Review

Current therapeutic options in the

management of diffuse idiopathic
skeletal hyperostosis
1. Introduction Reuven Mader
Ha’Emek Medical Center, Rheumatic Diseases Unit, Afula 18101, Israel, and Israeli Institute of
2. Therapeutic goals and
Technology, B. Rappaport Faculty of Medicine, The Technion, Haifa, Israel
limitations
3. Therapeutic interventions Diffuse idiopathic skeletal hyperostosis (DISH) is a condition characterised by
4. Expert opinion and conclusions calcification and ossification of soft tissues, mainly ligaments and enthesis.
Although DISH often coexists with osteoarthritis, this disorder differs from
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Otago on 01/13/15

primary osteoarthritis by a dissimilar prevalence within the general popula-

tion, gender distribution, anatomical site of primary involvement and magni-
tude and distribution in the spine and the peripheral joints. Little is known
about the pathogenesis of the disease and possible therapeutic interven-
tions. Treatment should be aimed at the symptomatic relief of pain and stiff-
ness; the prevention, retardation or arrest of progression; the treatment of
associated metabolic disorders and the prevention of spontaneous or
induced complications. Change of lifestyle, nutrition and therapeutic options
to alleviate pain and stiffness are measures that might improve quality of life
in patients affected by DISH. Control of associated metabolic disorders such
as hypertension, hyperinsulinaemia with or without hyperglycaemia, hyperli-
For personal use only.

pidaemia and hyperuricaemia may reduce the morbidities associated with

these disorders and prevent further progression of the condition. Recent
developments in our understanding of the molecular basis of the ligamen-
tous and entheseal changes that lead to the development of DISH might pave
the way to future, more targeted and effective therapies.

Expert Opin. Pharmacother. (2005) 6(8):1313-1318

1. Introduction

Diffuse idiopathic skeletal hyperostosis (DISH) is a condition characterised by calci-

fication and ossification of soft tissues, mainly ligaments and enthesis. This condi-
tion was described by Forestier and Rotes-Querol > 50 years ago [1], and was termed
senile ankylosing hyperostosis. There is a marked predilection to the axial skeleton,
particularly the thoracic spine. However, recognition that the condition is not lim-
ited to the spine, and may involve peripheral joints, led researchers to coin the name
DISH, a term now widely used [2].
The disease is characterised by the production of flowing osteophytes involving,
in particular, the right side of the thoracic spine with preservation of the interverte-
bral disk space, and by ossification of the anterior longitudinal ligament. Calcifica-
For reprint orders, please tion and ossification of the posterior longitudinal ligament appear to be additional
contact: skeletal manifestations of DISH [3]. Other entheseal regions in the peripheral joints
[email protected] might be affected, such as the peripatellar ligaments, the Achilles tendon insertion,
plantar fascia and olecranon [4,5].
In the absence of validated diagnostic criteria, the diagnosis is usually based on the
definition suggested by Resnick and Niwayama [5]. This radiographic approach requires
the presence of flowing, coarse osteophytes in the right side of the thoracic spine, con-
Ashley Publications necting at least four contiguous vertebrae, or ossification of the anterior longitudinal lig-
www.ashley-pub.com ament, preserved intervertebral disk height in the involved segment, and the absence of
apophyseal joint ankylosis and sacroiliac joint involvement [5]. In most textbooks, DISH

10.1517/14656566.6.8.1313 © 2005 Ashley Publications Ltd ISSN 1465-6566 1313

 Current therapeutic options in the management of diffuse idiopathic skeletal hyperostosis

of motion in all spinal segments, with the lumbar spine being

Box 1. Therapeutic targets in diffuse idiopathic
most commonly affected, followed by the cervical spine and
skeletal hyperostosis.
the thoracic spine [17-19]. Similar to inflammatory arthritis,
Symptomatic relief of pain and stiffness morning stiffness is present in a significant number of these
Prevent, retard or arrest progression patients [3]. The clinical and radiological appearance of the
Treatment of associated metabolic disorder
Prevent spontaneous complications peripherally involved joints is similar to joints affected by pri-
Prevent induced complications mary OA in terms of pain and stiffness and involves the upper
and lower extremities in similar proportions. However, the
prevalence of OA in patients with DISH is higher than non-
is described as a subgroup of osteoarthritis (OA). A recent review DISH patients, and is associated with the production of more
of the existing literature suggested that DISH, although affiliated hypertropic osteophytes [20]. Spinal stiffness and pain are
to OA, is a distinct clinical entity with somewhat different char- worsened by inactivity, wet or changing weather, and weight
acteristics [6]. In brief: i) predominant involvement of the tho- bearing [17]. There are few reports about remedies for these
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racic spine with preserved intervertebral height is characteristic symptoms, but some on the beneficial effects of light exercise,
for DISH, but not for OA; ii) clinical manifestations similar to, heat, use of analgesics and non-steroidal anti-inflammatory
or identical to, those of OA are prominent features of DISH in agents (NSAIDs) [5,17,19]. Recently, the use of locally acting
the peripheral joints. However, the peripheral joints affected by NSAIDs for the treatment of OA was demonstrated to be as
DISH have features that distinguish them from primary OA. effective as the same product administered orally, suggesting
One is the more frequent involvement of joints that are not usu- that it might also be successfully employed for the sympto-
ally affected in OA, such as metacarpophalangeal joints, elbows matic relief of pain and stiffness in the peripheral joints of
and shoulders [7-10]. Another feature is a more severe hypertropic patients with DISH [21,22]. Overall, it seems reasonable to
disease in the joints affected by DISH [11]; iii) whereas OA invar- assume that most of the treatments employed for the treat-
iably occurs with advanced age, DISH is not as common as OA ment of OA may be useful for the symptomatic relief of both
and more commonly affects males than females [12,13]; iv) the spinal and peripheral manifestations of DISH.
For personal use only.

primary event in DISH is thickening, calcification and/or ossifi- The early changes in spinal DISH, and probably in the
cation of ligaments and entheses. This is evident at the level of peripheral joints, are entheseal new bone formation [23]. Non-
the spine as well as in the peripheral joints [14,15]. Knowledge inflammatory enthesopathy is likely to be the hallmark of
about therapeutic options in DISH is scarce. DISH, not only in the spine, but also in many extraspinal
sites, which may become targets for therapy aiming to avoid,
2. Therapeutic goals and limitations arrest or retard its progress. The most common sites are the
tibial spines, posterior heal, superior patella, olecranon and
Treatment of DISH should address several issues. It is shoulder [14,20]. The enthesopathies are not necessarily symp-
expected to alleviate pain and stiffness; prevent, retard or tomatic, but may contribute to the more severe osteoarthritic
arrest progression; correct the associated metabolic disorders; changes due to stiffening of the joint capsule. Treatment
and prevent spontaneous or induced complications (Box 1). might be necessary in order to alleviate local pain and swell-
Specific therapeutic interventions in DISH have not been sys- ing. This can be achieved by local soft applications, such as
tematically explored. This is probably related to the inclusion of insoles for plantar spurs or protective bandages at other sites.
DISH in the spectrum of OA, and the assumption that the same Local infiltration of local anaesthetic and long-acting corticos-
therapeutic interventions for OA are suitable for DISH. Yet, it teroids might offer, at least temporary, relief in severely
was estimated that a period of at least 10 years is needed for the symptomatic cases. When multiple sites are involved, the
pathological process to evolve completely [16]; this notion implies same therapeutic modalities mentioned for the arthropathy
that a long observation period is required in longitudinal studies may be used.
in order to demonstrate that any therapeutic intervention might Several metabolic and constitutional factors, such as obes-
prevent the development of the disease, or hopefully reverse the ity, high waist circumference ratio, hypertension, diabetes
pathological changes. This review focuses on the therapeutic mellitus, hyperinsulinaemia, dyslipidaemia, elevated growth
options for the treatment of DISH based on the clinical manifes- hormone levels, insulin like growth factor-1 and hyperuricae-
tations, associated comorbidities, the possible pathogenetic mia, have all been reported to be associated with DISH [24-27].
mechanisms that lead to the development of the disease, and Some of these abnormalities are inter-related and may coexist
prevention of complications. in the same patient. Generally speaking, there is no doubt that
the coexistence of many cardiovascular risk factors pose
3. Therapeutic interventions patients with DISH at a higher risk for cardiovascular events.
It seems appropriate to screen these patients for known cardi-
The clinical manifestations of DISH may be related to spinal, ovascular risk factors, and as necessary, to correct them. Gen-
peripheral joint and soft tissue involvement. Spinal eral measures, such as weight reduction, adequate physical
involvement is often associated with pain and decreased range activity, low saturated fat and reduced carbohydrate intake,

1314 Expert Opin. Pharmacother. (2005) 6(8)

 Mader

General measures Symptomatic

therapy

Local heat
Physical activity
Protection of enthesopathic sites (insoles, bandages)
Weight loss
Analgesics
Low carbohydrate and saturated fat diet
NSAIDs
Avoid falls
Locally acting NSAIDs
Avoid aspiration
Local anaesthetic/corticosteroid injections
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Correction of metabolic abnormalities

Control of hyperglycaemia and/or hyperinsulinaemia, preferably by biguanides

Control of hyperuricaemia
Control of hypertension (ACE inhibitors, Ca2+ channel blockers and α-blockers
should be preferred to thiazide diuretics and β-blockers)
For personal use only.

Prevention of complications Future perspectives (?)

Extra precaution in patients undergoing endotracheal

Interventions at the molecular level to inhibit factors that
intubation or upper GI endoscopy
might promote mesenchymal differentiation to osteoblasts:
Prevention of heterotropic ossification following orthopaedic
NFκB, PDGF-BB, TGF-β1, PGI2, BMP-2
surgeries: antivitamin K, NSAIDs, irradiation

Figure 1. Therapeutic options in DISH.

ACE: Angiotensin converting enzyme; BMP-2: Bone morphogenic protein-2; NFκ-B: Nuclear factor-κB; NSAIDs: Non-steroidal anti-inflammatory drugs;
PDGF-BB: Platelet-derived growth factor-BB; PGI2: Prostaglandin I2; TGF-β1: Transforming growth factor-β1.

might all be important in preventing or arresting the progres- advantage over the use of sulfanylureas that increase insulin
sion of DISH. Some of these factors may have pathogenetic secretion. When coexisting hypertension is treated, the choice
implications and may, therefore, become therapeutic targets. of medications that might improve insulin resistance, such as
Hyperinsulinaemia has a profound effect on ligaments and angiotensin-converting enzyme inhibitors, Ca2+ channel
entheses, which is independent of age and obesity. The differ- blockers and α-blockers, should be preferred to medications
entiation of mesenchymal cells in ligaments into chondrocytes that might worsen insulin resistance, such as thiazide diuretics
and the subsequent enchondral ossification is promoted by and β-blockers [30].
insulin [28]. The enthesis provides the growth plate for tendons The enthesis may be under the influence of other growth
and ligaments in children and persists into adulthood. This promoting peptides. Elevated growth hormone (GH) levels
particular structure is composed of collagen fibres, fibroblasts, were reported in DISH. This hormone is capable of inducing
chondrocytes and calcified matrix, which is probably a target osteoblast cell proliferation, and may promote local produc-
for the ossification process promoted by insulin [29]. tion of insulin-like growth factor-1 (IGF-1), which in turn
Therapeutic interventions should aim at a reduction of can stimulate alkaline phosphatase activity in osteoblasts
insulin secretion and insulin resistance. In patients with non- [25,31,32]. There is no explanation, as yet, to why the new bone
insulin-dependent diabetes mellitus (NIDDM), the use of formation is mainly localised at the ligamentous and
biguanides that induce a better usage of insulin may offer an entheseal sites. However, it was suggested that, at least in the

Expert Opin. Pharmacother. (2005) 6(8) 1315

 Current therapeutic options in the management of diffuse idiopathic skeletal hyperostosis

spine, vertebral blood supply could be a factor in the onset DISH can avoid or minimise damage to the cervical spine or
or progression of DISH [33]. Intra-erythrocyte GH levels to soft tissues in patients who might need certain diagnostic
may exceed serum GH levels and could, therefore, be trans- or therapeutic interventions, such as upper gastrointestinal
ported to the vertebral site by the mechanism described ear- endoscopy or endotracheal intubation. Another preventable
lier [34]. While a therapeutic approach aiming at suppression complication, which might involve all spinal segments, is frac-
of GH secretion is unlikely, a targeted approach at the tures of the spine after minor trauma [43,44]. These fractures
vascular level might be feasible. tend to be unrecognised, unstable and associated with treat-
In recent years, a great interest in the molecular basis for ment delays and permanent neurological deficits. It is, there-
ossification of ligaments has emerged. Nuclear factor-κB fore, important to recognise these complications in order to
(NF-κB) is capable of regulating the differentiation of multi- offer a prompt therapeutic intervention, as well as adopting
potential cells, including the osteoblastic differentiation of the common measures to prevent falls and trauma, especially
undifferentiated ligamentous mesenchymal cells. It was in the elderly population. Heterotropic ossification following
shown that in patients with DISH, NF-κB is activated by orthopaedic surgeries, in particular hip arthroplasty, is com-
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Otago on 01/13/15

environmental stimuli that are partly promoted by the plate- mon among patients with DISH [45]. Several therapeutic
let-derived growth factor-BB and transforming growth interventions aiming to abolish the heterotropic ossification,
factor-β1 [35]. Other factors that may stimulate differentia- such as administration of NSAIDs, antivitamin K and irradia-
tion of ligamentous mesenchymal stem cells into osteoblasts, tion, have all been reported with variable success [46-49].
such as bone morphogenetic protein-2 and prostaglandin I2, Therefore, those with a high risk of developing this complica-
were described in ossified ligaments [36,37]. Therefore, in the tion, such as patients with DISH, should be considered candi-
future, these factors may become targets for specific thera- dates for one of these regimens. The therapeutic options are
peutic interventions. It is of note that some of these osteob- summarised in Figure 1.
lastic promoting factors were reported to be increased in
NIDDM and, therefore, may represent the molecular link 4. Expert opinion and conclusions
between the previously described associations between
For personal use only.

NIDDM and DISH [38,39]. Although DISH might contribute to the generation of OA,
The role played by administration of retinoid in the patho- or worsen primary OA, it should be regarded as a separate
genesis of DISH is controversial [40]. However, it was suggested, clinical entity with different prevalence, joint distribution,
that spinal hyperostotic changes, indistinguishable from those gender distribution and pathogenetic mechanisms. Its
seen in DISH, might emerge during treatment with retinoids. recognition as a distinct clinical entity will stimulate a
These changes usually affect patients < 45 years of age, and are more targeted research and, hopefully, better solutions
likely to be more common in patients treated with larger doses based on a true understanding of the pathogenetic mecha-
and for prolonged periods of time. Therefore, it is prudent to nisms underlying this common, yet under-recognised,
monitor musculoskeletal manifestations carefully in patients disease. At present, our knowledge enables us to offer
treated with retinoids and, whenever possible, reduce the doses empirical therapies based on the commonly employed
and the duration of therapy [41]. practices for the treatment of degenerative and metabolic
Reference should also be made to preventable or treatable joint diseases, rather than on a profound understanding of
complications of DISH. The manifestations and complica- the pathogenetic processes in DISH. In recent years,
tions of DISH of the cervical spine have been recently important steps toward better understanding of the
reviewed [42]. Although some of the manifestations constitute molecular processes that lead to calcification and
an integral part of the condition, some complications can be ossification of entheses and ligaments have emerged. These
avoided if taken into consideration. Aspiration pneumonia early, and still scarce, investigations will hopefully pave the
can be partially avoided if instructions for correct deglutition way to more targeted therapies, that will be able, not only
and preservation of an upright position after meals are to treat the signs and symptoms of this condition, but also
carefully explained to the patient. Physicians familiar with to change its course.

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Affiliation
derived growth factor-beta receptor by high Reuven Mader1,2
45. BELANGER TA, ROWE DE: Diffuse 1Ha’Emek Medical Center, Rheumatic Diseases
glucose. Involvement of platelet-derived
idiopathic skeletal hyperostosis: Unit, Afula 18101, Israel
growth factor in diabetic angiopathy.
musculoskeletal manifestations. J. Am. Tel: + 972 46 49 43 54;
Diabetes (1996) 45:507-512.
Acad. Orthop. Surg. (2001) 9:258-267. Fax: + 972 46 49 44 53;
For personal use only.

40. DOOREN-GREEBE RJV,

46. CELLA JP, SALVATI EA, SCULCO TP: E-mail: [email protected]
LEMMENS JAM, BOO TD, HANGX 2Israeli Institute of Technology, B. Rappaport
Indomethacin for the prevention of
NMA, KUIJPERS ALA, VAN DE
heterotropic ossification following total hip Faculty of Medicine, The Technion, Haifa, Israel
KERKHOF PCM: Prolonged treatment
arthroplasty. Effectiveness,
with oral retinoids in adults: no influence
contraindications, and adverse effects.
on the frequency and severity of spinal
J. Arthroplasty (1988) 3:229-234.

1318 Expert Opin. Pharmacother. (2005) 6(8)