Articles

Active vitamin D treatment in the prevention of sarcopenia
in adults with prediabetes (DPVD ancillary study):a randomised controlled trial
Tetsuya Kawahara, Gen Suzuki, Shoichi Mizuno, Naoki Tominaga, Mikio Toda, Nagahiro Toyama, Tetsuya Inazu, Chie Kawahara, Yosuke Okada,
Yoshiya Tanaka

Summary

Background Observational studies show inverse associations between serum 25-hydroxyvitamin D concentrations
and sarcopenia incidence; however, it remains unclear whether treatment with vitamin D prevents its development.
We aimed to assess whether treatment with active vitamin D (eldecalcitol [0·75 μg per day]) can reduce thedevelopment of sarcopenia among adults with prediabetes.
Methods This randomised, double-blind, placebo-controlled, multicenter trial as an ancillary study was conducted at
32 clinics and hospital sites in Japan. Participants were assigned (1:1) by using a central randomisation method inwhich a randomisation list was made for each hospital separately using a stratified permuted block procedure. The
primary endpoint was sarcopenia incidence during 3 years in the intention-to-treat population defined as weakhandgrip strength (<28 kg for men and <18 kg for women) and low appendicular skeletal muscle index (<7·0 kg/m²
for men and <5·7 kg/m² for women in bioelectrical impedance analysis). Although the usual criterion of
hypercalcaemia was 10·4 mg/dL (2·6 mmol/L) or higher, hypercalcaemia that was enough to discontinue the study
was defined as 11·0 mg/dL or higher. This study is registered with the UMIN clinical trials registry, UMIN000005394.
Findings A total of 1094 participants (548 in the eldecalcitol group and 546 in the placebo group; 44·2% [484 of 1094]
women; mean age 60·8 [SD 9·2] years) were followed up for a median of 2·9 (IQR 2·8–3·0) years. Eldecalcitol
treatment as compared with placebo showed statistically significant preventive effect on sarcopenia incidence(25 [4·6%] of 548 participants in the eldecalcitol group and 48 [8·8%] of 546 participants in the placebo group; hazard
ratio 0·51; 95% CI 0·31 to 0·83; p=0·0065). The incidence of adverse events did not differ between the two groups.
Interpretation We found that treatment with eldecalcitol has the potential to prevent the onset of sarcopenia amongpeople with prediabetes via increasing skeletal muscle volume and strength, which might lead to a substantial risk
reduction of falls.
Funding Kitakyushu Medical Association.
Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY
4.0 license.

Introduction
Sarcopenia is a condition associated with loss of skeletal
muscle mass, muscle strength, and physical function,
resulting in frailty and a propensity for falls and fractures.
In older adults, it increases the risk of long-term care anddeath, and affects the prognosis of various diseases.1,2
The global prevalence of sarcopenia varies between
10% and 27% according to the classification and cutoff
point used to define the condition.3 In addition, theprevalence of severe sarcopenia ranges from 2% to 9%.3
It has also been reported that prediabetes and diabetes
are independent risk factors for sarcopenia.4 In thecontext of an increasing global ageing population,
preventing sarcopenia has become an urgent social
matter that needs to be addressed.5
It has been shown that early intervention in sarcopenia
can extend healthy life expectancy, reduce care andmedical costs, slow disease progression, and even
www.thelancet.com/healthy-longevity Vol 5 April 2024

improvesarcopenia.6
Although
lower
serum
25-hydroxyvitamin D concentrations have been
associated with a higher incidence of sarcopenia in
observational studies,7 clinical intervention studies withvitamin D supple­mentation have reported inconsistent
results in muscle mass gain, muscle strength, and bodyfat loss.8–11 Additionally, two meta-analyses have showninconsistent conclusions about physical performance.12,13
However, the total sample size of both meta-analyses was
small, and the heterogeneity of various factors (eg,therapeutic effect and supplementation dose) was
observed; therefore, a large interventional study isneeded. Most importantly, there have been no large-scalerandomised controlled trials using an active form
vitamin D analog. Eldecalcitol, an active vitamin D
analog, has superior effects in increasing bone density
and inhibiting vertebral fractures compared with otheractive vitamin D, such as alfacalcidol,14,15 and is theLancet Healthy Longev 2024;
5: e255–63
Published Online
March 1, 2024
https://doi.org/10.1016/
S2666-7568(24)00009-6
See Comment page e239
For the Japanese translation of
the abstract see Online forappendix 1
The First Department ofInternal Medicine, Universityof Occupational andEnvironmental Health,
Kitakyushu, Japan(T Kawahara MD,
C Kawahara MD, Y Okada MD,
Prof Y Tanaka MD); Departmentof Endocrinology and Diabetes,
Shin Komonji Hospital,
Kitakyushu, Japan (T Kawahara,
N Tominaga MD, M Toda MD,
N Toyama MD); Department ofInternal Medicine,International University Healthand Welfare Clinic, Ohtawara,
Japan (Prof G Suzuki MD);
Division of Biostatics, National
Cancer Center EPOC, Kashiwa,
Japan (S Mizuno PhD);
Department of Pharmacy,
College of Pharmaceutical
Sciences, Ritsumeikan
University, Kusatsu, Japan(Prof T Inazu MD)
Correspondence to:
Dr Tetsuya Kawahara, The First
Department of Internal
Medicine, University ofOccupational and Environmental
Health, Kitakyushu 807-8555,
Japank-tetsuy@med.uoeh-u.ac.jp

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Research in context
Evidence before this study
There are various diagnostic criteria for sarcopenia, such as the
Asian Working Group for Sarcopenia 2019, the European
Working Group on Sarcopenia in Older People 2, and theFoundation for the National Institute of Health, with eachcutoff value being slightly different. However, they all share thesame diagnostic criteria items of skeletal muscle mass and grip
strength. Evidence from observational studies has shownassociations between low blood vitamin D concentrations andincreased sarcopenia incidence. Clinical trials of vitamin D
supplementation have not shown a consistent benefit formuscle mass and strength. We searched PubMed and Clinical
Trial Registrations on Sept 30, 2023, using the search terms“vitamin D”, “active vitamin D”, and “sarcopenia”. We searched
for clinical trials published between database inception and
Sept 30, 2023, in English, and found 31 randomised controlled
trials evaluating changes in muscle mass, muscle strength, andphysical performance as elements of sarcopenia with vitamin D
supplementation. These results have shown inconsistentconclusions about muscle mass gain and muscle strength.
Furthermore, there are no interventional studies that haveinvestigated the effect of vitamin D supplementation on theprevention of sarcopenia.

Added value of this study
Our Diabetes Prevention with active Vitamin D for sarcopenia
study is, to our knowledge, the first randomised clinical trial toassess the preventive effect of active vitamin D on sarcopenia
development. In this study, we have showed that treatment ofeldecalcitol, which is an active form vitamin D analog,
increased grip strength and skeletal muscle mass comparedwith placebo, and thus had a possibility of preventive effect on
the development of sarcopenia. In addition, it was found that
eldecalcitol treatment had a possibility of risk reduction of falls,
which is one of the sarcopenia-related clinical events.

approved for the treatment of osteoporosis in Japan and
China. Therefore, we aimed to investigate whether anactive vitamin D treatment would result in a lower
sarcopenia risk than a placebo among adults withprediabetes in an ancillary study of the Diabetes
Prevention with active Vitamin D (DPVD) trial.16

University of Occupational and Environmental Health,
Kokura Medical Association Health Testing Center, andFujisawa City Hospital.

Methods

Study design

See Online for appendix 3

See Online for appendix 2

e256

The DPVD trial was a multicentre, randomised, doubleblind, placebo-controlled trial investigating the effect ofactive vitamin D treatment (eldecalcitol 0·75 μg per day)on the primary prevention of type 2 diabetes incidence
among adults with prediabetes conducted at 32 clinics
and hospital sites in Japan. The selected vitamin D doseis used for osteoporosis prevention and treatment inJapan and China, with a favourable safety and efficacy
profile.17 Study participants agreed not to take any
additional vitamin D supplements or active vitamin D
drugs during the study period.16 In this ancillary study,
DPVD for sarcopenia, we examined the effects of active
vitamin D treatment compared with placebo on
sarcopenia development. Study eligibility criteria were
determined by diabetes-related indicators, the power
calculation for sample size was based on the primary
outcome of the incidence of type 2 diabetes in the
DPVD trial, and this study used the same participants
as the DPVD trial; however, a separate protocol was
created in advance (appendix 2). The study protocol wasapproved by the Institutional Review Boards of

Implications of all the available evidence
Our study can have an effect on future treatment guidelines forsarcopenia prevention because, until now, the only evidence
recommended in guidelines has been adequate protein intake
and moderate exercise. In the context of an increasing global
ageing population, eldecalcitol treatment could play animportant role in the prevention of sarcopenia. To validate andexpand our findings, we plan to conduct a clinical trial
targeting older people regardless of sarcopenia andprediabetes in the future.

Participants
Male and female participants were eligible for inclusion
if they were aged 30 years or older and had prediabetes
without sarcopenia. Hospitals and clinics in the vicinityof the three study centres invited their patients toparticipate in our study. We defined prediabetes as
meeting all three of the following glycaemic criteria:
fasting glucose concentration of less than 126 mg/dL(7·0 mmol/L), 2 h glucose concentration 140–199 mg/dL(7·8–11·0 mmol/L) during a 75 g oral glucose tolerance
test, and glycated haemoglobin of less than 6·5%
(48 mmol/L).18 Sarcopenia was defined as weakhandgrip strength (<28 kg for men and <18 kg for
women) and low appendicular skeletal muscle index(<7·0 kg/m² for men and <5·7 kg/m² for women inbioelectrical impedance analysis) based on thedefinition from the Asian Working Group for
Sarcopenia 2019.2 The definition criteria of theEuropean Working Group on Sarcopenia in Older
People 25 and the Foundation for the National Instituteof Health19 have been presented in appendix 3 (p 8) withthe complete inclusion and exclusion criteria(appendix 3, p 2). Participants were followed up every
3 months on an outpatient visit, with study completionat the sarcopenia onset, or until the 3-year follow-up
visit. Written informed consent was obtained from all
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participants before enrolment in the trial. Data on
gender were self-reported by the study participants
through free-text.

Randomisation and masking
Patients were randomly assigned (1:1) to either the active
vitamin D group (once-daily hard-gel pill containing
0·75 µg of eldecalcitol) or the matching placebo group,with both pills looking the same. Eldecalcitol and placebo
were prescribed by a sub-investigator (physician) every
3-month visit and exchanged for the prescription at an
independent pharmacy that had no association with any
members of the DPVD research group. The placebo waspurchased from Sunsho Pharmaceutical, Fujinomiya
city, Japan, which was responsible for the manufacturing,packing, and distribution of the placebo. This company
had no role in the design or conduct of the trial.
Sub-investigators (appendix 3, p 11) in the three trial
hospitals (University of Occupational and Environmental
Health, Kokura Medical Association Health Testing Center,and Fujisawa City Hospital) applied for registration andtreatment assignment to the Assignment Center.
Participants were assigned by using a central random­isation method in which a randomisation list was made foreach hospital separately using a stratified permuted block
procedure by TI at the Assignment Center before the firstparticipant’s entry. The number of strata was eightaccording to sex (male and female), age (30–54 years and≥55 years), and 75 g oral glucose tolerance test 2 h postload plasma glucose levels (<170 mg/dL and ≥170 mg/dL).
Based on the assignment list, which was kept in a locked
safe located in the Assignment Center, TI enrolled andallocated participants to either the eldecalcitol group or theplacebo group in the order of registration. The assignment
list was inaccessible to the investigators or sub-investigators
for the duration of the trial except in the event ofemergencies. All data obtained from the trial were collectedin the Assignment Center. The key was retrieved only after
the trial concluded and data were fixed.

ensure that the coefficient of variation was the same at all
centres. Serum 25-hydroxyvitamin D and 1, 25-dihydroxyvitamin D concentrations were measured by liquid
chromatography-tandem mass spectrometry at LSI
Medience Corporation (Tokyo, Japan). All data werecollected in the Assignment Centre.

Outcomes
The primary endpoint was the development ofsarcopenia. Secondary endpoints were the incidence offalls, the changes in handgrip strength, and that in bodycomposition: fat mass index, lean mass index, andappendicular skeletal muscle index during the 3-year
study period. However, the incidence of falls is post-hoc
because it was established as a secondary endpoint after
the study was completed. Falls were defined as
unintentionally coming to rest on the ground, floor, orother lower level. The sub-investigator (appendix 3, p 11)
interviewed participants for falls during outpatient visits
every 3 months. In subgroup analyses, we examined thetreatment effect after stratifying a risk factor forsarcopenia separately (ie, age, sex, BMI, fat mass index,
lean mass index, appendicular skeletal muscle index,
baseline serum 25-hydroxyvitamin D levels, and baseline
serum 1, 25-dihydroxy vitamin D levels).
3875 patients assessed for eligibility

2619 ineligible
2361 did not meet inclusion criteria
156 declined to participate
102 other

1256 randomly assigned

630 assigned to eldecalcitol
630 received assigned
intervention

Procedures
In every 3-month outpatient visit, all participants’ bodyweight, waist circumference, and handgrip strength were
measured. Handgrip strength was measured twice oneach side using a handgrip dynamometer (Takei
Scientific Instruments, Niigata, Japan). We used the
maximum value in the analysis. In addition, the volumesof skeletal muscle and body fat were measured with abody composition analyser (InBody720, InBody Japan,
Tokyo, Japan) using direct segmental multi-frequency
bioelectrical impedance analysis.20 Before the shipmentof the InBody analysers to the three study centres, themanufacturer measured the same sample for theseanalysers. After confirming that there was no differencein the measured values, they were shipped to each centre.
Every year, one sample was measured ten times at eachcentre, and the manufacturer calibrated the analysers to
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82 diagnosed with sarcopenia

548 in the eldecalcitol group

54 discontinued
16 adverse events
1 died1 poor compliance
4 withdrew consent
32 achieved normoglycaemia

548 included in intention-totreat analysis
545 included in per-protocol
analysis626 assigned to placebo
626 received assigned
intervention

80 diagnosed with sarcopenia

546 in the placebo group

51 discontinued
12 adverse events
1 died2 poor compliance
5 withdrew consent
31 achieved normoglycaemia

546 included in intention-totreat analysis
545 included in per-protocol
analysis

Figure 1: Trial profile

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Statistical analysis
The sample size and power calculation were originallybased on the primary outcome of the incidence of type 2
diabetes in the DPVD trial. However, if the accumulating
incidence of sarcopenia in the control group was 9·3%
(3·2% annually) for 3 years,21 and dropout ratio wasassumed to be 12%,16 546 participants in each group (atotal of 1092) would be sufficient to detect a 50% reduction
in sarcopenia development by eldecalcitol treatment
under 80% statistical power at a 5% significant level(two-sided).
Prespecified efficacy analyses were based on theintention-to-treat population. A log-rank test and Kaplan–
Meier analysis were used to estimate the time distribution
to sarcopenia and incidence of falls. The treatment effectwas expressed by hazard ratios (HRs) and 95% CI usinga Cox regression model. In addition, the results of Cox
regression analyses using the per-protocol population,
Total (N=1094)

Eldecalcitolgroup (N=548)

Placebo group(N=546)

Female484 (44·2%)245 (44·7%)239 (43·8%)Male

610 (55·8%)303 (55·3%)

307 (56·2%)

Sex

Ethnicity
Japanese1094 (100%)

548 (100%)

546 (100%)Age (years)

60·8 (9·2)

60·7 (9·0)

60·9 (9·4)

BMI (kg/m²)*

24·5 (2·5)

24·5 (2·5)

24·5 (2·3)

Fat mass index (kg/m²)

7·2 (2·1)

7·2 (2·1)

7·3 (2·1)

7·5 (2·1)

7·5 (2·1)

7·5 (2·1)

FemaleMale

7·0 (2·0)

7·0 (2·0)

7·1 (2·0)

17·3 (1·0)

17·3 (0·8)

17·3 (1·1)

Female16·9 (0·8)

16·8 (0·8)

16·9 (0·9)

Male

17·5 (1·0)

17·5 (0·9)

17·4 (1·2)

7·9 (0·9)

7·9 (1·2)

8·0 (1·3)

Female7·2 (1·1)

7·2 (1·1)

7·3 (1·2)Male

8·5 (1·0)

8·5 (1·0)

8·5 (1·1)

Lean mass index

Appendicular skeletal muscle index (kg/m²)

Grip strength (kg)29·9 (7·1)

29·9 (7·4)

29·9 (6·9)

Female23·1 (3·3)

23·2 (3·2)

23·0 (3·3)

Male

35·3 (5·0)

35·3 (5·0)

35·3 (5·0)

651 (59·5%)331 (60·4%)

320 (58·6%)

Family history of diabetes
Glycated haemoglobin (%)

5·9 (0·2)

5·9 (0·2)

6·0 (0·2)

Unintentional falls in the past year

228 (20·8%)

115 (21·0%)113 (20·7%)

Current smoker

64 (5·9%)32 (5·8%)31 (5·7%)

25-hydroxy vitamin D (ng/mL)

20·7 (6·0)

20·8 (6·1)

20·7 (6·0)

Distribution (ng/mL)
0 to <12

88 (8·0%)46 (8·4%)

42 (7·7%)≥12 to <20477 (43·6%)235 (42·9%)242 (44·3%)

20 to <30

549 (50·2%)

284 (51·8%)265 (48·5%)≥20 to ≥30

68 (6·2%)

29 (5·3%)

39 (7·1%)

41·2 (29·7–56·0)

41·0 (29·0–56·2)

41·5 (30·9–55·9)

1, 25-dihydroxy vitamin D (pg/mL)

Data are n (%), mean (SD), or median (IQR). Percentages might not total 100 because of rounding. *A total of
8·5% (93 of 1094 participants) were underweight (<22 kg/m²), 62·7% (686 participants) were normal weight (≥22 to<25 kg/m²), 25·8% (282 participants) were overweight (≥25 to <30 kg/m²), and 3·0% (33 participants) had obesity (≥30).

Table 1: Baseline characteristics of the intention-to-treat population*e258

and the adjustment for age, sex, and BMI were presented
as sensitivity analyses. We used t tests and analyses ofvariance to compare continuous variables acrossrandomised groups and χ² tests to compare proportions.
The results of the prespecified intention-to-treat analyses
in which missing data were imputed used the lastobservation-carried-forward method. In addition, as a
post-hoc analysis, we performed the multiple imputationof missing values by means of chained equations withfully conditional specification in R software (version 4.05);
data were assumed to be missing at random(appendix 3, p 3).22 In this study, we evaluated the changes
during 3 years in covariates (body composition measures)using the results of these two methods. We also
conducted a repeated measure ANOVA and Dunnett test
for the time trends of measurements. As statisticalanalyses were not adjusted for multiple hypotheses
testing, secondary endpoints and subgroup analysis
should be interpreted with caution. We considered
two-sided p values less than 0·05 to be statisticallysignificant. This trial is registered with the UMIN clinical
trials registry, UMIN000005394.

Role of the funding source
The funder of the study had no role in study design, datacollection, data analysis, data interpretation, or writing of
the report.

Results
From June 1, 2013, and Aug 31, 2015, a total of3875 individuals were screened (figure 1), and1256 were randomly assigned to receive eldecalcitol(630 participants) or matching placebo (626 participants).
For this study, 162 participants with sarcopenia diagnosedby the Asian Working Group for Sarcopenia 2019
criteria were removed from the analysis. A total of1094 participants (548 in the eldecalcitol group and
546 in the placebo group) were included in the intentionto-treat population.
Of the 1094 participants, 44·2% (484) were women and
59·5% (651 participants) had a family history of type 2
diabetes. Participants’ mean age was 60·8 (range 30–77)
years and BMI was 24·5 kg/m² (SD 2·5). Mean serum
25-hydroxyvitamin D levels were low (20·7 ng/mL[SD 6·0]; table 1; appendix 3, p 4). The trial was finishedin Aug 31, 2019. The median follow-up period was 2·9(IQR 2·8–3·0) years.
During the 3-year outpatient follow-up, 25 (4·6%) of
548 participants in the eldecalcitol group and 48 (8·8%)
of 546 participants in the placebo group developed
sarcopenia. Treatment of eldecalcitol, compared with thatof placebo, had a significant preventive effect on theincidence of sarcopenia (HR 0·51, 95% CI 0·31–0·83;
p=0·0065; figure 2). To assess the robustness of the
primary outcome based on the intention-to-treat
population, sensitivity analyses of the per-protocol
population and the population after adjustment for
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development of sarcopenia in participants who were older(≥64 years), female, had a low appendicular skeletal
muscle index (<7·4 kg/m²), and had low serum
25-hydroxyvitamin D levels (<18·3 ng/mL; appendix 3, p 7).
Duringthe
3-yearstudy
period,serum
25-hydroxyvitamin D concentrations were not changed
in both groups, whereas 1, 25-dihydroxy vitamin D
concentrations were substantially decreased in theeldecalcitol group compared with the placebo group(0·94% vs 0·72%; p=0·37; –21·4% vs 0·43%; p<0·0001),
in line with the parent study results (appendix 3, p 8).16
Eldecalcitol
Placebo

1·00
0·90
Cumulative incidence of sarcopenia

0·80
0·70
0·60
0·50
0·40
0·30

HR for sarcopenia 0·51 (95% CI 0·31–0·83); p=0·0065

0·20
0·10
0

0

Number at risk
Eldecalcitol 548
Placebo 546

3

6

9

12

15

18

21

24

27

30

33

36

422
403

410
387

399
374

314
293

Time since randomisation (months)
535
533

522
516

503
496

483
476

468
461

453
447

441
433

431
417

Figure 2: Kaplan–Meier plot for sarcopenia-free survival among adults with prediabetes
The study’s median follow-up was 2·9 years. The hazard ratio (HR) for new-onset sarcopenia between theeldecalcitol and placebo groups is derived from a log-rank test.
Eldecalcitol
Placebo

1·00
0·90
0·80
Cumulative incidence of falls

baseline age, sex, and BMI were performed. The results
showed HRs for eldecalcitol treatment of 0·51 (95% CI
0·31–0·84; p=0·0071) for the per-protocol population and
0·50 (0·29–0·79; p=0·0043) for the after-adjustment
population, which were consistent with the primary
analysis findings (appendix 3, p 5). In addition, although
this study investigated the incidence of sarcopenia
according to the diagnostic criteria of the Asian Working
Group for Sarcopenia 2019, the preventive effect ofeldecalcitol on sarcopenia development was also proved
using the criteria from the European Working Group on
Sarcopenia in Older People 25 and the Foundation for the
National Institute of Health.19 The diagnostic criteria forsarcopenia in the Asian Working Group for Sarcopenia
2019, the European Working Group on Sarcopenia in
Older People 2, and the Foundation for the National
Institute of Health slightly differ. The participants who
were diagnosed as sarcopenia according to these criteria
were excluded from total of 1256 participants in theoriginal DPVD study. As a result, 162 participants were
excluded by the Asian Working Group for Sarcopenia
criteria, resulting in 1094 participants; 57 were excludedby the European Working Group on Sarcopenia in Older
People 2 criteria, resulting in 1199; and 49 were excludedby the the Foundation for the National Institute of Healthcriteria, resulting in 1207. 28 (4·7%) of 601 participants inthe eldecalcitol group and 52 (8·7%) of 598 in the placebogroup developed sarcopenia based on the European
Working Group on Sarcopenia in Older People 2 criteria(HR 0·53, 95% CI 0·33–0·85; p=0·0064), and 27 (4·5%)of 606 participants in the eldecalcitol group and
51 (8·5%) of 601 in the placebo group developed
sarcopenia based on the Foundation for the National
Institute of Health criteria (HR 0·52, 95% CI 0·32–0·83;
p=0·0058; appendix 3, p 9).
Eldecalcitol treatment also showed a significant
reduction in the risk of falls compared with placebo,
which occurred in 135 (24·6%) of 548 participants in theeldecalcitol group and 179 (32·8%) of 546 participants inthe placebo group (HR 0·78, 95% CI 0·62–0·97;
p=0·0283; figure 3).
Changes in BMI and waist circumference did not show
significant differences between the eldecalcitol andplacebo groups (BMI –0·72% vs –0·35%; p=0·34 andwaist circumference –0·06% vs 0·02%, p=0·091).
However, the fat mass index was significantly reduced byeldecalcitol treatment compared with placebo(–0·15% vs 0·31%, p=0·028). On the contrary, theappendicular skeletal muscle index was significantly
increased in the eldecalcitol group compared with theplacebo group (0·45% vs –1·72%; p<0·0001) as well as
the handgrip strength (1·85% vs 0·45%; p=0·0003;
figure 4). The results using multiple imputation method
were consistent with the primary analysis findings(appendix 3, p 6).
In the subgroup analysis, we found a stronger
preventive effect of eldecalcitol treatment on the

HR for fall 0·78 (95% CI 0·62–0·97); p=0·0283

0·70
0·60
0·50
0·40
0·30
0·20
0·10
0

0

Number at risk
Eldecalcitol 548
Placebo 546

3

6

9

12

15

18

21

24

27

30

33

36

364
330

345
305

326
284

248
218

Time since randomisation (months)
528
524

510
502

488
477

464
448

443
425

426
404

403
377

383
352

Figure 3: Kaplan–Meier plot for fall-free survival among adults with prediabetes
The study’s median follow-up was 2·9 years. The hazard ratio (HR) for new-onset falls between the eldecalcitol andplacebo groups is derived from a log-rank test.

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Discussion

There were no significant differences in the incidenceof adverse events between the eldecalcitol and placebogroups (table 2). The incidences of hypercalcemia,
nephrolithiasis, and liver dysfunction resulting in
discontinuation were slightly higher in the eldecalcitolgroup, but the difference did not reach statisticalsignificance.
2·5
2·0

In this study, treatment with eldecalcitol at a dose of
0·75 μg per day showed the possibility of reducing theincidence of sarcopenia among people with prediabetes
via increasing the skeletal muscle volume and strengthand reducing body fat mass after a median follow-up of
2·9 years. As a result, increasing skeletal muscle volume
and strength and reducing body fat mass might lead to asignificant risk reduction of falls.
It has been shown in in-vivo experiments in mice that
insulin promotes protein kinase B (Akt) activation andphosphorylation of forkhead box protein O1 (FOXO1),
leading to suppression of muscle degradation (ie, muscle
maintenance and gain).23 This pathway is suppressed in
prediabetes and type 2 diabetes with insulin resistance.
Observational studies have shown that the incidence ofsarcopenia is higher in people with these diseases thanin those without these diseases.4 It has been shown inmice that active vitamin D enhances the Akt-FOXO1mediated pathway and insulin action, resulting inpreventing muscle atrophy.24 These results in miceexperiments are compatible with our results in humans.
Several intervention studies have investigated the effectof vitamin D supplementation on muscle strength andmuscle mass as diagnostic criteria of sarcopenia andphysical performance related to severe sarcopenia;
however, the results are inconsistent.8–11 Substantial
increases in muscle mass and decreases in body fat mass

p=0·0003

Eldecalcitol
Placebo

1·5
1·0

Change (%)

0·5

p=0·028
p=0·34

p=0·028

p<0·0001

Fat mass
index

Lean massindex

p<0·0001

p=0·091

0
–0·5
–1·0
–1·5
–2·0
–2·5
–3·0

BMI

Waist
Body fat (%)
circumference

Appendicular Grip strength
skeletal muscle
index

Figure 4: Percentage change in body composition measures during 3 years
Outcomes of adipose and lean tissues were assessed by bio-impedance analysis. T-bars indicate 95% CIs.
Eldecalcitol (N=548)

Placebo (N=546)

Number Event rate number/of events 100 person-years

Number Event rate number/of events 100 person-years

Discontinuations due to adverse events 17

1·03

13

0·79

Risk ratio (95% CI)

Risk difference(95% CI)1·30 (0·64 to 2·66)

0·24 (–0·41 to 0·89)

Laboratory tests
Hypercalcaemia*

4

0·24

2

0·12

1·99 (0·37 to 8·84)

0·12 (–0·17 to 0·41)

Hypercalciuria†

3

0·18

2

0·12

1·50 (0·25 to 7·91)

0·06 (–0·20 to 0·32)

Increased serum creatinine levels‡

2

0·12

2

0·12

1·00 (0·14 to 3·05)

0·00 (–0·24 to 0·24)

2

0·12

1

0·06

1·99 (0·18 to 9·91)

0·06(–0·14 to 0·26)

Hives

1

0·06

2

0·12

0·50 (0·05 to 5·48)–0·06 (–0·26 to 0·14)

Digestive symptoms

2

0·12

2

0·12

1·00 (0·14 to 3·05)

0·00 (–0·24 to 0·24)

Liver dysfunction

2

0·12

1

0·06

1·99 (0·18 to 9·91)

0·06(–0·14 to 0·26)

Nephrolithiasis

1

0·06

1

0·06

1·00 (0·06 to 4·89)

0·00 (–0·24 to 0·24)

Serious adverse events

Death

78

4·74

72

4·40

1·08 (0·80 to 1·45)

0·34 (–1·12 to 1·80)

Respiratory system

24

1·56

25

1·53

0·96 (0·55 to 1·65)

0·03 (–0·84 to 0·90)

Cardiovascular system

18

1·09

19

1·16

0·94 (0·50 to 1·78)–0·07 (–0·80 to 0·66)

Gastrointestinal system

13

0·79

12

0·73

1·08 (0·50 to 2·34)

0·06 (–0·54 to 0·66)

Urogenital system

11

0·67

7

0·43

1·57 (0·61 to 4·01)

0·24 (–0·27 to 0·75)

Muscle-skeletal system

9

0·55

7

0·43

1·28 (0·48 to 3·42)

0·12 (–0·36 to 0·60)

Skin

3

0·18

2

0·12

1·50 (0·25 to 7·91)

0·06 (–0·20 to 0·32)

Table shows participants who received at least one dose of eldecalcitol or placebo. *Hypercalcaemia was defined as corrected serum calcium concentration higher than
11·0 mg/dL (2·7 mmol/L), as confirmed on repeat testing. Although the usual criterion of hypercalcaemia was 10·4 mg/dL (2·6 mmol/L) or higher, hypercalcaemia that wasenough to discontinue the study was defined as 11·0 mg/dL or higher in this study. †Hypercalciuria was defined as fasting urine calcium: urine creatinine ratio of 0·28 orhigher. ‡Increased serum creatinine concentration was defined as a serum creatinine concentration higher than 1·5 mg per deciliter or the upper limit of the normal range forclinical laboratory at each clinical site.

Table 2: Frequency of adverse events in the safety populatione260

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were observed in two studies9,10 and in subgroup analysesof two other studies.8,11 Similarly, results from the metaanalyses were inconsistent. One meta-analysis hasreported a small but significant improvement in muscle
strength and performance, but no increase in muscle
mass by supplementation.6 These effects were more
noticeable for older women (aged ≥65 years) with a BMI of
less than 25 kg/m² and low baseline serum
25-hydroxyvitamin D concentrations.6 However, the othermeta-analysis indicated that vitamin D supplementation
worsened knee flexion strength, Timed Up-and-Go, andthe short physical performance battery, and did not reduce
the risk of falls and fractures.25 In 2022, two meta-analyses
showed inconsistent conclusions about physicalperformance. One meta-analysis12 reported that vitamin D
supplementation was effective in improving gait speed
and grip strength as factors in the diagnostic criteria forsarcopenia, whereas the other meta-analysis13 reported that
it worsened short physical performance battery. However,both meta-analyses did not have large total sample sizes(269 for one meta-analysis12 and 943 for the other13), andthe heterogeneity of the various factors was observed.
Our study found a significant increase in muscle
strength (handgrip strength) with eldecalcitol treatment.
Muscle mass was slightly increased compared with its
own baseline in the eldecalcitol group, whereas it wassignificantly decreased in the placebo group. As a result,eldecalcitol treatment significantly prevented the
reduction of muscle mass by ageing.
The weight of our study population (mean BMI of
24·2 kg/m²) might have helped to prove the therapeutic
effect of active vitamin D because (active) vitamin D is fat
soluble and less effective in people with obesity. In
addition, participants’ serum 25-hydroxyvitamin D
concentrations was relatively low (mean 20·7 ng/mL[51·8 nmol/L]) which might be another reason for thesignificant therapeutic effect seen. Furthermore, some
reports have shown that active vitamin D is more effective
than normal vitamin D in improving bone mineraldensity, fracture rate, physical performance, and Timed
Up-and-Go.26–28
Falls is one of the sarcopenia-related clinical events.
Several interventional studies have been conducted on
the prevention of falls with natural vitamin D and active
vitamin D, and meta-analyses have also showed
inconsistent results. The meta-analysis29 showed thatvitamin D and active vitamin D prevent the incidence offalls, especially in patients with low serum
25-hydroxyvitamin D levels (20 ng/mL [50 nmol/L]).29 On
the contrary, null preventive effects or even worsening
effects were reported for individuals with serum
25-hydroxyvitamin D concentrations greater than
40–45 ng/dL.30 In addition, there are reports that highdoses of vitamin D increases the risk of fractures andfalls.31 In this study, the participants’ serum
25-hydroxyvitamin D concentrations were relatively low(mean of 20·7 ng/mL). Incidentally, the average of serum
www.thelancet.com/healthy-longevity Vol 5 April 202425-hydroxyvitamin D concentrations of healthy male andfemale Japanese people are 20·3 ng/mL.4 Thus, anotherreason for the preventive effect of active vitamin D on
sarcopenia and falls in this study might be thevitamin D-insufficient status of the study population atbaseline.
The results of our subgroup analysis has suggested
that active vitamin D exerted a more preventive effect onparticipants prone to sarcopenia than healthy people. It
has been reported that muscle mass decreases byapproximately 1% per year for every year of age in adults
older than 30 years and by more accelerated rates inindividuals older than 70 years.32 Therefore, older people
are prone to sarcopenia. In addition, adults with lower
weight and a high percentage of body fat (ie, low musclemass) are more likely to develop sarcopenia. These adults
would need active vitamin D to maintain muscle mass
and increase muscle strength. Although the prevalenceof sarcopenia between sexes is not consistent, it is clearthat women are susceptible to postmenopausal
osteoporosis and that active vitamin D has a positiveeffect on bone mineral density.16 A former report has also
shown a strong correlation between bone mineral density
and muscle mass,33 with a tendency for more substantial
active vitamin D effects in women than in men.
Regarding drug safety, although the usual criterion of
hypercalcaemia is 10·4 mg/dL (2·6 mmol/L) or higher,
in this study hypercalcaemia leading to study discontinue
was defined as 11·0 mg/dl or higher. Eldecalcitol is
originally a drug for treating osteoporosis, which affects
the metabolism of serum vitamin D and phosphorus.
Therefore, although there was no significant differencein the incidence of adverse events between the two groups
in this study, previous clinical trials have showed that
there was a slightly higher trend of hypercalcaemia in theeldecalcitol group compared with the placebo group.15,16
We should not prescribe eldecalcitol unnecessarily andmonitor hypercalcaemia carefully.
The strengths of this study were the large sample size,and high participant adherence. In addition, we have a
protocol that was created separately from that of the
DPVD study (appendix 2).
This study also has limitations. First, we only evaluated
one active vitamin D dose (0·75 μg per day). Second, we
measured muscle mass and fat mass using InBody720 (abioimpedance analyser) with advantages in terms of
simplicity and cost compared with dual-energy x-ray
absorptiometry, magnetic resonance imaging, andcomputed tomography, but InBody720 is sometimes
misunderstood to be inaccurate. However, this analyser
has been assessed in normal populations, older adults,
athletes, and haemodialysis patients, and closely
correlates with the gold standard measurement by dualenergy x-ray absorptiometry, underwater weighing, andair displacement plethy­smography.20,34 Moreover, the tool
is not based on statistical data of any specific population;
therefore, it can accurately assess people with very
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different body types. Third, under the Asian Working
Group for Sarcopenia 2019 diagnostic criteria,2 thediagnosis of sarcopenia can be made if there is either low
grip strength or low physical performance (6 m walk,five time chair stand test, or Short Physical Performance
Battery score) in combination with decreased
appendicular skeletal muscle mass. However, thediagnosis of severe sarcopenia is made only when all
three of these criteria are met. Although the reference
values are different, the criteria of the European Working
Group on Sarcopenia in Older People 2 and theFoundation for the National Institute of Health can also
diagnose sarcopenia by low skeletal muscle mass and low
grip strength.5,19 Therefore, we diagnosed sarcopenia bymeasuring skeletal muscle mass and hand grip strength.
Finally, although this study investigated sarcopenia
incidence according to the diagnostic criteria of the Asian
Working Group for Sarcopenia 2019 guideline, thepreventive effect of eldecalcitol on sarcopenia
development was also proved using the criteria of theEuropean Working Group on Sarcopenia in Older
People 25 or the Foundation for the National Institute of
Health.19 However, as this study was conducted only in a
Japanese population, where individuals have a lower BMI
and lower serum 25-hydroxyvitamin D concentrations
than populations in other regions, such as Europe andNorth America, it is unknown whether the results apply
to other ethnicities. In addition, the use of active
vitamin D, especially eldecalcitol for the treatment of
osteoporosis, is approved in Japan and China based on
the following evidence,14,15,17 but not internationally owing
to the small number of clinical trials with active vitamin
D in Europe and North America.
In conclusion, treatment with eldecalcitol, which is anactive vitamin D analog, at a dose of 0·75 µg per day
resulted in lowering risks of sarcopenia incidence andfalls among adults with prediabetes. We plan to conduct
a clinical trial targeting older people regardless of
sarcopenia and prediabetes in the future.
Contributors
TK, GS, and TI conceived and designed the study and contributed to thewriting of the protocol. TK, GS, NTom, MT, NToy, and CK were
responsible for the collection and assembly of data. TI did the data
management. TK, GS, SM, and TI accessed and verified the data.
SM designed and performed the statistical analyses, and all authors
discussed the analysis plan and results, and provided input to themanuscript. All authors were responsible for the revision of the Article
for important intellectual content. All authors had full access to all datain the study and provided final approval to submit the manuscript for
publication.
Declaration of interests
We declare no competing interests.
Data sharing
Data from this study will be made available upon reasonable request. For
data access, please contact the corresponding author at dpvdtrial@mbox.
med.uoeh-u.ac.jp.
Acknowledgments
We thank the patients who participated in this trial, and their families
and caregivers, and we thank the staff and investigators at all trial sites,e262

and Tatsuro Takano for data collecting support. This trial was funded by
the Kitakyushu Medical Association.
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