Bioventus EXOGEN Guia Del Usuario página 13

CLINICAL STUDIES
Nolte et al.
confirmed the 86% (25/29) success rate and
showed the average heal time to be around 5
Treatment of Non-union Fractures
months without additional intervention. Average
non-union fracture age was 61 weeks. There
Study design were high success rates seen with atrophic and
oligotrophic non-unions (80% and 92% respec-
Three prospectively designed studies, undertak-
tively) where some biological deficiency may
en in the USA, Germany and the Netherlands,
contribute to the original non-union. Additionally
were submitted to the FDA as the basis for
1
the application of EXOGEN to hypertrophic
approval of the EXOGEN Ultrasound Bone
non-unions, which might usually be considered
healing system to treat established non-unions.
as requiring revised treatment to correct fracture
The studies had a self-paired control design with
instability, was successful in 80% of cases.
each non-union case serving as its own control,
Success was seen for a range of bones, all types
and with the prior treatment result of failed
of typical primary fracture management, and
orthopedic care as the control compared to
across all patient age ranges. For the United
ultrasound as the only new treatment. The
States study, the completed cases group had
criterion for the definition of non-union cases was
an 82% (352/429) heal rate.
the minimum time from fracture of nine months.
The primary efficacy outcome was healed due to
Other non-union studies:
EXOGEN treatment, as judged clinically (no pain
upon palpation or weightbearing) and radiograph-
Frankel and Mizuno
ically (3 out of 4 cortices bridged).
USA patient nonunion registry demonstrated that
for patients with risk factors that may impair
Clinical results fracture healing, such as substance abuse,
diabetes, vascular problems, or steroid use, there
Analyzing the data from Germany, the completed
was no significant change in the efficacy of the
cases had a healed rate of 86% (64/74) with a
EXOGEN Ultrasound Bone Healing System.
mean time to a healed fracture of 163±9.4 days.
Again high success rates were achieved for all
The median heal time was 142 days with a range
bones, regardless of fracture age, but there was a
of 53 to 375 days. The mean fracture age for the
trend towards higher success rates and faster
healed cases was 494 days with a range of
healing with earlier intervention.
257-6011 days. The scaphoid non-union heal rate
of 33% (2/6) was attributable to the three Duarte et al.
scaphoid non-union failures that were all more largest cohorts of patients treated with low
than 10 years in fracture age and, therefore, were
intensity pulsed ultrasound (1996). 380 nonre-
very difficult and challenging cases. Cases with
sponding delayed and non-unions (averaging 14
metal surgical fixation present during EXOGEN months old) were treated with the EXOGEN
treatment such as those with ORIF (Open ultrasound signal and achieved an 85% success
Reduction Internal Fixation) and those cases rate across a range of bones.
with intramedullary rods had an 88% (21/24)
Romano et al.
and 100% (16/16) healed rate, respectively. The
nal studies in infected non-unions and pseudoar-
results of this non-union paired design clinical
throsis respectively, suggesting high success
study established the safety and effectiveness
rates with low intensity pulsed ultrasound in both
of the EXOGEN bone healing system in treating
situations.
non-unions. This includes cases that had long
fracture ages of up to 5 years but suggests that Strauss and Gonya
non-unions over 5 years duration may have a
intensity pulsed ultrasound on two difficult cases
decreased response to ultrasound treatment.
of Charcot non-unions with multiple prior failed
The results are summarized in Table 1.
surgical procedures. Both cases healed within 5.5
months when treated with the EXOGEN bone
healing system.
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Acceleration of Conservatively
2 , reporting on the Netherlands study,
Treated Fresh Distal Radius
Fractures
Study design
Placebo-controlled, randomized, double-blind
multi-centre study with the prospectively defined
primary end-point of a combination of clinical and
radiographic healing (4 out of 4 cortices bridged
as judged by the blinded principal investigator).61
patients with conservatively treated cancellous
radial fractures were randomized into the
EXOGEN treated and control groups
(Kristiansen et al. 7 ).
Patient population and demographics
The demographics of the trial participants were
comparable across treatment and control groups
with regard to age, sex, fracture characteristics,
in their analysis of the 1,546
3 interval between fracture and commencement of
fracture, and duration of follow-up.
Evaluation schedule
Treatment was started within seven days of the
fracture, and patients instructed to use EXOGEN
until the 10 week follow-up visit. Duration of
immobilization in the cast was determined by
the site investigator.
Patients were scheduled to return for follow-up at
presented data from one of the 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16 weeks.
4
Clinical Results
EXOGEN treatment accelerated healing by 38%
(61±3.4 days in the active group versus 98±5.2
days in the control group; p<0.0001).
The effect of EXOGEN low intensity pulsed
reported on prospective longitudi-
5
ultrasound on fracture reduction during healing
was also assessed. The sub-set of fractures
which were satisfactorily reduced having
presented with at least 10 degrees of negative
volar angulation were analyzed. The active group
described the effects of low
6
demonstrated significantly smaller loss of
reduction compared to the placebo group
(p<0.01).
Acceleration of Conservatively
smokers. Using a 150 day definition of delayed
Treated Fresh Tibial Fractures union, Cook et al.
Ultrasound Bone Healing System had a statisti-
cally significant effect (p<0.003) on the rate of
Study Design
delayed unions (treated group 6% versus control
Placebo-controlled, randomized, double-blind group 36%). Cook et al.
multi-centre study with the prospectively defined significant reduction in the healing time of
primary end-point of a combination of clinical and smokers for fractures of the tibia and distal
radiographic healing (3 out of 4 cortices bridged radius.
as judged by the blinded principal investigator).
67 patients with conservatively treated closed
Other fresh fracture studies:
or grade-I open, cortical tibia fractures were
In addition to long bones the effect of the randomized into the EXOGEN treated and
EXOGEN Ultrasound Bone Healing System on
control groups (Heckman et al. 8 ).
fractures of other types of bone has also been
clinically studied. A single center, prospective,
Patient population and demographics
randomized, double-blind, placebo-controlled
The demographics of the trial participants were study of 40 scaphoid fractures
comparable across treatment and control groups a statistically significant 31% acceleration in the
with regard to age, sex, fracture characteristics, primary end-point of clinical plus radiographic
interval between fracture and commencement of healing (active 43 days; control 62 days; p<0.01)
fracture, duration of follow-up, and days to start and 41% improvement in percentage trabecular
bridging at 6 weeks (active 81%, control 55%,
weight-bearing.
p<0.05). A smaller (n=20) single-center, pro-
spective, randomized, double-blind, placebo
Evaluation schedule
controlled study of Jones' fractures
Treatment was started within seven days of the
all actively-treated fractures healed within 56
fracture, and continued for 20 weeks or until the
days whilst only 60% of placebo-treated fractures
clinical investigator judged the fracture to have
had healed by 87 days, and 20% had still not
healed. All patients were scheduled for follow-up
healed after 140 days. In addition the active-
radiographs at 4, 6, 8, 10, 12, 14, 20, 33 and 52
ly-treated group reached pain free status 31 to
weeks after the fracture. Clinical follow-up
70 days earlier than the placebo group, and on
evaluations were performed at the time of any
average took only half the rehabilitation time.
cast change (usually at 6 and 10 weeks) and at
the follow-up visit when radiographic evaluation
Safety
indicated the fracture had healed sufficiently to
allow removal of the cast.
a. Gross Pathology
Clinical Results
Several studies were conducted to assess the
safety of EXOGEN as part of the FDA summary
EXOGEN treatment induced a 38% acceleration
of safety & effectiveness. Results from a placebo
in achieving the prospectively defined primary
controlled in-vivo study on rabbits with bilateral
end-point of a combination of clinical and
midshaft fibular osteotomies showed no deleteri-
radiographic healing (96±4.9 days in the active
ous effects of EXOGEN as evidenced by
group versus 154±13.7 days in the control group;
pathological, hematological, and histological a
p<0.0001).
nalysis .
12
Analysis of fresh fracture studies:
b. DNA Analysis
Cook et al. 9 pooled the data from the tibia and
Analysis of the effects of EXOGEN on chromo-
distal radius studies to analyze the impact of low
some of bone marrow cells from a rabbit
intensity pulsed ultrasound on the incidence of
mid-shaft radius osteotomy reported no
delayed unions, and on the healing time of
measurable, significant, detrimental effects
c. Temperature
determined that the EXOGEN
9
EXOGEN's acoustic output is 20 to 100 times less
than that of other therapeutic ultrasound devices
currently available.
An independent university-based medical expert
also demonstrated a
9
in ultrasound 14 concluded EXOGEN
is incapable of producing temperature elevations
greater than 1°C. Such temperature elevations
are not considered significant and the potential
for detrimental thermal effects is not a concern.
d. Metals & Implants
Several reference articles have focused on
conventional therapeutic ultrasound's effect on
surgical metallic implants. Lehman et al.
reported that, based on histological studies,
, demonstrated
10
ultrasound applied in the presence of metal
implants did not produce any untoward effects.
In addition, it has been shown that low intensity
ultrasound does not compromise the integrity of
a standard orthopaedic stainless steel fixation
plate . After 30 hours of continuous exposure,
1
no changes or effects could be detected.
showed Temperature—Gersten reported that tempera-
11 16
ture rises were smaller with metal than with bone
at the same depth, and that the presence of metal
was not a contraindication to the use of ultra-
sound.
Migration—Lotsova 17 reported that investigations
carried out with Kirschner needles, used as
fixation in ultrasound-treated patients did not
affect migration of the pins or affect the structural
integrity of the pins as determined by metallo-
graphic analysis.
Degradation—Skoubo-Kristiansen and
Sommer 18 concluded that as a result of ultrasound
treatment no effect was observed on fixation
screws or the torques necessary for loosening
the screws in an in-vivo study. The compatibility
of the EXOGEN Ultrasound signal on bioabsorb-
able screws has also been investigated in-vitro
and clinically. Handolin et al. 19-20
with EXOGEN had no effect on the mechanical or
molecular properties of biodegradable self-rein-
forced poly L-lactide screws and thus biocompati-
bility between the screws and EXOGEN was
good, with no effect on the biodegradation rate.
.
13
15
showed treatment
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