Journal of Orthopaedic Science 27 (2022) 139e145

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Original Article

Effects of eldecalcitol alone or a bone resorption inhibitor with
eldecalcitol on bone mineral density, muscle mass, and exercise
capacity for postmenopausal women with distal radius fractures
Kazushige Maeda a, *, Junya Imatani b, Shiro Moritani b, Hidenori Kondo bab

Maeda Orthopedic and Surgery Clinic, Japan
Department of Orthopedic Surgery, Okayama Saiseikai General Hospital, Japana r t i c l e i n f o

a b s t r a c t

Article history:
Received 11 March 2020
Received in revised form
11 October 2020
Accepted 19 November 2020
Available online 19 December 2020

Background: Distal radius fractures are often the ﬁrst fractures experienced by adults with osteoporosis,
and such fractures provide an opportunity for treatment to prevent a domino effect of future fractures.
Most of these fractures result from falls, which may be related to the individual's limb muscle mass,strength, and exercise capacity. Active vitamin D3 positively affects muscle and bone mass. However, theeffect of a bone resorption inhibitor is unknown. This study aimed to determine the effects of eldecalcitol
alone or a bone resorption inhibitor with eldecalcitol on bone mass, limb muscle mass, and exercise
capacity of osteoporotic patients with distal radius fractures and to identify the preventive effects against
future fractures.
Methods: Participants were postmenopausal women(n ¼ 99) with distal radius fractures who visited theorthopedics outpatient department in a city general hospital from April 2015 to October 2017. Bone mass,
limb muscle mass, skeletal muscle mass index, and muscle strength (grip strength and quadriceps
muscle strength), walking speed, 2-step results, and timed up and go tests results were evaluated before
and after 1 year of treatment. The instances of fall recurrence and refracture were investigated using aquestionnaire.
Results: Eighty-ﬁve patients completed follow-up assessments for 1 year. After treatment, bone massand bone mineral density were signiﬁcantly improved in the lumbar spine and total proximal femur
compared to before treatment. Furthermore, skeletal muscle mass index, grip strength on the unaffectedside, quadriceps muscle strength, walking speed and 2-step test results after 1 year of treatment weresigniﬁcantly improved. Nineteen and 4 patients experienced fall recurrence and refracture, respectively.
Conclusions: Eldecalcitol alone or a bone resorption inhibitor with eldecalcitol improved bone mass andbone mineral density, and maintained skeletal muscle mass index, muscle strength, and exercise capacityof osteoporotic patients with distal radius fractures.
© 2020 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

1. Introduction
Distal radius fractures are the third most common fracture
following vertebral compression fractures and proximal femoral
fractures [1], and they are one of the most frequent fractures that
occur in older adults with osteoporosis. The risk of distal radius
fractures increases among women over the age of 55 years, and thistype of fracture tends to occur more frequently in patients between* Corresponding author. Meda Orthopedic and Surgery Clinic, 3-1-13, Muromachi, Sakaide City, Kagawa, 762-0007, Japan. Fax: þ81 87 746 5421.
E-mail address: kazushi_chick30@yahoo.co.jp (K. Maeda).

the ages of 50 and 70 years, when they are relatively active [2].
Patients with distal radius fractures often have initial fractures due
to osteoporosis. Furthermore, those with distal radius fractures are
5.67 times more likely to experience a proximal femur fracture
within 1 year of a previous fracture than are those without fractures. Patients with a history of distal radius fractures also have asigniﬁcantly increased risk of developing other major bone fragility
fractures within a 10-year period [3,4].
Most distal radius fractures occur in older adults due to falls, andit has been reported that these falls are associated with decreased
muscle mass, muscle strength, and exercise capacity [5,6].
Furthermore, bone mass and exercise ability, including muscle

https://doi.org/10.1016/j.jos.2020.11.009
0949-2658/© 2020 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

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Journal of Orthopaedic Science 27 (2022) 139e145

radius fractures [13]. At 6e8 weeks post-injury, bone mass wasmeasured in the lumbar spine, total proximal femur, and femoral
neck, along with the limb muscle mass and skeletal muscle massindex (SMI). The patients were also evaluated for any signs of sarcopenia and pre-sarcopenia [14]. For muscle strength, the grip
strength on the unaffected side and the strength of the quadriceps
in the thigh was measured; for exercise capacity, the ordinary
walking speed test, 2-step test (2ST), and timed up and go test
(TUG) test were performed. Bone mass and limb muscle mass were
measured every 6 months; muscle strength and exercise capacity
were measured 1 year following treatment initiation. At the time of
the ﬁnal survey, the instances of refracture and fall recurrence were
investigated using a questionnaire.
Measurement of muscle mass in the limb, lumbar spine, andproximal total femur, and measurement of bone mass in the femoral
neck was performed by dual-energy X-ray absorptiometry using abone densitometer (PROGIDY Fuga, General Electric Health Care
Japan). Bone mass was evaluated using Young Adult Mean (YAM)
values, and patients with YAM values <80% were diagnosed withbone loss based on the 2012 revised diagnostic criteria for primaryosteoporosis [15]. Sarcopenia was diagnosed based on the criteria of
the Asian Working Group for Sarcopenia consensus [16]. A diagnosis
of sarcopenia was also made if the SMI corrected for limb muscle
mass divided by the height squared was <7.0 kg/m2 for men and<5.4 kg/m2 for women. In addition, sarcopenia was indicated if there
was a decrease in the patient's walking speed (0.8 m/s) or grip
strength (<26 kg for men and <18 kg for women). Only those with adecreased SMI were diagnosed with pre-sarcopenia [14].
To evaluate muscle strength, grip strength was measured using
Grip - DT.K.K 5401(Takei Scientiﬁc Instrument Co., Ltd., Tokyo,
Japan). Grip strength of the unaffected side was measured 3 times
with the elbow extended in a standing position, and the averagevalue was used. The quadriceps femoris muscle strength was also
quantitatively measured using Isoforce GT330 (OG Wellness Technologies Co., Ltd., Okayama, Japan), which is an automatic exercise
training device coupled with a measurement device (Fig. 1). Eachpatient's walking speed was measured for 10 m. The 10-m walking
time and speed was calculated as seconds per meter. In the TUG
test, the time (in seconds) it took each patient to stand up from anarmchair, walk 3 m, turn, walk back, and sit in the chair wasmeasured [17]. In the 2ST, the patients stood with their toes aligned
at the starting line and took 2 steps in order to get as far as possible
from it as possible and then, aligned both their feet to complete thetest. The distance from the starting position of the toes to the end
position of the toes was measured, and the result was divided by
the patient's height [18].
The optimal treatment protocol to prevent the domino effect of
future fractures lacks a clear consensus. Patients in this study had adistal radius fracture, and according to osteoporosis diagnosis
guidelines, the YAM should be the basis for drug administration.
Herein, patients with a YAM value 80% for the lumbar spine andtotal proximal hip received eldecalcitol alone or with abisphosphonate, considering their age and other existing fractures.
Patients with a YAM value <80% received eldecalcitol andbisphosphonate or eldecalcitol and denosumab, considering theirage and other existing fractures. Eldecalcitol (0.75 mg) was administered daily after breakfast, and bisphosphonate (minodronate,
50 mg) was administered once a month in the morning directly
after waking. Denosumab (60 mg) was injected subcutaneously
once every 6 months.

strength and balance, need to be improved to prevent the domino
effect which can be observed following a secondary fragility fracture. Although there is no deﬁnite consensus on the optimaltreatment for osteoporosis in individuals who are at risk of thedomino effect following a fragility fracture, bisphosphonates areprescribed as the ﬁrst-line treatment to ensure that the patients’quality-of-life and disease prognosis are reasonably maintained. In
addition, bisphosphonates such as alendronate and risedronate canreduce the risk of vertebral body fractures and proximal femur
fractures [7,8]. Furthermore, denosumab is known to reduce therisk of osteoporotic fractures [9]. Additionally, given that distal
radius fractures related to bone fragility may occur at a relatively
young age (i.e., 50e60 years of age) female hormone replacement
therapies and active vitamin D3 preparations are often considered
as ﬁrst-line treatments for osteoporosis in these patients. Therefore, treatments with these vitamin D3 analogs (e.g alfacalcidol andeldecalcitol) are generally used for patients with distal radius
fractures, particularly in those with osteoporosis.
Pertinent ﬁndings from a meta-analysis show that vitamin D
treatment helps to prevent falls [10]. One active vitamin D3 analog,
alfacalcidol, has been shown to maintain limb muscle mass inhealthy individuals and improve limb muscle mass in patients withosteoporosis and sarcopenia [11]. Another vitamin D3 analog, eldecalcitol (0.75 mg/day), suppresses bone resorption more effectively
than alfacalcidol (1 mg/day). It increases vertebral body and hipbone mass, prevents vertebral body fractures, and signiﬁcantly
reduces the risk of forearm fractures [12].
However, the effect of eldecalcitol on muscle mass, muscle
strength, and exercise capacity is unclear. Furthermore, the effect ofa bone resorption inhibitor, such as bisphosphonate and denosumab, on these same parameters is also unknown. Investigating theeffects of these treatments for patients with distal radius fracture
will be very valuable, given the increased risks for these patients for
future catastrophic injury. Therefore, this study aims to examine
the effects of eldecalcitol alone or a bone resorption inhibitor with
eldecalcitol on bone mass, limb muscle mass, muscle strength, andexercise capacity in patients with distal radius fractures, and to
identify its preventive capabilities against the domino effect.
2. Materials and methods
From April 2015 to October 2017, postmenopausal women with
distal radius fractures who visited the orthopedic surgery outpatient department of a city general hospital were prospectively
evaluated. Patients with distal radius fractures who had sustained
injuries due to a fall and could walk independently were includedin this study. Exclusion criteria included injury not related to falls,
and patients with thyroid disease, metabolic bone diseases, ureteralcalculus, renal dysfunction, Cushing's syndrome, use of glucocorticoid hormone actives and vitamin D3 analogs, allergy to eldecalcitol, having undergone treatment for malignancy, hemoglobin
A1c  7.0, and diabetes. A total of 99 patients met the inclusion
criteria and provided written informed consent prior to participating in this study. This study was approved by the city general
hospital ethics committee.
Using a questionnaire before the start of treatment, information
was obtained on each patient's age, sex, body mass index (BMI;
weight divided by the height squared), and medical history(fragility fracture history, including proximal femoral fracture andvertebral fracture, and 6 non-vertebral fractures, namely distal
radius, proximal humerus, rib, pelvic, clavicle, and lower leg fractures; as well as a history of proximal femur fracture in the patient's
parents). Patients with distal radius fractures were treated,conservatively with a cast or surgically with a volar locking plate,based on the 2017 revised clinical practice guideline for distal

2.1. Statistical analysis
Per-protocol set analysis was adopted in this study. Data wereshown as the mean and standard deviation for each variable.
140

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Journal of Orthopaedic Science 27 (2022) 139e145

Fig. 1. The patient sits on the seat and is secured with the lumbar and thigh belts. The quadriceps femoris strength is then measured while the patient performs the isotonic, open
kinetic chain exercise of knee extension.

Wilcoxon signed-rank sum tests were used to compare the values
obtained before treatment with those obtained at 1 year after
treatment. All statistical analyses were performed on a modiﬁed
graphical user interface of R (version 2.13.2., The R Foundation for
Statistical Computing, Vienna, Austria), known as EZR (Saitama
Medical Center, Jichi Medical University). This modiﬁed version of R
commander (version 1.8e4) is designed to add statistical functions
that are frequently used in biostatistics. We considered p < 0.05
reﬂective of statistical signiﬁcance.

Table 1
Patient background data collected at baseline.
Age (years)
Body mass index (kg/m2)
Bone loss (YAM <80%)
History of fragile fracture
History of fracture treatment
Parental hip fracture

3. Results

Pre-sarcopenia

Of the initial 99 patients, 11 patients withdrew their consent, 2patients could not continue because of worsening dementia, and 1
patient died during the study period. Hence, a total of 85 patientscompleted the study, yielding a ﬁnal follow-up rate of 85.9% (85/99). No patient presented with bone union failure, and all patients
made good progress with their treatment. The patients’ mean age
was 70.1 ± 8.4 years, and their mean BMI was 24.2 ± 22 kg/m2. Of
the patients, 51 (60%) had decreased bone density (YAM
values < 80% for the lumbar spine or proximal total femur), and 24(28.2%) had a history of vertebral and non-vertebral fragility fractures (14 patients had vertebral fragility fractures, 10 patients had
non-vertebral fragility fractures); only 6 patients (7.1%) weretreated for osteoporosis. Moreover, 30 patients (35.3%) and 17 patients (20%) had pre-sarcopenia and sarcopenia, respectively. The
patient data obtained at baseline for this study is summarized inTable 1. Regarding the drugs used, 52.9% (45 patients) received
eldecalcitol alone, 37.6% (32 patients) received a combination ofeldecalcitol and a bisphosphonate, and 9.5% (8 patients) received a
combination of eldecalcitol and denosumab. The medication
possession ratio was 98.1%.
The serum calcium level of 2 patients who received eldecalcitol
alone and 2 others who received the eldecalcitol andSarcopenia

Mean ± SD
MedianMean ± SD
Median
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No

70.1 ± 8.4
69.0
24.2 ± 22
21.8
51 (60.0%)34 (40.0%)
24 (28.2%)
61 (71.8%)
6 (7.1%)79 (92.9%)
11 (12.9%)
74 (87.1%)
30 (35.3%)
55 (64.7%)
17 (20.0%)
68 (80.0%)

Data are presented as the number and percentage unless otherwise stated. SD,
standard deviation; YAM, Young Adult Mean.

bisphosphonate combination increased to 10.7 mg/dL during thisstudy; thus, the amount of eldecalcitol was reduced from 0.75 mg to
0.5 mg in these patients.
Patients' lumbar spine bone mass and bone density weresigniﬁcantly increased 1 year after treatment initiation comparedwith the baseline measurements (Post-treatment vs Pre-treatment:
0.955 g/cm2 vs. 0.917 g/cm2 and 85.8% vs. 81.9%, respectively; bothp < 0.001). In addition, proximal total femur bone mass, bonedensity, and femoral neck bone mass were signiﬁcantly increased at
1 year after treatment initiation compared with the values obtained
at baseline (Post-treatment vs Pre-treatment: 0.727 g/cm2 vs.
0.711 g/cm2, 78% vs. 75.9%, and 0.677 g/cm2 vs. 0.660 g/cm2,
respectively; all p < 0.001; Fig. 2). Regarding limb muscle mass, nosigniﬁcant difference was noted when comparing the baseline
measurements with those obtained at 1 year (Post-treatment vs141

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Journal of Orthopaedic Science 27 (2022) 139e145

Pre-treatment: 13,546 g vs. 13,683 g, p ¼ 0.0589). The SMI at 1 year
was signiﬁcantly increased when compared with the ﬁrst measurement (Post-treatment vs Pre-treatment: 5.80 kg/m2 vs. 5.73 kg/
m2, p < 0.05; Fig. 3). As for muscle strength, both the grip strengthand the quadriceps femoris muscle strength were signiﬁcantly
increased at 1 year relative to the baseline measurements (Posttreatment vs Pre-treatment: 19.6 kg vs. 20.54 kg, p < 0.05 and
290 N・m vs. 296 N・m, p < 0.05, respectively; Fig. 4). With regard
to the patients’ exercise capacity, the speed, for the ordinary
walking speed test and 2ST, were also signiﬁcantly increased at 1
year after treatment initiation (Post-treatment vs Pre-treatment:
1.26 m/s vs. 1.33 m/s, p < 0.05, 1.17 vs. 1.22, p < 0.01 respectively;
Fig. 5). However, TUG speed did not change signiﬁcantly (Posttreatment vs Pre-treatment: 7.74 m/s vs. 7.53 m/s, p ¼ 0.0515;
Fig. 5). Regarding fall recurrence and refracture, there were 19
patients (22.3%) who fell again, and 4 patients (4.7%) withrefracture.

strength, and exercise capacity is warranted. Although fragility
hip fractures generally known to occur from falling, distal radius
fracture may be the ﬁrst fracture in a domino effect of fracture, so
it is important that the start of treatment for secondary fracture isdone at this point. No study could be found that examined
whether eldecalcitol alone or a bone resorption inhibitor with
eldecalcitol increased bone mass, muscle mass, muscle strength,and exercise capacity of patients with other fragility fractures
including hip fractures simultaneously. Based on our results,
those treatments are effective for patients with distal radius
fracture to improve bone mass, muscle strength, and exercise
capacity.
Treatment with eldecalcitol alone or a bone resorption inhibitorwith eldecalcitol signiﬁcantly increased bone mass and bone density of the lumbar spine, total proximal femur, and femoral neckcompared to those measured prior to treatment initiation. Previous
studies have likewise demonstrated increases in bone mass andbone density after osteoporosis treatments including eldecalcitol
alone or minodoronate with eldecalcitol [21,22]. In addition, theeffectiveness of denosumab with vitamin D and calcium treatment
has been demonstrated [23]. In particular, bisphosphonate anddenosumab is more effective than eldecalcitol for bone mass, andso it is thought that these medicines contribute to thisimprovement.
Herein, after treatment, the SMI (corrected for height) signiﬁcantly increased, and muscle mass tended to increase, although thechange was not signiﬁcant, compared to baseline measurements.
Ito et al. [11] reported that osteoporotic patients receiving alfacalcidol maintained their muscle mass and SMI, while sarcopenia
patients showed signiﬁcantly increased limb muscle mass and SMI.
According to Glerup et al. [24], a vitamin D receptor is present in therhabdomyoma nucleus. They report that, by attaching active
vitamin D, 1,25 (OH) 2D3, to the receptor, mRNA gene transfer isregulated in the sarcoplasmic reticulum and in the mitochondrial
inner membrane in muscle plasma, which promotes the synthesisof myoﬁbrillar proteins. Such ﬁndings suggest that active vitamin D
may be beneﬁcial to maintain or increase muscle mass. On theother hand, we could ﬁnd no study suggesting that bisphosphonate

4. Discussion
This study aimed to examine the effects of eldecalcitol alone ora bone resorption inhibitor with eldecalcitol on bone mass, limb
muscle mass, muscle strength, and exercise capacity in patientswith distal radius fractures, and to identify its ability to preventthe domino effect. The results showed that these treatments
signiﬁcantly improved bone mineral density, SMI, muscle
strength, and exercise capacity, such as walking speed and 2ST,
compared to values at the start of the study and 1 year after
treatment.
Distal radius fractures often precede proximal humeral/femoral
fractures [2]. Individuals who have distal radius fractures are at a
3.3, 1.9, and 1.7 times higher risk of forearm bone fractures, hipbone fractures, and vertebral bone fractures, respectively [19].
Approximately 90% of distal radius fractures in older adults are
attributed to falls [20]. The relationship between falls and muscle
mass, muscle strength, and exercise capacity has been clariﬁed[5,6]. For the prevention of the domino effect and fractures due tofalls, an effective treatment that improves bone mass, muscle

Fig. 2. Changes in bone mass and bone density in the lumbar spine, femur neck, and proximal total femur. YAM, Young Adult Mean.
142

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Journal of Orthopaedic Science 27 (2022) 139e145

Fig. 3. Changes in limb muscle mass and skeletal muscle mass index (SMI).

Fig. 4. Changes in grip strength on the unaffected side and quadriceps muscle strength.

Fig. 5. Changes in exercise capacity. Normal walking speed, 2-step test, and timed up and go test.

that in a randomized controlled trial of 50 postmenopausal
women with osteoporosis, eldecalcitol signiﬁcantly improved backextensor strength, iliopsoas muscle strength, TUG speeds, anddynamic sitting balance. Iwamoto et al. [26] comparatively tested
106 postmenopausal women with osteoporosis who werereceiving bisphosphonates alone or bisphosphonates plus eldecalcitol, and reported that the chair rising time (a dynamic balance evaluation) was signiﬁcantly improved in the group that
additionally received eldecalcitol. Further, Suzuki et al. [27]compared an eldecalcitol-administered patient group with aand denosumab improved muscle mass and SMI for patients with
distal radius fracture. The results of this study suggest that a bone
resorption inhibitor treatment including bisphosphonate anddenosumab with eldecalcitol treatment may also act effectively on
the muscles.
Regarding muscle strength and exercise capacity, a signiﬁcant
improvement was observed in the grip strength of the unaffectedside, quadriceps muscle strength, normal walking speed and 2ST(reﬂecting the total motor ability), and TUG tended to improve,
although the change was not signiﬁcant. Saito et al. [25] reported
143

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Journal of Orthopaedic Science 27 (2022) 139e145

Acknowledgementsbisphosphonate-administered patient group in a randomized
clinical trial that targeted 120 female patients with primaryosteoporosis aged >65 years, and found that improvements inlower extremity muscle strength and physical balance in bothgroups. The ﬁndings from these previous reports and the current
study collectively suggest that treatment with eldecalcitol alone orbisphosphonate with eldecalcitol treatment contributes to theimprovement of both muscle strength and exercise capacity. These
results suggest that denosumab with eldecalcitol may also
contribute to improving those parameters.
Although there was a statistically signiﬁcant difference in SMI,
muscle strength, and exercise capacity, this result had a margin oferror that may not make this treatment effective clinically. Still, we
think that these treatments maintained SMI, muscle strength, andexercise capacity at 1 year relative to the baseline measurements.
Moreover, when it comes to recurrent fall and refracture, 19 patients (22.3%) in this cohort fell again, and 4 patients (4.7%) had
refracture during this study. van Geel et al. [28] reported that 56(6.1%) of 924 postmenopausal women with a ﬁrst fracture had asubsequent fracture within 1 year. Therefore, it is unknown
whether recurrent fall and refracture can be prevented. The resultsof this study provide new knowledge of these treatments for patients with distal radius fracture, which is the beginning of a
possible domino effect, and preventing future more devastating
fractures.
This study had a few limitations. A small sample size wasstudied over a short period (1 year), which might not be sufﬁcient
to examine the treatment's effects. Further studies including morepatients conducted over longer periods are required to elucidate
the effects of eldecalcitol. Second, serum 25-hydroxyvitamin Dlevels were not measured. When the study commenced, serum 25hydroxyvitamin D levels could not be measured because insurance
did not cover these tests. Considering that low vitamin D is a risk
factor for distal radius fractures [29], vitamin D evaluation isessential. Third, because the tests were not performed directly after
the injury but rather 6e8 weeks later, rehabilitation may haveaffected the results. However, the grip strength of the hand on theunaffected side was measured, which was probably less affected byrehabilitation. Because there is no speciﬁc guidance on rehabilitation or exercise for the trunk or lower limbs, its inﬂuence on exercise capacity was likely also relatively low. Fourth, results in thisstudy were not compared to those of treatment with minodoronate
alone or denosumab alone, but it was considered that these treatments would have a similar effect in a year after distal radius
fracture. It will be necessary to compare these results with treatment with a single agent, such as minodoronate and denosumab in
the future.
In conclusion, treatment with eldecalcitol alone or a bone
resorption inhibitor with eldecalcitol for 1 year was effective insigniﬁcantly increasing bone density and bone mass in the
lumbar spine and total proximal femur 1 year in patients with
distal radius fractures. The ﬁndings in this study also suggest thatthese treatments may maintain SMI, muscle strength and exercising capacity such as walking speed and 2ST results in thesepatients.

I wish to thank Dr. Hayashi for the advice on experimental
design.
We would like to thank Editage (www.editage.com) for English
language editing.
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Funding
This research did not receive any speciﬁc grant from funding
agencies in the public, commercial, or not-for-proﬁt sectors.
Declaration of competing interest
None.
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