Diabetes And Joint Disease

Introduction
Diabetes mellitus that characterized by chronic hyperglycemia which is accompanied by protein and lipid metabolic disorders could affect the bone and joint in a variety of ways. It is not surprisingly that the complex metabolic disturbances in diabetes cause a wide range of alteration in the musculo-skeletal system. For example, diabetes could play a role in osteoporosis, hyperostosis such as DISH or diffuse idiopathic skeletal hyperostosis (particularly in type II diabetes), osteoarthritis, diabetic osteoarthropathy, diabetic hand syndrome, rheumatoid arthritis and shoulder calcific periarthritis.
These conditions mentioned above appear not only as independent disease (e.g. diabetic osteoarthropathy), but also as modifications in frequency and course of various rheumatic processes. Several rheumatic condition in diabetes mellitus will be discussed in this paper except osteoporosis.

Diabetes and Hyperostosis
The association of diabetes and hyperostosis was recognized as early as 1954. The radiological appearance noted that the changes could be differentiated from spondylosis deformans and ankylosing spondylitis.
The pathology of hyperostosis is essentially metaplastic calcification and ossification of the anterior longitudinal ligaments of the spine. This calcification almost accompanied by generalized ossification of ligaments and tendons. Resnick et al summarized these changes under the name diffuse idiopathic skeletal hyperostosis (DISH).
In diabetic patient the frequency of hyperostosis is markedly increased compared to normal population. It occurs in diabetics and normal population in 13-49% and 1.6-13% respectively. Almost three times of the diabetic patient with hyperostosis had type II diabetes rather than type I. Although hyperostotic process develops earlier in diabetics, DISH is a disease of the elderly which frequently increases with age.
The relationship between diabetes and hyperostosis is not clearly understood. It has already proven that insulin or insulin-like growth factors-1 (IGF-1) at prolonged and high level promotes bone formation particularly in the entheseal region. This explanation perhaps could answer why hyperostosis most common seen in type II diabetes due to prolonged hyperinsulinemia. Furthermore this changes is nearly three times more frequent among diabetic patient with hyperlipoproteinemia. In post menopausal women commonly seen an overproduction of growth hormone and hyperostosis have features in common with acromegaly. It is difficult to answer the question weather hyperostosis is a diabetic feature. So do the overproduction of growth hormone in postmenopausal women in relationship with hyperostosis. DISH is not specific diabetic complication and hyperostosis is not a direct consequence of diabetes.

Diabetes and Osteoarthritis
One of the most common rheumatologic diseases is osteoarthritis (OA) in correlation with or without diabetes. It is distributed in all part of the world with the frequency less than 5% below 45 years of age and sharply increased in the sixth, seventh and eight decade. The radiological change is much higher than clinical manifestation giving up to 83%. In one study of OA in Malang, Indonesia, the prevalence in urban and rural area is 10.0% and 13.5% respectively, while in USA as reported by Altman, the OA prevalence is 12% among total population.
This rheumatic alteration seems more frequent in type II diabetes. In type II diabetes the disease is insulin resistant, due to insulin receptor and postreceptor abnormalities. Insulin itself known as a potent growth factor for connective tissue. Horn et al conducted a study on radiographic features from 25 diabetic patients with OA compare to those without diabetes and the result suggested that diminished availability of insulin at the cellular level or diabetic microvascular disease attenuates the chondro- and osteogenesis required for osteophyte formation in the joints of patients with OA.
There is lack of specific explanation regarding the correlation between diabetes and OA. Since the diabetic patients are obese and it is well known that obesity is one of risk factor for OA independent of diabetes, so the connection is more likely due to obesity rather than diabetes itself. Obesity in women is known cause of hyperoestrogenism, occurring through the peripheral formation of estrogen from androstenedione in fat tissues. After the menopause this route becomes the principal source of estrogen. It is understandable that OA and obesity also suggest a role for endocrine influences in the development of OA. An unanswered question is which pathogenic pathway obesity causes OA.
Weight bearing joint such as knee joint is the most affected joint. Kalim reported that knee OA is much higher seen in diabetics with good metabolic controlled and those with high estradiol and insulin level. Duration of diabetes and poor metabolic controlled diabetes increases the risk for having symptomatic OA. His study failed to support the role of IGF-1 and growth hormone as other factors in the occurrence of OA. As we know that IGF-1 could stimulate the synthesis of proteoglycan, one of the essential structure in the cartilage matrix. In diabetics, IGF-1 level had significantly lower than normal subject up to 50% as mentioned by Tan and Baxter did.
There are no significant differences in the management of OA in diabetic patient. It is advisable to bring the patient’s body weight down to normal or ideal body weight since Felson et al analysis the data from Framingham OA study and was founded that weight loss reduces the risk for symptomatic knee OA in women. The need of hyperglycemic controlled; various modalities in physiotherapy including joint protection and the use of medication particularly painkiller, non-steroidal anti inflammatory drugs or other nutraceutical agents such as chondroitin sulfate, and glucosamine sulfate is mandatory. Unfortunately there is no drugs acting on chondrocyte function as disease modifying anti osteoarthritic drugs. Attention must be given to those with hormone replacement therapy even though that estrogen use in women is not associated with increased risk of radiographic OA. In theory estrogen will bring the subchondral bone relatively stiffer and it cause a higher transmission of impulse loading force to the overlying cartilage leading to cartilage damage. This will initiating the cartilage changes as the main abnormalities in OA.

Diabetic Osteoarthropathy
This terminology applies to destructive lytic bone changes mainly in the pedal bones and it is a severe late complication of diabetes. The changes more frequently seen among the 50- to 69-year-old patients with no sex differences in sex distribution.
Metatarsophalangeal (31.5%) joint is the most affected site in diabetic osteoarthropathy, followed by tarsometatarsal joint (27.4%), tarsus (21.8%), ankle joint (10.2%) and interphalangeal joints (9.1%). The bone abnormality increases with the duration of diabetes. The duration of diabetes more than 10 years giving more than half the incidence of diabetic osteoarthropathy.
Neuropathy plays the important role in the development of diabetic osteoarthropathy beside some other factors aggravating the pathologic process such as infection, vasculopathy (diabetic micro- and macro-angiopathy) and joint trauma.
The clinical symptoms are not related with the severity of radiological findings, so it is often revealed after severe irreversible bone changes have developed. The clinical manifestation can be divided in four groups as neurological symptoms appear the first and then the skin involvement developed, subsequently followed by loosening of joints and articular swelling and those leading to joint deformities.
The x-ray examination is the instrument to make the diagnosis of diabetic osteoarthropathy and there are three characteristic changes. The first radiological change is the appearance of circumscribed osteoporosis, mostly at the subchondral region and gradually turn into osteolysis. At this initial stage other abnormalities such as cortical defect and subluxation or dislocation can be demonstrated. The second stage or progression stage will give further severe osteolysis, fragmentation, fractures and periosteal reaction. The last stage, namely the healing stage, it is not pointed to the recovery of the pathologic process but more likely the end stage or deforming one. At this stage the filling process of cortical defect resulting in pointed bones, development of arthrosis deformans, ankylosis and total restitution.
It is advisable to differentiate between diabetic osteoarthropathy with inflammatory, tumorous, degenerative processes and of neurogenic arthrophaties origin.
The clinical management referred to the controlled of pathogenic factors. Conservative treatment is indicated in most cases. Remember that neuropathy is the dominating factor. It is advisable to maintain the good metabolic controlled, which is often mean to use insulin rather than oral hypoglycemic agents. Other important thing is joint protection from weight bearing and the use of orthotic device is much of help. Amputation and resection is justifiable in cases with severe infection (macroangiopathy or gangrenous) or in cases of nonhealing plantar ulcer particularly for the maintenance of remission after recovery. Usually this was limited to removal of destroyed capitulum or the base of the phalanx. The fundamental consideration in preventing diabetic osteoarthropathy is good diabetic controlled and foot hygiene.

Diabetes and Rheumatoid Arthritis
There is some similarities on several factors that plays a role in the disease process that can be seen in diabetic (type I) and rheumatoid arthritic (RA) patient. These factors detected in similar frequency between the two, such as HLA-DR3 and / or DR4, decreases in C4 level, islet cell antibodies and other systemic and organ specific antibodies. Although other study conducted by Pile demonstrated that interaction between DR4 and a locus on chromosome 11p is not common to all DR4 associated autoimmune disease, but in type I diabetes the susceptibility to have RA enhances (RR=5-6) in the present of HLA DR4. It is still debatable how the pathologic process of RA is modified by concomitant diabetes. Thomas et al mentioned for the first time that there is increase in prevalence of type 1 diabetes in the close relatives of patients with RA. They founded that 13% of 295 patients satisfy the classical RA had a first or second degree relative with type I diabetes and of 13% had a close relative with autoimmune thyroid disease. Cornelis F et al, in their genome study demonstrated that there is no other locus than HLA giving similarity between RA and types I diabetes mellitus.

Diabetes and Shoulder Problems.
Commonly the shoulder problem in type II diabetes is calcific periarthritis or tendinitis. Mavrikakis et al had founded that 31.8 % of 824 diabetics had shoulder calcification in compared with 10.3% of 320 non-diabetics. The calcific periarthritis occurs in younger patients and the sites of calcification most common on the right shoulder particularly lies within the supra spinatus tendon. Calcification influenced by the factor of long duration of having diabetes particularly those treated with insulin for a long time.
The deposition of calcium-containing crystal around joint will appear radiologically as diffuse or small dense opacities. This appearance is not significantly related with clinical manifestation. In acute periarthritis which can be so painful that examination of the shoulder become impossible. This occurs when the calcium containing material penetrate into the neighboring bursa and the crystal induce an acute synovitis.
The management is symptomatic and at the acute stage draining the chalk-like material is much of help. If not drained, the calcific material is resorbed and dissapears from the radiograph.

Diabetic Hand Syndrome
In diabetics limited joint mobility was associated with several factors including microangiopathy and collagen changes. It is not clear yet weather microangiopathy occurs first with several complication such as ischemia and fibrosis of the connective tissue or the collagen changes cause small vessel disease. It occurs in 8-50% of type I diabetics. The symptoms developed after a long duration of diabetic metabolic disturbances. Most of the cases started in childhood. Clarke CF et al founded that 31% of 70 diabetic children have limited joint mobility and the prevalence increases with age and duration of diabetes.
Clinically, slight pain and paresthesias developed first and then the pain will aggravated by hand movement. The patient is unable to press both hands together.
There is no specific management for these abnormalities, but the main task is to maintain the diabetic control and perhaps the use of periphery vasodilator and symptomatic treatment are recommended.

References
1. Thomas DJ, Young A, Gorsuch AN, Bottazo GF, Cudworth AG. Evidence for an association between rheumatoid arthritis and endocrine disease. Ann Rheum Dis 1983; 42:297-300.
2. Mavrikakis ME, Drimis S, Kontoyannis DA, Rasidakis A, Moulopoulou ES, Kontoyannis S. Calcific shoulder periarthritis (tendinitis) in adult onset diabetes mellitus: a controlled study. Ann Rheum Dis 1989; 48:211-4.
3. Vischer TL. Non-articular rheumatism. In Dieppe PA, Bacon PA, Bamji AN, Watt I. Atlas of clinical rheumatology. London: Gower Medical Publishing 1986: 20.20 2
4. Forgacs SS. Endocrine and hemoglobin arthropathies. In Klippel ed. Textbook of Rheumatology. …… 7.20.1 – 6.
5. Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JA. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. Ann Intern Med 1992; 116:535-9.
6. Hart DJ, Spector TD. The relationship of obesity, fat distribution and osteoarthritis in women in the general population: The Chingford study. J Rheumatol 1993;20:331-5.
7. Felson DT, Anderson DJ, Naimark A, Walker AM, Meenan RF. Obesity and knee osteoarthritis. Ann Intern Med. 1988;109:18-24.
8. Cornelis F, Faure S, Martinez M, et al. New susceptibility locus for rheumjatoid arthritis sugessted by genom-wide linkage study. PNAS 1998;95:10746-50.
9. Kawahito Y, Cannon GW, Gulko PS, et al. Localization of quantitative trait loci regulating adjuvant-induced arthritis in rats: Evidence of genetic factors common to multiple autoimmune disease. J Immunol 1998;161: 4411-9
10. Hannan MT, Felson DT, Anderson DJ, Naimark A, Kannel WB. Estrogen use and radiographic osteoarthritis of the knee in women. Arthritis Rheum 1990;33: 525-32
11. Pile KD, Wordsworth BP, Bell JI. Does the locus on chromosome 11 implicated in susceptibility to HLA-DR4 dependent type I diabetes mellitus also affect susceptibility to rheumatoid arthritis?. Ann Rheum Dis 1992;51:1250-1
12. Horn CA, Bradley JD, Brandt KD, et al. Impairment of osteophyte formation in hyperglycemic patients with type II diabetes mellitus and knee osteoarthritis. Arthritis Rheum 1992;35:336-42
13. Tan K, Baxter RC. Serum insulin-like growth factor I level in adfult diabetic patients: The effect of age. J Clin Endocrinol Metab 1986;63:651-5
14. Hartz AJ, Fischer ME, Bril G, et al. The association of obesity with joint pain and osteoarthritis in the HANES data. J Chron Dis 1986;39:311-9.
15. Spector TD, Campion GD. Generalized osteoarthritis: a hormonally mediated disease. Ann Rheum Dis 1989;523-7
16. Chander CL, Spector TD. Oestrogen, joint disease and cartilage. Ann Rheum Dis 1991;50:139-40.