Abstract
Background: Vertebroplasty with use of polymethylmethacrylate cement
is gaining popularity in the treatment of some specific painful lesions of the
spine. It remains unclear, however, what possible side effects this type of
cement might have upon the vertebral body. We performed a histologic and
radiographic analysis of the end plate and disc to determine whether there was
a difference between vertebroplasty with polymethylmethacrylate cement and
vertebroplasty with calcium phosphate cement in the surrounding tissue of the
goat spine. Furthermore, we assessed whether a defect in the end plate,
simulating end-plate fracture and allowing for direct contact of cement with
disc tissue, had any effect on end-plate or disc degeneration.
Methods: Twenty-four mature goats were divided between two follow-up
periods (six weeks and six months). All animals underwent a bilateral
transpedicular vertebroplasty at two lumbar levels, where one of the following
treatments was applied: vertebroplasty with calcium phosphate cement with or
without an end-plate defect, and vertebroplasty with polymethylmethacrylate
cement with or without an end-plate defect. The effect of the various
treatments on the integrity of the intervertebral disc, end plate, and
surrounding tissue was examined with semiquantitative histologic analysis and
radiography.
Results: No sign of disc or end-plate degeneration was seen in any
of the analyzed sections. The mean disc height did not decrease from the
postoperative period to the time that the animals were killed in any group,
thereby supporting the histologic findings. A mild inflammatory reaction was
found in four vertebral bodies in the polymethylmethacrylate groups only.
Conclusions: Calcium phosphate cement and polymethylmethacrylate
cement both seem to be adequate bone-void fillers in terms of biological
behavior in the vertebral body.
Clinical Relevance: The results of this animal study suggest that
vertebroplasty with either of these cements can be performed without an
increased risk for disc or end-plate degeneration even when end-plate
discontinuity is present.
Vertebroplasty with use of polymethylmethacrylate is rapidly gaining
popularity in the treatment of some specific painful lesions of the spine,
such as osteoporotic compression fractures, spinal myeloma, hemangioma, and
metastatic
lesions1-12.
It remains unclear by which pathway the procedure achieves pain reduction and
what possible side effects the cement might have after a prolonged period of
time in the vertebral body. The widespread assumption that stabilization of
the vertebral body is the key to pain reduction has led many physicians to try
to achieve a cement pillar from end plate to end plate during the
procedure11.
Following the publication of several in vitro studies pertaining to
vertebroplasty with calcium phosphate cement, Nakano et al. were the first, as
far as we know, to describe the results of calcium phosphate-based
vertebroplasty in osteoporotic
patients13-15.
Interestingly, the response of their twelve patients to treatment in terms of
pain reduction was similar to that of patients treated with
polymethylmethacrylate cement. Their data provide further support to the
assumption that stabilization of the vertebral body is an important factor for
the reduction of pain as opposed to thermal or chemical destruction of
nociceptors16.
Although the histologic effects of polymethylmethacrylate cement have been
studied extensively in arthroplasties, limited data are available on spine
applications17-20.
Surprisingly, considering the large number of patients already treated with
polymethylmethacrylate vertebroplasty, no study has been conducted, as far as
we know, to assess the effects of the injection of polymethylmethacrylate in
the proximity of the end plate. Since the end plate is the main nutritional
pathway to the disc, a disturbance of this structure could lead to an
impairment in the transport of nutrients and waste
products21-23.
Some fractures, both the traumatic burst type and the osteoporotic compression
type, are accompanied by fractures of the end plate; therefore, direct contact
of cement with disc tissue can be expected at least in some patients. However,
the interaction of these materials with disc or end-plate tissue has not been
studied in vivo. For instance, it can be questioned whether
polymethylmethacrylate cement should be used for vertebroplasties in younger
patients, as it is a permanent cement and does not have the potential of
calcium phosphate cement to be replaced by host
tissue24-27.
In the present study, a histologic and radiographic analysis of the end
plate and intervertebral disc was performed to determine whether there was a
difference between vertebroplasty with polymethylmethacrylate cement and
vertebroplasty with calcium phosphate cement in the surrounding tissue of the
goat spine. Furthermore, we assessed whether the presence of a defect in the
end plate, simulating an end-plate fracture and allowing for direct contact
between cement and disc tissue, had an effect on end-plate or disc
degeneration.
Study Design
After approval from the local institutional review board for animal
experiments, twenty-four mature dairy goats (approximately 2.5 years of age)
were obtained from a professional stockbreeder. The animals were divided
between a follow-up period of six weeks or six months. All animals underwent a
bilateral transpedicular vertebroplasty at two levels of the lumbar spine (L3
and L5), where one of the following treatments was applied according to a
randomized, balanced implantation schedule: vertebroplasty with calcium
phosphate cement with or without an end-plate fracture, and vertebroplasty
with polymethylmethacrylate cement with or without an end-plate fracture. This
resulted in a sample size of six for each of the treatments per follow-up
period. At the end of the implantation period, the animals were killed and the
effect of the various treatments on the integrity of the adjacent
intervertebral disc, end plate, and surrounding tissue was examined with
semiquantitative histologic analysis and radiography. To assess the natural
history of disc degeneration in the goat, we obtained six lumbar spines from
goats from a different study (not spine-related) but of the same breed and
same age. The vertebral bodies and cranial discs of L3 and L5 from these six
spines served as controls for the study.
Surgical Procedure
The animals received an intravenous line for the administration of an
anesthetic (10 mg/kg of thiopental) and antibiotics (500 mg of amoxicillin)
and were intubated endotracheally for inhalation anesthesia (2% isoflurane).
The goats were prepared for surgery in a prone position. After shaving,
draping, and disinfecting the lumbar area, a midline incision at the L2 to L6
level was performed, followed by dissection and hemostasis of the dorsal
musculature to access the entrance of the pedicles of L3 and L5. Through a
transpedicular approach from both sides, a 2.5-mm-diameter high-speed drill
was used to gain access to the cranial part of the vertebral body
(Fig. 1). The orientation and
length of the drill trajectory was practiced beforehand on cadaveric material,
to minimize the risk of pedicle-wall penetration. Two mills of increasing
diameter (3.0 and 4.0 mm) were used to ream a central cavity in the cranial
part of the vertebral body, under continuous cooling with physiologic saline
solution. In half of the goats (those that had vertebroplasty with calcium
phosphate cement with end-plate fracture and those that had vertebroplasty
with polymethylmethacrylate cement with end-plate fracture), a defect (2.5 mm
in diameter) was reamed in the cranial end plate, to allow for direct contact
of nucleus pulposus material with the cavity, thereby simulating an end-plate
fracture, as frequently encountered in vertebral fractures.
After rinsing of the defect with physiologic saline solution and drying by
suction with a small-diameter cannula through the pedicles, the cement was
injected. For the group that received polymethylmethacrylate cement, 20 g of
Simplex-P radiopaque bone cement (Stryker Howmedica Osteonics, Allendale, New
Jersey), a polymethylmethacrylate copolymer cement with barium sulfate (13%)
frequently used for vertebroplasty, was prepared. The liquid and powder
components (stored at room temperature) were thoroughly hand-mixed in an
aluminum bowl with a wooden spatula for one minute and then were transferred
to a 10-mL syringe. For the group that received calcium phosphate cement, 10 g
of BoneSource (Stryker Howmedica Osteonics) and 3.4 mL of physiologic saline
solution were hand-mixed for one minute with use of the same type of
instruments. Depending on the implantation schedule, the appropriate cement
was slowly injected through the right pedicle, until clean cement flowed out
the left pedicle (indicating complete filling of the cavity). The cement was
not pressurized since the preceding cadaveric practice showed that complete
and intimate bone contact was easily achieved without pressure. All excess
cement was subsequently removed from the operative field while keeping the
pedicle entrances dry. Approximately five minutes after injection of the
cement into the second vertebral body, the muscles and skin were closed in
layers with use of 2-0 Vicryl sutures (polyglactin; Ethicon, Somerville, New
Jersey), and the inhalation anesthesia was stopped. An anteroposterior
fluoroscopic image was made of the lumbar spine to determine the disc height.
After recovery, the animals were housed separately for three days and received
intramuscular analgesics (buprenorphine, twice a day) and antibiotics
(neomycin and penicillin) during this period. Thereafter, the animals were
housed in groups until they were killed at six weeks or six months after
surgery.
Postmortem Sample Acquisition
All animals were killed with use of an overdose of barbiturates, and
anteroposterior fluoroscopic images were made while the animal was on the
operating table in the same position as during surgery. After removal and
inspection of the lumbar spine (L2 to L6), the vertebral bodies of L3 and L5
were cut out and fixed in glutaraldehyde (Karnovsky) fixative. After stepwise
ethanol dehydration, the bodies were embedded in polymethylmethacrylate and
were cut in four sagittal slices of 4.0 mm, with use of an electric band saw
(Exakt 300; Exakt Vertriebs, Norderstedt, Germany). Following staining with
methylene blue and basic fuchsin, 10 µm was cut from the four slices with a
Leica microtome (Leica SP1600; Leica Microsystems, Rijswijk, The Netherlands).
The fourth slice was cut on both sides resulting in a total of five tissue
sections that were subsequently prepared for histologic evaluation
(Fig. 2). The same histologic
preparation was used for the twelve vertebral bodies from the control
group.
Histologic and Radiographic Scoring System
Two authors (P.J.S. and J.J.V.) assessed the following parameters using
low-magnification light microscopy: inner anulus failure (absent or present),
according to the criteria of Osti et
al.28; nuclear
degeneration (absent, moderate, or marked), according to the criteria of Osti
et al.; narrowing of the disc space (absent, moderate, or marked), according
to the criteria of Osti et al.; degeneration of the disc (absent, mild,
moderate, or marked), according to the criteria of Moore et
al.29; secondary
changes to the end plate (absent, moderate, or marked); former growth plate
(absent, partly present, or present); herniation of the nucleus pulposus into
the vertebral body (absent or present); inflammatory reaction surrounding the
cement (absent, mild [solitary lymphocytes and/or macrophages], moderate
[focal aggregations of lymphocytes and/or macrophages], or marked [general
presence of lymphocytes and/or macrophages]); fibrous layer surrounding the
cement (absent, incomplete, or complete); bone formation following cement
resorption (absent, moderate, or marked); and zone (approximately 2 mm)
surrounding cement (woven [immature] bone, lamellar [mature] bone, or tissue
other than bone).
For each vertebral body, the histologic scores were reduced to four main
parameters: signs of disc degeneration (inner anulus failure, nuclear
degeneration, or narrowing of the disc space), signs of end-plate degeneration
(secondary changes or end-plate erosion), inflammatory reaction surrounding
the cement, and the type of tissue in the zone surrounding the cement.
Any sign of disc degeneration in any of the five slices would render the
disc degeneration outcome as "present"; otherwise, it was
"absent." Any sign of end-plate degeneration in any of the five
slices would render the end-plate degeneration outcome as
"present"; otherwise, it was "absent." The
inflammatory reaction surrounding the cement was determined for the vertebral
body by the histologically most unfavorable score (with "absent"
being the most favorable and "marked" being the least favorable
score) in any of the five slices. Similarly, the zone surrounding the cement
was determined for each vertebral body by the histologically most unfavorable
score (with "lamellar" being the most favorable and "other
tissue than bone" being the least favorable score) in any of the five
slices.
The anteroposterior fluoroscopic images were digitized and, because it was
technically difficult to get exact 1:1 (life-size) fluoroscopic images that
could be compared postoperatively and after termination, the ratio of the
maximum disc height and the width of the lower end plate from the adjacent
cranial vertebra was determined. Since we were mainly interested in a change
of disc height instead of the absolute values, this approach ensured a
dimension-free and repeatable measurement of the disc height without
calibration.
Statistical Methods
The radiographic postoperative values were compared with the values at
termination with use of a two-tailed paired t test for dependent samples to
assess the changes in disc height (p = 0.05).
All surgical procedures and the subsequent recovery of all animals were
uneventful. The estimated amount of cement that could be injected into the
vertebral body was 0.5 to 0.8 mL, corresponding to a vertebral body filling
percentage of 14% to 22% (based on measurements on the cadaveric material),
which is comparable with the vertebroplasty situation in humans. In two goats,
leakage of cement was observed after the animal was killed. In one case, some
calcium phosphate cement entered the spinal canal; in the other case, some
polymethylmethacrylate cement entered the psoas compartment. Both animals had
recovered from surgery without apparent disability. Two goats had a
superficial wound infection that resolved within a week without additional
treatment.
Overall, no sign of disc degeneration or end-plate degeneration was seen in
any of the 300 analyzed sections, which included the controls (Figs.
3-A,3-B,3-C,3-D,3-E,3-F).
An inflammatory reaction was found in four vertebral bodies. In all four
cases, it was a mild reaction and occurred only in animals treated with
polymethylmethacrylate cement. The zone surrounding the cement consisted of
bone in all vertebral bodies (Table
I). In the controls, all bone was mature (lamellar), and the
former growth plate was always visible. A summary of the findings in the eight
groups follows.
Vertebroplasty with Polymethylmethacrylate Cement and End-Plate
Fracture at Six Weeks
The cement was completely covered by a fibrous layer in all vertebral
bodies (Figs. 4-A and
4-B). A mild inflammatory
reaction surrounded the cement in two vertebral bodies. In one vertebral body,
the former growth plate was absent. In the other, the zone around the cement,
at the outer side of the fibrous layer, consisted of mature bone as opposed to
the other five in which the zone consisted of immature bone.
Vertebroplasty with Polymethylmethacrylate Cement without End-Plate
Fracture at Six Weeks
No inflammatory reactions were seen in any of the vertebral bodies. A
complete fibrous layer around the cement was seen in five specimens. In one
section, some nucleus pulposus material had herniated into the corpus
(Fig. 5). In the same vertebral
body, the zone at the outer side of the fibrous layer around the cement was
composed of partly mature and partly immature bone. In the other vertebral
bodies, this zone consisted of immature bone.
Vertebroplasty with Calcium Phosphate Cement and End-Plate Fracture
at Six Weeks
No inflammatory reactions were seen in any of the specimens. An incomplete
fibrous layer was present around the cement in three specimens. Immature bone
was deposited against the cement in one specimen. Some cement resorption was
found in one specimen. The former growth plate was partly present in one
specimen, and the zone surrounding the cement consisted of immature bone in
all specimens.
Vertebroplasty with Calcium Phosphate Cement without End-Plate
Fracture at Six Weeks
No inflammatory reactions and no fibrous layers were found in any of the
vertebral bodies. In two, immature bone was formed as a result of replacement
of cement by bone. The former growth plate was found to be absent in one
specimen and partly present in two. The zone around the cement consisted of
immature bone in all vertebrae.
Vertebroplasty with Polymethylmethacrylate and End-Plate Fracture at
Six Months
In this group, a mild inflammatory reaction was found in one vertebral
body; in two other specimens, the presence of an inflammatory reaction could
not be determined because the cement was located too lateral in the corpus to
be present in the sections (this was probably due to our efforts not to damage
the anterior cortex, thereby staying lateral of the midline). A complete
fibrous layer around the cement was present in four specimens, and it could
not be determined in two specimens for the same reasons stated above. The
former growth plate was partly present in four specimens and was absent in
one. In three vertebral bodies, the zone around the cement, at the outer side
of the fibrous layer, consisted of mature bone. In the other three, there was
immature bone.
Vertebroplasty with Polymethylmethacrylate without End-Plate Fracture
at Six Months
A mild inflammatory reaction was found in one vertebral body and could not
be determined in two (for the same reason as stated above). A complete fibrous
layer was found in three vertebral bodies and could also not be determined in
two. Absence of the former growth plate was found in one body as was a slight
herniation of nucleus pulposus material in one. All surrounding bone was
mature.
Vertebroplasty with Calcium Phosphate Cement and End-Plate Fracture
at Six Months
No inflammatory reactions or fibrous layers were seen. The former growth
plate was partly present in three specimens. The zone of surrounding bone was
mature in four specimens and immature in two.
Vertebroplasty with Calcium Phosphate Cement without End-Plate
Fracture at Six Months
No inflammatory reactions or fibrous layers were seen in any of the
specimens. Some bone formation after cement resorption was found in two
vertebral bodies. The former growth plate was partly present in four vertebral
bodies, and a slight herniation of nucleus pulposus material was found in one.
The surrounding bone was mature in four vertebral bodies and immature in
two.
Summary of Results
Regarding the degeneration of the disc and the end plate, no differences
were found between any of the treatment groups and the controls since no
degeneration was detected at all. Regarding the inflammatory reaction
surrounding the cement, a difference was found between the
polymethylmethacrylate cement group and the calcium phosphate cement group. A
mild inflammatory reaction was present in four vertebral bodies treated with
polymethylmethacrylate cement (two of twelve in the six-week group and two of
eight in the six-month group; it could not be determined in four) but was
absent in all specimens that received calcium phosphate cement. A thin fibrous
layer surrounding the cement, indicating incomplete osseo-integration, was
found in almost all vertebral bodies that received polymethylmethacrylate
cement (eleven of twelve in the six-week group and seven of eight in the
six-month group; it could not be determined in four). In three bodies that
received calcium phosphate cement (three of twelve in the six-week group and
none in the six-month group), an incomplete, thin layer of fibrous tissue was
found, indicating that in the majority of cases the osseointegration was
complete. An end-plate defect did not seem to induce disc degeneration or
end-plate degeneration or to influence the integration of the cement in the
vertebral body. Bone formation following cement resorption was present in five
specimens from the group that received calcium phosphate cement (three of
twelve in the six-week group and two of twelve in the six-month group),
whereas, not surprisingly, it was not present in the group that received
polymethylmethacrylate cement. The mean disc height did not decrease from the
postoperative period to the time that the animals were killed in any group,
thereby supporting the histologic findings of a healthy intervertebral disc
(Table II).
We demonstrated in this goat model that, regardless of which of the two
types of cement is used or whether an end-plate defect is present,
vertebroplasty does not lead to degeneration of the disc or end plate. The
current literature does not provide any clues as to what the long-term fate of
these structures might be after vertebroplasty in humans, since the follow-up
periods have typically not been more than a few years and histologic
evaluations of human retrievals have rarely been
reported30. Several
human anatomical studies have pointed out that degeneration as part of the
natural history of the disc can start as early as the second or third decade
of life, while the quality of the disc can be reduced dramatically in the
seventh decade and
thereafter31-35.
Many studies have clearly demonstrated the progressive degeneration and
poor regenerative capacity of the disc once part of the anulus has been
damaged35-42.
Some of the studies already mentioned (and the current study) have used
quadruped models, and therefore questions can arise about the relevance for
the clinical situation. However, the predominant trabecular bone orientation
in sheep and goats as well as in human beings is in the cranial to caudal
direction, suggesting that loading of the spine is mainly in the axial plane
in all
three43-45.
Furthermore, the high bone density in the animals (much higher than that in
humans even when corrected for age) suggests that the compressive forces that
quadruped spines sustain are
substantial43.
Creating a control group with reamed defects in the cranial vertebral body
(and end plates) combined with high axial loading could very well lead to a
mechanical failure of the disc or end plate. However, since we were mainly
interested in the biocompatibility of the cements (and not the biomechanical
properties of the cements compared with untreated defects), spines from
unrelated research were used as controls to reflect the natural history of
disc aging in the goat.
There are minimal histologic data on the short or long-term effects of
polymethylmethacrylate cement on the integrity of the end plate and
intervertebral disc. Although several, mostly in vitro, studies have described
the temperature elevation caused by the polymerization of
polymethylmethacrylate to be high enough to cause tissue necrosis, a recent in
vivo study in goats did not support these
findings16,46,47.
Consistent with those studies, the data in the current study support the
absence of thermal necrosis around polymethylmethacrylate cement. Calcium
phosphate cements cure isothermically and thus do not pose this potential
problem.
Although both cements had good outcomes in the present study, the
calcium-phosphate cement group demonstrated superior osseointegration compared
with the polymethylmethacrylate cement group. No long-term (more than
five-year) clinical follow-up studies have been published yet on the
application of calcium phosphate cements, but several studies have shown the
biological properties of calcium phosphate cement to be superior to
polymethylmethacrylate
cement48-50.
In a recent biomechanical and histomorphological study in goats, calcium
phosphate cement was gradually replaced by bone while maintaining its
mechanical integrity in subchondral defects of the
femur51. Thus, we
postulate that calcium phosphate cements may be preferred over
polymethylmethacrylate cement particularly when vertebroplasty is to be
performed in younger patients and long-term biocompatibility becomes an
issue27.
In the present study, the histologic effects of two types of cement were
studied in a vertebral body with either an intact disc or a deliberately
created defect in the end plate to simulate the local environment after an
end-plate fracture. In contrast to previous studies pertaining to anular
lesions and subsequent disc degeneration, a considerable defect in the end
plate did not lead to disc degeneration in any of our
specimens36,52.
The nucleus pulposus has been shown to be inflammatogenic after disc
herniation, but direct contact of vertebral bone and/or cement with nucleus
pulposus material was not followed by histologic evidence of inflammation in
our
model53,54.
Therefore, it is hypothesized that the end-plate defect led to a condition
similar to a Schmorl
node55. Further
support for the hypothesis that end-plate defects or fractures do not lead to
disc degeneration but probably have a benign course comes from the magnetic
resonance imaging study by Oner et
al.56. They found
that a fracture of the end plate resulted in a redistribution of disc material
through the end plate in the vertebral body but did not lead to disc
degeneration.
One of the limitations of the goat model is that the high bone density and
probably higher bone turnover of these animals does not reflect the typical
population of humans managed with vertebroplasty, who have a high prevalence
of osteoporosis. Also, in contrast to vertebral compression fractures in
humans, the cortex in the treated vertebral bodies was intact and thus could
continue to transmit loads without (macroscopic) deformation. The resulting
stability might have influenced some of the study parameters, such as new-bone
formation, immune cell response, or fibrous tissue formation.
Although our longest follow-up was only six months, we think that the time
was sufficient for detection of the first signs of degeneration by histologic
analysis.
In conclusion, we demonstrated in an in vivo vertebroplasty model, with and
without end-plate defects, that calcium phosphate cement and
polymethylmethacrylate cement both seem to be adequate bone-void fillers in
terms of biological behavior in the vertebral body. Histologic or radiographic
evidence of degeneration of the disc or end plate was not found in any of the
specimens. Calcium phosphate cements might be a better choice than
polymethylmethacrylate cement if long-term biocompatibility becomes an issue,
although its mechanical properties have yet to be determined in the clinical
setting.
Note: The authors thank Marieke Ostendorf for her invaluable
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