An overview of drug effects on bone healing on animal research models
ISSN 2588-1299
VJAS 2021; 4(1): 978-988
Vietnam Journal
of Agricultural
Sciences
An Overview of Drug Effects on Bone
Healing on Animal Research Models
Nguyen Hoai Nam1 & Naruepon Kampa2
1Faculty of Veterinary Medicine, Vietnam National University of Agriculture, Hanoi
131000, Vietnam
2Faculty of Veterinary Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Abstract
Bone fracture is a common health problem in humans and animals,
and the healing of the bone fracture is a complicated process. Several
drugs may be used concurrently with the treatment of fractures, but
they may interfere with the healing process of the bone. The present
research reviewed previously published studies with the objective to
enhance the understandings of the effects of different drugs on bone
healing. There is clear evidence that antibiotics, corticosteroids, non-
steroidal inflammatory drugs, and chemotherapeutic drugs all affect
bone healing. By contrast, the effect of anticoagulants on bone
healing is controversial, so more research is needed to determine its
efficacy. In addition, there is no direct evidence to approve the effect
of anesthetics on bone healing, so this is another area in need of
further research.
Keywords
Animal model, bone healing, drug, rat femur
Introduction
Bone fracture causes harmful effects to patients’ health, degrades
their quality of life, and is responsible for costly treatments.
Annually, millions of musculoskeletal procedures are performed
worldwide (Jahangir et al., 2008). Each year, billions of dollars have
been spent for the treatments of bone fracture and hip replacement,
and the number has been increasing over time. In 2005, more than
USD 20 billion was spent on medical care for over 300,000 spinal
fusions (Porter et al., 2009). Pathogenic bone defects caused by
cancer were responsible for more than 3,000 pediatric
hospitalizations, and cost over USD 70 million (Porter et al., 2009).
In animals, about 800,000 pets are involved in vehicle crashes
annually in USA (Strickland, 2014). High rise syndrome may cause
limb fracture in 46.2% of fallen cats, of which 38.5% of fractures are
in forelimbs and 61.5% were in the hind limbs are. Tibiae are most
commonly fractured followed by the femur (Vnuk et al., 2004). The
treatment cost of bone fractures in companion animals can procure
Received: May 19, 2019
Accepted: January 25, 2021
Correspondence to
978
Nguyen Hoai Nam & Naruepon Kampa (2021)
several million Vietnam Dong per case.
treatment of wear particle-induced osteolysis and
aseptic loosening (Zhang et al., 2007).
Antibiotics, anti-inflammatory drugs and
anesthetics are usually used during treatment of
bone fracture. Sometimes, anticoagulants or
chemotherapy drugs may be applied in
orthopaedic animals treatments. All of these
drugs may have some effects on the course of
bone healing. The pharmacological factors
associated with bone healing in humans and
animals are similar in many aspects; therefore,
understanding these factors is useful and can
enhance the successful treatment. This narrative
review focuses on the effects of drugs used on the
bone healing process based on the information
retrieved from an extensive literature review.
The negative effects of antibiotics on bone
healing may be due to their high doses such as
100 mg/kg/day for cefuroxime (Natividad-
Pedreno et al., 2016) and ciprofloxacin
(Huddleston et al., 2000), 70 mg/kg/day for
trovafloxacin and 50 mg/kg/day for levofloxacin
(Perry et al., 2003), and due to long treatment
durations, such as 3-4 weeks (Huddleston et al.,
2000; Perry et al., 2003; Natividad-Pedreño et
al., 2016). Antibiotics play a pivotal role in
prevention and treatment of bacterial infection in
many diseases and procedures, especially,
orthopedic cases. The use of antibiotics is
inevitable as long as their doses and durations are
carefully calculated and followed.
Effects of Drugs on Bone Healing
Prevention and/or treatment of diseases may
involve many types of drugs. They can be
generally divided into 6 groups including
antibiotics, corticosteroids, non-steroidal anti-
inflammatory drugs (NSAIDs), anticoagulants,
chemotherapeutic agents and anesthetics. When
used in animals with bone fractures, some of
these drugs may interfere with the bone healing
process. Tables 1-5 present the effects of such
drugs on fracture healing in animal models.
Effects of corticosteroids on Bone
Healing
In vivo studies have demonstrated that many
corticosteroids including cortisone (Sissons &
Hadfield, 1955), prednisolone (Luppen et al.,
2002; Yaghini et al., 2017), prednisone (Bostrom
et al., 2000; Waters et al., 2000),
methylprednisolone (Xie et al., 2011) and
dexamethasone (Sawin et al., 2001) affected the
bone healing process. The common aspect of
these studies wa that the duration of treatments
was prolonged, i.e., 42 days for dexamethasone
(Sawin et al., 2001), 56-78 days for prednisolone
(Luppen et al., 2002; Yaghini et al., 2017) and 96
days for prednisone (Bostrom et al., 2000;
Waters et al., 2000). On the other hand, when
used for a shorter duration, i.e., 14-21 days,
corticosteroid doses were very high, i.e.,
20mg/kg/day for methylprednisolone (Xie et al.,
2011), and 10-20 mg/kg/day for cortisone
(Sissons & Hadfield, 1955). With a similar
duration of treatment (21 days) but several times
lower doses (0.5 mg/kg/day), no significant
effect of prednisolone on fracture healing was
observed although the numeric values of the
mechanical parameters were lower in the treated
group (Bissinger et al., 2016). Being used for 4
consecutive days, methylprednisolone at 2
Effects of Antibiotics on Bone Healing
Many antibiotics have been reported to
affect bone healing including quinolones (Gough
et al., 1996), ciprofloxacin (Huddleston et al.,
2000), levofloxacin and trovafloxacin (Perry et
al., 2003), tetracycline (Kim et al., 2004) and
cefuroxime (Natividad-Pedreño et al., 2016).
Effect of gentamicin on bone healing is
controversial. Kim et al. (2004) reported that it
decreased bone formation, however, Fassbender
et al. (2013) and Haleem et al. (2004) did not find
similar results. Cefazolin had no effect on
fracture healing parameters including callus
mechanical resistance and histological scores
(Natividad-Pedreno et al., 2016). Also,
vancomycin did not influence biomechanical and
radiographic scores of healing bone (Haleem et
al., 2004). Interestingly, doxycycline inhibited
osteolysis, and is suggested for prevention and
mg/kg/day
(Hogevold et al., 1992) and
prednisone at 0.02 mg/kg/day (Aslan et al., 2005)
had no effect on bone healing.
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An overview of drug effects on bone healing on animal research models
Table 1. In vivo effects of different antibiotics on bone healing
Animal and
Drug and dosage
bone
Results
References
Cefazolin: 50 mg/kg per day, daily for
4 weeks. Cefuroxime: 100 mg/kg per
day, daily for 4 weeks.
Cefuroxime decreased callus mechanical
resistance and lowered histological grade.
Cefazolin did not influence studied parameters.
Natividad-
Pedreno et al.
(2016)
Rat femur
Gentamicin: 10% gentamicin coated
implant.
Local application of gentamicin did not influence
tibial fracture healing.
Fassbender et al.
Rat tibia
(2013)
Doxycycline inhibited osteolysis. Suggestion for
use of doxycycline for treatment or prevention
of wear particle-induced osteolysis and aseptic
loosening.
Doxycycline: 2 and 10 mg/kg per day
for 7 days.
Zhang et al.
(2007)
Mouse calvaria
Rat calvaria
Tetracycline: 30 mg/graft.
Gentamicin: 15 mg/graft.
Antibiotics impaired bone formation.
Kim et al. (2004)
Gentamicin: 1.5 mg/kg, twice per day
for 3 weeks. Vancomycin: 25 mg/kg,
twice per day for 3 weeks.
Antibiotics had no effects on biomechanical and
radiographic scores.
Haleem et al.
Rat calvaria
Rat femur
Rat femur
(2004)
Levofloxacin: 25 mg/kg,
trovafloxacin: 35 mg/kg. Both drugs
were used twice a day for 3 weeks,
started 1 week post femoral fracture.
Antibiotic induced less woven bone and more
cartilage in the fracture sites.
Perry et al. (2003)
Decreased radiographic results, lowered
torsional strength, and abnormal cartilage
morphology were observed in the treatment
group.
Ciprofloxacin: 50 mg/kg, twice a day
for 3 weeks, 1 week post femoral
fracture.
Huddleston et al.
(2000)
Drug caused degenerated or hypertrophic
chondrocytes, loss of collagen and
proteoglycan. Effects were not clearly dose-
related.
Rabbit joints:
shoulder, hip,
knee
Quinolones: 100, 350, 500, 750
mg/kg per day for 5 days.
Gough et al.
(1996)
The negative effect of corticosteroids on
bone healing was consistent in the literature,
especially if the high doses and/or long
treatments were applied. Nonetheless, there is
also some evidence that corticosteroids can be
used for a short time with appropriate doses if
their benefits outweigh their potential side
effects.
(Endo et al., 2002), diclofenac (Bissinger et al.,
2016; Krischak et al., 2007), ibuprofen (Kidd et
al., 2013; Leonelli et al., 2006), dexketoprofen
and meloxicam (Inal et al., 2014), aspirin (Lack
et al., 2013), parecoxib (Gerstenfeld et al., 2003),
rofecoxib (Leonelli et al., 2006) and celecoxib
(Simon & O'Connor, 2007). Most of these
NSAIDs doses were below or comparable to the
recommended dosage for treatment of diseases in
humans. Only some of these studies used high
doses of NSAIDs, i.e., indomethacin at 12.5
mg/kg/day, aspirin at 100-300 mg/kg/day (Lack
et al., 2013), and rofecoxib at 8 mg/kg/day
(Leonelli et al., 2006). Impaired fracture healing
may be partially due to long-term exposure to
drugs, including diclofenac for 21 days
(Bissinger et al., 2016), rofecoxib and ibuprofen
Effects
of
non-steroidal
anti-
inflammatory drugs on Bone Healing
The inhibitory effect on bone fracture
healing is attributable to many NSAIDs,
including indomethacin (Brown et al., 2004;
Hogevold et al., 1992; Lack et al., 2013),
ketorolac (Gerstenfeld et al., 2003), etodolac
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Nguyen Hoai Nam & Naruepon Kampa (2021)
Table 2. In vivo effects of corticosteroids on bone healing
Drug and dosage
Animal and bone
Dog mandible
Results
References
Prednisolone: 4 mg/day for 4
weeks, followed by 2 mg/day for
another 4 weeks.
Yaghini et al.
Prednisolone decreased bone-implant contact.
(2017)
No significant effect of prednisolone on bone
healing was evident although the absolute values
of mechanical parameters in prednisolone group
were lower in comparison with the control.
Prednisolone: 0.5 mg/kg per day,
daily for 21 days.
Bissinger et al.
Rat femur
(2016)
Methylprednisolone: 20 mg/kg per
day, three times on day 16, 15 and
14 pre-surgery.
Methylprednisolone induced osteonecrosis,
impaired healing and maturation of bone tissue.
Rabbit femur
Rat femur
Xie et al. (2011)
Prednisone: 0.02 mg/kg, 4
consecutive days started prior to
surgery.
Aslan et al.
(2005)
Prednisone had no effect on bone healing.
Prednisolone: 0.35 mg/kg per day,
three times a week for 6 weeks
before surgery.
Prednisolone inhibited bone healing characterized
by a small callus area, low torsional strength.
Luppen et al.
Rabbit ulna
Rabbit spine
(2002)
Dexamethasone: 0.05 mg/kg per
time, twice every day for 42 days
since surgery.
Dexamethasone decreased the rate of bone graft
union.
Sawin et al.
(2001)
Prednisone: 0.15 mg/kg per day,
60 days before osteotomy until 6
weeks postosteotomy.
Bostrom et al.
Rabbit ulna
Prednisone induced bone loss.
(2000)
Prednisone: 0.15 mg/kg per day,
60 days before osteotomy to 6
weeks post-surgery.
Prednisone caused lower results in callus size,
radiographic density, bone mineral content and
mechanical strength.
Waters et al.
Rabbit ulna
Rat femur
(2000)
Methylprednisolone: 2 mg/kg, 4
consecutive days started prior to
surgery.
Methylprednisolone had no inhibitory effect on
bone healing.
Hogevold et al.
(1992)
Longitudinal bone growth instantly stopped after
the commencement of cortisone administration.
The cartilage was thinned as soon as day 6. By
day 24 extensive destruction of metaphyseal
trabeculae was apparent.
Cortisone: 10, 20 mg/kg per day for
14 days.
Rabbit femur and
tibia
Sissons &
Hadfield (1955)
Cortisone: 20 mg/kg per day for 21
days.
Rat femur and
tibia
The harmful effect of cortisone on bone growth in
rats was less severe than in rabbits.
for 28 days (Leonelli et al., 2006), ketorolac and
parecoxib for 35 days (Gerstenfeld et al., 2003),
indomethacin, celecoxib for 28, 56 or 112 days
(Brown et al., 2004). The inhibitory effect of
NSAIDs on fracture healing was observed even
when the treatment durations and doses were
comparable to ordinary prescription, ie.,
indomethacin at a dose of 2 mg/kg/day for 4 days
(Hogevold et al., 1992), etodolac at 20
mg/kg/day for 7 days (Endo et al., 2002) and
celecoxib at 4 mg/kg/day for 5 days (Simon &
O'Connor, 2007).
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An overview of drug effects on bone healing on animal research models
Although there are a few studies supporting
the use of some NSAIDs, such as ketorolac
(Cappello et al., 2013; Fracon et al., 2010),
paracetamol, etoricoxib (Fracon et al., 2010)
during bone healing treatment, there are far more
studies reporting the newgative impact of bone
healing. Therefore, use of NSAIDs during
fracture healing should only be considered when
the drugs’ benefits over-ride their negative
impacts (Table 3).
but decreased bone mineral density resulting in
unchanged mechanical parameters (Kluter et al.,
2015; Prodinger et al., 2016). It appears that
negative effects of anticoagulants on bone
fracture healing is still minimal. A definitive
conclusion of the effect of anticoagulants on
bone healing is impossible discern due to the
differences in drugs used, time of drug exposure,
drug doses, animal models, fractured bones, time
of evaluation and means of evaluation. Therefore,
these drugs are still a gold standard for prevention
of thrombosis and pulmonary embolism in
animals with bone fracture(s). Nevertheless, more
well-designed studies are required to determine
the true effects of anticoagulants on bone fracture
healing (Table 4).
Effects of anticoagulants on Bone
Healing
The use of anticoagulants for prevention of
thrombosis and pulmonary embolism in
traumatic and orthopedic cases is common
(Prodinger et al., 2016). Anticoagulants may
elicit inhibitory effects on osteoblast formation,
and may intensify bone resorption (Kapetanakis
et al., 2015). Enoxaparin has been found to exert
a negative effect on fracture healing in rabbit ribs
(Street et al., 2000, whereas this drug does not
influence bone healing of rat femur (Curcelli et
al., 2005; Demirtas et al., 2013; Say et al., 2013).
Bone fracture healing is independent of many
anticoagulants, including heparin (Curcelli et al.,
2005; Erli et al., 2006), dalteparin (Erli et al.,
2006; Hak et al., 2006; Say et al., 2013),
certoparin (Erli et al., 2006), nadroparin (Say et
al., 2013), and rivaroxaban (Demirtas et al.,
2013). Rivaroxaban increased the callus volume
Effects of chemotherapeutic agents on
Bone Healing
Chemotherapeutic agents are commonly
prescribed for treatment of cancers and chronic
inflammation. High doses are recommended for
oncological treatment, and low doses are for
chronic inflammation (Cavalcanti et al., 2014).
Results show that these drugs are also
significantly involved in the bone healing
process. Fracture healing was completely
prevented by angiogenesis inhibitor TNP-470 via
suppression of both intramembranous and
endochondral ossifications (Hausman et al.,
2001).
Histological and
radiographical
Table 3. In vivo effects of NSAIDs on bone healing
Animal and
Drug and dosage
bone
Results
References
Diclofenac decreased stiffness, trabecular
thickness and callus volume.
Bissinger et
al. (2016)
Diclofenac: 5 mg/kg per day for 21 days.
Rat femur
Rat fibula
Dexketoprofen: 0.98 mg/kg per half a day,
meloxicam: 0.2 mg/kg per day, diclofenac:
1mg/kg per day. All drugs were used for 10
days.
Dexketoprofen and meloxicam inhibited bone
fracture healing while diclofenac did not.
Inal et al.
(2014)
Indomethacin: 12.5 mg/kg per day. Aspirin:
2.7 mg/kg per day, 10 mg/kg per day, 50
mg/kg twice per day, 100 mg/kg three times
per day. All drugs were used for 8 weeks.
Aspirin at 10 mg/kg and 100 mg/kg, and
indomethacin decreased bone healing.
Lack et al.
(2013)
Rabbit ulna
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Nguyen Hoai Nam & Naruepon Kampa (2021)
Animal and
bone
Drug and dosage
Results
References
Ketorolac: 5 mg/kg per day for either 7, 14
or 21 days.
No effect of ketorolac on bone healing was
seen at any time point of evaluation.
Cappello et
al. (2013)
Rat tibia
Treatment of ibuprofen decreased bone
resorption and reduced bone formation which
resulted in lower length and area of lamellar
bone.
Ibuprofen: 30 mg/kg per day for either 2, 4,
or 6 weeks.
Kidd et al.
(2013)
Rat ulna
Paracetamol: 80 mg/kg per day. Ketorolac:
4 mg/kg per day. Etoricoxib: 10 mg/kg per
day. All drugs were daily used, for 2 weeks
since surgery.
Rat tooth
socket
No drug had an inhibitory effect on volume
fraction of trabecular bone.
Fracon et al.
(2010)
Histomorphometric evaluation revealed that
long-term instead of short-term treatment of
diclofenac resulted in a higher amount of
cartilage and less bone.
Diclofenac: 5 mg/kg per day for either 7 or
21 days.
Krischak et
al. (2007)
Wistar rats
Celecoxib: 2, 4, 8 mg/kg per day for 15
days, started 4h post fracture.
Use of celecoxib for 15 days at any studied
doses increased the rate of bone nonunion. A
dose of 4 mg/kg for 5 days decreased the
mechanical strength and increased the
nonunion rate. No harmful effect was
detected when the use of celecoxib was
commenced at 5th day prior to or at 14th day
after operation.
Simon &
O'Connor
(2007)
4 mg/kg per day for either 5, 10, 21, or 28
days started 4h postfracture.
Rat tibia
4 mg/kg per day, started at 5 days
prefracture, or 1, 7, 14 days postfracture,
until day 28.
Incidence of nonunion in rofecoxib and
ibuprofen groups was higher than that in the
control group.
Rofecoxib: 8 mg/kg per day for 4 weeks.
Ibuprofen: 30 mg/kg per day for 4 weeks.
Leonelli et al.
Rat femur
Rat femur
(2006)
Indomethacin: 1 mg/kg per day for 4,8,12
weeks. Celecoxib: 3 mg/kg per day for
4,8,12 weeks.
Both indomethacin and celecoxib delayed
bone healing at 4 and 8 weeks post
operation.
Brown et al.
(2004)
Ketorolac: 4 mg/kg per day, for either 21 or
35 days. Parecoxib: 0.3 and 1.5 mg/kg per
day for either 21 or 35 days.
Both parecoxib and ketorolac impaired bone
healing, but ketorolac expressed more
harmful effects.
Gerstenfeld
et al. (2003)
Rat femur
Etodolac: 20 mg/kg per day for 3 weeks
started from surgery until day 21, or for 1
week started from surgery until day 7, or for
1 week started from day 14 until day 21.
In all groups of treatment, radiographic and
mechanical testing showed lower scores
which predisposed fractures to delayed
healing.
Endo et al.
(2002)
Rat femur
Rat femur
Indomethacin impaired bone healing. This
effect was more severe when fracture healed
under unstable condition.
Indomethacin: 2 mg/kg, 4 consecutive days
started prior to surgery.
Hogevold et
al. (1992)
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An overview of drug effects on bone healing on animal research models
assessments revealed that doxorubicin and
cisplatin affect both quantity and quality of the
healing bone of rabbit segmental radial
diaphyseal fractures (Morcuende et al., 2004).
Even a single dose of doxorubicin at the time of
surgery significantly inhibited the process of
spinal fusion (Tortolani et al., 2004). Similarly, a
single dose of methotrexate at either 30 or 250mg
at surgery decreases bone formation resulting in
impaired bone healing (Cavalcanti et al., 2014;
Satoh et al., 2011). By contrast, methotrexate at
a low dose (3mg every week, for 1-4 weeks) did
not delay fracture healing process (Cavalcanti et
al., 2014; Satoh et al., 2011). The effect of
chemotherapeutic agents on bone healing may
depend on drug types, and the doses of drugs.
Although the effects of chemotherapeutic agents
on bone healing are apparent, their use in some
cases, including cancer, can not be avoided. In
such cases, adjunctive treatment such as growth
factors may be considered to reduce the drugs’
negative effects and normalize bone healing
process (Table 5).
Table 4. In vivo effects of anticoagulants on bone healing
Animal and
Drug and dosage
bone
Results
References
Rivaroxaban increased callus volume which
corresponded to reduced bone density.
Treatment of both rivaroxaban and enoxaparin
resulted in enlarged callus surface, trabecular
thickness, and degree of bone anisotropy.
Biomechanical characteristics were not
influenced by any drugs administered.
Rivaroxaban: 600 ppm/g of
medicated food, enoxaparin: 100
IU/kg twice every day for 21 days.
Prodinger et
al. (2016)
Rat femur
Rivaroxaban increased callus volume and
induced a marginal increase in bone mineral
density, but torsional rigidity was not affected by
the treatment.
Rivaroxaban: 3 mg/kg per day for
either 28 or 49 days.
Klüter et al.
(2015)
Rat femur
Rat femur
Enoxaparin: 1000 anti Xa IU/kg per
day, rivaroxaban: 3 mg/kg per day,
fondaparinux: 0.2 mg/kg per day
for 21 days.
No effects of enoxaparin, rivaroxaban and
fondaparinux on fracture healing was noticed
via radiographic and histopathological
examinations.
Demirtas et
al. (2013)
Fondaparinux: 1 mg/kg per day,
dalteparin: 140 µg/kg per day,
nadroparin: 200 µg/kg per day,
enoxaparin: 1 mg/kg per day for 28
days.
Fondaparinux had a stimulatory effect on bone
healing. Dalteparin, nadroparin, and enoxaparin
had no effect on fracture healing.
Say et al.
(2013)
Rat femur
Heparin: 133 IE/kg per day,
certoparin: 50 anti-Xa-units/kg per
day, dalteparin: 50 anti-Xa-units/kg
per day for 42 days.
Histological examination revealed that there
was no significant effect of anticoagulants on
bone healing.
Erli et al.
(2006)
Rabbit femur
Dalteparin: 70 unit/kg per day for
14 days.
Dalteparin did not alter radiographic,
histological and, mechanical results.
Hak et al.
(2006)
Rat femur
Rat femur
Heparin: 400 IU/kg per day,
enoxaparin: 2 mg/kg per day for 28
days.
Heparin and enoxaparin had no effect on
histological and mechanical grades.
Curcelli et al.
(2005)
Enoxaparin: 2 mg/kg per day for
either 3, 7, 14, or 21 days.
Inhibitory effect of enoxaparin on bone healing
was detected at all times of evaluation.
Street et al.
(2000)
Rabbit rib
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Nguyen Hoai Nam & Naruepon Kampa (2021)
Table 5. In vivo effects of chemotherapetic agents on bone healing
Animal and
Drug and dosage
bone
Results
References
High dose of methotrexate impaired
bone healing characterized by
decreased bone formation.
Methotrexate: 3 mg per week for 1, 2, 4 weeks or a
single dose of 30 mg/kg.
Rat
mandible
Cavalcanti et
al. (2014)
Methotrexate: High dose: 250 mg/kg on the day of
surgery. Low dose: 3 mg/kg per week for 4 weeks
before surgery until either 1 or 4 weeks after surgery.
High dose rather than low dose of
methotrexate significantly impaired
bone healing.
Satoh et al.
(2011)
Rat femur
Rabbit
spine
Bone fusion rate was reduced in the
treatment group.
Tortolani et al.
Doxorubicin: 2.5 mg/kg at surgery.
(2004)
2.5 mg/kg of both doxorubicin and cisplatin three
times, i.e. at 4 days prior to 7 and 14 days after
operation.
Rabbit
radius
Chemotherapy decreased bone area
and bone density.
Morcuende et
al. (2004)
Angiogenesis inhibitor TNP-470: 30 mg/kg per day,
every other day for either 7, 14, or 21 days.
Antiangionic drug prevented bone
formation.
Hausman et al.
Rat femur
(2001)
inflammatory cytokines are apparent. The bone
healing process is, on the other hand, involved in
the inflammatory mechanism. Therefore, it may
be hypothesized that some anesthetics such as
isoflurane and ketamine may influence bone
fracture healing (Histing et al., 2011). Because
the true effect of anesthetics on bone healing has
not been determined to date, their use still
contributes to the success of millions of
orthopedics procedures worldwide.
Effects of Anesthetics on Bone Healing
Anesthetics are routinely utilized in many
surgical procedures, particularly in orthopedics.
Besides their anesthetic properties, they also
have
anti-inflammatory
characteristics.
Isoflurane reduces the systemic release of TNF-
α and IL-1β (Flondor et al., 2008). TNF-α, IL-6
and IL-8 production from human whole blood
culture was also suppressed by ketamine
(Kawasaki et al., 1999). Furthermore, ketamine
lowers TNF-α activity and mortality of
carrageenan-sensitized endotoxemic rats (Koga
et al., 1994), and decreases TNF-α production in
LPS-induced endotoxemia in mice (Taniguchi et
al., 2001). Interestingly, ketamine did not exert
those effects if entotoxins were absent. The
Conclusions
This overview showed that the course of
bone healing may be influenced by several drugs
and treatment regimes. However, the negative
effects of several antibiotics and steroids on bone
healing may be due to their high doses and/or
long treatments because such effects were absent
when normal doses and treatment periods were
applied. The use of such drugs in partients with
bone fracture(s) is reasonable if the normal doses
and durations of treatments are followed. In
contrast, many non-steroidal inflammatory drugs
may affect bone healing even at their standard
treatment usage. Hence, these drugs should not
mechanism
of
ketamine-induced
anti-
inflammation is believed to be partially due to its
effect on cyclooxygenase activity (Suliburk et
al., 2005). Furthermore, in rats, the anti-
inflammatory effect of ketamine was seen only at
sub-anesthetic dosages (0.5-5 mg/kg), whereas at
high dosage (50 mg/kg) it enhanced the TNF-α
production (Sun et al., 2004). Although there are
no direct results showing that anesthetics
influence bone fracture healing, their effects on
985
Modified atmosphere packaging reduces pericarp browning and maintains the quality of ‘Huong Chi’ longan fruit
of Enoxaparin, Fondaparinux, and Rivaroxaban used
in thromboembolism prophylaxis on fracture healing
in rats. European Review for Medical and
Pharmacological Sciences. 17(14): 1850-1856.
be prescribed for orthopedic animals treatments.
There is a large body of research demonstrating
negative effects of chemotherapy agents on bone
healing. However, a low dose of methotrexate
Endo K., Sairyo K., Komatsubara S., Sasa T., Egawa H.,
may be appropriate for animals that have cancer
or chronic inflammation and acquire bone
fracture(s). More well-designed studies are
needed before a conclusion on the effect of
anticoagulants and anesthetics on bone healing
process can be ascertained. The use of some
drugs is inevitable during the treatment of bone
fractures, therefore, understandings of their
effects on bone healing are imperative to increase
the chances of successful treatments.
Yonekura D., Adachi K., Ogawa T., Murakami R. &
Yasui N. (2002). Cyclooxygenase-2 inhibitor inhibits
the fracture healing. Journal of Physiological
Anthropology and Applied Human Science. 21(5):
235-238.
Erli H., Melchert M. & Rüger M. (2006). The effect of low-
dosed unfractioned and low-molecular weight heparins
on bone healing in vivo. The Internet Journal of
Orthopedic Surgery. 3(2). DOI: 10.5580/1f1d.
Fassbender M., Minkwitz S., Kronbach Z., Strobel C.,
Kadow-Romacker A., Schmidmaier G. & Wildemann
B. (2013). Local gentamicin application does not
interfere with bone healing in a rat model. Bone. 55(2):
298-304.
References
Flondor M., Hofstetter C., Boost K. A., Betz C., Homann
M. & Zwissler B. (2008). Isoflurane inhalation after
induction of endotoxemia in rats attenuates the
systemic cytokine response. European Surgical
Research. 40(1): 1-6.
Aslan M., Simsek G. & Yildirim U. (2005). Effects of
short-term treatment with systemic prednisone on bone
healing: an experimental study in rats. Dental
Traumatology. 21(4): 222-225.
Fracon R.N., Teofilo J. M., Moris I. C. & Lamano T.
(2010). Treatment with paracetamol, ketorolac or
etoricoxib did not hinder alveolar bone healing: a
histometric study in rats. Journal of Applied Oral
Science. 18(6): 630-634.
Bissinger O., Kreutzer K., Götz C., Hapfelmeier A., Pautke
C., Vogt S., Wexel G., Wolff K. D., Tischer T. &
Prodinger P. M. (2016). A biomechanical, micro-
computertomographic and histological analysis of the
influence of diclofenac and prednisolone on fracture
healing in vivo. BMC Musculoskeletal Disorders.
17(1): 383.
Gerstenfeld L. C., Thiede M., Seibert K., Mielke C.,
Phippard D., Svagr B., Cullinane D. & Einhorn T. A.
(2003). Differential inhibition of fracture healing by
non-selective and cyclooxygenase-2 selective non-
steroidal anti-inflammatory drugs. Journal of
Orthopaedic Research. 21(4): 670-675.
Bostrom M. P., Gamradt S. C., Asnis P., Vickery B., Hill
E., Avnur Z. & Waters R. V. (2000). Parathyroid
hormone-related protein analog RS-66271 is an
effective therapy for impaired bone healing in rabbits
on corticosteroid therapy. Bone. 26(5): 437-442.
Gough A., Johnson R., Campbell E., Hall L., Tylor J.,
Carpenter A., Black W., Basrur P. K., Baragi V. M.,
Sigler R. & Metz A. (1996). Quinolone arthropathy in
immature rabbits treated with the fluoroquinolone, PD
117596. Experimental and Toxicologic Pathology.
48(4): 225-232.
Brown K. M., Saunders M. M., Kirsch T., Donahue H. J. &
Reid J. S. (2004). Effect of COX-2-specific inhibition
on fracture-healing in the rat femur. The Journal of
Bone and Joint Surgery. 86A(1): 116-123.
Cappello T., Nuelle J. A., Katsantonis N., Nauer R. K., Lauing
K. L., Jagodzinski J. E. & Callaci J. J. (2013). Ketorolac
administration does not delay early fracture healing in a
juvenile rat model: a pilot study. Journal of Pediatric
Orthopaedics. 33(4): 415-421.
Hak D. J., Stewart R. L. & Hazelwood S. J. (2006). Effect
of low molecular weight heparin on fracture healing in
a stabilized rat femur fracture model. Journal of
Orthopaedic Research. 24(4): 645-652.
Cavalcanti S. C., Correa L., Mello S. B. & Luz J. G. (2014).
The effect of methotrexate on the bone healing of
mandibular condylar process fracture: an experimental
study in rats. Journal of Cranio-Maxillofacial Surgery.
42(7): 1133-1139.
Haleem A. A., Rouse M. S., Lewallen D. G., Hanssen A.
D., Steckelberg J. M. & Patel R. (2004). Gentamicin
and vancomycin do not impair experimental fracture
healing. Clinical Orthopaedics and Related Research.
427: 22-24.
Curcelli E. C., Müller S. S., Ueda A. K., Padovani C. R.,
Maffei F. H. & Hossne W. S. (2005). Effect of heparin-
sodium and enoxaparin on rats tibial fracture healing:
clinical, anatomopathological, and biomechanical
approach. Acta Ortopédica Brasileira. 13(1): 13-16.
Hausman M. R., Schaffler M. B. & Majeska R. J. (2001).
Prevention of fracture healing in rats by an inhibitor of
angiogenesis. Bone. 29(6): 560-564.
Histing T., Garcia P., Holstein J. H., Klein M., Matthys R.,
Nuetzi R., Steck R., Laschke M. W., Wehner T., Bindl
R., Recknagel S., Stuermer E. K., Vollmar B.,
Demirtas A., Azboy I., Bulut M., Ucar B. Y., Alabalik U.
& Necmioglu N. S. (2013). Investigation of the effects
Vietnam Journal of Agricultural Sciences
986
Nguyen Hoai Nam & Naruepon Kampa (2021)
Wildemann B., Lienau J., Willie B., Peters A., Ignatius
A., Pohlemann T., Claes L. & Menger M. D. (2011).
Small animal bone healing models: standards, tips, and
pitfalls results of a consensus meeting. Bone. 49(4):
591-599.
animal model. Archives of Orthopaedic and Trauma
Surgery. 127(1): 3-9.
Lack W. D., Fredericks D., Petersen E., Donovan M.,
George M., Nepola J., Smucker J. & Femino J. E.
(2013). Effect of aspirin on bone healing in a rabbit
ulnar osteotomy model. The Journal of Bone and Joint
Surgery. 95(6): 488-496.
Hogevold H. E., Grogaard B. & Reikeras O. (1992). Effects
of short-term treatment with corticosteroids and
indomethacin on bone healing A mechanical study of
osteotomies in rats. Acta Orthopaedica Scandinavica.
63(6): 607-611.
Leonelli S. M., Goldberg B. A., Safanda J., Bagwe M. R.,
Sethuratnam S. & King S. J. (2006). Effects of a
cyclooxygenase-2 inhibitor (rofecoxib) on bone
healing. American Journal of Orthopedics. 35(2): 79-
84.
Huddleston P. M., Steckelberg J. M., Hanssen A. D., Rouse
M. S., Bolander M. E. & Patel R. (2000). Ciprofloxacin
inhibition of experimental fracture healing. The
Journal of Bone and Joint Surgery. 82(2): 161-173.
Luppen C. A., Blake C. A., Ammirati K. M., Stevens M. L.,
Seeherman H. J., Wozney J. M. & Bouxsein M. L.
(2002). Recombinant human bone morphogenetic
protein-2 enhances osteotomy healing in glucocorticoid-
treated rabbits. Journal of Bone and Mineral Research.
17(2): 301-310.
Inal S., Kabay S., Cayci M. K., Kuru H. I., Altikat S., Akkas
G. & Deger A. (2014). Comparison of the effects of
dexketoprofen trometamol, meloxicam and diclofenac
sodium on fibular fracture healing, kidney and liver: an
experimental rat model. Injury. 45(3): 494-500.
Morcuende J. A., Gomez P., Stack J., Oji G., Martin J.,
Fredericks D. C. & Buckwalter J. A. (2004). Effect of
chemotherapy on segmental bone healing enhanced by
rhBMP-2. Archive of The Iowa Orthopaedic Journal.
24: 36-42.
Jahangir A., Nunley R. M., Mehta S. & Sharan A. (2008).
Bone-graft substitutes in orthopaedic surgery
American
Academy
of
Orthopaedics
org/news/aaosnow/jan08/reimbursement2asp
November 15, 2017.
on
Natividad-Pedreno M., Nunez-Chia A., Cobo-Valenzuela
N., Alcantara-Martos T., Carrascal M. T. & Delgado-
Martinez A. D. (2016). Effect of cefazolin and
cefuroxime on fracture healing in rats. Injury. 47(3):
S3-S6.
Kapetanakis S., Nastoulis E., Demesticha T. & Demetriou
T. (2015). The effect of low molecular weight heparins
on fracture healing. The Open Orthopaedics Journal. 9:
226-236.
Perry A. C., Prpa B., Rouse M. S., Piper K. E., Hanssen A.
D., Steckelberg J. M. & Patel R. (2003). Levofloxacin
and trovafloxacin inhibition of experimental fracture-
healing. Clinical Orthopaedics and Related Research.
414: 95-100.
Kawasaki T., Ogata M., Kawasaki C., Ogata J., Inoue Y. &
Shigematsu A. (1999). Ketamine suppresses
proinflammatory cytokine production in human whole
blood in vitro. Anesthersia and Analgesia. 89(3): 665-
669.
Porter J. R., Ruckh T. T. & Popat K. C. (2009). Bone tissue
engineering: a review in bone biomimetics and drug
delivery strategies. Biotechnology Progress. 25(6):
1539-1560.
Kidd L. J., Cowling N. R., Wu A. C., Kelly W. L. &
Forwood M. R. (2013). Selective and non-selective
cyclooxygenase inhibitors delay stress fracture healing
in the rat ulna. Journal of Orthopaedic Research. 31(2):
235-242.
Prodinger P. M., Burgkart R., Kreutzer K., Liska F., Pilge
H., Schmitt A., Knodler M., Holzapfel B. M.,
Hapfelmeier A., Tischer T. & Bissinger O. (2016).
Does anticoagulant medication alter fracture-healing?
A morphological and biomechanical evaluation of the
possible effects of rivaroxaban and enoxaparin using a
rat closed fracture model. Public Library of Science
One. 11(7): e0159669.
Kim S. G., Chung T. Y., Kim M. S. & Lim S. C. (2004).
The effect of high local concentrations of antibiotics
on demineralized bone induction in rats. Journal of
Oral and Maxillofacial Surgery. 62(6): 708-713.
Klüter T., Weuster M., Brüggemann S., Menzdorf L.,
Oestern S. F., Steubesand N., Acil Y., Pufe T., Varoga
D., Seekamp A. & Lippross S. (2015). Rivaroxaban
does not impair fracture healing in a rat femur fracture
model: an experimental study. BMC Musculoskeletal
Disorders. 16(79). DOI: 10.1186/s12891-015-0502-9.
Satoh K., Mark H., Zachrisson P., Rydevik B., Byrod G.,
Kikuchi S., Konno S. & Sekiguchi M. (2011). Effect
of methotrexate on fracture healing. Fukushima
Journal of Medical Science. 57(1): 11-18.
Koga K., Ogata M., Takenaka I., Matsumoto T. &
Shigematsu A. (1994). Ketamine suppresses tumor
necrosis factor-alpha activity and mortality in
carrageenan-sensitized endotoxin shock model.
Circulatory Shock. 44(3): 160-168.
Sawin P. D., Dickman C. A., Crawford N. R., Melton M.
S., Bichard W. D. & Sonntag V. K. (2001). The effects
of dexamethasone on bone fusion in an experimental
model of posterolateral lumbar spinal arthrodesis.
Journal of Neurosurgery. 94(1): 76-81.
Krischak G. D., Augat P., Sorg T., Blakytny R., Kinzl L.,
Claes L. & Beck A. (2007). Effects of diclofenac on
periosteal callus maturation in osteotomy healing in an
Say F., İltar S., Alemdaroğlu K. B., Özel İ., Aydoğan N. H.
& Gönültaş M. (2013). The effect of various types low
987
Modified atmosphere packaging reduces pericarp browning and maintains the quality of ‘Huong Chi’ longan fruit
molecular weight heparins on fracture healing.
Thrombosis Research. 131(3): e114-e119.
Tortolani P. J., Park A. E., Louis-Ugbo J., Attallah-Wasef
E. S., Kraiwattanapong C., Heller J. G., Boden S. D. &
Yoon S. T. (2004). The effects of doxorubicin
(adriamycin) on spinal fusion: an experimental model
of posterolateral lumbar spinal arthrodesis. The Spine
Journal. 4(6): 669-674.
Simon A. M. & O'Connor J. P. (2007). Dose and time-
dependent effects of cyclooxygenase-2 inhibition on
fracture-healing. The Journal of Bone and Joint
Surgery. 89(3): 500-511.
Vnuk D., Pirkic B., Maticic D., Radisic B., Stejskal M.,
Babic T., Kreszinger M. & Lemo N. (2004). Feline
high-rise syndrome: 119 cases (1998-2001). Journal of
Feline Medicine and Surgery. 6(5): 305-312.
Sissons H. A. & Hadfield G. J. (1955). The influence of
cortisone on the structure and growth of bone. Journal
of Anatomy. 89(1): 69-78.
Street J. T., McGrath M., O'Regan K., Wakai A.,
Waters R. V., Gamradt S. C., Asnis P., Vickery B. H.,
Avnur Z., Hill E. and Bostrom M. (2000). Systemic
corticosteroids inhibit bone healing in a rabbit ulnar
osteotomy model. Acta Orthopaedica Scandinavica.
71(3): 316-321.
McGuinness A.
&
Redmond H. P. (2000).
Thromboprophylaxis using a low molecular weight
heparin delays fracture repair. Clinical Orthopaedics
and Related Research. 381: 278-289.
Strickland D. (2014). Wearing your seat belt costs you
nothing but not wearing one certainly will.[online].
June 9, 2018.
Xie X. H., Wang X. L., Zhang G., Liu Z., Yao D., Hung
L. K., Hung V. W. & Qin L. (2011). Impaired bone
healing
in
rabbits
with
steroid-induced
osteonecrosis. Journal of Bone and Joint Surgery.
93(4): 558-565.
Suliburk J. W., Helmer K. S., Gonzalez E. A., Robinson E.
K. & Mercer D. W. (2005). Ketamine attenuates liver
injury attributed to endotoxemia: role of
cyclooxygenase-2. Surgery. 138(2): 134-140.
Yaghini J., Abed A. M., Izadi M., Birang R., Torabinia N.
& Tavakoli M. (2017). Effect of short-term steroid use
(Prednisolone) on bone healing around implants: An
experimental study on dogs. Journal of Oral Health and
Dental Management. 16(2): 1-4.
Sun J., Li F., Chen J. & Xu J. (2004). Effect of ketamine on
NF-kappa B activity and TNF-alpha production in
endotoxin-treated rats. Annals of Clinical and
Laboratory Science. 34(2): 181-186.
Zhang C., Tang T. T., Ren W. P., Zhang X. L. & Dai K. R.
(2007). Inhibiting wear particles-induced osteolysis
with doxycycline. Acta Pharmacologica Sinica.
28(10): 1603-1610.
Taniguchi T., Shibata K. & Yamamoto K. (2001).
Ketamine inhibits endotoxin-induced shock in rats.
Anesthesiology. 95(4): 928-932.
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