An initial loading-dose vitamin D versus placebo after hip fracture surgery: randomized trial

Abstract

Background
Improving vitamin D (25-OHD) status may be an important modifiable factor that could reduce disability severity, fall-rates and mortality associated after hip fracture surgery. Providing a loading-dose post-surgery may overcome limitations in adherence to daily supplementation. Method
In this randomized, double-blind, placebo-controlled trial, 218 adults, aged 65-years or older, requiring hip fracture surgery were assigned to receive a single loading-dose of cholecalciferol (250,000 IU vitamin-D3, the REVITAHIP - Replenishment of Vitamin D in Hip Fracture strategy) or placebo, both receiving daily vitamin-D(800 IU) and calcium (500 mg) for 26-weeks. Outcome measures were 2.4 m gait-velocity, falls, fractures, death (Week-4), 25-OHD levels, quality-of-life measure (EuroQoL) and mortality at weeks-2, 4 and 26. ResultsMean age of 218 participants was 83.9(7.2) years and 77.1 % were women. Baseline mean 25-OHD was 52.7(23.5)nmol/L, with higher levels at Week-2 (73 vs 66 nmol/L; p = .019) and Week-4 (83 vs 75 nmol/L; p = .030) in the Active-group, but not at Week-26. At week-4, there were no differences in 2.4 m gait-velocity (0.42 m/s vs 0.39 m/s, p = .490), fractures (2.7 % vs 2.8 %, p = .964) but Active participants reported less falls (6.3 % vs 21.1 %, χ2 = 4.327; p = 0.024), with no significant reduction in deaths at week-4 (1 vs 3, p = 0.295), higher percentage reporting ‘no pain or discomfort’ (96.4 % vs 88.8 %, p = 0.037), and trended for higher EuroQoL-scores (p = 0.092) at week-26. One case of hypercalcemia at week-2 normalised by week-4. Conclusion
Among older people after hip fracture surgery, the REVITAHIP strategy is a safe and low cost method of improving vitamin-D levels, reducing falls and pain levels. Trial registrationThe protocol for this study is registered with the Australian New Zealand Clinical Trials Registry ANZCTRN ACTRN12610000392066 (Date of registration: 14/05/2010).

Full text

R E S E A R C H A R T I C L E Open Access
An initial loading-dose vitamin D versus
placebo after hip fracture surgery:
randomized trial
Jenson CS Mak
1,4*
, Rebecca S. Mason
2
, Linda Klein
3
and Ian D. Cameron
1
Abstract
Background: Improving vitamin D (25-OHD) status may be an important modifiable factor that could reduce
disability severity, fall-rates and mortality associated after hip fracture surgery. Providing a loading-dose post-surgery
may overcome limitations in adherence to daily supplementation.
Method: In this randomized, double-blind, placebo-controlled trial, 218 adults, aged 65-years or older, requiring
hip fracture surgery were assigned to receive a single loading-dose of cholecalciferol (250,000 IU vitamin-D3, the
REVITAHIP - Replenishment of Vitamin D in Hip Fracture strategy) or placebo, both receiving daily vitamin-D(800 IU)
and calcium (500 mg) for 26-weeks. Outcome measures were 2.4 m gait-velocity, falls, fractures, death (Week-4),
25-OHD levels, quality-of-life measure (EuroQoL) and mortality at weeks-2, 4 and 26.
Results: Mean age of 218 participants was 83.9(7.2) years and 77.1 % were women. Baseline mean 25-OHD was
52.7(23.5)nmol/L, with higher levels at Week-2 (73 vs 66 nmol/L; p= .019) and Week-4 (83 vs 75 nmol/L; p= .030)
in the Active-group, but not at Week-26. At week-4, there were no differences in 2.4 m gait-velocity (0.42 m/s vs
0.39 m/s, p= .490), fractures (2.7 % vs 2.8 %, p= .964) but Active participants reported less falls (6.3 % vs 21.1 %,
χ
2
=4.327;p= 0.024), with no significant reduction in deaths at week-4 (1 vs 3, p= 0.295), higher percentage
reporting ‘no pain or discomfort’(96.4 % vs 88.8 %, p= 0.037), and trended for higher EuroQoL-scores (p=0.092)at
week-26. One case of hypercalcemia at week-2 normalised by week-4.
Conclusion: Among older people after hip fracture surgery, the REVITAHIP strategy is a safe and low cost method of
improving vitamin-D levels, reducing falls and pain levels.
Trial registration: The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry
ANZCTRN ACTRN12610000392066 (Date of registration: 14/05/2010).
Keywords: Hip fracture, Vitamin D, Randomized controlled trial, Falls, Rehabilitation
Background
Hip fractures and related disabilities are important
public health issues for older people around the world
[1–6]. Despite the age-adjusted hip fracture rates re-
ducing in countries such as Australia and the United
States, the actual numbers of fractures are increasing
steadily due to the increasing proportion of the elderly
population. By 2040, an estimated 512,000 hip fractures
will occur in the United States each year at a cost of $16
billion per year, [2] and by 2050, an estimated 76.7 billion
Euros will be spent on this problem in Europe [3].
Outcomes for people who survive hip fracture are of
concern, with more than one-quarter dying within a
two-year period [7], and most not recovering their
previousleveloffunction[4,5].Morethan10%of
survivors will be unable to return to their previous
residence. Most of the remainder will have some re-
sidual pain or disability [6]. Given that people require
assistance to recover from a hip fracture, personal
and societal costs are often incurred following surgery
due to the need for rehabilitation, outpatient visits for
* Correspondence: jenson.mak@gmail.com
1
John Walsh Centre for Rehabilitation Research, Sydney Medical School
Northern, University of Sydney, Sydney, New South Wales, Australia
4
Faculty of Health and Medicine, The University of Newcastle, Newcastle,
NSW, Australia
Full list of author information is available at the end of the article
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Mak et al. BMC Musculoskeletal Disorders (2016) 17:336
DOI 10.1186/s12891-016-1174-9
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

follow-up treatment, temporary residential aged care
facility placement if required, and assistance with ac-
tivities of daily living at home during the recovery
period [8]. Given these factors, the quest in improv-
ing function after a hip fracture has the potential to
be of enormous benefit to elderly people by reducing
disability and improving quality of life. This can then
reduce direct treatment costs and costs of long-term
community or residential aged care services. The abil-
ity to mobilise is the key activity underlying function-
ing and quality of life [9].
Hypovitaminosis D is commonly associated with hip
fracture in older people. It occurs because of several
factors including decreased sun exposure with re-
duced skin production of vitamin D and low dietary
D2/D3 intake. Vitamin D replacement, mostly with
calcium, has been used successfully to reduce such
fractures, as well as falls among older people [10–12].
Without preventive treatment, however, hypovitami-
nosis D following hip fracture may result in proximal
muscle weakness, pain, reduced dynamic balance and
performance speed, [13] affecting mobilization during
the acute postoperative and rehabilitation periods
[14–16]. This study assessed the efficacy and safety of
a loading dose of cholecalciferol for the improvement
of gait velocity, 25-hydroxycholecalciferol (25-OHD)
levels, falls, fractures, functional outcomes and mortality
in women and men who had undergone recent surgical
repair of a hip fracture over a 26 week period.
Methods
Study design
The Replenishment of Vitamin D in Patients with Hip
Fracture (REVITAHIP) Trial was a multicenter, random-
ized, double-blind, placebo-controlled trial involving pa-
tients with recent hip fracture [17]. Patients were
randomly assigned to receive either an oral loading dose
of cholecalciferol (at a dose of 250,000 IU vitamin D3)
or placebo, both receiving daily supplementation with oral
vitamin D (800 IU) and calcium (500 mg).
1
Deviation
from this protocol occurred for two participants (one in
each group) with an initial serum 25-hydroxyvitamin D
level of 10 nmol/L or less due to the known risks. These
cases received an additional 14-day loading dose of vita-
min D3 (at a dose of 4000 IU given orally), continuing on
as per other patients for the remainder of the trial.
Patients were monitored for up to 26 weeks with
telephone interviews or clinic/home visits at 2, 4, 12 (tele-
phone interview only) and 26 weeks. All study procedures
were approved by the local institutional review board
(Northern Sydney Local Health District (NSLHD) - HREC
Number 10/ HARBR/14). The study is registered with
both the Australian Clinical Trial Registry (ACTR No.
12610000392066). This research was carried out in com-
pliance with the Helsinki Declaration.
The academic investigators initiated the concept of the
study. A data and safety monitoring board consisting of
site investigators and the chief investigator met quarterly
to oversee the conduct and safety of the study. Data ana-
lysis was performed by a statistician at the Office of
Medical Education, Sydney Medical School, University
of Sydney, New South Wales, Australia.
Patients
All patients who were enrolled in the trial had under-
gone hip fracture surgery at one of three hospitals in
Sydney and the Central Coast, New South Wales,
Australia [17, 18]. They were invited to participate if
they were aged 65 years or over and able to provide in-
formed consent, either directly or via the person legally
responsible for making decisions on their behalf, were
deemed suitable by the treating medical team, and were
able to take a loading dose of vitamin D within seven
days after surgery [17]. Patients with delirium or demen-
tia were included only after consent had been obtained
from both the patient and the legal surrogate. The mo-
bility and functional status of participants have been pre-
viously reported [18].
Exclusion criteria were: being bed-bound prior to
fracture, or having a life expectancy deemed less than
1 month by the treating clinical staff; hypercalcemia
(serum calcium >2.65 mmol/L); history of nephro-
lithiasis; thyrotoxicosis; Paget’s disease; sarcoidosis;
malignancy (except skin cancer) and associated patho-
logical fractures; significant renal impairment (serum
creatinine >0.15 mmol/L); liver disease (alanine ami-
notransferase or aspartate aminotransferase level >2
times the upper limit of the normal range); undergo-
ing treatment with calcitriol, or already undergoing
treatment with > =1000 IU daily oral vitamin D3.
Mean (SD) age of participants was 83.9 (7.2) years and
77.1 % were women. Most participants (81.7 %) were
born in Australia and 93.6 % spoke English as the first
language. Approximately 83 % of participants had a pre-
injury residence in the community, with 44 % living
alone [18].
Randomization and blinding
Patients were randomly assigned to treatment groups at
a central location, accessed through a central telephone
number and using a computer-generated random num-
ber schedule with variable block sizes of 2 to 6. Study
patients, investigators, steering committee members, and
faculty who adjudicated the clinical and safety end
points remained unaware of study-group assignments
throughout the trial.
Mak et al. BMC Musculoskeletal Disorders (2016) 17:336 Page 2 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

End points
The primary outcome measure was gait velocity over 2.4 m
[19] and was measured at weeks 2, 4, and 26, with baseline
assumed to be 0 immediately following surgery. Secondary
outcome measures were the number of falls, fractures and
hospitalizations, activities of daily living (using the Barthel
Index [20]), quality of life (EQ5D [Euroqol] [21]), 25-OHD
and calcium levels, grip strength, adherence to calcium and
vitamin D supplements, and adverse events (including car-
diovascular events and death).
Assessment of outcomes (Table 1)
Falls were recorded at 2 and 4 weeks using calendars
where participants lived in the community, or using resi-
dential aged care facility or hospital records where par-
ticipants were in care. A fall was defined according to
the Kellogg definition [22] as an incident in which the
body unintentionally comes to rest on the ground or
other lower level which was not as a result of a violent
blow, loss of consciousness, and sudden onset of paralysis
as in a stroke or an epileptic seizure. Where a fall was re-
corded, determination according to this definition would
follow via interview with the patient or their carer.
Fractures and hospitalizations (measured at 2 and
4 weeks) were recorded by the participants if living in
the community or by care facility records and were veri-
fied by contact with the participant’s general practitioner
or hospital. Quality of life was assessed at 4, 12 and
26 weeks using the EQ5D, a valid and reliable measure
of quality of life in older people [21]. 25-OHD levels
were determined using the DiaSorin assay [23] from the
same laboratory for the three sites and measured at initial
assessment, 2, 4, and 26 weeks. Grip strength in kilograms
was assessed at initial assessment, 2, 4, and 26 weeks using
a portable dynamometer (JAMAR hydraulic Hand Dyna-
mometer manufactured by Sammons Prestons: Access
Health. Unit 1 Rear, 194–196 Whitehorse Rd, BLACK-
BURN VIC 3130 Australia). Calcium/vitamin D adherence
was recorded at initial assessment, 2, 4, 12 and 26 weeks
by participants or their carer if living in the community or
confirmed by care facility records. Rate of adherence was
expressed as a percentage of doses taken up to each meas-
urement point.
Adverse events and laboratory measures
The site investigator reported adverse events and serious
adverse events at each measurement point. Such events
were categorized with the use of the Medical Dictionary
for Regulatory Activities [24]. The expert committee
whose members were unaware of the study-group as-
signment adjudicated laboratory criteria, adverse events
and primary cause of death.
Statistical analysis
Calculations were based on statistical power of 80 %
with the alpha set at .05 (2-sided test). To address the
primary hypothesis of the study, a sample size of 125 per
group was initially estimated to show a 10 % difference
in mean gait velocity improvement at the 4-week follow-
up assessment. The number of 250 was not recruited
due to feasibility of funding of 218 participants. Data
were coded to permit blinding to group allocation in the
initial statistical analysis. Differences in the primary out-
come measure between the two groups over time were
analyzed using repeat-measures analysis of variance
(GLM in IBM SPSS version 21.0). Separate analyses
assessing change over time relative to baseline were per-
formed at each follow-up point to maximize use of the
data available. Mean gait velocity change scores relative
to baseline at weeks 2, 4 and 26 follow up, as well as be-
tween follow-up points, were calculated. Similar methods
were used for secondary outcomes where data were con-
tinuous. Pearson chi-square test was used where outcome
measures were categorical, supplemented with use of Fish-
er’s exact Chi square test when cell counts were small.
Missing data at week 2 were imputed for one case with
otherwise complete data using the within case mean of
baseline and week 4 data. Imputation of missing data at
other follow up points was not possible. Analyses followed
the intention-to-treat principle. The study protocol speci-
fied that a 25-OHD assay be performed prior to the load-
ing dose. However, despite requests prior to the loading
dose, in 62 (28.4 %) cases the 25-OHD assay was con-
ducted within 24–48 hours after the loading dose. These
62 participants were excluded from analyses using base-
line 25-OHD as an independent or dependent variable.
These 62 participants were, however, included in all other
analyses. Logistic regression was used to determine the
odds ratio for having a fall within the study period.
Results
Baseline characteristics and follow-up (Table 2)
Of a total of 218 patients, 111 patients were randomly
assigned to receive loading dose cholecalciferol (Active)
and 107 patients were assigned to receive placebo; 74.1 %
Table 1 REVITAHIP Outcome Measures
Outcome Measure Time Measurement
2.4 m gait-velocity Baseline, Weeks 2, 4
Grip strength Baseline, Weeks 2, 4
Falls Baseline, Weeks 2, 4
Fractures Baseline, Weeks 2, 4
Mortality Baseline, Weeks 2, 4
25-OHD levels Baseline, Weeks 2, 4, 26
Quality-of-life measure (EuroQoL) Baseline, Weeks 2, 4, 12, 26
Mak et al. BMC Musculoskeletal Disorders (2016) 17:336 Page 3 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Table 2 Summary Baseline Demographic and Clinical Characteristics of REVITAHIP Participants
a
Variables Active (n= 111) Placebo (n= 107) Pvalue
Sex –n (%)
- Female 84 (75.7) 84 (78.5) 0.633
- Male 27 (24.3) 23 (21.5)
Country of Birth –n (%)
- Australia 92 (82.9) 86 (80.4) 0.727
- Other 19 (17.1) 21 (19.6)
Age
Mean (years)
b
83.7+/−7.5 84.1+/−7.0 0.726
Grouped –n (%)
- 65-74 yr 15 (13.5) 10 (9.3) 0.772
- 75-84 yr 43 (38.7) 42 (39.3)
- 85-94 yr 47 (42.3) 50 (46.7)
- 95+ yr 6 (5.4) 5 (4.7)
Body mass index (kg/m2)
b
24.2+/−3.4 25.1+/−3.8 0.099
Number of days from admission to loading dose
b
4.8+/−2.1 5.4+/−2.3 0.049
Pre-injury mobility –n (%)
d
- Fully independent 80 (72.1) 72 (67.9) 0.156
- Minimum help 15 (13.5) 15 (14.2)
- Moderately help 8 (7.2) 7 (6.6)
- Substantial help 1 (0.9) 8 (7.5)
- Unable to perform task 7(6.3) 4(3.8)
Pre-injury Modified Barthel index 87.5+/−19.9 86.9+/−22.2 0.852
Pre-injury Functional Comorbidity Index
b
3.37+/−2.1 2.9+/−1.7 0.063
Hip Fracture Subtype –n (%)
d
- Undisplaced subcapital 6 (5.7) 3 (2.8) 0.442
- Displaced subcapital: 50 (47.2) 48 (45.3)
- Pertrochanteric simple (2-part) 5 (4.7) 5 (4.7)
- Pertrochanteric complex (3-part) 27 (25.5) 34 (21.1)
- Intertrochanteric/basicervical 5 (4.7) 9 (8.5)
- Subtrochanteric 13 (12.3) 7 (6.6)
Time from fracture to surgery (in hours)
b
43.8+/−38.9 38.9+/−25.9 0.272
Hip Fracture Surgery
d
0.655
- Cannulated screws 4 (3.7) 1 (0.9)
- Uncemented hemiarthroplasty 15 (14.0) 14 (13.2)
- Cemented hemiarthroplasty 8 (7.5) 9 (8.5)
- Total hip replacement 19 (17.8) 20 (18.9)
- Dynamic hip screw with short plate 14 (13.1) 8 (7.5)
- Dynamic hip screw with long plate 19 (17.8) 20 (18.9)
- Gamma nail 28 (26.2) 34 (32.1)
MMSE score (mean, standard deviation)
b
26.32+/−4.3 25.7+/−4.4 0.282
Total number of medications used
b
5.1+/−2.6 4.9+/−2.6 0.201
25-hydroxyvitamin D level (nmol/L)
c
Mean 55.6+/−26.4 49.6+/−19.7 0.112
Mak et al. BMC Musculoskeletal Disorders (2016) 17:336 Page 4 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

of the patients completed the trial, whilst 95.5 % were
successfully followed up to primary outcome at week
4 (Fig. 1). The median follow-up time was 24.8 weeks.
Overall 18 % of participants were lost to follow-up,
predominantly due to an inability to contact patients
by phone for assessment. The rate of loss was similar
in the two groups. The percentage of patients who re-
ported adherence of at least 80 % or better to vitamin
D and calcium supplements was 95.7 % at week 4,
95.9 % at week 12 and 96.3 % at week 26. Adherence
did not differ significantly between the groups at any
assessment point.
Table 2 Summary Baseline Demographic and Clinical Characteristics of REVITAHIP Participants
a
(Continued)
Grouped values: n (%)
e
- <30 13 (16.5) 11 (14.3) 0.621
- 30-49 22 (27.8) 27 (35.1)
- > = 50 44 (55.7) 39 (50.6)
Grip strength (kgs)
b
16.4+/−7.3 15.7+/−6.2 0.478
a
Plus-minus values are means +/−SD
b
Continuous variables were compared with the use of a two-sample t-test. Categorical variables were compared with the use of a chi-square test
c
For participants given the intervention loading dose after 25-OHD levels were taken (n= 156), (Placebo = 77; Active = 79)
d
The following categories contained missing variables: hip fracture subtype (6 missing, n= 212), hip fracture surgery (6 missing, n= 212), premorbid mobilit y (1
missing, n= 217)
e
Nowson CA, McGrath JJ, Ebeling PR, Haikerwal A, Daly RM, Sanders KM, Seibel MJ, Mason RS; Working Group of Australian and New Zealand Bone and Mineral
Society, Endocrine Society of Australia and Osteoporosis Australia. Vitamin D and health in adults in Australia and New Zealand: a position statement. Med J Aust.
2012;196(11):686–7[25]
Fig. 1 Enrolment and Flow of the Patients from REVITAHIP
Mak et al. BMC Musculoskeletal Disorders (2016) 17:336 Page 5 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Most baseline demographic and clinical characteris-
tics did not differ significantly between the two group
with three exceptions. A higher percentage of the Ac-
tive group reported comorbid diabetes (25.2 % vs 9.4 %;
p= 0.002) and depression (21.6 % vs 8.5 %; p=0.008)
compared to the Placebo group. Also time from admission
to loading dose was marginally less in the Active group
than the Placebo group (4.8 vs 5.4 days, p=0.049). The
most common coexisting medical conditions in this
population at baseline were arthritis, osteoporosis,
upper gastrointestinal disease, visual impairment and
diabetes [18].
Gait velocity
Mean 2.4 m gait velocity at weeks 2, 4 and 26, as well as
change scores between assessment points, are shown in
Table 3. Patients across both groups showed consistent sig-
nificant improvements over time. As expected, at week 4
both groups increased significantly in mean gait velocity to
a combined mean of 0.404+/−0.30 m/s from a baseline of 0
(p= 0.000). However, there were no significant differences
between the groups in improvements over time. Specifically,
mean improvement in gait velocity at 4 weeks from baseline
in the Active group was 0.419+/−0.295 m/s compared with
0.389+/−0.325 m/s in the Placebo groups (p= 0.490).
25-hydroxyvitamin D (25-OHD) levels (Fig. 2)
For patients in which 25-OHD levels were assessed
prior to the intervention loading dose (n= 156), mean 25-
OHD was 52.7+/−23.5 mmol/L (median = 54.2). Hypovita-
minosis D (<50 nmol/L) was present in 46.8 % of these
participants. Vitamin D levels among participants have
been reported in an earlier paper where it was noted that
15.4 % of participants had levels <30 nmol/L and only 2
participants had levels <10 nmol/L.(36) Among these 156
participants there was a significantly higher percentage
with adequate 25-OHD (> = 50 nmol/L) at week 4 (96.8 vs
84.6 %, p= 0.031) in the Active group when compared to
the Placebo group. At week 2 and week 4 mean 25-OHD
levels were significantly higher for the Active group versus
the Placebo group (at week 2, 72+/−20. vs 66+/−19 nmol,
p= 0.019; and at week 4, 80+/−20 vs 72+/−23 nmol/L,
p= 0.049), but not at week 26. However, the groups
did not differ significantly in the changes over the
time intervals from baseline to weeks 2, 4, or 26.
Falls and fractures
A total of 44 new falls occurred in 30 patients by week
four. To week 4, seven (6.3 %) participants in the Active
group reported 1 or more falls compared to twenty-three
(21.1 %) in the Placebo group (χ
2
=4.327; p=0.024). At
week 4, the Active group was associated with a falls rate of
250.0 (number of falls/days x 1000), as compared with
821.4 in the Placebo group; an absolute risk reduction of
57.1 % and a relative reduction of 69.6 % (Figs. 3 and 4).
The odds ratio of any fall, for the Placebo group in com-
parison to the Active group, within the first 4 weeks of the
study was 3.332 (CI: 1.340 to 8.235, p= 0.010). At week 4,
three (2.7 %) of participants in the Active group had 1 or
more fractures compared with 3 (2.8 %) in the Placebo
group (p= .964). The risk reduction was very similar in
the intention-to-treat and per-protocol populations. Fur-
ther, at week 2, there was trend for lower 25-OHD (65.4
vs 71.8 nmol/L, F=3.669, p= 0.057) among participants
that fell, and at week 4, 25-OHD levels were significantly
lower for those that fell (70.0 vs 82.1 nmol/L, F= 10.458,
p= 0.001). There was a trend for statistical significance in
25-OHD concentrations between those who sustained a
fracture compared to those who did not at week 4 (70.4 vs
78.5 nmol/L, F=2.781,p=0.097).
Function and quality of life
Among patients in the Active group, the mean Barthel
Index was 88.0+/−16.6, compared with 86.9+/−17.2
(p= 0.62) in the Placebo group at 4 weeks. Mean dif-
ferences in Barthel Index at 4 weeks from premorbid
functioning in the Active group was 0.55 compared
with 0.05 in the Placebo groups (p=0.96). There
were no significant differences at each of the time
points between the groups. Further, regarding grip
strength, there were also no significant differences
Table 3 Changes in gait velocity as a function of time and treatment group
Active N Placebo n Significance
a
Change in Gait Velocity
- Baseline to week 2 0.173 +/−0.259 107 0.155 +/−0.255 106 0.608
- Baseline to week 4 0.419 +/−0.295 106 0.389 +/−0.325 104 0.490
- Baseline to week 26 0.753 +/−0.264 83 0.738 +/−0.258 80 0.718
- Week 2 to Week 4 0.250 +/−0.238 106 0.232 +/−0.249 104 0.582
- Week 2 to Week 26 0.549 +/−0.307 83 0.568 +/−0.282 80 0.694
- Week 4 to Week 26 0.316 +/−0.300 83 0.359 +/−0.356 80 0.404
a
Significance level is shown for the time by group interaction (note for comparisons to baseline of 0, group and group by time interactions are identical). All
changes over time across both groups reached significance at p= 0.000
Mak et al. BMC Musculoskeletal Disorders (2016) 17:336 Page 6 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

between the two groups at week 4 (18.6+/−7.8 vs
18.7+/−8.3kgs, F= .055, p= .815).
The health related quality of life data were as follows.
Overall, there was no significant difference in total Euro-
QoL at Week 4 but a higher total EuroQoL score was
noted for Active participants (88.1+/−13.2 vs 84.3+/−15.8,
F=2.87, p= 0.092), although not significant. EuroQoL
subscales between the Active and Placebo groups were
similar at Week 4 or 26, except for the EuroQoL pain sub-
scale. Participants in the Active group were more likely to
have ‘no pain or discomfort’at Week 26 following hip
fracture surgery (96.4 % vs 88.8 %, p=0.037).
Safety analysis
In the safety analysis, 4 of 218 patients (1.8 %) died during
the study, of whom 1 (0.9 %) were in the Active group and
3 (2.8 %) were in the Placebo group. The hazard ratio of
3.054 (95 % CI, 0.816 to 15.133; p=0.295) indicated the
observed difference was not significant. The numbers of
death were small relating to a combination of cardiovascu-
lar morbidity, and sepsis-related morbidity. Due to the
small numbers there was an inability to detect a significant
difference. No serious adverse events occurred in the two
groups. One patient in the Active group (0.3 %) and no pa-
tient in the Placebo group had adjudicated hypercalcemia
(serum corrected calcium > 2.65 nmol/L). There were no
significant differences in mean serum corrected calcium
levels at each of the assessment points.
Discussion
TheREVITAHIPstudyhasshownthatinolderpatientsfol-
lowing hip fracture surgery, a loading dose of 250,000 IU
vitamin D3 (“Active”) compared with Placebo, followed by
treatment with vitamin D (800 IU) and calcium (500 mg)
daily in both groups, resulted in higher 25-OHD levels and
a greater percentage with target ‘sufficient’25-OHD levels
(>50 nmol/L, [25, 26]), with no significant differences in gait
velocity at 4 weeks. A significantly reduced incidence of falls
but not fractures was noted in the Active group compared
with Placebo over four weeks. This is surprising because in
the study cohort the baseline level of 25-OHD was higher
than in other studies of patients with hip fracture [27].
Further, the differences in 25-OHD from initial measure-
ment to weeks 2 and 4 respectively between the Active and
Placebo groups, while significant, were not large.
Older patients with hip fracture experience increased
morbidity, functional decline, and death, as well as in-
creased use of health care services, and therefore repre-
sent an important population to investigate for advancing
improvements in quality of life and function, and the pre-
vention of falls and secondary fractures. Our study pro-
vides much needed data to help determine whether
vitamin D replenishment strategies are effective in such
Fig. 2 Mean 25-hydroxyvitamin D levels over 26 weeks (* significance noted at Week 2 and 4)
Fig. 3 Cumulative number of falls over 4 weeks (** denotes statistical difference)
Mak et al. BMC Musculoskeletal Disorders (2016) 17:336 Page 7 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

patients with osteoporosis. Because the patients in our
study were older and had more coexisting conditions and
a higher risk of falls than patients in many clinical trials of
treatment for osteoporosis, our findings contain helpful
information for clinicians and for patients who have had a
hip fracture.
Poor adherence to vitamin D therapy has been shown to
compromise the efficacy of this treatment for fracture re-
duction and, therefore, to increase medical costs [28].
Such findings have been particularly notable in frail older
adults [29]. Vitamin D deficiency is frequently observed in
older patients and is associated with an increased risk of
hypocalcemia when intravenous bisphosphonates are ad-
ministered before a normal vitamin D level has been
achieved [13]. Due to the very high rates of vitamin D de-
ficiency noted in the HORIZON Recurrent Fracture study
(observed in the first 385 patients [30]), the REVITAHIP
investigators adopted a similar loading dose vitamin D
followed by maintenance Vitamin D at 800 IU (and cal-
cium) daily supplied to the participants (with an overall
adherence of >80 %). The results were that almost all the
participants in the Active treatment group reached target
vitamin D (>50 nmol/L) at week 2 and 4 compared with
the Placebo group.
The Active group showed a non-significant lower mor-
tality rate compared with the Placebo group which is
likely related to the study being underpowered to detect
a difference, or due to random variation. However, from
results of the Dubbo Osteoporosis Study [1] that all low-
trauma fractures were associated with increased mortal-
ity risk for 5 to 10 years, and subsequent fracture was
associated with increased mortality risk for an additional
5 years, a significant reduction in falls and in the Active
REVITAHIP group is likely to confer a mortality reduc-
tion in this high-risk population. Further, data from a
large meta-analysis of eight prospective studies (26018
men and women) suggest those with vitamin D defi-
ciency (in the bottom quintile) were 1.57 times more
likely to die compared with those in the top quintiles.
[31] Finally, there is a strong signal for mortality reduc-
tion from high-dose vitamin D in severely deficient ICU
patients in the hospital period but not 6 months, sug-
gesting the mortality reduction benefit is likely to be
within the first 21 days of administration [32].
The safety profile for high-dose loading dose of vita-
min D indicated few areas of concern, consistent with
previous findings [1]. There was one case of biochemical
hypercalcemia. We did not find an increased incidence
of renal adverse events. With the loading dose of
250,000 IU vitamin D in a group of subjects who had
already sustained a hip fracture, our findings contrast
with those of Sanders et al. who reported increased falls
and fractures following a loading dose of 500,000 IU in
healthy post-menopausal females [31].
An interesting point of discussion deserves mention.
Whilst there was a significant difference in the 25-OHD
levels between the Active and Placebo groups at the
early stages of rehabilitation (Week 2 and Week 4), it
was a surprise finding that a 6.3 and 7.7 nmol/L differ-
ence in these levels, with no difference in gait velocity
could translate into significant reductions in falls rates.
These results showed that the vitamin D levels did not in-
crease after 4 weeks even in the Active group with the
high dose of vitamin D. This might be because of the half-
life of serum 25- hydroxyvitamin D (normally 3 weeks) ac-
cording to Holick [33]. There was also a large effect with
falls reduction rate (relative reduction of 69.6 % at
Week 4) in the Active group compared with other
studies [34, 35]. However our results may have been a
chance finding or influenced by unidentified factors. Fi-
nally, there was a small but significant difference (0.6 days)
between the delivery of the loading-dose vitamin D such
that this was provided earlier in the Active compared to
the Placebo group. Possible explanations of this include
optimization of proximal muscle strength [14, 15] and dy-
namic balance parameters, [15] to enable earlier effective
rehabilitation. Our results suggest that other factors will
need further investigation in the future.
Fig. 4 Fall, Fractures and Deaths over 4 weeks by Intervention Group (** denotes statistical difference)
Mak et al. BMC Musculoskeletal Disorders (2016) 17:336 Page 8 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Our study had several limitations. The study pa-
tients were, on average, slightly younger and healthier
than are patients with hip fracture in the general
population (83 vs 84 years old), [36] as suggested by
data regarding 1-year mortality. However, patients in
our study ranged widely in age (up to 101 years), and
some had cognitive impairment. Perhaps due to inclusion
and exclusion criteria, there was under-recruitment of
people with very low 25-OHD levels compared to the
usual population with hip fractures due to the low number
of participants from residential aged care facility (10 %)
and participants with fewer total comorbidities. Our co-
hort of participants had relatively good function with
moderate independence prior to their hip fracture.
However, the investigators believe that this could also
be considered a strength as it alerts clinicians to poten-
tial problems (e.g. in ADLs, mobility, high psychotropic
medication use) even in a relatively well functioning co-
hort. Furthermore, it proved difficult to obtain an ac-
curate diary of falls from all participants over the
longer term. So falls data from weeks 12 and 26 could
not be included in the presentation of the data. Indeed,
our data contrasts with that from Vital-D study (which
showed increased falls and fractures in the first
3 months of the study) [37]. Whilst Vital-D had a lon-
ger follow-up period for falls (3 years vs 4 weeks), there
were vast differences in participant characteristics and
study protocol with REVITAHIP, with the former study
being (1) community-dwelling women only, (2) younger
population (age 74 versus 84, by 10 years), (3) partici-
pants given yearly higher boluses of 500,000 IU for
3 years, and (4) participants not provided with any
regular maintenance vitamin D/calcium therapy. Fur-
ther, a higher percentage of the Active group reported
comorbid diabetes compared to the Placebo group.
Whilst there is a higher association of patient groups
with osteoporosis who have diabetes, overall fracture
rates in the Active group did not show a significance
difference compared with the placebo group. Finally,
our participants had a higher level of baseline 25-OHD
compared to expected, likely owing to a less frail par-
ticipant population. There is still significant discussion
in the literature regarding the optimal 25OHD level for
benefit, and a number of reports suggest progressive
decline in fall risk at levels above 80 nmo/L [37],
whilst others recommended level of 60 nmo/L in
Summer [38]. Another limitation was that the planned
sample size of 250 could not be achieved due to time and
funding limitations in participant recruitment. Neverthe-
less, as 25-OHD levels in the REVITAHIP trial at baseline
were higher than usual concentrations, and all patients re-
ceived daily supplementation with vitamin D and calcium,
the trial may have underestimated effects on falls, frac-
tures and death. The rate of follow-up to final interview
was lower than ideal at 74 %. Also, the length of follow-up
for mortality was short (4 weeks) compared to other stud-
ies which have a longer follow-up time (5–10 years)
[37]. It was the study team’s aim to complete a total
follow-up of 26 weeks, but this was not possible. How-
ever, there was no evidence of differential loss to
follow-up between the study groups. Next, the limited
number of participants (n= 62) who had 25-OHD level
measured prior to loading dose precluded a complete
examination of the true value of baseline 25-OHD
levels (leading to an over-estimation of 25-OHD levels
in the groups. However, our intention-to-treat analyses
on primary and secondary outcomes ensures that the
results are accurate and true to the ‘a priori' hypotheses
of the REVITAHIP study. Further, we understand that
the significant finding regarding pain would not main-
tain significance if strict correction for multiple out-
comes was undertaken (e.g. Bonferroni correction),
however, we believe that the results are best interpreted
for their clinical relevance and significance. Finally, the
inclusion of a history of falls and osteoporotic fractures
over the preceding 12 months, as well as a detailed
dietary history of calcium and vitamin D and the degree
of sun-exposure, parathyroid hormone levels and ana-
lyses examining their relationship with baseline vitamin
D status would have strengthened the study.
Conclusion
In conclusion, our findings indicate that treatment with
250000 IU cholecalciferol within 7 days after hip fracture
surgery is associated with higher percentage of replete
25-OHD, reduced rates of falls and reduced pain levels.
Given the relatively low expense of this intervention,
and beneficial impact on the burden of morbidity and
mortality from hip fracture, further evidence (in the
form of longitudinal safety studies) is required to con-
firm the findings of our study.
Endnote
1
Since the protocol paper, there had been concerns re-
garding the safety of high-dose oral calcium supplements
on participants on cardiovascular morbidity and mortality
and thus the dosage of calcium was altered.
Abbreviations
25-OHD, 25-hydroxycholecalciferol [vitamin D]; EQ5D, Euroquol; HORIZON,
Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly;
REVITAHIP, replenishment of vitamin D in hip fracture; Vital-D, ‘vitamin D’study
Acknowledgments
We thank all the clinical and administrative staff in the orthopaedic wards for
their assistance in completing this clinical project. We recognize the enormous
contribution to patient care that our orthopedic services provide to our elderly
patients following hip fractures. The paper was presented at the 20th IAGG
World Congress of Gerontology and Geriatrics in Seoul, Korea (June 2013) as well
as the 3rd FFN Fragility Fracture Congress in Madrid, Spain (September 2014).
The following investigators participated in the REVITAHIP Steering
Mak et al. BMC Musculoskeletal Disorders (2016) 17:336 Page 9 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Committee —Jenson Mak (chair), Ian Cameron, Rebecca Mason, Linda Klein,
Terry Finnegan. The following investigators (who participated in the Safety
Committee) are listed according to clinical site: Ashley Harding, Mei Min Soong,
Khin Swe Ohn, Thwin Bape, Chris Farrugia (Gosford); Ravi Dhawan (Mona Vale),
Sheila Li (Royal North Shore).
Funding
The author received financial support for the research via a scholarship from
the Royal Australasian College of Physician (RACP) AFRM Research Establishment
Scholarship, the RACP Foundation Arnott Research Foundation as well as the
Central Coast Area Health Research Advisory Committee from the Central Coast
Area Health Service (University of Newcastle, Australia).
Authors’contributions
Jenson Mak contributed to the study concept and design, acquisition of
subjects and/or data, analysis and interpretation of data, and preparation of
manuscript. Linda Klein contributed to the study concept and design, data
analysis and interpretation of data, and preparation of manuscript. Rebecca
Mason contributed to the study concept and design, interpretation of data,
and preparation of manuscript. Ian Cameron contributed to the study
concept and design, interpretation of data, and preparation of manuscript.
Competing interests
JM has received speaker’s fees from Boeringer-Ingelheim Pty Ltd and
Mundipharma Pty Ltd. RSM has received speaker’s fees from Amgen Pty
Ltd and Abbvie Pty Ltd. IC’s salary is supported by an Australian National
Health and Medical Research Council Practitioner Fellowship.
Consent for publication
Not applicable.
Ethics approval and consent to participate
All study procedures were approved by the local institutional review board
(Northern Sydney Local Health District (NSLHD) - HREC Number 10/ HARBR/
14). The study is registered with both the Australian Clinical Trial Registry
(ACTR No. 12610000392066). This research was carried out in compliance
with the Helsinki Declaration. All patients gave informed consent to
participate in the study.
Author details
1
John Walsh Centre for Rehabilitation Research, Sydney Medical School
Northern, University of Sydney, Sydney, New South Wales, Australia.
2
Department of Physiology, School of Medical Sciences, The University of
Sydney, Sydney, NSW, Australia.
3
Office of Medical Education, Sydney Medical
School, University of Sydney, Sydney, NSW, Australia.
4
Faculty of Health and
Medicine, The University of Newcastle, Newcastle, NSW, Australia.
Received: 17 November 2015 Accepted: 20 July 2016
References
1. Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality
risk associated with low-trauma osteoporotic fracture and subsequent
fracture in men and women. JAMA. 2009;301(5):513–21.
2. Cummings SR, Rubin SM, Black D. The future of hip fractures in the United
States: numbers, costs, and potential effects of postmenopausal estrogen.
Clin Orthop. 1990;252(1):163–6.
3. Kanis J, Johnell O, Oden A. Smoking and fracture risk: a meta-analysis.
Osteoporosis Int. 2005;16(2):155–62.
4. Frost SA, Nguyen ND, Black DA, et al. Risk factors for in-hospital post-hip
fracture mortality. Bone. 2011;49:553.
5. Kannegaard PN, van der Mark S, Eiken P, Abrahamsen B. Excess mortality in
men compared with women following a hip fracture. National analysis of
comedications, comorbidity and survival. Age Ageing. 2010;39(2):203–9.
6. Keene GS, Parker MJ, Pryor GA. Mortality and morbidity after hip fracture.
BMJ. 1993;307:1248–50.
7. Burns A, Younger J, Morris J, Baldwin R, Tarrier N, Pendleton N, Cohen P,
Horan M, Banerjee S. Outcomes following hip fracture surgery: a 2-year
prospective study. Am J Geriatr Psychiatry. 2014;22(8):838–44.
8. Cooper C, Cole ZA, Holroyd CR, et al. Secular trends in the incidence of hip
and other osteoporotic fractures. Osteoporos Int. 2011;22(5):1277–88.
9. Australian Institute of Health and Welfare (AIHW): The Problem of
Osteoporotic Hip Fracture in Australia. March 2010.
10. Murad MH, Elamin KB, Abu Elnour NO, Elamin MB, Alkatib AA, Fatourechi
MM, Almandoz JP, Mullan RJ, Lane MA, Liu H, Erwin PJ, Hensrud DD,
Montori VM. Clinical review: The effect of vitamin D on falls: a systematic
review and meta-analysis. J Clin Endocrinol Metab. 2011;96(10):2997–3006.
11. Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D,
Haentjens P. Need for additional calcium to reduce the risk of hip fracture
with vitamin d supplementation: evidence from a comparative metaanalysis
of randomised controlled trials. J Clin Endocrinol Metab. 2007;92(4):1415–23.
Epub 2007 Jan 30.
12. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or
calcium in combination with vitamin D supplementation to prevent
fractures and bone loss in people aged 50 years and older: a meta-analysis.
Lancet. 2007 Aug 25;370(9588):657–66. Review. Erratum in: Lancet. 2012 Sep
1;380(9844):806.
13. Holick MF. Vitamin D, deficiency. N Engl J Med. 2007;357(3):266–81.
14. Stockton KA, Mengersen K, Paratz JD, Kandiah D, Bennell KL. Effect of
vitamin D supplementation on muscle strength: a systematic review and
meta-analysis. Osteoporos Int. 2011;22(3):859–71.
15. Muir SW, Montero-Odasso M. Effect of vitamin D supplementation on
muscle strength, gait and balance in older adults: a systematic review and
meta-analysis. J Am Geriatr Soc. 2011;59(12):2291–300.
16. Avenell A, Mak JC, O'Connell D. Vitamin D and vitamin D analogues for
preventing fractures in post-menopausal women and older men. Cochrane
Database Syst Rev. 2014;4, CD000227.
17. Mak JCS, Mason RC, Klein L, Cameron ID. Improving Mobility and Reducing
Disability in Older People Through Early High-Dose Vitamin D Replacement
Following Hip Fracture: A Protocol for a Randomized Controlled Trial and
Economic Evaluation. Geriatr Orthop Surg Rehabil. 2011;2:94–9.
18. Mak JC, Klein LA, Finnegan T, Mason RS, Cameron ID. An initial loading-dose
vitamin D versus placebo after hip fracture surgery: baseline characteristics
of a randomized controlled trial (REVITAHIP). BMC Geriatr. 2014;14:101.
19. Guralnik JM, Ferrucci F, Pieper CF, Leveille SG, Markides KS, Ostir GV,
Studenski S, Berkman LF, Wallace RB. Lower extremity function and
subsequent disability: Consistency across studies, predictive models, and
value of gait speed alone compared to the short physical performance
battery. J Gerontol Med Sci. 2000;55:M221–231.
20. Shah S, Cooper B, Maas F. The Barthel Index and ADL Evaluation in Stroke
Rehabilitation in Australia, Japan, the UK and the USA. Aust Occup Ther J.
1992;39(1):5–13.
21. Euroquol and The EQ5D Group. EQ5D –a new facility for the measurement
of health-related quality of life. Health Policy. 1990;16(3):199–208.
22. Gibson MJ, Andres RO, Isaacs B, Radebaugh T, Worm-Petersen J. The
prevention of falls in later life. Dan Med Bull. 1987;34 suppl 4:1–24.
23. Ersfeld DL, Rao DS, Body JJ, Sackrison Jr JL, Miller AB, Parikh N, Eskridge TL,
Polinske A, Olson GT, MacFarlane GD. Analytical and clinical validation of
the 25 OH vitamin D assay for the LIAISON automated analyzer. Clin
Biochem. 2004;37(10):867–74.
24. Therapeutic Goods Australia (TGA). Medical dictionary for regulatory
activities (MedDRA). Reston, VA: Northrup Grumman, 2003. https://www.tga.
gov.au/medical-dictionary-regulatory-activities-meddra.
25. Nowson CA, McGrath JJ, Ebeling PR, Haikerwal A, Daly RM, Sanders KM,
Seibel MJ, Mason RS, Working Group of Australian and New Zealand Bone
and Mineral Society, Endocrine Society of Australia and Osteoporosis
Australia. Vitamin D and health in adults in Australia and New Zealand: a
position statement. Med J Aust. 2012;196(11):686–7.
26. Institute of Medicine (US). Dietary reference intakes for calcium and vitamin
D. Washington, DC: The National Acadamies Press; 2010. https://www.
nationalacademies.org/hmd/~/media/Files/Report%20Files/2010/Dietary-
Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%
20Calcium%202010%20Report%20Brief.pdf. Accessed Mar 2014.
27. Mak JCS, Stuart-Harris J, Cameron ID, Mason RS. Oral vitamin D
replacement following hip fracture: a comparative review. J Am Geriatr
Soc. 2010;58(2):382–3.
28. Huybrechts KF, Ishak KJ, Caro JJ. Assessment of compliance with
osteoporosis treatment and its consequences in a managed care
population. Bone. 2006;38:922–8.
29. van Eijken M, Tsang S, Wensing M, de Smet PA, Grol RP. Interventions to
improve medication compliance in older patients living in the community:
a systemic review of the literature. Drugs Aging. 2003;20:229–40.
Mak et al. BMC Musculoskeletal Disorders (2016) 17:336 Page 10 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

30. Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C,
Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J,
Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF,
Boonen S, for the HORIZON Recurrent Fracture Trial. Zoledronic Acid in
Reducing Clinical Fracture and Mortality after Hip Fracture. N Engl J Med.
2007;357:nihpa40967.
31. Schöttker B, Jorde R, Peasey A, Thorand B, Jansen EH, Groot L, Streppel M,
Gardiner J, Ordóñez-Mena JM, Perna L, Wilsgaard T, Rathmann W, Feskens E,
Kampman E, Siganos G, Njølstad I, Mathiesen EB, Kubínová R, PająkA,
Topor-Madry R, Tamosiunas A, Hughes M, Kee F, Bobak M, Trichopoulou A,
Boffetta P, Brenner H, Consortium on Health and Ageing: Network of
Cohorts in Europe and the United States. Vitamin D and mortality: meta-
analysis of individual participant data from a large consortium of cohort
studies from Europe and the United States. BMJ. 2014;348:g3656.
32. Amrein K, Schnedl C, Holl A, Riedl R, Christopher KB, Pachler C, Urbanic
Purkart T, Waltensdorfer A, Münch A, Warnkross H, Stojakovic T, Bisping E,
Toller W, Smolle KH, Berghold A, Pieber TR, Dobnig H. Effect of High-Dose
Vitamin D3 on Hospital Length of Stay in Critically Ill Patients With Vitamin
D Deficiency The VITdAL-ICU Randomized Clinical Trial JAMA. 2010 Sep 30;
2014 (online). doi:10.1001/jama.2014.13204
33. Holick MF. The use and interpretation of assays for vitamin D and its
metabolites. J Nutr. 1990;120 Suppl 11:1464–9.
34. Cameron ID, Gillespie LD, Robertson MC, Murray GR, Hill KD, Cumming RG,
Kerse N. Interventions for preventing falls in older people in care facilities
and hospitals. Cochrane Database Syst Rev. 2012;12, CD005465.
35. Gillespie LD, Robertson MC, Gillespie WJ, Sherrington C, Gates S, Clemson
LM, Lamb SE. Interventions for preventing falls in older people living in the
community. Cochrane Database Syst Rev. 2012;9, CD007146.
36. Zeltzer J, Mitchell RJ, Toson B, Harris IA, Ahmad L, Close J. Orthogeriatric
services associated with lower 30-day mortality for older patients who
undergo surgery for hip fracture. Med J Aust. 2014;201(7):409–11.
37. Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D,
Nicholson GC. Annual high-dose oral vitamin D and falls and fractures in
older women: a randomized controlled trial. JAMA. 2010;303(18):1815–22.
doi:10.1001/jama.2010.594.
38. Osteoporosis Australia: http://www.osteoporosis.org.au/vitamin-d [accessed
25 June 2016]
• We accept pre-submission inquiries
• Our selector tool helps you to find the most relevant journal
• We provide round the clock customer support
• Convenient online submission
• Thorough peer review
• Inclusion in PubMed and all major indexing services
• Maximum visibility for your research
Submit your manuscript at
www.biomedcentral.com/submit
Submit your next manuscript to BioMed Central
and we will help you at every step:
Mak et al. BMC Musculoskeletal Disorders (2016) 17:336 Page 11 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1.
2.
3.
4.
5.
6.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
apply.
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
not:
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
control;
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
writing;
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
content.
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
onlineservice@springernature.com