The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019

Metabolic Factors in Diffuse Idiopathic Skeletal Hyperostosis – A Review of Clinical Data



Sruti Pillai , Geoffrey Littlejohn*
Departments of Rheumatology and Medicine, Monash Health and Monash University, 246 Clayton Road, Clayton, Victoria, 3168, Australia

Abstract

Objectives:

We aimed to review the literature linking metabolic factors to Diffuse Idiopathic Skeletal Hyperostosis (DISH), in order to assess associations between growth factors and DISH.

Method:

We identified studies in our personal database and PubMed using the following keywords in various combinations: “diffuse idiopathic skeletal hyperostosis”, “ankylosing hyperostosis”, “Forestier’s disease”, “diabetes”, “insulin”, “obesity”, “metabolic”, “growth factors”, “adipokines”, “glucose tolerance” and “chondrocytes”.

Results:

We were not able to do a systematic review due to variability in methodology of studies. We found positive associations between obesity (especially abdominal obesity), Type 2 diabetes mellitus, glucose intolerance, hyperinsulinemia and DISH.

Conclusion:

Current research indicates that certain metabolic factors associate with DISH. More precise studies deriving from these findings on these and other newly identified bone-growth factors are needed.

Keywords: Bone, diabetes, DISH, diffuse idiopathic skeletal hyperostosis, growth factors, insulin, metabolic, obesity..


Article Information


Identifiers and Pagination:

Year: 2014
Volume: 8
First Page: 116
Last Page: 128
Publisher Id: TORJ-8-116
DOI: 10.2174/1874312901408010116

Article History:

Received Date: 24/4/2014
Revision Received Date: 21/10/2014
Acceptance Date: 8/11/2014
Electronic publication date: 19 /12/2014
Collection year: 2014

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© Pillai and Littlejohn; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Suite H, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, 3168, Australia; Tel: 613 95942575; Fax: 613 95945588; E-mail: geoff.littlejohn@monash.edu




INTRODUCTION

Diffuse idiopathic skeletal hyperostosis (DISH) is a common skeletal disorder characterised by the presence of new bone formation. The new bone is particularly prominent in entheseal areas, where ligaments, tendons, joint capsule and annulus fibrosis fibres insert into bone. In addition, there is also an increase in the amount of normal cancellous and cortical bone, as well as generalised hyperostosis and a tendency to form post-operative heterotopic new bone [1Hochberg M, Silman A, Weinblatt M, Weisman M, Littlejohn GO. Diffuse idiopathic skeletal hyperostosis Rheumatology. Philadelphia Mosby Elsevier 2011; 1801-6.].

DISH is a systemic condition and not just the result of local mechanical factors present in each of the involved areas of the skeleton. Since the early descriptions of DISH there have been associations with a variety of metabolic factors. Many of these have subsequently been further studied to better define any associations between a particular metabolic factor and DISH. In this report we review the available literature on a number of the putative metabolic factors that have been studied in patients with DISH. Our aim was to identify associations between such factors and DISH in order to better focus future research in this area.

METHODS

Papers discussed in this review were identified from the authors’ own databases and were supplemented with searches on PubMed and online journals. The following keywords were used in various combinations: “diffuseidiopathic skeletal hyperostosis”, “ankylosing hyperostosis”, “Forestier’s disease”, “diabetes”, “insulin”, “obesity”, “metabolic”, “growth factors”, “adipokines”, “glucose tolerance” and “chondrocytes”. The bibliography of relevant identified papers was scanned and information from abstracts and non-English sources was included as deemed relevant. The derived information is presented in summary form. Differences in patient identification and other methodology varied to the degree that formal systematic review was not valid.

The anatomical, radiological and clinical features of DISH have been described under various names for over 150 years. These studies also use different definitions for the diagnosis of DISH. These range from hyperostosis linking two vertebral bodies, without intervening disc disease and extend to different numbers of vertebrae linked by confluent anterior longitudinal ligament related new bone. The different criteria used are summarised in Table 1. In this review we have included studies using different criteria in order to maximize any associations with putative metabolic factors.

Table 1.

Criteria definitions for diffuse idiopathic skeletal hyperostosis.




Table 2.

Paleopathological studies associating DISH in adults with obesity.




Table 3.

Selected contemporary observations and studies associating DISH with obesity.




Table 4.

Selected studies of impaired glucose tolerance [IGT], including diabetes mellitus, in patients with DISH.




Table 5.

Selected estimates of the prevalence of DISH in patients with abnormal glucose tolerance, including type 2 diabetes mellitus.




Table 6.

Selected studies of growth hormone and related peptides in DISH.




Table 7.

Selected studies of Insulin and related hormones in DISH.




Table 8.

Selected studies of adipokines in DISH-related disorders.




Obesity and DISH

In the defining paper of Forestier and Rotes-Querol it was noted that six of the nine males described with DISH, then termed ankylosing hyperostosis, were stated to be obese [11Forestier J, Rotes-Querol J. Senile ankylosing hyperostosis of the spine. Ann Rheum Dis 1950; 9: 321-0.]. Other subsequent studies have also noted this association.

A series of paleopathological studies is summarized in Table 2. These studies show that there is a significant difference in the prevalence of DISH between groups with different social status, with specific material from monastic and high-status burial sites being more affected by DISH than remains from laymen burials [12van der Merwe AE, Maat GJ, Watt I. Diffuse idiopathic skeletal hyperostosis diagnosis in a palaeopathological context. Homo 2012; 63: 202-15.]. The proposition is that the higher social status groups were excessively nourished, with probable increased rates of obesity, compared to the poorer laymen [8Rogers J, Waldron T. DISH and the monastic way of life. Int J Osteoarcheol 2001; 11: 357-65.]. It is noted that these studies vary in their criteria for defining DISH and that different definitions result in different rates of diagnosis in the same populations [12van der Merwe AE, Maat GJ, Watt I. Diffuse idiopathic skeletal hyperostosis diagnosis in a palaeopathological context. Homo 2012; 63: 202-15.]. Nevertheless, it is the differences between rates of DISH in the higher and lower social status classes that imply an association between DISH and nutritional factors, particularly those relating to obesity.

In one study the prevalence of DISH in skeletons from cemeteries in churches and chapels, serving priests, monks and lay benefactors, was compared to lay cemeteries in adjacent regions serving the general population [8Rogers J, Waldron T. DISH and the monastic way of life. Int J Osteoarcheol 2001; 11: 357-65.]. By combining data from the Wells Cathedral and the Royal Mint sites, the authors found that skeletons deemed to derive from high social status individuals had a significantly higher prevalence of DISH compared to those deemed to be of lower social status (P<0.001). The diet of high social status individuals, such as those living in mediaeval monasteries, was high in animal fat and alcohol [8Rogers J, Waldron T. DISH and the monastic way of life. Int J Osteoarcheol 2001; 11: 357-65.]. A diet rich in animal fat and alcohol and low in vegetables and fruit has been detailed in members of the Medici family found to have DISH [13Fornaciari G. Food and disease at the renaissance courts of naples and florence a paleonutritional study. Appetite 2008; 51: 10-4.].

These findings are consistent across many regions and in different countries even when variations of criteria for diagnosis of DISH are used.

More contemporary clinical data on associations between DISH and obesity are presented in Table 3.

Many of these studies are observational and of historical interest, with no appropriate comparator group. Schilling et al. found higher levels of obesity in patients with DISH compared to controls [24Schilling F, Schacherl M, Camp A, Bopp A. Die beziehungen der spondylosis hyperostotica zur konstitution and zu stoffwechselstorungen. Med Klin 1965; 60: 165.]. Additionally, Julkunen et al. found a significant association between DISH and obesity in a large population survey in Finland [3Julkunen H, Heinonen OP, Pyorala K. Hyperostosis of the spine in an adult population.Its relation to hyperglycaemia and obesity. Ann Rheum Dis 1971; 30: 605-12.]. DISH patients had a higher weight - height index compared to controls without DISH, particularly in those over the age of sixty.

An age and sex-matched comparative study of patients with DISH and those with spondylosis showed a significantly higher body mass index [BMI] in the DISH group and as well a higher weight at the age of 25 years in the DISH group (all p<0.001) [25Kiss C, Szilagyi M, Paksy A, Poor G. Risk factors for diffuse idiopathic skeletal hyperostosis a case-control study. Rheumatology (Oxford) 2002; 41: 27-30.].

Mader et al. found significantly higher waist circumference, a marker of obesity and metabolic syndrome [26Schneider HJ, Glaesmer H, Klotsche J, et al. Accuracy of anthropometric indicators of obesity to predict cardiovascular risk. J Clin Endocrinol Metab 2007; 92: 589-94.], in both men and women with DISH [27Mader R, Novofestovski I, Adawi M, Lavi I. Metabolic syndrome and cardiovascular risk in patients with diffuse idiopathic skeletal hyperostosis. Semin Arthritis Rheum 2009; 38: 361-5.]. The BMI was statistically higher in both the men and women with DISH compared to the controls and the percentage of DISH patients with BMI above 30, indicating obesity, was also significantly higher.

In a review of patients with psoriatic arthritis [PsA] from the one cohort [28Haddad A, Thavaneswaran A, Toloza S, Chandran V, Gladman DD. Diffuse Idiopathic Skeletal Hyperostosis in Psoriatic Arthritis. J Rheumatol 2013; 40(8): 1367-73.], 78 patients were identified with DISH using the spinal criteria of Utsinger [7Utsinger PD. Diffuse idiopathic skeletal hyperostosis. Clin Rheum Dis 1985; 11: 325-51.]. These patients were compared to 234 PsA patients without DISH from the same

cohort. There was a significant increase in BMI in the PsA patients with DISH compared to those with PsA without DISH. Obesity rates were higher in the PsA patients without DISH [mean ± standard deviation = 50 ± 33.8 versus the PsA plus DISH group [31 ± 70.5]. The very high variance in the data makes interpretation of the association of DISH and obesity in this population unclear, although the BMI was significantly elevated.

Diabetes and DISH

Overlapping and subsequent studies have focussed on the association between DISH and altered glucose tolerance and adult onset Type 2 diabetes mellitus. These studies have looked at various aspects of glucose intolerance defined in different ways. The studies used contemporaneous criteria for the diagnosis of diabetes and/or criteria based on different thresholds for glucose intolerance, following different glucose challenges.

The studies seeking association between DISH and glucose intolerance and/or diabetes have addressed the issue in two ways. Firstly, studies have looked for abnormalities of glucose intolerance in patients defined as having DISH. These are summarized in Table 4.

In a Finnish study Julkunen [3Julkunen H, Heinonen OP, Pyorala K. Hyperostosis of the spine in an adult population.Its relation to hyperglycaemia and obesity. Ann Rheum Dis 1971; 30: 605-12.] found a significant difference between the rates of hyperglycaemia in patients with and without DISH [p<0.05]. Hyperglycaemia, was defined as >250mg/100ml one hour after an oral glucose tolerance test or the presence of established diabetes. Analyses of intercorrelations between glucose tolerance and obesity in this series suggested that decreased glucose tolerance and obesity contributed at least in part to DISH, independently of each other.

Mader found higher fasting glucose levels in DISH patients compared to controls but many in each group were diabetic and medication was not taken into account. Overall these studies are very suggestive of an increased rate of Type 2 diabetes and/or impaired glucose tolerance in patients with diagnosed DISH, although there is marked inconsistency in diagnosis of DISH, selection of controls and definitions used to define diabetes and impaired glucose tolerance.

Another series of studies have sought to assess the rates of DISH in patients with abnormal glucose tolerance or diabetes. These studies also vary significantly with respect to diagnostic criteria and study design and are summarized in Table 5.

Although the quality of these studies varies, there is a general theme indicating that there is an excess prevalence of DISH in patients with diabetes or abnormal glucose tolerance compared to those with normal glucose tolerance. There is an increased prevalence of DISH in diabetic patients recruited from hospital clinics, likely reflecting bias due to comorbidity factors [57Hajkova Z, Streda A, Skrha F. Hyperostotic spondylosis and diabetes mellitus. Ann Rheum Dis 1965; 24: 536-43.]. However, when non-diabetics, aged 60 - 69 years, were compared to diabetics of the same age the prevalence of DISH increased from 4% to 21% [p<0.001] [58Julkunen H, Karava R, Viljanen V. Hyperostosis of the spine in diabetes mellitus and acromegaly. Diabetologia 1966; 2: 123-6.].

Additionally, glucose intolerance and obesity seem to act as independent risk factors in their association with DISH [3Julkunen H, Heinonen OP, Pyorala K. Hyperostosis of the spine in an adult population.Its relation to hyperglycaemia and obesity. Ann Rheum Dis 1971; 30: 605-12.]. There has been no relationship found between the degree of hyperglycaemia and the severity of the bony change in DISH [48Lequesne M, Cassan P, Nallet J. Hyperostose vertebrale et diabete sucre. Rev Rhum Mal Osteoartic 1970; 37: 281-6.]. Importantly no patient with juvenile onset, i.e., Type 1 [primary insulin deficient] diabetes has been recorded as having DISH.

Growth Hormone and Related Hormones and DISH

It has been proposed that growth hormone or related hormones may be involved in the new bone growth, and also the increased rates of diabetes, that characterize DISH. Table 6 summarizes selected studies of growth hormone and related peptides in patients with DISH. Growth hormone measured in one study, both after an overnight fast and after a glucose challenge, showed no difference between DISH patients and weight-matched controls [61Littlejohn GO, Smythe HA. Marked hyperinsulinemia after glucose challenge in patients with diffuse idiopathic skeletal hyperostosis. J Rheumatol 1981; 8: 965-8.]. In contrast, in a study that involved DISH subjects that were significantly heavier than the controls the basal growth hormone was also significantly higher [62Denko CW, Boja B, Moskowitz RW. Growth promoting peptides in osteoarthritis and diffuse idiopathic skeletal hyperostosis--insulin, insulin-like growth factor-I, growth hormone. J Rheumatol 1994; 21: 1725-30.]. IGF-1 levels were not different to controls. In this study basal insulin was also significantly elevated. Overall, however there is no conclusive data to indicate elevation of growth hormone or Insulin-like growth factor in patients with DISH.

Insulin and Related Hormones and DISH

Insulin is elevated in Type 2 diabetes mellitus and is a bone growth promoting peptide [69Akune T, Ogata N, Seichi A, Ohnishi I, Nakamura K, Kawaguchi H. Insulin secretory response is positively associated with the extent of ossification of the posterior longitudinal ligament of the spine. J Bone Joint Surg Am 2001; 83-A: 1537-44.]. Various studies seeking associations of these hormones with DISH are summarized in Table 7.

Insulin, measured both after an overnight fast and after a glucose challenge, showed significant elevation in DISH patients compared to weight and BMI–matched controls [p<0.001] [61Littlejohn GO, Smythe HA. Marked hyperinsulinemia after glucose challenge in patients with diffuse idiopathic skeletal hyperostosis. J Rheumatol 1981; 8: 965-8.]. The change in insulin was noted despite no significant change in blood glucose levels, either at base-line or after glucose stimulation. Insulin levels, measured 2 hours after glucose challenge showed highly significant correlation to BMI in the DISH group. Some studies support this finding [68Denko CW, Malemud CJ. Body mass index and blood glucose correlations with serum insulin, growth hormone, and insulin-like growth factor-1 levels in patients with diffuse idiopathic skeletal hyperostosis (DISH). Rheumatol Int 2006; 26: 292-7.], while others (as outlined in Table 7) do not.

The fact that insulin levels correlate with being overweight [55Vezyroglou G, Mitropoulos A, Antoniadis C. A metabolic syndrome in diffuse idiopathic skeletal hyperostosis.A controlled study. J Rheumatol 1996; 23: 672-., 60Sencan D, Elden H, Nacitarhan V, Sencan M, Kaptanoglu E. The prevalence of diffuse idiopathic skeletal hyperostosis in patients with diabetes mellitus. Rheumatol Int 2005; 25: 518-21., 68Denko CW, Malemud CJ. Body mass index and blood glucose correlations with serum insulin, growth hormone, and insulin-like growth factor-1 levels in patients with diffuse idiopathic skeletal hyperostosis (DISH). Rheumatol Int 2006; 26: 292-7., 70Silveri F, Brecciaroli D, Argentati F, Cervini C. Serum levels of insulin in overweight patients with osteoarthritis of the knee. J Rheumatol 1994; 21: 1899-902.] is a potential confounder in these studies.

Adipokines

The increased rates of obesity, particularly abdominal fat, in patients with DISH might imply a role for various adipokines in the pathogenesis of this disorder. Many of these fat-derived cytokine-like hormones have significant effects on bone metabolism [71Lago F, Dieguez C, Gomez-Reino J, Gualillo O. Adipokines as emerging mediators of immune response and inflammation. Nat Clin Pract Rheumatol 2007; 3: 716-24.].

Leptin is encoded in the obese gene, secreted by adipose tissues and involved in maintenance of weight. Leptin has effects on bone in mice promoting osteoblast numbers and activity through peripheral pathways [72Turner RT, Kalra SP, Wong CP , et al. Peripheral leptin regulates bone formation. J Bone Miner Res 2013; 28: 22-34.]. In humans leptin levels associate with increase cortical but not cancellous bone [73Li H, Jiang LS, Dai LY. Hormones and growth factors in the pathogenesis of spinal ligament ossification. Eur Spine J 2007; 16: 1075-84.]. Hereditary obese rats [Zucker fatty (fa/fa) rats] have an aberration of the leptin receptor gene and develop ossification of spinal ligaments [OSL], a condition with similarities to DISH that targets the posterior longitudinal spinal ligament [74Shirakura Y, Sugiyama T, Tanaka H, Taguchi T, Kawai S. Hyperleptinemia in female patients with ossification of spinal ligaments. Biochem Biophys Res Commun 2000; 267: 752-5.]. Japanese female patients with OSL, but not males have elevated leptin, which correlates with elevated insulin levels [74Shirakura Y, Sugiyama T, Tanaka H, Taguchi T, Kawai S. Hyperleptinemia in female patients with ossification of spinal ligaments. Biochem Biophys Res Commun 2000; 267: 752-5.]. There is a positive correlation with extent and severity of ligamentous ossification in OSL [75Ikeda Y, Nakajima A, Aiba A , et al. Association between serum leptin and bone metabolic markers, and the development of heterotopic ossification of the spinal ligament in female patients with ossification of the posterior longitudinal ligament. Eur Spine J 2011; 20: 1450-8.]. The leptin receptor is expressed in human spinal ligaments, although in vitro studies did not show increased collagen synthesis after exposure to leptin [74Shirakura Y, Sugiyama T, Tanaka H, Taguchi T, Kawai S. Hyperleptinemia in female patients with ossification of spinal ligaments. Biochem Biophys Res Commun 2000; 267: 752-5.]. Both leptin and its receptor are also expressed in the annulus, increasing with advanced age [76Zhao CQ, Liu D, Li H, Jiang LS, Dai LY. Expression of leptin and its functional receptor on disc cells contribution to cell proliferation. Spine (Phila Pa1976 2008; 33: E858-64.]. Leptin is found in high levels in osteophytes of patients with osteoarthritis [77Presle N, Pottie P, Dumond H , et al. Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis.Contribution of joint tissues to their articular production. Osteoarthr Cartil 2006; 14: 690-5.]. Leptin has not been specifically studied in DISH but the studies in the related ossifying disorder of OSL are shown in Table 8. Leptin levels were significantly elevated in females with OSL in this study.

In 37 patients with DISH the serum levels of the osteoblast inhibitor Dickkopf-related protein-1 DKK-1 were significantly lower compared to 22 healthy, age–matched controls. Lower levels associated with more spinal hyperostosis independent of age, sex, bone-turnover markers or bone mineral density [78Senolt L, Hulejova H, Krystufkova O , et al. Low circulating Dickkopf-1 and its link with severity of spinal involvement in diffuse idiopathic skeletal hyperostosis. Ann Rheum Dis 2012; 71: 71-4.]. However, another study did not find an association between DKK-1 and DISH [79Aeberli D, Schett G, Eser P, Seitz M, Villiger PM. Serum Dkk-1 levels of DISH patients are not different from healthy controls. Joint Bone Spine 2011; 78: 422-3.] making this observation difficult to interpret.

BONE REGULATORY PROTEINS

Co-Morbid Metabolic Factors

Patients with DISH have significant associations with gout, hyperuricemia and dyslipidaemia, likely through the shared association with obesity [27Mader R, Novofestovski I, Adawi M, Lavi I. Metabolic syndrome and cardiovascular risk in patients with diffuse idiopathic skeletal hyperostosis. Semin Arthritis Rheum 2009; 38: 361-5., 55Vezyroglou G, Mitropoulos A, Antoniadis C. A metabolic syndrome in diffuse idiopathic skeletal hyperostosis.A controlled study. J Rheumatol 1996; 23: 672-., 80Littlejohn GO, Hall S. Diffuse idiopathic skeletal hyperostosis and new bone formation in male gouty subjects. A radiologic study Rheumatol Int 1982; 2: 83-6.-84Mader R, Verlaan JJ. Bone Exploring factors responsible for bone formation in DISH. Nat Rev Rheumatol 2012; 8: 10-2.]. There is no evidence that these factors in their own right cause the new bone formation characteristic of DISH

Vitamin A

Vitamin A –related products can cause hyperostosis in animals and man [85Nesher G, Zuckner J. Rheumatologic complications of vitamin A and retinoids. Semin Arthritis Rheum 1995; 24: 291-6., 86Ling TC, Parkin G, Islam J, Seukeran DC, Cunliffe WJ. What is the cumulative effect of long-term, low-dose isotretinoin on the development of DISHκ. Br J Dermatol 2001; 144: 630-2.]. Vitamin A has been shown to be elevated in patients with DISH [87Abiteboul M, Arlet J, Sarrabay MA, Mazieres B, Thouvenot JP. [Metabolism of vitamin A in Forestier-Rotes-Querol hyperostosis]. Rev Rhum Mal Osteoartic 1986; 53: 143-5.] but it remains unclear as to the exact role of Vitamin A in DISH.

Animal Models

DISH has been described in numerous animal species but there are no well-designed animal experiments to demonstrate the causal relationship between metabolic factors and DISH [88Lagier R. Spinal hyperostosis in comparative pathology.A useful approach to the concept. Skeletal Radiol 1989; 18: 99-107., 89Kranenburg HC, Westerveld LA, Verlaan JJ , et al. The dog as an animal model for DISHκ. Eur Spine J 2010; 19: 1325-9.].

Metabolic Factors and Targets in DISH

The metabolic factors present in patients with DISH, such as insulin, likely interact with key candidate cellular targets linking to new bone formation. These include chondrocytes and periosteal mesenchymal cells within the enthesis [90Littlejohn GO. Insulin and new bone formation in diffuse idiopathic skeletal hyperostosis. Clin Rheumatol 1985; 4: 294-300., 91Berthelot JM, Le Goff B, Maugars Y. Pathogenesis of hyperostosis A key role for mesenchymatous cellsκ. Joint Bone Spine 2013; 80: 592-6.] (See Fig. 1). These cells have been shown to proliferate under the influence of transforming growth factor- β1, insulin and bone morphogenic protein (BMP2) to form fibroblasts, myoblasts and osteoblasts [91Berthelot JM, Le Goff B, Maugars Y. Pathogenesis of hyperostosis A key role for mesenchymatous cellsκ. Joint Bone Spine 2013; 80: 592-6.]. Metabolic factors, such as insulin, growth hormone and insulin-like growth factor 1, all have the ability to promote bone formation through stimulation of proliferation of osteoblasts, chondrocytes and fibroblasts [82Sarzi-Puttini P, Atzeni F. New developments in our understanding of DISH (diffuse idiopathic skeletal hyperostosis). Curr Opin Rheumatol 2004; 16: 287-92., 84Mader R, Verlaan JJ. Bone Exploring factors responsible for bone formation in DISH. Nat Rev Rheumatol 2012; 8: 10-2.]. The exact mechanisms that contribute to the new bone growth, particularly in entheseal regions, in patients with DISH are unknown. However, relevant important signalling pathways are likely to include the Wnt -β-catenin pathway, nuclear factor κB, BMP2, prostaglandin I2 and endothelin1 [92Mader R, Verlaan JJ, Buskila D. Diffuse idiopathic skeletal hyperostosis clinical features and pathogenic mechanisms. Nat Rev Rheumatol 2013; 9: 741-50.].

Fig. (1)

Growth factors present in patients with DISH, such as growth hormone, insulin or insulin-like growth factor, target the chondrocytes and mesenchymal cells in the uncalcified portion of the enthesis. Proliferation of these cell types results in new bone formation. The components of the enthesis are detailed in the diagram to the right. Molecular mechanisms within the entheseal cells have been recently summarized [92].



FUTURE STUDIES

There is a need for further studies to better define the important background metabolic factors that promote the new bone formation that characterizes DISH. These need to include a group of interacting factors, including genetic, epigenetic, metabolic and bone-related signalling pathways. Study of younger patients with early DISH may better identify important metabolic factors but this approach is limited by current diagnostic criteria that identify well-established DISH, with high rates of confounding co-morbidities [93Mader R, Buskila D, Verlaan JJ, et al. Developing new classification criteria for diffuse idiopathic skeletal hyperostosis back to square one. Rheumatology (Oxford) 2013; 52: 326-0.]. It is important for future studies to incorporate direct examination of the cellular elements of the key target organ of DISH, the enthesis.

SUMMARY

This review examines the available literature on metabolic factors in patients with DISH. The identified literature was not considered robust enough to perform a structured systematic review due to inconsistencies with study methodologies. These include different criteria for diagnosis of DISH, and different definitions for diabetes, and impaired glucose tolerance. Metabolic studies varied in the protocols used, with different time frames and stimulation protocols. Controls were often lacking or poorly matched for metabolic factors. We have commented on these issues in the summary tables.

Nevertheless we aimed to make this review a contemporary summary on the topic to act as a reference standard for future studies.

Despite the above comments this review of metabolic factors in DISH does allow for certain conclusions. There is a general theme that metabolic factors are of great importance in DISH. Obesity, particularly abdominal obesity, is strongly linked to DISH. Further exploration of the role adipokines in patients with DISH is required. Type 2 diabetes is increased in DISH, independent of obesity. The link between obesity, type 2 diabetes and insulin elevation is strong. Of all the potential growth factors examined in patients with DISH, insulin is likely to have a key role in the pathophysiology of DISH.

Finally, it is clear that more studies are required on this important aspect of DISH, a condition that is increasing in frequency and significance.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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