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New developments in our understanding of DISH

(diffuse idiopathic skeletal hyperostosis)


Piercarlo Sarzi-Puttini and Fabiola Atzeni
Purpose of review
Diffuse idiopathic skeletal hyperostosis (DISH) or Forestiers
disease is a common disorder among older adults. The
diagnosis is based solely on radiographic abnormalities
defined using the Resnick criteria. DISH is characterized by
ossification of the anterior longitudinal ligament of the spine
and various extraspinal ligaments. DISH often coexists with
OA, but patients affected by this disorder differ from patients
with primary OA in several aspects: prevalence in the general
population, gender distribution, anatomic site of primary
involvement, magnitude and distribution in the spine and the
peripheral joints. Purpose of this review is to summarize new
clinical, pathogenetic and therapeutic insights of this disease.
Recent findings
Recent studies confirm that patients with DISH have a greater
body mass index, higher serum uric acid levels and are more
likely to have diabetes mellitus. In addition, DISH is most
probably related to abnormal bone cell growth/activity
reflecting the influence of metabolic factors that lead to new
bone formation. Serum matrix Gla protein may be a marker of
osteometabolic syndromes, such as DISH, that cause
hyperostosis.
Summary
Many recent developments of DISH are described in this
review. Possible pathogenetic mechanism driving bone
deposition are discussed. DISH is still recognized
radiographically; no specific drug has been yet identified.
Keywords
diffuse idiopathic skeletal hyperostosis, ossification of
posterior longitudinal ligament, ossification of ligamentum
flavum, matrix Gla protein, Forestiers disease
Curr Opin Rheumatol 16:287292. 2004 Lippincott Williams & Wilkins.
Rheumatology Unit, University Hospital L Sacco, Via GB Grassi 64,
20157 Milano, Italy
Correspondence to: Piercarlo Sarzi-Puttini, MD, Rheumatology Unit, University
Hospital L Sacco, Via GB Grassi, 74, 20157 Milano, Italy
E-mail: sarzi@tiscali.it
Current Opinion in Rheumatology 2004, 16:287292
Abbreviations
DISH
OPLL
OLF
IGF-I
PGI2
MGP
CT
MR

diffuse idiopathic skeletal hyperostosis


ossification of posterior longitudinal ligament
ossification of ligamentum flavum
insulin-like growth factor I
prostaglandin- I2
matrix Gla protein
conventional tomography
magnetic risonance

2004 Lippincott Williams & Wilkins


10408711

Introduction
Diffuse idiopathic skeletal hyperostosis (DISH) is a skeletal disease characterized by the ligamentous ossification
of the anterolateral spine that was first described by Forestier and RotesQuerol [1] more than 50 years ago. It is
often classified as a form of osteoarthritis but, although it
often coexists with osteoarthritis, there are a number of
differences between the two diseases: their prevalence
in the general population, gender distribution, anatomic
site of primary involvement, and their entity and distribution in the spine and peripheral joints. DISH is therefore a distinct clinical entity [2].

Clinical and radiologic findings


DISH is characterized by the calcification and ossification of soft tissues, particularly ligaments and entheses
[3]. It has a marked predilection for the axial skeleton
(particularly the thoracic spine), but it may also involve
peripheral joints. It leads to the ossification of the anterior longitudinal ligament of the spine and causes the
production of flowing osteophytes that particularly involve the right side of the spine while preserving the
intervertebral disc space [4]. Other entheseal regions in
the peripheral joints may be affected, including the peripatellar ligaments, the Achilles tendon insertion, the
plantar fascia, olecranon, and others [5]. Diagnosis is
based solely on radiographic abnormalities defined using
the criteria of Resnick and Niwayama [6].

Spinal involvement
The portion of the spine that is classically involved in
DISH is the thoracic spine [7]. Its most common clinical
presentation is stiffness and a decreased range of spinal
motion, and there be mild pain if ankylosis has occurred.
The condition is recognized radiographically by the presence of flowing ossification along the anterolateral
margins of at least four contiguous vertebrae and the
absence of the changes associated with spondyloarthropathy or degenerative spondylosis [4]. Even in patients presenting with lumbar or cervical complaints, the
radiographic findings are almost always seen on the right
side of the thoracic spine. The ossification is not always
localized to the anterior longitudinal ligament, but is
sometimes more extensive [8]. DISH is frequently associated with OPLL and ossification of the ligamentum
flavum, but the distribution of the ossifications show a
clear trend: DISH in the thoracolumbar spine, OPLL in
287

288 Crystal deposition diseases


Table 1. Types of ligamentous ossification
Ankylosing spondylitis

Reiters syndrome and


psoriatic arthritis

DISH
OPPL
OLF

Syndesmophyte ossification of the outer


layer of the anulus fibrosus of the disk
(Sharpeys fibres) and the deep layers of
the longitudinal ligaments.
Syndesmophytes are thin and succinct,
and ascend the spine in a symmetrical
fashion to produce a bamboo appearance
Syndesmophytes are asymmetrical and do
not usually have this ascending order of
formation. These syndesmophytes start
from the middle of one vertebral body and
extend to the same area of the adjacent
vertebral body
Hyperostosis affecting the anterior
longitudinal ligament
Ossification of the posterior longitudinal
ligament
Ossification of the ligamentum flavum

the cervical spine, and ossification of the ligamentum


flavum in the lower spine [8,9] (Table 1).
The potential sequelae of hyperostosis in the cervical
and lumbar spine include lumbar stenosis, dysphagia,
cervical myelopathy, and dense spinal cord injury resulting from even minor traumas [10,11,12,13,14].
In older patients, osteophyte compression resulting from
DISH [12] or cervical spondylosis may cause dysphagia
because cervicodorsal spine radiographs reveal large anterior osteophytes creating pharyngeal encroachment.
There may be a delay in the diagnosis of spinal fractures
in DISH patients because they often have a baseline
level of spinal pain and the injury may be relatively
trivial. The incidence of delayed neurologic injury resulting from such fractures is high as a result of the unrecognized instability and subsequent deterioration
[10,14].

Peripheral joint involvement


The peripheral joints most frequently involved are the
metacarpophalangeal joints, elbows, and shoulders
[15,16], which are characteristically affected by severe
hypertrophy attributed to a thickening of their collateral
ligaments that constrain movement. The primary event
in DISH is the thickening, calcification, and/or ossification of ligaments and entheses. Enthesopathy is common
[17,18], and the radiographic appearance of peripatellar
cruciate ligament insertion and pericapsular osseous enthesopathies are just some examples of the contribution
of DISH to the stiffening of the soft tissue surrounding
a joint.

Prevalence and risk factors for diffuse


idiopathic skeletal hyperostosis
DISH is more common in people older than 50 years. Its
reported prevalence varies: It has been said to be slightly
more than 10% in subjects older than 70 years [19,20],
but other studies of different populations have found a

prevalence in men and women older than 50 years of


25% and 15% respectively, and 35% and 26% respectively in those older than 70 years [21]. However,
throughout life, the disease is more common and more
severe in men than in women [19].
The etiology of the condition remains unknown, but a
number of risk factors have been implicated on the basis
of its frequent association with various metabolic conditions, including hyperinsulinemia with or without diabetes mellitus, obesity, hyperuricemia, dyslipidemia, hypertension, coronary artery disease, and the prolonged
use of isoretinol [2225].

Etiopathogenesis
DISH is a common disorder of unknown etiology, although genetic, metabolic, endocrinologic, anatomic, environmental, and toxic factors have all been suggested as
playing a possible pathogenetic role in the new bone
growth characterizing it (Fig. 1).
Studies of human leukocyte antigen factors have led to
conflicting results [26]. There are published reports that
the thoracic spine is more frequently involved, but the
ligament ossification requires the two preexisting components of disuse related to vertebral immobility and
rarefaction of the adjacent bone [6,27]. Furthermore,
Smith et al. [28] suggested that immobilization may increase the likelihood of dedifferentiated connective tissue being transformed into bone. Resnick and Niwayama found that thoracic abnormalities were more
frequent in the 7th to 10th thoracic vertebrae, and also
noted a lower incidence in the upper thoracic vertebrae
[6]. On the basis of anatomic comparisons of the lower
and upper thoracic vertebrae, the cartilage of the lower
five ribs does not join the sternum. Because this contributes to making the lower thoracic vertebrae freer and
more movable (especially in flexion and extension), the
theory of thoracic spine immobility as a predisposing factor for DISH seems unlikely. Furthermore, it does not
explain the involvement of DISH in the lumbar and
cervical spine or extraspinal sites.
One pathologic study found a significant increase in the
number and width of the nutrient foramina (which indicates hypervascularity of the involved ossified ligaments
and vertebrae), and a significant increase in the size
of the affected vertebrae. This suggests that a vascular
disorder may be involved in the pathogenesis of the disease [29].
Metabolic disorders such as obesity, hyperlipidemia, diabetes mellitus, and hypertension are frequent in patients
with DISH [22].
How is the process initiated and what is the link between
these metabolic disorders and new bone formation? The
ossification process starts in the innermost layer of the
anterior longitudinal ligament, at the site of its attachment to the vertebral body, and then extends to meet the

Diffuse idiopathic skeletal hyperostosis SarziPuttini and Atzeni 289


Figure 1. Possible pathogenetic mechanism driving bone deposition

other arm of ossification coming from the vertebra above


and/or below. It is believed that this new formation is the
result of abnormal osteoblast cell growth/activity in the
bonyligamentous region, which may be a clue to the
pathogenesis of DISH [29]. The growth of osteoblasts is
maintained by a number of growth factors that may not
be confined to bone [30]. It has been found that insulinlike growth factor-I stimulates alkaline phosphatase
activity and type II collagen in osteoblasts [31], and that
growth hormone can induce the local production of insulinlike growth factor-I and insulinlike growth factorbinding proteins in chondrocytes and osteoblasts. Denko
et al. [32] found that DISH patients had high insulin and
growth hormone levels, which may explain the osteoblast cell growth/proliferation. Because the ossification
starts in certain sites, El Miendany et al. [29] suggested
that hypervascularity could be the localizing factor in the
process. Furthermore, in predisposed patients with hyperlipidemia, diabetes mellitus, or (possibly) hyperinsulinemia, there is an increased likelihood of atherosclerosis, the earliest stages of which leads to endothelial
damage and the aggregation of blood platelet-derived
growth factor, with the end result of osteoblast proliferation [30].

The pathogenesis of OPLL is still unclear, but some


etiologic factors have been identified. High serum levels
of retinol and retinol-binding protein have been observed in DISH patients [33], which suggests that vitamin A may play a role in the development of OPLL.
Kosaka et al. [34] indicate the possibility that, after being
stimulated by environmental factors involving plateletderived growth factor-BB and transforming growth factor-1 in ligament cells, nuclear factor B influences the
osteoblastic differentiation of undifferentiated mesenchymal cells.
Ohishi et al. [35] suggested that mechanical stress on
the posterior ligaments is an important factor in the progression of OPLL. They found that uniaxial cyclic
stretching enhances the expression of prostaglandin-I2
(PGI2) synthase and the production of PGI2, which interacts with a specific G protein-coupled cell surface receptor known as IP, and the PGI2/cAMP system activates osteogenic differentiation probably in spinal
ligament cells.
Matrix Gla protein (MGP) is a member of the family of
extracellular mineral-binding Gla proteins expressed in

290 Crystal deposition diseases

several tissues with a high accumulation of bone and


cartilage [36]. Although its precise molecular mechanism of action remains unknown, all the available data
indicate that it plays a role in inhibiting mineralization by
suppressing bone morphogenetic protein-2 (BMP-2), a
potent osteogenic factor [3739,40]. The function of
human MGP is mediated by vitamin K-dependent -carboxylation of MGP glutamate residues, and the expression of the MGP gene depends on growth factor
[41,42]. SarziPuttini et al. [43] found higher serum
MGP concentrations in male and female DISH patients
than in healthy control subjects (5.7 nmol/L vs 3.3
nmol/L, P < 0.001), and concluded that MGP may be a
marker of hyperostosis because it is produced in larger
amounts by patients with hyperostosis-inducing osteometabolic syndromes such as DISH.
In conclusion, DISH is a widespread systemic condition
that is most probably related to abnormal bone
growth/activity reflecting the influence of the metabolic,
environmental, genetic, and endocrinologic factors that
lead to new bone deposition. Vertebral blood supply is a
predisposing factor that contributes to the onset, progression, and/or localization of DISH. MGP deficiency or
altered carboxylation causes a high level of BMP-2 activity that leads to hyperostosis.

Diagnosis
DISH is recognized radiographically by the presence of
flowing ossification along the anterolateral margins of
at least four contiguous vertebrae, and the absence of the
changes characterizing spondyloarthropathy or degenerative spondylosis. Its diagnosis is based solely on the radiographic criteria defined by Resnick and Niwayama [6]
(Table 2).
The flowing paravertebral ossification is mainly located
in the region of the anterior longitudinal ligament, but
the extent of the ossification is usually wider. A lucent
cleavage between the ossification and the vertebral body
is considered to be a characteristic that helps to differentiate the ossification from osteophytes [44].
Although conventional radiography clearly confirms the
diagnosis of DISH, CT and MRI are more capable of
Table 2. Resnicks diagnostic criteria [6]
1) Presence of flowing calcification and ossification along the
anterolateral aspects of at least four contiguous vertebral bodies
with or without associated localised pointed excrescences at the
intervening vertebral body-disc junctions
2) A relative preservation of intervertebral disc height in the involved
vertebral segments and the absence of extensive radiographic
changes of degenerative disc disease, including vacuum
phenomena and vertebral body marginal sclerosis
3) Absence of apophyseal joint bony ankylosis and sacro-iliac joint
erosion, sclerosis or bony fusion.

detecting associated findings (eg, OPLL) and complications (eg, spinal cord compressive myelomalacia).
OPLL is readily demonstrated by lateral radiography [8],
but because of the presence of overlying osseous structures, CT is occasionally indicated for the purposes of
confirmation, and MRI can demonstrate a narrowing of
the spinal cord even though the ossification itself is not
clear. MRI can occasionally confirm ossification when
OPLL contains fatty bone marrow [45], and it can detect
the ligament hypertrophy that is an early change in
OPLL.
The ankylosed vertebrae seen in DISH patients are vulnerable to trauma [46], but the radiologic findings of
fractures and dislocations are often subtle, and MRI is
often indicated to confirm the level of spinal cord injury.
Scintigraphy is suitable for the early detection of abnormalities with unclear clinical symptoms, and may indicate the correct level of the cervical spine for MRI or CT
[47].

Treatment
Very little has been published concerning the pharmacologic or nonpharmacologic management of DISH patients, who often complain of pain and a limited range of
motion. Because no specific drug has yet been identified,
simple analgesics or nonsteroidal antiinflammatory drugs
are usually prescribed.
A recent paper described a patient who underwent chiropractic manipulation and drop-table adjustments, together with range-of-motion, extension, and standing
lumbar extension traction exercises. These improved
flexibility and daily living activities, and the effect was
maintained for 19 months after the end of the active
rehabilitation treatment period [48].
Mears [49] reported a case of an elderly woman whose
low back pain and Forestier disease were markedly improved by acupuncture, whereas other treatments had
been ineffective.
Price et al. [50] described the discovery of a fetuin
MGPmineral complex in the serum of rats treated with
bone-active bisphosphonate etidronate and showed that
this correlates with etidronate-induced inhibition of
bone mineralization. This finding may indicate a possible new treatment for DISH patients [51,52].
The failure of conservative care often leaves surgery as
the only option. Dysphagia is rare in Forestier disease
and hence often goes unrecognized [53]. Most dysphagic
patients are initially treated conservatively and later by
means of the excision of osteophytes through the lateral
cervical or perioraltranspharyngeal route [54].

Diffuse idiopathic skeletal hyperostosis SarziPuttini and Atzeni 291


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Conclusion
In conclusion, DISH is a widespread systemic condition
that is most probably related to abnormal bone
growth/activity reflecting the influence of various metabolic, environmental, genetic, and endocrinologic factors
that lead to new bone deposition. Vertebral blood supply
is a predisposing factor contributing to the onset, progression, and/or localization of DISH. MGP probably
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Of special interest
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