Keywords
bone union - vitamin D deficiency - tibial fracture - vitamin D supplementation
Introduction
Vitamin D plays a role in the homeostasis of several physiological processes in the
human body, particularly bone union.[1]
[2]
[3]
[4] Serological concentrations of 25-hydroxyvitamin D ([25(OH)-D]) ≥ 30 ng/mL are within
normal ranges; values from 20 ng/mL to 29 ng/mL are insufficient, and those < 20 ng/mL
are deficient.[5]
[6]
Various studies have shown deficient plasma levels of vitamin D in 2% to 90% of the
patients evaluated.[7] This range varies according to cut-off points and populations, with 37.3% and 88.1%
of deficiency and insufficiency rates respectively.[7] In Chile, the prevalence of vitamin D deficiency has been determined among the pediatric
population,[8] pre- and postmenopausal women,[9]
[10] healthy elderly people,[11] and elderly patients with hip fractures.[12]
The Endocrine Society[5] recommends a dose of 50,000 IU per os (PO) of vitamin D2 or D3 once a week for 8
weeks for adults with vitamin D deficiency, followed by a maintenance dose of 1,500 IU
to 2,000 IU/day PO. This treatment reportedly normalizes [25(OH)-D] levels in up to
72% of healthy patients.[13]
[14]
[15]
The levels of vitamin D decrease during fracture healing.[16] Consistently, the weekly administration of 50,000 IU resulted in a low rate of normalization
of the levels of [25(OH)-D] in fracture patients.[13]
[17] The metabolic change generated by a traumatic injury may require a higher supplementation
dose to normalize the values and avoid complications regarding bone healing.[3]
[18]
[19]
The effectiveness of vitamin D supplementation in bone union remains controversial;
some clinical series and a systematic review[1] showed no clear benefits of correcting [25(OH)-D] deficiency[20] or a decrease in complication rates.[17]
Toxic [25(OH)-D] levels are > 150 ng/mL.[21] In contrast, it has been suggested that cholecalciferol doses of 100,000 IU/week
for 5 weeks are safe and normalize vitamin D levels in a higher percentage of patients.[22]
Based on these findings, vitamin D supplementation with a dose higher than usual in
adult patients with fractures could benefit bone healing. The present pilot study
aims to determine the prevalence of hypovitaminosis D and the safety and effectiveness
of an established dose of vitamin D in patients with tibial fractures. We hypothesize
that the weekly administration of 100,000 IU of cholecalciferol effectively normalizes
serological values without generating toxic [25(OH)-D] levels.
Materials and Methods
The present is a study involving a prospective cohort of 56 consecutive patients aged
18 to 65 years who presented a tibial fracture and were admitted to a level-1 trauma
center from May 1st, 2017, to April 30, 2018. The institutional ethics committee approved
the study.
The recruited patients had a tibial fracture treated with an intramedullary nail.
After admission to the emergency department, we invited them to participate in the
study. Those who agreed signed an informed consent form. The following subjects were
excluded from the sample: those with a glomerular filtration rate < 60 mL/minute,
history of kidney disease or calculi, under current supplementation with multivitamins,
history of cancer, pathological bone fracture, difficulty receiving oral treatment,
preexisting conditions that alter vitamin D metabolism (liver failure, parathyroid
disorders, hypocalcemia, or hypercalcemia), allergy or contraindications to vitamin
D, pregnant patients, those with no serological sample for the determination of the
level of [25(OH)-D], subjects with normal [25(OH)-D] levels (≥ 30 ng/mL), and patients
who refused to participate in the study.
We enrolled 56 patients, and 18 (32.1%) were excluded, including 1 (1.8%) who presented
normal levels of vitamin D at admission, 1 (1.8%) who refused treatment, and 16 (28.6%)
who did not comply with the stipulated timeframe for cholecalciferol administration
([Figure 1]). The incidence of hypovitaminosis D was of 98.2% (55/56 patients). The analysis
included 38 patients, 33 (86.9%) men and 5 (13.1%) women. Their average age was 40
years (range: 21 to 90 years; standard deviation [SD] = 14.4 years) ([Table 1]).
Table 1
|
Gender
|
Total
|
Statistical analysis
|
|
Male
|
Female
|
|
Frequency
|
33 (86.9%)
|
5 (13.1%)
|
38 (100%)
|
*p < 0.05
|
|
Age in years: mean(± standard deviation)
|
42(± 14.9)
|
35(± 14.1)
|
40(± 14.4)
|
**p = 0.33
|
Fig. 1 Baseline vitamin D levels (ng/mL) per month.
Serological levels of [25(OH)-D] were obtained in the emergency department or up to
2 days after admission using chemiluminescence (ADVIA Centaur XP, Siemens Healthineers,
Erlangen, Germany). The reference values were ≥ 30 ng/mL. Levels ranging from 20 ng/mL
to 29 ng/mL and those lower than 20 ng/ml characterized insufficiency and deficiency
respectively.
At the outpatient care center, a paramedic technician administered a dosis of 100,000 IU
of cholecalciferol once a week for 3 weeks to patients with vitamin D deficiency and
for 5 weeks to patients with vitamin D deficiency. Each dose was recorded at the time
of administration. A serum sample was collected 4 days to 2 weeks after the last administration
of cholecalciferol to evaluate the level of [25(OH)-D] after the supplementation.
The Shapiro-Wilk test was used to analyze the normal distribution of continuous variables.
The parametric variables were expressed as mean ± SD. The Student t-test was used to analyze the parametric variable [25(OH)-D] levels after the supplementation.
Chi-squared tests were used to analyze the categorical variables. Statistical significance
was set at p < 0.05. The statistical analysis was performed using the Stata (StataCorp LLC, College
Station, TX, United States) software, version 12.0.
Results
Among our patients, 28 (73.7%) and 10 (26.3%) had vitamin D deficiency and insufficiency
respectively ([Table 2]). The baseline levels of vitamin D showed a tendency to decrease during winter ([Figure 1]).
Table 2
|
N (%)
|
Baseline level of vitamin D: mean(± standard deviation)
|
Postsupplementation level of vitamin D: mean(± standard deviation)
|
Statistical analysis
|
|
Insufficiency
|
10 (26.3%)
|
24.84(± 2.97)
|
49.19(± 10,38)
|
*p < 0.05
|
|
Deficiency
|
28 (73.7%)
|
10.89(± 4.53)
|
41.98(± 10,87)
|
*p < 0.05
|
|
Total
|
38 (100%)
|
14.56(± 7.47)
|
43.88(± 12,67)
|
*p < 0.05
|
Most patients (35/38; 92.1%) presented normal serological concentrations of vitamin
D. The postsupplementation levels were significantly higher than the baseline levels
for the entire sample (14.56 ng/mL versus 43.88 ng/mL; p < 0.05), as well as in the insufficiency subgroup (24.84 ng/mL versus 49.19 ng/mL;
p < 0.05) and the deficiency subgroup (10.89 ng/mL versus 41.98 ng/mL; p < 0.05) ([Table 2]). All patients (3; 7.9%) with abnormal postsupplementation concentrations had baseline
[25(OH)-D] levels lower than 10 ng/mL: in one of them, the postsupplementation [25(OH)-D]
level was of 25.9 ng/mL, while the remaining 2 subjects still presented deficient
values, although higher than 10 ng/mL ([Table 2]).
All subjects presented [25(OH)-D] levels lower than 80 ng/mL after the administration
of cholecalciferol. There were no treatment-related adverse effects, and no patients
withdrew from the study due to adverse effects secondary to the intervention.
Discussion
The prevalence of vitamin D deficiency is highly variable among the published studies,
ranging from 2% to 90%.[7]
[23] Several factors influence this prevalence, including age, ethnicity, gender, seasonality,
comorbidities, and serological cut-off point.[7]
The dosage for vitamin D normalization (30 ng/mL) is also debatable. The National
Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM),[6] and the Endocrine Society[5] recommends the administration of [25(OH)-D] in dosages of 50,000 IU PO per week
or 6,000 IU PO per day until serological normalization, followed by a daily maintenance
dose of 1,000 IU to 2,000 IU PO.
Despite this recommendation, the supplementation scheme was partially effective in
our population of interest. A study[13] in trauma patients showed normalization of serological vitamin D levels in 54% and
0% of those with insufficiency and deficiency respectively after a weekly supplementation
of 50,000 IU. These findings suggest that this dosage is ineffective.
In some studies, vitamin D supplementation with higher doses, of up to 600,000 IU
PO per month, resulted in no hypercalcemia or other adverse effects,[6]
[24]
[25] and led to the effective normalization of plasma levels.[24] As such, we instituted a dosage of 100,000 IU PO per week for 3 weeks in subjects
with vitamin D insufficiency and for 5 weeks in those with deficiency. This scheme
resulted in a high normalization rate in our study population (92.1%) with no secondary
adverse effects. The plasma levels of [25(OH)-D] were always lower than 70 ng/ml,
which is consistent with the lack of toxicity due to hypervitaminosis D, which is
usually observed with serological concentrations above 150 ng/mL.[5]
[21]
Few reports associate vitamin D deficiency with bone union. Evaluating fusion in spinal
arthrodesis after 1 year, Ravindra et al.[26] showed a longer time until union in patients with [25(OH)-D] deficiency. In addition,
they identified hypovitaminosis D as an independent risk factor for non-union (odds
ratio [OR]: 3.4).
Brinker et al.[20] investigated a consecutive series of 683 patients, including 37 with unexplained
non-union, and observed a rate of hypovitaminosis D of 68% in this subgroup of patients.
Interestingly, some achieved bone union after [25(OH)-D] supplementation and no surgical
reintervention.
In contrast, normal vitamin D levels in patients with fractures are not decisive in
reducing associated complications from bone union issues and do not lower the probability
of reintervention for the same cause.[17] Per these findings, some systematic reviews and meta-analyses[1]
[27]
[28] have failed to objectively identify the benefit of vitamin D supplementation for
bone healing. However, studies are scarce, with small populations, high sample heterogeneity,
and use supplementation schemes ineffective in normalizing vitamin D levels.
The main strengths of our study are its prospective design, the follow-up of 100%
of the patients meeting the inclusion criteria, the delivery of all doses assigned
to each patient individually by a paramedic technician, and the administration of
a new, safe, and effective scheme for vitamin D supplementation. Its weaknesses are
the lack of randomization and a control group, which reduce the power of the information
obtained, and a high percentage of patients leaving the study (28.6%) and not completing
the supplementation scheme.
This is the first part of a comparative study to analyze the effect of vitamin D supplementation
on bone healing in patients with tibial fractures. To do so, we first determined the
prevalence of hypovitaminosis D in our population. Next, we demonstrated a safe and
effective supplementation scheme, which will enable future comparisons with a group
not treated with vitamin D.
Conclusion
There is a high prevalence of vitamin D deficiency in adult patients with tibial fractures.
The new cholecalciferol supplementation scheme in patients with tibial fracture is
effective and safe. The prevalence observed and the effectiveness of the dosage administered
will help the development of prospective studies evaluating the benefit of vitamin
D supplementation in bone union after tibial fracture.
