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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_6034_Библиотеки_им_академика_М_И_Перельмана.pdf
CHAPTER 7/FRACTURE AND REPAIR OF LUMBAR VERTEBRAE / 93
Bone-forming cells (osteoblasts) have been shown to
undergo thermal necrosis when exposed to relatively
lower temperatures than cement polymerization (as low
as 50°C for more than 1 minute) (78,79). Clinically the
complication rate (between 1% to 3%) associated with
PMMA-induced temperature elevation and PMMA
extravasation is insignificant for treatment of vertebral
fracture (74), but long-term effects are still being investigated. Another noteworthy complication from the resulting increased strength and stiffness of cement-augmented
vertebrae is the modif ied load transfer to adjacent vertebral bodies. Recent findings suggest that the cement augmentation results in higher stresses and strains to adjacent vertebrae, thus facilitating their future collapse (80).
Biomechanical Studies of Cement Augmentation
Biomechanical studies of cement augmentation have
demonstrated that vertebroplasty treatment of experimentally created compression fractures is an effective means
to restore the strength, and to a lesser extent, the stiffness
of the damaged vertebrae (81). These authors noted that
2 mL of PMMA cement restored the strength of thoracolumbar and lumbar vertebrae, but 8 mL and 4 mL of
cement were necessary to restore the stiffness of the
thoracolumbar and lumbar vertebrae, respectively, to
predamage levels using a bipedicular approach. Furthermore, it has been shown that lumbar vertebral strength
can be significantly restored using either a unipedicular
(6 mL injection through one pedicle) or bipedicular (5
mL injections through each pedicle) approach (70).
The biomechanical aspects of kyphoplasty are less
well understood. Reductions in risk of cement extravasation and vertebral height restoration have been suggested
as the main advantages of kyphoplasty compared to vertebroplasty (16). Researchers have reported a 47%
restoration in vertebral height in 70% of the collapsed
vertebral bodies following kyphoplasty (16). Furthermore their findings support that lower pressure, higher
viscosity cement injections reduced the rate of cement
extravasation as compared to published f indings for vertebroplasty.
Computer models and numerical tools to simulate
and guide surgical repair are becoming more routine,
and are rapidly advancing treatment of musculoskeletal
disorders (82). One of the main advantages of computer
models is that they can be used as their own repeated
measure. Different cement repair strategies can be studied using a single bone specimen and can be evaluated
in an unlimited manner using different loading modes
and boundary conditions. The ability of microstructural
finite element models to represent complex structures
lends this technique to the study of trabecular bone
microdamage and repair. Numerical examples of cement augmentation repair are discussed and presented
in the following sections.
Numerical Simulations of Cement Augmentation
Validated finite element models can act as replacements to experimental testing (44). Liebschner et al. (67)
used an experimentally validated apparent lumbar vertebral damage model to investigate vertebroplasty cement
repair. In their study, cement repair was modeled by the
introduction of PMMA cement elements within the vertebral centrum. Four PMMA cement bolus volumes (1.0,
3
3.5, 5.0, and 7.0 cm
) were investigated with an assumed
cylindric cement shape. Using this repair modeling
approach, the authors reported that only small amounts
3
of PMMA (approximately 14% fill or 3.5 cm
) were
required to restore apparent stiffness to intact levels, and
that symmetric PMMA placement was preferential compared to asymmetric distributions.
The EPMR damage simulation scheme and finite element method was recently used to investigate damagerepair of human vertebrae (64). Microstructurally damaged finite element models were repaired using four
different PMMA cement repair strategies:
• replacement of marrow elements by PMMA cement
elements at each of the four interior corners of the midsagittal model (referred to as model A)
• central placement of cement consistent with a para-
pedicular surgical approach (model B)
• strategic placement of equivalent cement quantities at
five damage initiation sites (model C), and
• complete vertebral cement fill (replacement of all mar-
row elements) (model D) (Table 7-1).
The first three repair strategies used equivalent
amounts of cement elements (25% of the marrow elements were replaced by PMMA bone cement). For the
third strategy, the five trabecular microdamage initiation sites were used as the central locus for repair (each
TABLE 7-1. Summar y of finite element simulations of several
PMMA cement repair strategies
Normalized Bone element
Loading Vertebroplasty modulus concentrations
regimen repair regimen (ER/E0) (% >3)
Uniform Undamaged 1.0 4.5
Ramped Undamaged 1.0 4.6
PMMA, polymethylmethacrylate.
a
See text for definitions of repair regimens.
Damaged 0.68 5.5
Repair A 1.67 3.5
Repair B 1.60 3.3
Repair C 2.10 3.4
Repair D 4.06 0.0
Damaged 0.05 20.1
Repair A 1.26 14.4
Repair B 0.38 17.5
Repair C 1.52 11.6
Repair D 3.53 0.4
apparent stress
a
94 /SECTION I/BASIC SCIENCE
site with PMMA comprising 5% of the marrow elements). The motivation for studying partial cement f ill
was the notion that reductions of cement volume during
vertebroplasty may reduce the likelihood of cement
leakage. Plane stress, static finite element analyses were
performed on each of the damage-repair models (eight
in total). Loading profiles used for the repair models
were identical to the EPMR damage simulation (uniform and nonuniform). Stress-strain results (apparent
modulus) were normalized to undamaged vertebral
body results.
Examination of the eight-vertebroplasty repair models
revealed that only the ramp-loaded central placement
cement regimen (model B) did not restore the microstructurally damaged vertebral body apparent modulus to the
initial undamaged apparent modulus (E
= 444 MPa). The
0
repair strategy using a central placement, cement regimen
(model B), was the least effective of all the partial f ill
repair strategies for both loading conditions in increasing
vertebral body structural stiffness (Table 7-1). In the case
of the uniform-loaded microdamage regimen, model B
resulted in a repair modulus/initial modulus ratio E
R/E0
1.60, which is still significantly (135%) above the damaged apparent modulus (E
= 302 MPa). Of the strategic
D
partial cement f ill regimens, model C was most effective
in increasing the apparent modulus above the initial
undamaged apparent modulus for both the uniform
(E
= 2.10) and ramped (ER/E0= 1.52) microdamage
R/E0
models. Each of the partial cement repair strategies
(models A through C) resulted in complete recovery of
the apparent modulus above the undamaged levels except
model B for the severely damaged ramp-loaded case.
In the case of the complete fill repair regimen (model
D), the number of highly stressed elements (trabecular
bone stress concentrations greater than 3) decreased to
less than 0.4% (98% reduction) of the total bone elements
for the ramp-loaded model and were completely removed
(100% reduction) for the uniform-loaded microdamage
model. The least effective cement repair strategy for
reducing the number of highly stressed bone elements
was model A for the uniform-load microdamage model
(36% reduction with respect to the untreated damage
model), and model B for the ramp-load microdamage
model regimen (14% reduction with respect to the
untreated damage model) (Table 7-1). Strategic placement of cement at damage initiation sites, model C,
resulted in a 38% and 43% reduction in the number of
highly stressed elements for the uniform-loaded and
ramp-loaded microdamage models, respectively, compared to the untreated damaged model.
The previous analysis was limited to a single vertebral body. Keller et al. (10) studied the effects of spinal
deformity and vertebral height loss associated with
osteoporosis using an anatomically accurate sagittal
plane postural loading model of the anterior spinal col-
umn (C2-S1) in conjunction with the EPMR scheme.
This analytic model was found to reproduce the salient
features of thoracic spinal deformities caused by osteoporotic wedge fractures (Fig. 7-8A). This model was
used to simulate the effects of vertebral cement augmentation (vertebroplasty) on spinal deformity. Spine
stiffness was parametrically varied over the range of 1×
to 2× that of a normal healthy spine. An increase of 2×
in vertebral body stiffness corresponds to complete
cement fill of the nor mal vertebral body (64). Increases
in thoracic kyphosis and decreases in vertebral body
height resulted in a 34.9% overall decrease in spinal
height (C2-S1), 12.0% decrease in body height, and a
22.8 cm anterior translation of C2. The resulting thoracic kyphotic deformity (86.4° T2-T10) qualitatively
resembled deformities observed in elderly individuals
with osteoporotic compression fractures.
To prev ent se v ere thoracic deformity (greater than 70°)
cement augmentation of three or more thoracic segments
and a 60% increase in vertebral body stiffness was
required. Doubling the vertebral body stiffness of one
=
segment resulted in only a 10° reduction in thoracic
kyphosis deformity , w hereas stif fness doub ling combined
with augmentation of 11 segments (T2-T12) reduced the
kyphotic deformity to 50° (height change = 2.4%, C2
translation = 10.9 cm) (Fig. 7-8B). The effects of cement
augmentation on postural load-induced osteopenic thoracic kyphosis are summarized in Figure 7-8C. These
analytic results suggest that cement augmentation of vertebrae can reduce the severity of osteoporotic spine
deformities. Model data provide insight for surgical procedures (optimal cement material and volume, number of
treatment levels) designed to prevent or treat vertebral
fractures and deformity of the thoracolumbar skeleton.
Ultimately, identification of subjects who are at risk for
vertebral microdamage and fracture may facilitate early
prophylactic treatments using cement augmentation.
Clinical repair of fractures using small cement quantities
at locations where damage is greatest or where damage
initiates may become comparable to current cement-filling regimens used during vertebroplasty.
CONCLUSION
Lumbar vertebral compression fractures are primarily
caused by o verloading, but even postural loads may result
in vertebral body height reduction, deformity, myelopathy, and pain. Restoration of vertebral geometry and
mechanical properties to undamaged levels using cement
repair strategies is dependent on a number of factors
including bone density, damage, cement quantity, quality
(modulus) and placement (within a single and at multiple
vertebral segments), and surgical approaches and techniques. These factors, together with the complexity of
vertebral bone geometry and material proper ties, suggest
CHAPTER 7/FRACTURE AND REPAIR OF LUMBAR VERTEBRAE / 95
FIG. 7-8. Graphic depiction showing the resulting spinal deformity
and anterior wedge-type fractures of the T7 and T8 vertebral bodies
following osteoporosis simulations (A) and multisegment vertebroplasty repair (B). The three-dimensional surface plot depicts thoracic
angle changes (vertical axis) with respect to cement augmentation
(represented by changes in segment stiffness from 1× to 2× normal)
and the number of augmented segments (thoracic levels, T1T12) (C).
that computational tools and algorithms using anatomically precise tw o-dimensional and three-dimensional v ertebral geometry derived from radiographic images may
prove to be valuable for clinical management of vertebral
osteoporotic compression fractures and tumors. In this
regard, simple analytic models and more complex
microstructural finite element models provide a framework for understanding microdamage and fracture of vertebrae, and investigating surgical treatment, including
design and development of tissue-engineered fracture
repair materials. Additional work is needed to identify the
effects of cement augmentation on the load transfer and
stress distributions of adjacent vertebrae. Whether or not
altered load transfer is sufficient to facilitate collapse of
adjacent (untreated) vertebral bodies, as has been recently suggested (80), remains to be determined.
ACKNOWLEDGMENTS
Research supported by Department of Energy Experimental Program to Stimulate Competitive Research
(EPSCoR) and National Aeronautics and Space Administration (NASA) EPSCoR.
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CHAPTER 8
Genetic Transmission of Common Spinal Disorders
Michele C. Battié and Tapio Videman
Spinal disorders such as disc degeneration and herniation, sciatica, and back pain have commonly been attributed to the accumulation of environmental effects, primarily mechanical insults and injuries, imposed on
normal aging changes. Accordingly, environmental factors received much attention as possible risk factors during the prior half-century, and only recently have studies
on hereditary aspects of disc degeneration, disc failure,
and back symptoms begun to accumulate (1).
A decade ago, in reviewing the epidemiology of
degenerative disc disease, Frymoyer wrote: “Among the
factors associated with its occurrence are age, gender,
occupation, cigarette smoking, and exposure to vehicular vibration. The contribution of other factors such as
height, weight, and genetics is less certain” (2).
Research since that time has dramatically changed
views of genetic and environmental determinants of
many common spinal disorders. When reviewing the
same topic of “disc disease” in 2002, Ala-Kokko came
to the following conclusion: “Even though several environmental and constitutional risk factors have been
implicated in this disease, their effects are relatively
minor, and recent family and twin studies have suggested that sciatica, disc herniation and disc degeneration may be explained to a large degree by genetic factors” (3). We concur and will discuss the basis for this
tentative conclusion in this chapter.
The role of genetics in common musculoskeletal disorders has been studied more in primary osteoarthritis
than in spinal disorders. In a recent review article,
Loughlin concluded that primary osteoarthritis has a
major genetic component, but that osteoarthritis “is
rarely transmitted as a Mendelian trait and that environmental factors play a significant role in disease expression. ” He also classified osteoarthritis as a common, oligogenic, multifactorial genetic disease (4). These views
are concordant with those on common spinal disorders,
which would be lo gical because joints and intervertebral
discs are to a major part composed of the same proteins.
To date more than a dozen gene loci associated with
osteoarthritis have been identified, and a half dozen
associated with disc degeneration, mainly from chromosomes 2, 4, 6, 7, 11, 16, and X. Only a few loci have
been associated with both joint and spine degeneration.
How e v er , it is lik el y that the genes representing the most
significant genetic susceptibility to these common conditions have yet to be identif ied. (4).
We will briefly review the evidence suggesting genetic
transmission, from case reports and more formal studies
of familial aggregation to classic twin studies attempting
to separate genetic and shared environmental influences,
to the identification of gene for ms. The primary focus of
this chapter is on genetic influences on common spinal
disorders, including disc degeneration and herniation,
sciatica, and back pain.
IDENTIFYING AND CONFIRMING GENETIC
INFLUENCES
Studies of the genetic epidemiology of common spinal
disorders begin with determining whether familial aggregation of the disease or disorder is present. This is done
by examining the frequency of disease in relatives of
those affected as compared to the frequency of disease in
the general population. If relatives are at increased risk,
the pattern of familial aggregation can be further defined
through various types of family studies (5). Most of the
studies on common spinal disorders fall into this category. Once evidence for familial aggregation has been
obtained, there is a need to distinguish between biologic
(genetic) and social (cultural inheritance) sources of
familial similarity (6). One method of accomplishing this
is through classic twin studies of monozygotic and dizygotic twin pairs.
98
CHAPTER 8/GENETIC TRANSMISSION OF COMMON SPINAL DISORDERS / 99
The genetic architecture of a trait includes information
on how man y gene loci are in v olv ed and w hich of the loci
are polymorphic, with at least two common forms of the
genes or alleles. The number of alleles and their frequencies are then determined for each gene locus. Allele frequencies and average effects associated with the alleles
determine the contribution of allelic variation to the overall genetic variation. These can be further partitioned into
additive genetic v ariance, due to gene “dosage,” and variance due to dominance (7).
A growing number of monogenic diseases have been
successfully analyzed down to the molecular level and
have shown how a biochemical defect ev olv es from a single mutation, which parts of a gene are indispensable for
normal function, and how phenotypes develop from different mutations. Based on these insights, molecular
genetics can yield information on normal traits and common diseases. Normal traits and common diseases generally have a genetic contribution from more than one gene
locus.
Genes suspected of involvement in the etiology of disease are called candidate genes. Candidate genes may be
used as targets, with potential genetic variation leading to
differences in the proteins encoded by the genes. These
proteins are part of the physiologic system that, when disturbed, gives rise to the disease being studied. Also, for
specific genes and some environmental factors, gene-gene
interactions and gene-environment interactions may exist.
For example, Solovieva et al. presented evidence suggesting that the effect of weight on lumbar disc de generation is
modified by COL9A3 gene polymorphisms in Finnish
men (8). Simple linear models may, therefore, fail to grasp
the complexity of the real world, and unraveling the contribution of genes and environment in diseases of multifactorial etiology is a challenging proposition (9).
DISC HERNIATION AND SCIATICA
The clearest association between back-related symptoms and the disc is for severe sciatica, often leading to
surgery to remove an offending herniated disc. This condition also has been the focus of several investigations
into genetic influences on common spinal disorders. As is
typically the case, observations of familial aggregation
lead to hypotheses of genetic susceptibility for sciatica
and disc herniation.
It should be noted, however, that in juveniles and
adults, persons identified as having disc herniations are
those who access and receive spine surgery for pain with
the diagnosis of disc herniation. Although discectomy
may appear to be a clear indicator of the presence of a
symptomatic disc herniation, the significant regional
variations in rates of spine surgery demonstrate that this
outcome is likely to be significantly influenced by other
factors as well (10). Thus, some degree of classif ication
error is involved when studying the occur rence of severe
symptomatic disc herniation using the surrogate of discectomy.
Familial Aggregation of Juvenile Lumbar Disc
Herniation
Two reports in 1990 documented cases of identical
twins with similar histories of radicular symptoms and
lumbar disc herniation. Matsui et al. documented a case
of a 16-year-old girl who was admitted to a hospital for
low back and left leg pain (11). Myelography and subsequent laminotomy revealed a protruded mass at the L4-5
level with left L5 root compression. Two years later, the
patient’s identical twin was admitted complaining of back
pain of 2 years’ duration and right leg symptoms of
approximately 8 months. Results from myelography and
discography prompted the surgeon to perform laminotomy and discectomy at the L4-5 and L5-S1 levels. The
observation that herniated lumbar discs in young patients
are relatively rare and the absence of a history of trauma,
suggested that the similarity of the local disc pathology in
the twins was not a chance occurrence. Matsui et al. thus
concluded that their findings suggest that genetic f actors
are involved in the development of juvenile herniated
nucleus pulposus (11).
Gunzburg et al. documented a similar case of identical
twin girls who experienced radicular pain within 1 year of
one another when they were approximately 13 years of
age (12). Computed tomography scans revealed posterior
bulging at the L4-5 level and herniation at the L5-S1 level
in both. As in the case presented by Matsui et al., the
onset of symptoms was similar and neither twin cited an
injury or trauma (11). The twins experienced progressive
symptoms that led to surgery in one case and chemonucleolysis in the other, with subsequent pain relief and
return to normal activities.
These case reports demonstrate that familial aggregation occurs, but clarifying whether or not it occurs more
often than would be expected through random occurrence
requires comparison to controls or a reference group. The
generally lo w incidence of juv enile disc herniation would
suggest that such aggregation as seen in the cases just
described would be extremely unlikely chance events. A
rare population-based study of the incidence of surgeries
for juvenile disc herniation was conducted among more
than 75,000 Japanese elementary, junior high, and high
school students. It revealed incidence rates of 1.69 per
100,000 person-years for 10- to 12-year-olds, 3.2 for 13to 15-year-olds, and 9.4 for 16- to 18-year -olds. The mean
incidence rate for all the schoolchildren was 5.4 per
100,000 person-years (13).
Two subsequent papers reported on the degree of
familial aggregation in cases versus control groups. Varlotta et al. investigated the incidence of severe low back
pain, sciatica, and surgically treated herniated discs
among the parents of 63 patients under 21 years of age
100 /SECTION I/BASIC SCIENCE
who had herniated lumbar discs and the parents of a control group of nonback patients (14). They also tried to
eliminate reporting bias by family members by requiring
confirmation from medical records. The estimated risk of
developing a herniated disc before the age of 21 was four
to five times greater for patients who had a positive family history, as compared to those who did not.
A year later Matsui et al. reported on the occurrence of
lumbar disc herniation in the siblings and parents of 40
patients under 18 years of age who had undergone
surgery for lumbar disc herniation and a referent group
composed of the families of 120 controls (patients treated
in the same department who had “normal spines”) (13).
The odds ratio of a patient with juvenile disc herniation
to have a family history of disc surgery was 5.61 times
that of a patient without disc herniation. The authors concluded that their results “strongly suggest that lumbar
disc herniation in patients aged 18 years or younger
shows familial predisposition and clustering.”
Because family members can become affected even
though the disease is not familially transmitted , the risk in
family members ideally should be compared with the
population risk. The finding by Matsui et al. of a higher
incidence of a positive family history in juveniles with
disc herniation, yielding an odds ratio of 5.61, is directly
useful clinical information when combined with the incidence of 5.4 per 100,000 children and adolescents (13).
Varlotta et al. used matched patient-control pairs in their
series of 63 disc herniations in patients under 21 years of
age (14). The age-adjusted relative risk of herniation in
family members of patients compared to family members
of controls was 4.5, which w as quite similar to that found
by Matsui et al. despite differences in methods and sample populations (13).
Younger patients who had undergone discectomy also
were found to be significantly more likely to have a family history of back disorders by Nelson et al. in a study
comparing three age groups, those 9 through 15, 16
through 19, and 20 through 25 years of age (15). Such a
finding would be consistent with genetic epidemiologic
literature, indicating that stronger genetic effects are
associated with earlier onset.
Familial Aggregation of Lumbar Disc Herniation in
Adults
There also have been over a half-dozen reported observations of familial aggregation of lumbar disc herniation
in adults, raising interest in the possibility of genetic susceptibility (16–19). Scapinelli described a striking family
history of a 44-year-old patient who had undergone
surgery for lumbosacral disc herniation (17). Six of the
patient’s 14 siblings (five brothers and one sister) also
had undergone surgery for lumbar disc herniation, with
unusually large volumes of herniated disc material noted.
In addition, two other sib lings, one brother and one sister,
had been diagnosed as having lumbar disc herniation and
were treated conservatively. The author noted an early
onset of symptoms, usually in the third decade, which
was not precipitated by trauma. He concluded that the
high proportion of members of this generation affected
could be due to transmission by both branches of the family of a genetic predisposition to premature degeneration
or soft tissue weakness. He also hypothesized that a
defective autosomal-dominant major gene with low penetrance may be responsible for increasing risk among
some persons.
Similarly, Varughese and Quar tey reported on the case
histories of four brothers who had spinal surgery between
27 and 39 years of age for severe le g pain associated with
disc herniation and concomitant spinal stenosis (18).
Both parents reported similar histories of symptoms and
spine surgery. The authors concluded that the familial
aggregation, along with the relatively young ages of the
brothers at the time of their acute radicular symptoms,
suggest that developmental or hereditary factors may
have been responsible for the pathogenesis of spinal
problems in this family.
These observations were followed by sev eral case-control studies of familial aggregation of disc herniation or
“discogenic” low back pain. For example, Postacchini et
al. studied the occurrence of “discogenic” low back pain
in the relatives of patients attending a low back pain
clinic for persistent and recurrent symptoms, patients
who had undergone discectomy for lumbar disc herniation, and individuals with no history of low back pain
(20). They identif ied familial aggregation in families of
discogenic lo w back pain and surgery for herniated discs.
Of the patients with discogenic low back pain and discectomy, 35% and 37%, respectivel y, had first-degree relatives with a history of discogenic low back pain. Five
percent of patients with discogenic pain and 10% of those
with discectomy had first-degree relatives who had
undergone disc surgery. In comparison, only 12% of subjects without a history of back pain problems had relatives with discogenic low back pain and 1% had relatives
with discectomy (20).
In one other case-control study, Simmons et al. investigated the family histories of back problems in first- and
second-degree relatives of 65 patients who underwent
surgery for “degenerative disc disease,” as compared to
67 controls who had undergone orthopedic surgery for
nonspine-related problems (21). Patients who had undergone spine surgery were 2.4 times more likely to have a
positive family history of recurrent, incapacitating low
back pain as those in the control group. In the spine
surgery group, 18.5% of the relatives had a history of
having spinal surgery, as compared with only 4.5% of the
control group, yielding an odds ratio of 4.8 (21).
Richardson et al. noted methodologic limitations in
earlier investigations of familial aggregation of discrelated low back problems, including unknown reliability
CHAPTER 8/GENETIC TRANSMISSION OF COMMON SPINAL DISORDERS / 101
of questionnaires to identify “discogenic” low back pain,
overly exclusive control group criteria, and failure to control for potentially confounding extrinsic factors (22).
They attempted to address these methodologic issues in a
study of symptoms of lumbar disc herniation in the
immediate relatives of 38 patients with disc herniation
confir med at surgery and 50 control subjects with upper
extremity disorders. Although the numbers of subjects
were relatively small and response rates limited, subjects
with disc herniation confirmed at surgery were 16.5
times more likely to have a family history of symptoms
of disc herniation as compared to the control subjects.
Matsui et al. assessed disc degeneration and herniation
in 24 subjects with a history of disabling low back pain or
unilateral leg pain who sought medical care and who also
had immediate relatives who had undergone surgery for
disc herniation (23). The frequency and extent of degenerative changes were then compared to those of 72 ageand sex-matched controls with a similar symptom history,
but without a family history of disc surgery. The grade of
disc degeneration according to magnetic resonance imaging (MRI) signal intensity was significantly more severe,
and the incidence of lower lumbar herniation/bulging was
higher in cases with a family history of disc surgery compared to controls. These findings led the authors to speculate that a familial predisposition for disc herniation may
be an expression of disc degeneration (23).
Collectively, the observations and studies of familial
aggregation make a convincing case that intervertebral
disc herniations for which care is sought in juveniles and
adults are indeed influenced by familial factors. The studies do not, however, provide data on the relative contributions of genetic and shared environmental factors and
their complex interactions.
Classic Twin Studies of Disc Herniation and Sciatica
Classic twin studies comparing concordance of findings within monozygotic and dizygotic twin pairs provide
a methodologic strategy for disentangling genetic and
shared environmental influences. Heikkilä et al. conducted such a study of sciatica and hospitalization for
disc herniation by comparing pair-wise concordance of
monozygotic and dizygotic twins (24). The data from this
Finnish study are valuable in that both self-report and
hospital data are availab le, co v ering mild cases, w hich are
less reliably reported, and generally more severe cases,
which are more reliabl y categorized but more selected. In
addition, the series was large (more than 9,000 same-sex
twin pairs) and representative. Heritability estimates w ere
21% for sciatica and 11% for associated hospitalizations.
The difference in the observed versus expected incidence
of sciatica between monozygotic and dizygotic pairs
decreased with increasing age. Thus, genetic influences
were more significant in persons under 40 years of age.
This finding is consistent with the literature, which indi-
cates that stronger genetic effects are associated with an
earlier onset of disease (5). The apparently greater genetic influence in younger subjects may be due, in part,
however, to a higher rate of misclassification caused by
forgetfulness that occurs with advancing age.
Direct Genetic Evidence for Disc Herniation and
Sciatica
Two collagen IX alleles have been recently identif ied
to be associated with sciatica and lumbar disc herniation,
confirming the role of genetics in spinal disorders. A
study from 1999 reported that a tryptophan allele (Trp2)
in the human COL9A2 gene was associated with sciatica,
although it was present only in about 4% of the patients
(25). There was also a trend for increased prevalence of
radial tears in nonherniated discs among the Trp2
allele–positive subjects (3 of 6 patients with sciatica and
3 of 11 family members) (26). More recently it was discovered that 12.2% of patients with sciatica had a Trp3
allele in the COL9A3 compared with 4.7% among controls (27). Ala-Kokko has concluded from these f indings
that disc disease is not one entity, but instead is likely to
consist of several related phenotypes (3).
LUMBAR DISC DEGENERATION
It is of little surprise that the size and shape of spinal
structures in family members are more similar than in
unrelated individuals. The reports of twin pairs that
demonstrate similarities in spinal and other skeletal morphology simply provide confirmatory evidence (11,
28–31). Such similarities have been amply demonstrated
for other anthropometrics, such as height and dental
structure (16,32). Of greater interest is the possibility that
degenerative changes commonly attributed primarily to
environmental factors may be, in part, a function of
genetic predisposition, and that this influence may be
substantial. Disc degeneration is of interest because it is
believed to be a factor in the pathogenesis of disc herniation and may play a contributory role in back symptoms.
Familial Aggregation of Disc Degeneration
We presented evidence of substantial familial aggregation of disc degeneration in terms of extent and location
of changes in two earlier studies of monozygotic twins
published in 1995 (33,34). The f irst study assessed the
degree of similarities in degenerative findings by spinal
level in the lumbar discs of 20 pairs of monozygotic twins
from 36 to 60 years of age, relative to what would be
expected by chance based on the prevalence of the f indings by lev el among all 40 subjects (33). The MRI assessments were conducted blinded to twinship and revealed a
higher degree of twin similarities than would be expected
by chance. Only 15% of the variance in disc bulging/her-
102 /SECTION I/BASIC SCIENCE
niation was explained by age and smoking, but the variance explained rose to 54% with the addition of a variable
representing familial aggregation in the L1-L4 discs.
Approximately 26% of the variance was explained by
familial aggregation in the L4-5 and L5-S1 levels. These
results suggested a substantial familial influence on lumbar disc degeneration and warranted further investigation.
In a later study spine MR images of 115 pairs of male
identical twins were assessed blinded to twinship and
exposure history to estimate the effects of commonly suspected risk factors on disc degeneration, as determined
from signal intensity, bulging, and height narrowing, relative to the effects of age and familial agg regation (34).
In the multivariable analysis of the T12-L4 region, occupational physical loading conditions explained 7% of the
variance in disc degeneration scores among the 230 subjects; this rose to 16% with the addition of age and to
77% with the addition of a variable representing familial
aggregation. In the L4-5 and L5-S1 region, leisure-time
physical loading was the only behavioral or environmental factor investigated that entered the multivariate model
and it explained only 2% of the variance in disc degeneration summary scores. The portion of the variance in
lower lumbar disc degeneration scores explained rose to
9% with the addition of age and to 43% with the addition
of familial aggregation. Examples of spine MR images
from three pairs of twin siblings from this study cohort
are provided in Figure 8-1.
Significantly more of the variance in degeneration
remained unexplained in the lower lumbar region, as
compared to the upper lumbar region. This discrepancy
could be due to environmental conditions, which are
likely mechanical in nature, and interact with spinal
anthropometrics in such a way as to have a disproportional effect on the lo w er lumbar le vels. However, the factors involved are not simply a function of the magnitude
A
FIG. 8-1. Examples of spine magnetic resonance
images of three pairs of male, monozygotic twin siblings from the Finnish Twin Cohort. A: 64-year-old
sales managers. Both twins have similar disc
changes at the two lower lumbar levels. B: 49-year-
old product packager/taxi driver. Both twins have
severe disc degeneration at the L5-S1 levels with
end-plate irregularities, and both have posterior
bulges at the L4-5 level. C: 56-year-old office
worker/truck driver .The twins have very similar upper
B
end-plate irregularities.
C