“Where the silence of diabetes is broken into pain”…A narrative
As modern treatments for type 2 diabetes mellitus (T2DM) improve, more and more affected patients are likely to live longer and skeletal concerns may become more prevalent. It is high time for skeletal complications to become part of the routine discussion of the long-term outlook in T2DM in order to offset serious challenges in this population as they age. Until very recently, the list of target organs affected by T2DM did not always include the skeleton. Yet, there is now substantial evidence that T2DM is an independent risk factor for fractures, which is not attributable to increased body mass index or the other classical osteoporosis risk factors.1
Any clinician who has handled an elderly diabetic with a frozen shoulder would vouch for this clinical entity as a harsh reality. As “Rheumatology” reckons a body tight in pain and a face taut with fear, a tempting thought of a tautogram comes to the mind very timely to initiate an introduction to the chapter with an alliteration—repetition, reiteration, and reaffirmation. These are similar sounding words. That India is the epicenter of diabetes mellitus is repetition ad nauseam. “Nephropathy, neuropathy, and retinopathy are major complications of diabetes” is reiteration ad infinitum.2
But what needs reaffirmation is that the fracture risk is increased by an average of six times in type 1 diabetes mellitus (T1DM), and most patients with T2DM are at an increased risk (which is about twice the risk in the general population) and this is caused by inferior quality of bone.3 This gives us ample opportunity to establish ad lucem that altered skeletal integrity due to diabetes mellitus, can no longer be ignored or considered solely in the context of an adverse event. Hence, what was often overlooked, now needs highlighting, followed by reaffirmation that the skeleton is an important end organ that is affected relatively rapidly by impaired metabolic control, particularly during the vulnerable period of peak bone acquisition. Despite being “commonly” present, they are “uncommonly” addressed and tend to get dwarfed by the more popularly publicized micro- and macrovascular complications of the disease. These “mundane” manifestations, however, have the potential to exert a significant negative influence on quality of life in diabetics.2
Skeletal involvement in diabetes was first suggested more than 80 years ago, prompted by radiological findings of retarded bone development and bone atrophy in children with T1DM.4 Diabetes may affect the musculoskeletal system in a variety of ways. The metabolic perturbations in diabetes (including glycosylation of proteins; microvascular abnormalities with damage to blood vessels and nerves; and collagen accumulation in skin and periarticular structures) result in changes in the connective tissue. Musculoskeletal complications are most commonly seen in patients with a longstanding history of T1DM, but they are also seen in patients with T2DM (Table 1 and Fig. 1).5,6
Some of the complications have a known direct association with diabetes, whereas others have a suggested but unproven association. The tale that is told in the following chapters will review the musculoskeletal and rheumatological manifestations commonly seen in patients with diabetes (Table 2).
Figure 1: Extracellular and intracellular effects of advanced glycation end-products.6AGE, advanced glycation end-products; CDC, centers for disease control and prevention; CML, chronic myeloid leukemia; ERK, extracellular signal-regulated kinase; HMGB1, high-mobility group box 1; ICAM, intercellular adhesion molecule; IL, interleukin; INF, tumor necrosis factor; MAP, mitogen-activated protein; NAD, nicotinamide adenine dinucleotide; NO, nitric oxide; NOS, nitric oxide synthase; TGF, transforming growth factor; RAGE, receptor for advanced glycation end-products; RAS, renin-angiotensin system; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor; ROS, reactive oxygen species.
“It is very clearly apparent … how great is the usefulness of a knowledge of the bones, since the bones are the foundation of the rest of the parts of the body and all the members rest upon them and are supported, as proceeding from a primary base. Thus if anyone is ignorant of the structure of the bones it follows necessarily that he will be ignorant of very many other things along with them.”7