinal analysis again lower Vitamin D levels were associated with increased odds of frailty, OR 1.56, 1.07-2.27, 95% CI).
An Australian study (the CHAMP Study) found an association between Vitamin D and frailty in older community dwelling men (Hirani et al., 2013). Vitamin D was measured using 25(OH)D and also 1,25(OH)2D3 and frailty was defined as having three out of the five following markers; weight loss, weakness/reduced muscle strength, slow walking speed, exhaustion and low activity level. The mean age of the 1,659 participants was 77 years, mean Vitamin D was not provided. The prevalence of frailty was 9.2% in those with 25(OH)D measured and 8.6% for those with 1,25(OH)2D3 measured. Logistic regression
2.66 (1.32-5.26, 95% CI) and increased odds in those with 1,25(OH)2D3 levels <62mmol/L, OR 1.86 (1.04-3.59, 95% CI).
A cross sectional and longitudinal study from the LASA study population reported an association between Vitamin D deficiency and functional limitations (Sohl et al., 2013). The study population was divided into two cohorts based on age at time of study recruitment. Functional limitations were assessed using a questionnaire. The mean age of participants in the older cohort was 75.3 years versus 60.0 years in the younger cohort and the mean 25(OH)D levels were 53.9nmol/L versus 56.7nmol/L. Regression analysis showed an increased odds of functional limitation in those with Vitamin D levels <50nmol/L compared with higher levels, in the older cohort, OR 1.7 (1.2-2.5, 95% CI) and younger cohort, OR 2.1 (1.2-3.5, 95% CI). In longitudinal analysis, Vitamin D deficiency (50nmol/L) was associated with increased risk of functional limitation after three years in the older participants, OR 2.9 (1.1-3.5, 95% CI) but not at six years, the association was present in younger participants after six-years, OR 3.3 (1.1-10.1, 95% CI).
In 2014 Wang et al found an association between 25(OH)D levels, Vitamin D Binding Protein (VDBP) and frailty (Wang et al., 2014). Participants (n=418) had a mean age of 76.4 years, and mean Vitamin D level of 41.6nmol/L. Frail participants (defined using Fried criteria) were older, less educated, higher DBP and lower Vitamin D levels than their non frail counterparts. The odds of being frail versus non-frail was assessed across Vitamin D quartiles and showed increased odds of frailty in those with in the lowest quartile of Vitamin D and highest quartile of DBP, OR 3.18 (1.46-4.56, 95% CI) and also increased odds of frailty in those with lowest quartile of Vitamin D and lowest quartile of DBP, OR 2.63 (1.31-3.68, 95% CI) compared with those in the reference group (lowest quartile of DBP and highest quartile Vitamin D).
Wang et al also evaluated the relationship between Vitamin D deficiency and outcomes after hip fractures in a case control study (Wang et al., 2015). Participants were admitted with a first acute hip fracture (n=265) over an eighteen-month period. A similar number of
age and sex matched cases were also recruited. The median age of patients was 69 years. Cases were more likely to have lower serum calcium and 25(OH)D levels than controls, 77% of cases were Vitamin D deficient versus 57.4% of controls. Those with hip fractures had significantly lower 25(OH)D levels at 40.6nmol/L than the control group, 46nmol/L. Functional outcome was based on the Barthel Index (BI), with a favourable outcome score defined as 50-100. At discharge 24% were defined as having poor functional outcome. In multivariate analysis, 25(OH)D deficiency was found to be associated with poorer functional outcome, OR 5.25 (3.12-8.16, 95% CI).
A further prospective study reported an association between 25(OH)D and frailty and all- cause mortality (Vogt et al., 2015). The KORA Age Study was a follow-up study of four German cross-sectional studies of community dwelling adults. Of the original participants who took part in the baseline assessment, 822 participants were re-examined after a median of 2.9 years. Participants unable to attend the study centre were re-examined at home. Frailty was assessed using the Fried criteria. The mean age of participants was 75.5 years and the mean 25(OH)D level was 46.7nmol/L. The incidence of frailty at follow up was 29% and the incidence of pre-frailty was 21.1%. Those with Vitamin D levels <30nmol/L at baseline had higher odds of becoming pre-frail, OR 2.43 (1.17-5.03, 95%CI) and becoming frail, OR 2.53 (1.23-5.22, 95% CI). For individual markers of frailty, 25(OH)D levels <30nmol/L were found to be significantly associated with slow walking speed, OR 3.8 (1.53-9.25, 95% CI) and physical inactivity, OR 5.1 (1.63-16.17, 95% CI).
A Chinese post hoc analysis study evaluated the effects of Vitamin D levels and functional outcome in women with hip fractures (Liu et al., 2015). The population included 261 postmenopausal women admitted with their first hip fracture to an Orthopaedic Unit, not taking Calcium/Vitamin D supplementation. Median 25(OH)D was 37.9nmol/L and median age was 68 years. The median Barthel Index (BI) on discharge was 70 and 29.1% of participants were classified as having a poor functional outcome. Authors found a correlation between Vitamin D and BI (r=0.384, p<0.0001). In those with unfavourable functional outcome Vitamin D levels were lower compared with those with favourable
an unfavourable outcome, OR 0.83 (0.79-0.90, 95% CI).
A further study from the KORA Age study population was published reporting an association between Vitamin D and frailty. Frailty was defined using the Fried criteria (Pabst et al., 2015). The mean age of the 940 participants was 75.6 years with a mean serum 25(OH)D level of 46.8nmol/L. With the lowest levels of Vitamin D as the reference range, 25(OH)D levels >75nmol/L were less frequently frail or pre-frail compared with those with Vitamin D levels 30 - <50nmol/L, OR 0.38 (0.23-0.60, 95% CI) versus OR 0.51 (0.33-0.78, 95 %CI) respectively. Vitamin D was also found to be associated with the individual frailty criteria of exhaustion, physical inactivity and slowness.
In a study evaluating the prevalence of muscle weakness and its association with Vitamin D in people living in Ecuador an association was noted between 25(OH)D concentrations and muscle strength (Orces, 2016). Muscle weakness was measured via Grip strength. The study comprised 2,205 participants with a mean age of 71.7 years with mean Vitamin D concentrations of 67nmol/L. Multivariate analysis showed a significant mean difference in Vitamin D levels based on grip strength category; intermediate -3.2 and weak -3.2, p=0.05.
In a cohort of older women residing in nursing homes, Vitamin D deficiency at baseline was found to be associated with functional decline (Kotlarczyk et al., 2017). Participants (n=137) were nursing home residents aged 65 years and older and were followed for two years. Functional assessment was based on Katz Activities of Daily Living (ADLs) and Instrumental ADLs and the nursing home Physical Performance Test (PPT). Cognition was measured with SPSMQ. Participants had a mean Vitamin D level of 66.1nmol/L and mean age of 85.4 years. Those deficient in Vitamin D at baseline were more likely to have slower gait speed and also lower IADL scores. Those deficient in Vitamin D were supplemented with 800IU of Vitamin D daily and serum levels increased from 34.4 to 88.6nmol/L after two years, no information was available on compliance. However, at follow up, those initially deficient in Vitamin D showed greater functional decline than those sufficient at baseline; decreased IADL score -2.5 compared with -1.2 (p=0.0153), decline in PPT score -
3.1 compared with -0.5 and greater decline in cognitive score on SPSMQ. Those deficient in Vitamin D experienced a greater number of falls, 88.5% compared with sufficient participants, 66.2 with AOR 4.01 p=0.037.
Buta et al evaluated the relationship between Vitamin D and frailty in a female population from The Women’s Health and Ageing Study (WHAS II) (Buta et al., 2017). Frailty was defined as having three out of the following five criteria; weight loss, weakness, exhaustion, slowness, and less physical activity. Participants, n=369, were non-frail at baseline and were followed for a mean of 8.5 years and 23.8% developed frailty over that time. The incidence of frailty in women with 25(OH)D levels <25nmol/L was 32.2/1,000 person years compared with 12.9/1,000 person years in those with Vitamin D levels >75nmol/L. In Cox regression analysis lower Vitamin D levels (<25nmol/L) were associated with increased risk of frailty in fully adjusted models, HR 2.55 (1.04-6.29, 95% CI) p<0.05. When the model was adjusted for cardiovascular risk factors, this association remained, but lost statistical significance, HR 2.29 (0.92-5.69, 95% CI) p=0.07.
In a study involving 3,369 men, authors found an association between Vitamin D status and frailty, with higher levels of serum Vitamin D associated with reduced risk of progression of frailty (Swiecicka et al., 2017b). Participants were part of the EMAS study and were followed for a median of 4.3 years. The mean age was 59 years and mean 25(OH(D level was 64.6nmol/L. Frailty was measured using the EMAS Frailty Index (FI) and Frailty Phenotype (FP). Fully adjusted multivariate models showed reduced risk of frailty with baseline Vitamin D levels, OR 0.84 (0.75-0.95, 95% CI) p=0.007.
Negative Studies
A US study evaluated the association of Vitamin D and frailty (using Fried criteria) in a cohort of 4,551 community dwelling women classed as robust/non-frail at baseline (Ensrud et al., 2010). These women were followed after approximately 4.5 years and their frailty status was reassessed. Those with one or two components were considered intermediate frailty and those with greater than three components were considered to be frail. The mean age of participants was 76.7 years with mean Vitamin D levels of 57.8nmol/L. In cross-
frailty (frail versus robust/intermediate) in basic and multivariate models, OR 1.47 (1.19- 1.82, 95% CI). Of the 4,119 participants with repeat frailty assessment at year ten, 432 (9.2%) had died prior to follow-up examination. There was no association between baseline 25(OH)D levels and odds of becoming intermediate/frail/dead (versus robust) at follow-up.
Ensrud et al also evaluated the relationship between 25(OH)D and frailty in 1,606 older men in the MrOS study population (Ensrud et al., 2011). Of these, 1,476 were defined as non-frail at baseline. Frailty status was defined using the Fried criteria. The mean age at baseline was 73.8 years. Those with lower Vitamin D levels at baseline were more likely to be frail or intermediately frail compared with those with higher Vitamin D levels and they had higher prevalence of each individual component of frailty. In cross sectional, fully adjusted, analysis those with 25(OH)D levels <50nmol/L had greater odds of frailty than those with levels >75nmol/L, OR 1.60 (1.19-2.16, 95% CI). In longitudinal analysis, men defined as non-frail (robust or intermediate frailty), were followed for a mean of 4.6 years. In multivariate models 25(OH)D levels were not associated with increased odds of frailty, OR 1.01 (0.71-1.45, 95% CI).
A Belgian study found no association between Vitamin D and physical performance in older adults (Mathei et al., 2013). This prospective study included 367 participants aged greater than 80 years with physical performance measured by static balance, gait speed and