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Citation: Christianson, E.; Thomas,
M.; Sprague, S.; Rivera, J.; Chapple,
A.; Zura, R. Nutritional Indicators of
Bone Nonunion: A Systematic Review.
J. Clin. Med. 2024,13, 6553. https://
doi.org/10.3390/jcm13216553
Academic Editor: Marco Alessandro
Minetto
Received: 23 October 2024
Revised: 28 October 2024
Accepted: 29 October 2024
Published: 31 October 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Journal of
Clinical Medicine
Systematic Review
Nutritional Indicators of Bone Nonunion: A Systematic Review
Eleanor Christianson 1, * , Margaret Thomas 2, Sheila Sprague 3, Jessica Rivera 2, Andrew Chapple 2
and Robert Zura 2
1Department of Orthopedic Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
2Department of Orthopedic Surgery, Louisiana State University Health Sciences Center,
New Orleans, LA 70112, USA
3Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada
*Correspondence: echristianson@tulane.edu
Abstract: Background/Objectives: Bone nonunion remains a clinical challenge in orthopedic surgery
with significant impacts on mental and physical wellbeing for patients. There are several previously
established risk factors of nonunion that are connected to nutrition, but this has yet to be substantially
explored. This review seeks to assess all studies that present associations between nutrition and
nonunion to understand the potential for clinical relevance in nonunion prevention. Methods: Case–
control and cohort studies comparing nonunion risk based on nutritional factors were gathered
through PubMed in July 2024. Data were extracted with dual verification through Covidence and
assessed for bias using the Newcastle–Ottawa Scale. Results: A total of 21 studies were included in
this literature review. Vitamin D deficiency was a significant risk factor of nonunion in six studies and
not significant in six other studies. Albumin was significant in three of the five studies addressing
this lab value. Iron deficiency anemia was significant in a study assessing its impact on nonunion.
Calcium was not significant in the one study mentioned. ICD-10-coded malnutrition was significant
in one of the two studies. Sarcopenia, nutritional care plans, and dietitian-diagnosed malnutrition
were statistically significant clinical indicators for predicting nonunion, but food insecurity was
insignificant. Conclusions: Vitamin D, calcium, albumin, iron deficiency anemia, sarcopenia, and
clinically diagnosed malnutrition have all been associated with an increased risk of nonunion in
observational studies and should be considered when preventing nonunion development.
Keywords: nonunion; nutrition; vitamin D; sarcopenia
1. Introduction
Bone nonunion remains a significant clinical challenge in orthopedic surgery. Large
cohort studies have shown the nonunion rate to be approximately 5% and higher for certain
populations and fracture types [
1
]. The US Food and Drug Administration (FDA) defines
bone nonunion as any fracture that does not heal for nine months or shows no signs of
healing for three months [
2
]. Nonunion creates heightened psychological stress and is
associated with lower overall physical health in patients [3].
Although the exact etiology of nonunion is not established, the source is likely mul-
tifactorial. Many risk factors have been previously associated with nonunion including
the type of fracture, treatment, underlying medical conditions (e.g., osteoporosis), and
demographic and lifestyle factors (e.g., smoking, obesity.) Several of these risk factors are
linked to nutrition, yet few studies have focused specifically on nutrition as a risk factor for
nonunion. Both macro- and micronutrients including vitamins and minerals are critical for
both bone growth, maintenance, and healing [
4
]. Deficiencies in these nutrients can have
drastic impacts on bone health and have been shown to increase bone loss and fracture risk
in various studies [
4
]. Since nutritional deficiencies are a demonstrated risk factor for other
negative orthopedic outcomes, this creates the question of whether these deficiencies carry
the same risk for nonunion development.
J. Clin. Med. 2024,13, 6553. https://doi.org/10.3390/jcm13216553 https://www.mdpi.com/journal/jcm
J. Clin. Med. 2024,13, 6553 2 of 12
This review seeks to assess all studies that investigate associations between nutrition
and nonunion with the overall goal of determining which tests and diagnoses may serve as
useful clinical indicators in preventing nonunion after fracture.
2. Materials and Methods
2.1. Literature Search
This literature review was conducted by EC using PubMed searches for all relevant
publications related to nutritional indicators of nonunion (Table 1). Initial query terms were
chosen by EC based on nutritional indicators identified as relevant for bone health and
fracture healing [
4
]. Additional searches with topics connected to nutrition were included
by EC to ensure the complete inclusion of all relevant studies.
Table 1. PubMed search information. All PubMed inquiries used for this review. This in-
cludes the 112 duplicates that were identified by Covidence and automatically removed before
abstract screening.
Search Query Terms Studies Added Date
Searched
PubMed
Search 1
(nonunion) AND ((calcium) OR (vitamin D) OR
(25-dihydroxycholecalciferol) OR (calcitriol) OR (sodium) OR (phosphorus)
OR (copper) OR (zinc) OR (manganese) OR (magnesium) OR (vitamin K)
OR (vitamin B6) OR (DHA) OR (EPA) OR (iron) OR (potassium) OR
(magnesium) OR (folic acid) OR (vitamin C) OR (vitamin A) OR (vitamin
B12) OR (lysine) OR (proline) OR (bisphosphonates) OR (protein) OR
(carbohydrates) OR (lipids)) data
1840 2 July 2024
PubMed
Search 2
2 papers were manually imported based on previous knowledge of
literature that were not included in the previous search. 2 2 July 2024
PubMed
Search 3
(nonunion) AND ((nutrition) OR (malnutrition) OR (nutritional deficiency)
OR (sarcopenia) OR (Vitamin) OR (nutrients)) 218 3 July 2024
2.2. Eligibility Criteria
Studies were excluded if they were biochemical studies, literature reviews, animal
models, and case studies along with abstracts and studies with a sample size of under
20 people. For full text review exclusion criteria, studies were excluded if nonunion was
not a main outcome, if the outcome compared different types of nonunion, if there was
an underlying endocrine disorder for all participants including controls, or if nutritional
indicators were not a main exposure of the study. Case–control and cohort studies with
sample sizes of 20 or more people comparing nonunion risk based on nutritional factors
were included in this study.
2.3. Article Screening
All studies identified from the PubMed searches were initially included by EC. Covi-
dence identified and removed duplicates. All subsequent screening phases were performed
by MT and EC independently to avoid bias and prevent exclusion of relevant studies. In
the abstract screening and full text review phases, studies that did not meet the eligibility
criteria were excluded.
2.4. Data Extraction and Analysis
Data extraction was conducted through Covidence independently by MT and EC [
5
].
The significance, risk ratios, fracture type, population, and data of various nutritional values
were extracted from full text by EC and MT and compared for accuracy. These values
were used to assess the impact of each nutritional factor on nonunion. Any conclusions
discussed in this text were based only on the information clearly presented in the included
texts. Based on an in-depth review of literature, articles were grouped in the analysis
based on vitamin D, other serum values, and nutrition-related diagnoses. Texts addressing
J. Clin. Med. 2024,13, 6553 3 of 12
both or all of these sections were included in their relevant discussions and not limited to
one section.
2.5. Bias Assessment
All studies included were quality assessed for potential biases using the Newcastle–
Ottawa Scale which is for cohort and case–control studies. Each study was reviewed
independently by EC and MT.
3. Results
The three PubMed searches resulted in the initial inclusion of 2060 studies (Figure 1).
Covidence removed 112 studies that were duplicates. Additionally, 1745 irrelevant stud-
ies were excluded before abstract screening. Of the 203 remaining articles, there were
12 biochemical
studies, 34 literature reviews, 33 animal models, and 28 case studies. There
were four studies with only abstracts available, and three studies where the sample size
was below 20. This resulted in 89 studies for full text review. In full text review, sixteen
studies did not have nonunion as a main outcome; three studies had different types of
nonunion; thirty studies included cohorts with underlying metabolic disorders; and, lastly,
nineteen studies did not have nutritional indicators as a main outcome.
J. Clin. Med. 2024, 13, x FOR PEER REVIEW 3 of 13
2.4. Data Extraction and Analysis
Data extraction was conducted through Covidence independently by MT and EC [5].
The signicance, risk ratios, fracture type, population, and data of various nutritional
values were extracted from full text by EC and MT and compared for accuracy. These
values were used to assess the impact of each nutritional factor on nonunion. Any
conclusions discussed in this text were based only on the information clearly presented in
the included texts. Based on an in-depth review of literature, articles were grouped in the
analysis based on vitamin D, other serum values, and nutrition-related diagnoses. Texts
addressing both or all of these sections were included in their relevant discussions and
not limited to one section.
2.5. Bias Assessment
All studies included were quality assessed for potential biases using the Newcastle–
Oawa Scale which is for cohort and case–control studies. Each study was reviewed
independently by EC and MT.
3. Results
The three PubMed searches resulted in the initial inclusion of 2060 studies (Figure 1).
Covidence removed 112 studies that were duplicates. Additionally, 1745 irrelevant studies
were excluded before abstract screening. Of the 203 remaining articles, there were 12
biochemical studies, 34 literature reviews, 33 animal models, and 28 case studies. There
were four studies with only abstracts available, and three studies where the sample size
was below 20. This resulted in 89 studies for full text review. In full text review, sixteen
studies did not have nonunion as a main outcome; three studies had dierent types of
nonunion; thirty studies included cohorts with underlying metabolic disorders; and,
lastly, nineteen studies did not have nutritional indicators as a main outcome.
Therefore, 21 case–control and cohort studies were included in this review. These
studies were subdivided into three main themes including vitamin D (twelve studies),
other serum lab values (seven studies), and malnutrition-related diagnoses (six studies).
Some studies addressed two or all of these themes. All included studies had a relatively
low risk of bias based on the Newcastle–Oawa Scale assessment.
Figure 1. PRISMA chart which summarizes the literature review process.
3.1. Vitamin D Studies
There were 12 studies identied that focused on vitamin D (Table 2). Of these, six
papers found signicant results associating vitamin D deciency to nonunion. Zura et al.
Figure 1. PRISMA chart which summarizes the literature review process.
Therefore, 21 case–control and cohort studies were included in this review. These
studies were subdivided into three main themes including vitamin D (twelve studies),
other serum lab values (seven studies), and malnutrition-related diagnoses (six studies).
Some studies addressed two or all of these themes. All included studies had a relatively
low risk of bias based on the Newcastle–Ottawa Scale assessment.
3.1. Vitamin D Studies
There were 12 studies identified that focused on vitamin D (Table 2). Of these, six
papers found significant results associating vitamin D deficiency to nonunion. Zura et al. [
1
]
performed a study analyzing the risk factors for nonunion across 18 different bones in
adults and found vitamin D deficiency to be a significant risk factor, showing a univariate
OR of 1.44 (CI: 1.34, 1.54) and a multivariate OR of 1.14 (1.05–1.22; p< 0.001). In a similar
study, Zura et al. [
6
] performed a separate inception cohort study of 237,033 pediatric
patients that analyzed vitamin D among various others as a risk factor for nonunion. The
results showed a significant univariate OR of 3.98 (CI: 2.70, 5.84) and a multivariate OR of
2.91 (1.91, 4.42; p= < 0.0001). These paired studies suggest that the associated risk factors
J. Clin. Med. 2024,13, 6553 4 of 12
for nonunion are similar for pediatric and adult populations, but the correlation of vitamin
D deficiency and nonunion seems to be stronger in pediatric populations.
Table 2. Vitamin D studies. All studies that included vitamin D (vit D) as a main exposure or risk
factor of nonunion.
Paper Study Design Bone Studied Result Significance
Zura, 2016 [1]
Risk factors analyzed for nonunion
for 309,330 fractures in 18 bones.
Metatarsal, radius, ankle,
metacarpals, trunk, tarsal,
humerus, tibia, ulna, clavicle,
scaphoid, patella, pelvis,
fibula, femur
Nonunion rate was 4.9%. Nonunion
risk increased with vitamin D deficiency
(OR, 1.14; p< 0.001).
significant
Zura, 2018 [6]
Risk factors analyzed for nonunion
in 237,033 pediatric
fracture patients.
Metacarpal, radius, ankle, patella,
ulna, fibula, pelvis, clavicle,
humerus, femur, tibia, metatarsal,
tarsal, scaphoid
Nonunion rate: 0.85%. Multivariate
analysis shows deficiency has
significant OR (p< 0.001).
significant
Ravindra, 2015 [7]
Vit D levels of 133 adults
pre-elective spinal fusion
(<20 ng/mL = deficient) to
determine predictor of nonunion.
Cervical, thoracic, and
lumbar vertebrae
Nonunion rate: 20% adequate Vit D
level vs. 38% deficient patients
(p= 0.063). Time to fusion longer in the
deficient group (12 vs. 6 mo., p= 0.001).
Multivariate analysis vit D deficiency is
significant (OR 3.45, p= 0.045).
significant
Zhou, 2022 [8]
Vit D levels of 58 nonunion and
692 union cervical spondylotic
cases measured
Cervical vertebrae
Serum Vit D (OR = 0.81, p< 0.001) was a
significant predictor of nonunion. significant
Ramanathan,
2022 [9]
Preop Vit D levels of 47 patients
were split into deficient
(<30 ng/mL) vs. normal
(
31–80 ng/mL
) and reoperation for
nonunion was assessed.
Ankle
The deficient group (n = 17; 36.2%) vs.
normal (n = 30; 63.8%) Vit D levels were
16.9 and 46.4 ng/mL. Reoperations for
nonunion occurred only in the deficient
cohort (23.5%; p= 0.013).
significant
Moore, 2017 [10]
29 nonunion and 29 union patients
with elective foot/ankle
reconstruction were matched to
assess nonunion risk factors
including vit D.
Foot and ankle
Patients with vit D
deficiency/insufficiency were 8.1 times
more likely to have nonunion (p= 0.02,
CI: 1.996–32.787).
significant
Hendrickson,
2019 [11]
373 patients with operative fracture
screened using questionnaire and
dietitian. If moderate-to-high risk,
25(OH) Vitamin D
measured preoperatively.
Clavicle, scapula, shoulder,
humerus, radius, forearm, pelvis,
acetabulum, knee, patella, tibia,
foot, ankle
Of 373 patients, 17% were at risk. Vit D
was not a significant predictor
of nonunion.
not
significant
Donnally, 2019 [12]
Pre and postop vit D levels
measured in 150 patients for
impact on rates of postop
pseudarthrosis, revision,
or complications.
Lumbar vertebrae
Vit D levels were not significantly
associated with rates of postoperative
pseudarthrosis, revision, or hardware
complications (p> 0.05).
not
significant
Clark, 2021 [13]
Vit D levels of 33 patients with
corrective osteotomy for distal
radius malunion measured to
predict nonunion.
Radius
Seven patients (21%) had nonunion
after osteotomy. Vit D deficiency is
not significant.
not
significant
Gudeman, 2023 [14]
Vit D deficiency (<30 ng/mL) of
370 patients with operative tibia
and fibula fractures to predict
nonunion.
Tibia, fibula
98% (n = 210) of fractures had vit D
insufficiency with a median of
22.7 ng/mL. No statistical difference
between union rates.
not
significant
Gregersen, 2015 [15]
Vit D of 322 femoral neck fractures
fixed with cannulated screws
were assessed.
Femur 29% underwent reoperation. Vit D was
not a significant nonunion predictor.
not
significant
Haines, 2017 [16]
100 vitamin D deficient/sufficient
(<20 and <30 ng/mL) patients with
long bone fractures; 50 received
single dose of vitamin D (3) orally
(100,000 IU) within two weeks of
injury, 50 were placebo.
Humerus, femur, tibia
The initial median vit D levels were
16 ng/mL in both groups (p= 0.885).
Nonunion rate was 4% (two per group).
not
significant
Ravinda et al. [
7
] measured preoperative vitamin D levels of 133 adults undergoing
elective spinal fusion and found a significant difference of vitamin D levels with nonunion
rates of 20% and 38% in adequate and deficient vitamin D levels, respectively (p= 0.063).
There was also an increased OR of 3.45 for nonunion (p= 0.045) and longer times to
fusion (p= 0.001) [
7
]. Zhou et al. [
8
] assessed vitamin D levels for cervical fusion rates
of spondylotic spines and found that serum vitamin D was a significant predictor of
nonunion. Ramanathan et al. [
9
] assessed patients who underwent ankle fusion procedures
J. Clin. Med. 2024,13, 6553 5 of 12
and evaluated the incidence of reoperation with available vitamin D levels. A significant
association was found with zero of thirty patients in the control cohort and four of seventeen
of the vitamin D deficient cohort and underwent reoperation secondary to nonunion
(
p= 0.013) [9]
. In a case–control study of 58 patients conducted by Moore et al. [
10
], it
was found that patients with vitamin D deficiency were 8.1 times more likely to have a
nonunion (p= 0.02, CI: 1.996–32.787).
Six studies did not find a significant association between vitamin D levels and fracture
healing. Using a cohort of musculoskeletal trauma patients, one study evaluating the medi-
cal complications and preoperative vitamin D levels of 373 patients found an insignificant
association (0.72 (CI: 0.41, 1.26; p= 0.25)) [
11
]. Donnaly et al. [
12
] found no association
between vitamin D levels and rates of postoperative pseudarthrosis, revision, or hardware
complications after lumbar spinal fusion across a 150-patient population (p> 0.05). In
Clark et al. [
13
], thirty-three patients undergoing corrective distal radial malunion were
investigated; seven patients had a nonunion, and vitamin D deficiency was not found to be
a significant risk factor of nonunion.
Two studies investigated long bone nonunion of the lower extremities. The first
included 370 patients with tibia and fibula fractures that required surgical intervention,
and 90% (n = 210) had vitamin D insufficiency; however, there was no statistical difference
in union rates [
14
]. The second study investigated patients with femoral neck fractures that
required cannulated screws. Of these patients, 29% required reoperation and vitamin D
status was not a significant predictor of nonunion [
15
]. One study investigated the effect of
implementing a one-time 100,000 IU oral vitamin D supplement to patients with vitamin D
deficiency (<20 ng/mL) and vitamin D insufficiency (<30 ng/mL), but these treatments
were found to have no significant effect on nonunion between the treatment and control
group [
16
]. Overall, low vitamin D levels were found to be associated with nonunion in
certain populations, but not others.
3.2. Other Serum Values
Albumin is a well-established marker of malnutrition that was analyzed in five of
the studies in this literature review (Table 3). Bajada et al. [
17
] retrospectively assessed
the preoperative serum albumin of 111 undisplaced intracapsular hip fractures treated
with cannulated screws and found that patients with fixation failure had on average
5 g/mL lower albumin levels compared to properly healed cases (p= 0.02); the odds
ratio of albumin in a multivariate analysis was 0.188 (CI: 0.046–0.765, p= 0.008). The
proposed mechanism for this relationship was based on the connection between low bone
mineral density and hypoalbuminemia along with increased risk of falls in malnourished
people [
17
]. In a retrospective review of 251 femoral neck fractures, Riaz et al. [
18
] showed
that lower preoperative albumin levels were a significant independent risk factor associated
with fixation failure including nonunion and explained that it could be a helpful tool for
deciding between fixation or arthroplasty (p= 0.01). They cited similar reasoning for this
connection as Bajada’s explanation. In the Hendrickson et al. study [
11
], 373 patients with
operative fixation were screened by a dietitian, and albumin labs were drawn if they were
at medium to high risk; 41% of patients had hypoalbuminemia (<3.5 mg/dL) and the OR
for complication risk including nonunion was 1.79 (p= 0.045). Hendrickson proposed that
albumin may be increased in these cases more so due to the movement of plasma during
the acute phase reaction of trauma versus any connection with nutrition, citing that current
nutritional guidelines do not recommend albumin as a reliable clinical measure of nutrition.
Lastly, two other studies did not find albumin to be a significant risk factor, including
Chen et al. [
15
], who reviewed 204 nonunion cases, and Gregerson et al. [
19
], who assessed
nonunion risk factors for 322 operative femoral neck fractures (p> 0.05).
J. Clin. Med. 2024,13, 6553 6 of 12
Table 3. Other serum lab value studies. All studies that assessed serum values other than vitamin D.
Paper Study Design Bone Studied Result Significance
Bajada, 2015 [17]
Albumin levels measured
for 111 patients with
undisplaced intracapsular
hip fractures treated with
cannulated screws.
Femur
16% of fixations failed and had
a significantly lower albumin
(35 g/L vs. 40 g/L, p= 0.02)
than non-failure patients
becoming independent
risk factors.
significant
Riaz, 2016 [18]
Preoperative albumin
levels of 251 undisplaced
intracapsular femoral neck
fracture patients measured
to assess fixation failure
including nonunion.
Femur
12 (5%) patients had fixation
failure from nonunion. Low
serum albumin levels were
significantly associated with
failure (p= 0.01).
significant
Hendrickson,
2019 [11]
373 patients with operative
fracture screened by
dietitian. If
moderate-to-high risk,
albumin, transferrin, and
total lymphocyte
count measured.
Clavicle, scapula,
shoulder, humerus,
radius, forearm, pelvis,
acetabulum, knee,
patella, tibia, foot, ankle
Of 373 patients, 17% were at
risk, ~50% of patients had 1+
serum deficiency.
Complications occurred in 19%
of patients. Hypoalbuminemia
(OR 1.79, p= 0.045)
was significant.
significant
Gregersen,
2015 [15]
Vit D and albumin of
322 operative femoral neck
fractures assessed for
outcomes
including nonunion.
Femur
After 2 years, 29% underwent
reoperation. Albumin was not
significant.
not
significant
Chen, 2024 [19]
Nonunion risk factors of
204 patients with defective
bony nonunion compared
to controls.
Tibia, humerus, fibula,
femur, radius, ulna
Serum calcium levels were
lower in the nonunion group
(p= 0.01). Albumin was not
significant. Glucose levels
were higher in the nonunion
group (p= 0.01).
not
significant
Sanchez, 2023 [20]
ORIF for PHFs were
divided into nonunion
(n = 1020) and union
(n = 51,209) to compare
risk factors.
Humerus
Iron deficiency anemia (OR:
1.32; p= 0.0001) was significant
for nonunion within 6 months
of ORIF for PHF.
significant
Liu, 2021 [21]
Preoperative calcium,
phosphorus, and PLT were
collected for 468 patients
(170 posttraumatic OM,
130 aseptic bone nonunion,
168 controls).
Not specified
No statistical difference
between ABN and control for
serum calcium (p= 0.197).
Serum phosphorus level of
control (1.24 mmol/L) were
lower compared to ABN
(1.29 mmol/L) (p= 0.011)
not
significant
Iron deficiency anemia is a nutritional deficiency that was shown to be a significant
predictor of nonunion in two of the studies included in this literature review (Table 3).
Anderson et al. published that in a cohort of 9482 metatarsal fractures, fractures with
delayed healing were associated with higher rates of iron deficiency anemia (p= 0.016). In
Sanchez et al. [
20
], 1020 nonunion cases of proximal humerus fractures were compared to
controls, and iron deficiency anemia had an OR of 1.32 6 months after open reduction and
internal fixation (ORIF) (p< 0.0001). Sanchez et al. proposed that iron deficiency anemia
has a role in nonunion due to osteoporosis development through a reduction in vitamin D
activation and hypoxia.
Lastly, Liu et al. [
21
] analyzed different lab values in 170 posttraumatic osteomyelitis
and 130 aseptic nonunion patients in comparison to 168 controls (Table 3). There was
J. Clin. Med. 2024,13, 6553 7 of 12
no statistical difference between the nonunion and control groups for serum calcium
(p= 0.197)
. Serum phosphorus levels of control (1.24 mmol/L) were lower compared to
nonunion cases (1.29 mmol/L) (p= 0.011).
3.3. Malnutrition and Related Diagnoses
In this literature review, six papers assessed the connection between various nutri-
tional diagnoses with the risk of nonunion (Table 4). Zura et al. [
1
] retrospectively an-
alyzed 209,330 fractures and did not find a significant association between malnutrition,
measured by record of an International Classification of Diseases (ICD)-coded diagnosis,
and nonunion (p> 0.05). Wilkinson et al. [
22
] assessed 178,283 femur fractures by dividing
them based on the presence of ICD-9 and 10-coded malnutrition; in this case, malnutrition
significantly increased the risk of nonunion (1.89; 95% CI: 1.69–2.11; p< 0.0001). Vander Voort
et al. [
23
] measured sarcopenia, a diagnosis related to malnutrition, based on the psoas index
(women <3.85 m
2
/m
2
, men <5.45 cm
2
/m
2
) in 111 patients with operative tibia or ankle
fractures; the risk ratio for sarcopenia and nonunion was 2.42 (CI: 1.08–5.43, p= 0.0314).
Table 4. Nutritional diagnoses studies. All studies that assessed nutrition-related diagnoses.
Paper Study Design Bone Studied Result Significance
Zura, 2016 [1]
Risk factors analyzed for
nonunion for 309,330 fractures
in 18 bones.
Metatarsal, radius,
ankle, metacarpals,
trunk, tarsal, humerus,
tibia, ulna, clavicle,
scaphoid, patella,
pelvis, fibula, femur
Malnutrition was not
significant.
not
significant
Wilkinson,
2022 [22]
178,283 patients (65+) with
operative femur fractures
divided into malnutrition
compared to
non-malnourished cases.
Clavicle, scapula,
humerus, radius,
forearm, pelvic ring,
femur, patella, tibia,
foot, ankle
Patients with malnutrition are
at increased risk of nonunion
(1.89; 95% CI 1.6946–2.1095;
p< 0.0001).
significant
Vander Voort,
2020 [23]
111 patients with operative
fixation of open tibia/ankle
fractures. Sarcopenia = psoas
index at the L3 pedicle with
<3.85 (women) and
<5.45 cm2/m2(men).
Tibia, ankle
16/100 (16%) patients had
sarcopenia. Nonunion
occurred in 6 patients with
sarcopenia (38%) and
12 without (18%) (RR = 2.42,
CI = 1.08–5.43, p= 0.0314).
significant
Vo, 2024 [24]
Food insecurity screening
surveys of 100 (18+) patients
surgically treated for fracture
divided into food insecure and
non-food insecure.
Not specified
37% were food insecure. There
were no differences for
nonunion risk.
not
significant
Hendrickson,
2019 [11]
Patients (18+) with operative
fracture screened using a
malnutrition screening
questionnaire (MSQ) and
assessed by dietitian if
moderate-to-high risk. Lab
values measured
preoperatively.
Clavicle, scapula,
shoulder, humerus,
radius, forearm, pelvis,
acetabulum, knee,
patella, tibia, foot, ankle
17% had increased risk, 4.3%
were clinically malnourished
from dietitian. 19% had
complications including
nonunion. Dietitian-diagnosed
malnutrition was predictor
(OR 3.49, p= 0.017). MSQ score
was not correlated.
significant
Lu, 2024 [25]
80 patients with infectious
bone defects had
multidisciplinary team with
nutritionist that provided oral,
NG tube, or IV nutrition to
malnourished patients. They
were compared with 40 people
without traditional care.
Tibia, femur
Delayed bone healing was
higher in conventional care
group (p= 0.006) with 27.5%
compared to 5%. Changes in
body weight, albumin,
pre-albumin, hemoglobin, and
sodium were higher in the
MDT group (p< 0.05).
significant
J. Clin. Med. 2024,13, 6553 8 of 12
Vo et al. [
24
] took a public health approach and compared patients with fractures who
were food insecure to others who were not. They did not find a statistically significant
association to nonunion. As mentioned briefly before, Hendrickson et al. assessed the
nutritional status of 373 fracture patients via a malnutrition questionnaire, lab values,
and a clinical consultation with a dietitian. While the questionnaire score did not yield
a significant result, the dietitian-diagnosed malnutrition was a significant predictor of
complications including nonunion (OR 3.49, p= 0.017) [
11
]. Hendrickson et al. noted that
clinical diagnosis for malnutrition was less common than abnormal serological values, and
it also had a sensitivity of 21% and a specificity of 87%. Finally, Lu et al. compared the
outcomes of 40 patients with conventional care to 40 patients with a multidisciplinary care
team that included a nutritionist who provided supplemental nutrition to malnourished
patients. Patients with additional care had better rates of bone healing and increased body
weight and albumin levels (p< 0.05) [
25
]. The authors explained that the addition of a
nutritionist aided in wound healing.
Several of these studies show associations between nutritional values and diagnoses
with nonunion. While there is some uncertainty, it is an area that can be further incorporated
into the orthopedic setting through the integration of testing for factors related to nutrition
when assessing patients. Nutritional supplementation can also potentially support further
fracture healing to prevent nonunion. Figure 2shows a depiction of nutritional integration
into an orthopedic care plan.
J. Clin. Med. 2024, 13, x FOR PEER REVIEW 9 of 13
were compared with 40 people
without traditional care.
higher in the MDT group (p <
0.05).
Several of these studies show associations between nutritional values and diagnoses
with nonunion. While there is some uncertainty, it is an area that can be further
incorporated into the orthopedic seing through the integration of testing for factors
related to nutrition when assessing patients. Nutritional supplementation can also
potentially support further fracture healing to prevent nonunion. Figure 2 shows a
depiction of nutritional integration into an orthopedic care plan.
Figure 2. An inclusion of nutrition in orthopedic practice. Several nutritional risk factors may impact
initial fracture and risk of nonunion. Labs, questionnaires, and imaging can be used together to
create a clinical picture. From there, surgical intervention and supportive nutritional care can
prevent nonunion.
4. Discussion
4.1. Summary
The purpose of this literature review was to assess the association between nonunion
development and nutritional factors in various fracture patient populations. While
nutrition has been assessed in several studies on fracture risk, few studies mentioned
nutrition in relation to nonunion risk. Vitamin D, serum lab values including albumin,
and iron deciency anemia, and nutritional diagnoses such as sarcopenia or malnutrition
are the main topics in previous publications in relation to nonunion specically. The
studies in this literature review have varying levels of signicance for the association
between nonunion and nutritional factors, requiring further research on this topic.
4.2. Vitamin D
The relationship between nonunion and vitamin D levels was most frequently
studied in this literature review. There was an inconsistency in the signicance of this
relationship, which can likely be aributed to issues of statistical power, a potentially
weak but signicant relationship between the two factors, and less severe deciencies
present within the selected patient populations. For bone mineralization and subsequent
union to occur after a fracture, there must be sucient available calcium and phosphate
to be secreted into the osteoid layer of the healing bone. Without adequate vitamin D, the
body can absorb only 10–15% of calcium, rather than the 30–40% absorption achieved with
sucient vitamin levels [26]. This deciency is highly prevalent; an analysis of the Third
National Health and Nutrition Examination Survey by Khazai found that 61% of white
and 91% of Black Americans were considered vitamin D decient with a serum 25[OH]D
concentration of <32 ng/mL [26].
While The Journal of Endocrinology cites insuciency as 21–29 ng/mL and deciency
as <20 ng/mL, there is variation in the terminology used in these studies [27]. Zhou
describes normal vitamin D levels as within the range of 30–100 ng/mL. The study by
Figure 2. An inclusion of nutrition in orthopedic practice. Several nutritional risk factors may
impact initial fracture and risk of nonunion. Labs, questionnaires, and imaging can be used together
to create a clinical picture. From there, surgical intervention and supportive nutritional care can
prevent nonunion.
4. Discussion
4.1. Summary
The purpose of this literature review was to assess the association between nonunion
development and nutritional factors in various fracture patient populations. While nutrition
has been assessed in several studies on fracture risk, few studies mentioned nutrition in
relation to nonunion risk. Vitamin D, serum lab values including albumin, and iron
deficiency anemia, and nutritional diagnoses such as sarcopenia or malnutrition are the
main topics in previous publications in relation to nonunion specifically. The studies in this
literature review have varying levels of significance for the association between nonunion
and nutritional factors, requiring further research on this topic.
4.2. Vitamin D
The relationship between nonunion and vitamin D levels was most frequently studied
in this literature review. There was an inconsistency in the significance of this relationship,
which can likely be attributed to issues of statistical power, a potentially weak but significant
relationship between the two factors, and less severe deficiencies present within the selected
patient populations. For bone mineralization and subsequent union to occur after a fracture,
there must be sufficient available calcium and phosphate to be secreted into the osteoid
J. Clin. Med. 2024,13, 6553 9 of 12
layer of the healing bone. Without adequate vitamin D, the body can absorb only 10–15%
of calcium, rather than the 30–40% absorption achieved with sufficient vitamin levels [
26
].
This deficiency is highly prevalent; an analysis of the Third National Health and Nutrition
Examination Survey by Khazai found that 61% of white and 91% of Black Americans were
considered vitamin D deficient with a serum 25[OH]D concentration of <32 ng/mL [26].
While The Journal of Endocrinology cites insufficiency as 21–29 ng/mL and deficiency as
<20 ng/mL, there is variation in the terminology used in these studies [
27
]. Zhou describes
normal vitamin D levels as within the range of 30–100 ng/mL. The study by Donnally
et al., which found no significant results, defined vitamin D deficiency as lab levels below
31 ng/mL. Another study with no significant results, conducted by Clark et al. [
13
], states
that patients are vitamin D deficient but does not define this term. The lack of significance
is likely due to the small margins of difference between the control and deficient groups.
This idea is reinforced by the Zura et al.’s 2016 paper [
1
], which evaluated 309,330 adult
fractures. Vitamin D deficiency was a significant risk factor, but the univariate odds ratio
(OR) was weaker with values of only 1.44 (CI: 1.34, 1.54). The other Zura et al. (2018)
study [
6
] shows a higher OR of 3.98 (CI: 2.70, 5.84), but this study involved a pediatric
population, and the higher demand for calcium due to the developing skeleton must be
considered. Of the six papers that reported no significant effect, the sample sizes ranged
from 33 to 468. Given the likely multifactorial nature of nonunion etiology, vitamin D may
be more impactful in some cases of nonunion and a less impactful in others. Age, fracture
type, muscle mass, and other nutritional deficiencies may play a larger role in nonunion
development. Overall, the fluctuation in results is likely attributable to a combination of
small sample sizes, mildly deficient patient populations, and a weakly positive correlation.
4.3. Other Serum Values
Only one study investigated serum calcium levels related to nonunion, and there was
no significant correlation between nonunion and serum calcium levels, but this is not an
adequate picture of the role of calcium. Part of the exclusion criteria for this review was
studies that investigated the role of exogenous parathyroid hormones since they are not
considered a part of dietary intake or multivitamins. For consistency, all other studies
investigating the role of parathyroid hormones and calcium homeostasis were excluded.
This resulted in a limited view of the role of calcium in fracture nonunion in this review.
Of the twenty-one studies included in this literature review, five provided insights into
the relationship between serum albumin levels and nonunion. Albumin has historically
been used as a biomarker for nutritional assessment due to its sensitivity to changes in
protein status and liver function. While serum albumin concentrations are indicative of
protein synthesis capacity, there have been criticisms for the accuracy of this metric due to
its lack of specificity and long half-life [
28
]. Hendrickson et al. provided additional insight
on the utility of this test more as a marker of trauma response versus malnutrition, which is
more of a chronic process. In this review, three of the five studies analyzing albumin found
a significant difference in nonunion rates for patients with hypoalbuminemia. It is likely
that while imperfect, albumin may be able to provide insight into a patient’s overall health,
especially when included as a value in a nutrition score like the prognostic nutrition index
(PNI). This score was recently shown as a mortality predictor in hip fracture patients and
could potentially be applied to nonunion risk [
19
]. While albumin alone has mixed success
in predicting nonunion, it may be a helpful indicator when measured within a panel of
nutritional tests.
Only one study in this review analyzed the relationship between iron deficiency
anemia and nonunion and found a statistically significant association between the two.
Anderson et al. published that in a cohort of 9482 metatarsal fractures, fractures with
delayed healing had higher rates of iron deficiency anemia (p= 0.016). Iron deficiency
anemia has also been linked to increased stress fracture, implant failure, and surgical
complications in various cohorts [
29
–
31
]. This could be explained by the fact that iron
deficiency anemia is connected with the loss of bone mineral density, which increases the
J. Clin. Med. 2024,13, 6553 10 of 12
risk of bone fragility, but causality has not been definitively established [
32
]. Iron is a key
factor for mitochondrial metabolism, which plays a part in both osteoblastic and osteoclastic
differentiation in the body; iron is also a critical factor in preventing hypoxic conditions,
producing collagen, and regulating vitamin D activation, which are all important processes
for bone healing [
32
]. For these reasons, it is logical that iron deficiency anemia is an
important indicator for nonunion risk and should be screened for in fracture cases.
4.4. Nutrition-Related Diagnoses
Six of the twenty-one studies included in this review explored associations between
nutrition and nonunion through various metrics including ICD-10 codes, public health sur-
veys, and nutritionist assessments. ICD-10-coded malnutrition was significant in Wilkinson
et al. but not in Zura et al., 2016 [
1
]. This is likely due to the differences in the age inclusion
of each study population; Zura et al. only included patients between 18 and 63 years of
age, while Wilkinson included a patient cohort of 65 years and older. Malnutrition may
play a greater role in nonunion for older patients since this population is more likely to
be malnourished and has a higher risk for fracture as well [
33
]. Malnutrition is often the
underlying cause of sarcopenia, which makes the results of Vander Voort et al. particularly
relevant for this review [
34
]. The relationship between frailty, nutrition, and sarcopenia has
been well described previously [
35
]. The logical extension to nonunion is that a continued
state of nutritional deficit and frailty prevents the patient’s bone from properly healing.
This is a helpful indicator that should be screened for, especially in elderly populations.
Vo et al. [
24
] did not find statistical significance when analyzing food insecurity, but this
metric may not have the best specificity for metabolic malnutrition. The food insecurity
screening questionnaire asks about access to food in the past 12 months, which might not
be descriptive of the patient’s current nutritional state at the time of fracture admission.
Both Hendrickson et al. and Lu et al. underscore the importance of incorporating a mul-
tidisciplinary care approach for orthopedic patients who are nutritionally compromised.
In Hendrickson et al [
11
], dietitian-diagnosed malnutrition was the best predictor of com-
plication risk compared to questionnaires and lab values. In Lu et al. [
25
], patients with
nutritional support had better outcomes as well. Nutritionist consultation and support
allows for the proper identification of at-risk patients and adequate supplementation to aid
in proper healing progression.
Current nutritional practices for orthopedic surgeons mainly include vitamin D sup-
plementation, but this is wholly inadequate in addressing the nutritional deficits that
nonunion cases often present with. Nutritional lab values, screening questionnaires, and
nutritional consultation are all useful clinical tools that can decrease risk for fracture pa-
tients. Nonunion risk may be impacted by a variety of factors beyond nutrition; the
multifactorial nature of this process makes prevention even more complex. Poor nutrition
is likely one of several risk factors that cause nonunion. Importantly, nutrition may be
the one of the more modifiable risk factors that can be improved with minimal effort and
expense. By addressing nutritional deficits at the time of fracture, surgeons can mitigate
some risk later in the healing process which improves patient quality of life, avoids cost,
and lowers risk of nonunion.
4.5. Strengths, Limitations, and Future Directions
This literature review had a broad initial inclusion of articles to make sure all relevant
articles were included. After this inclusion, rigorous exclusion criteria were adopted to
identify only the relevant articles. Dual screening prevented bias and improper exclusion
or inclusion of articles. This literature review was limited by the availability of research on
nutrition with nonunion specifically. After the initial literature searches and inclusion into
Covidence, additional articles were not screened for, leading to the potential exclusion of
more recently published articles. Lastly, few articles in this literature review had similar
methods and statistical impact, which makes comparison between papers difficult.
J. Clin. Med. 2024,13, 6553 11 of 12
This review prompts the need for further research on (a) the extent of impact on
nonunion development in comparison to other nonunion risk factors, (b) the variability of
impact on different types of nonunion or bone involvement, (c) the potential difference in
nutrition risk factors for nonunion based on age and gender, and (d) the determination of
lab values that are most important in identifying nutritional risk for nonunion.
5. Conclusions
This review assessed the association between nutritional indicators and nonunion.
Vitamin D, calcium, albumin, iron deficiency anemia, sarcopenia, and diagnosed malnu-
trition have been associated with an increased risk of nonunion in observational studies;
however, the literature is highly variable and inconsistent. Given the multifactorial nature
of nonunion, it is likely that poor nutrition is one of several variables that can lead to
nonunion development. Further research on the utility of nutritional screening and supple-
mentation is needed to create nutritional recommendations that aid orthopedic surgeons in
counselling their patients on nutrition and reducing the risk of nonunion.
Author Contributions: Data collection and writing, E.C. and M.T.; editing, S.S., J.R., and A.C.;
supervision, R.Z. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: All data can be accessed through PubMed searches. Any information is
available upon request.
Conflicts of Interest: The authors declare no conflicts of interest.
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