Chronic hyperglycemia due to either insulin deficiency (T1D) or insulin resistance (T2D) is associated with multiple end organ complications including neuropathy, retinopathy, macrovascular diseases (stroke, cardiac disease, and peripheral vascular disease) and fatty liver. Less often recognized is the long term effect of high glucose on the skeleton.

In the five years since I wrote an editorial in the Journal of Bone and Mineral Research detailing how little we understand about diabetic bone disease, new data has emerged from basic and translational studies concerning the pathophysiology of this disorder(1-4). In addition, recent imaging and clinical trials have provided novel insights into potential targets to modify or potentially prevent this manifestation. Indeed, there are now agents that can enhance insulin sensitivity but at the same time support skeletal maintenance (5). The public health implications of such bench to bedside discoveries are immense particularly in light of the ever-growing epidemic of obesity in our ever-aging population. Hence, a sweeter story may be in the making.

What have we learned to change our perspective about the skeletal changes with diabetes? First, we have a much clearer picture of insulin’s actions on the skeletal remodeling unit. Work from the Karsenty and Clemens laboratories have shown that insulin binds to the insulin (not the IGF) receptor to down regulate Twist2, an inhibitor of Runx2, the essential osteoblast transcription factor. This action fits with recent data suggesting that in T1D Runx2 expression is markedly down regulated throughout osteoblast differentiation, which in turn leads to reduced bone formation. In addition to insulin’s actions on osteoblasts, insulin-receptor activation enhances bone remodeling thereby increasing bone resorption which in turn releases undercarboxylated osteocalcin from the skeletal matrix (6). This unique form of osteocalcin is an insulin sensitizer for adipocytes, possibly working through the enhancement of adiponectin production. Undercarboxylated osteocalcin can also stimulate insulin release from beta cells of the pancreas. Thus the skeleton plays an active role in glucose homeostasis and reinforces clinical studies that active exercise not only improves glucose transport in muscles, but may indeed, through loading, stimulate insulin sensitivity in osteoblasts and increase bone remodeling thereby further improving glucose handling.

Second, we have a clearer understanding of the risks of osteoporosis related to both T1D and T2D. Recent observational studies suggest that insulin deficiency can enhance hip fracture risk by nearly five fold. Such patients usually have low bone mineral density and the additional complication of diabetic neuropathy which can lead to falls and subsequent fractures. A more confusing picture arises in T2D where obesity is a clinical feature and bone mineral density is often normal or high. Recent studies from Ann Schwartz and the UCSF Radiology group have shed some light on this apparent paradox. Although bone quantity may be normal in T2D, qualitative changes are quite remarkable and include increased cortical porosity and enhanced marrow adiposity (5). Both may have biomechanical implications, particularly the former, since porosity in the cortical skeleton leads to greater bone fragility during ex vivo testing. Also, it is apparent that progressive increases in marrow fat can lead to the elaboration of adipokines which suppress bone formation and uncouple bone remodeling within the marrow niche. Finally, obesity itself may be a major risk factor for fracture in some populations including older men. The reason for this is not entirely clear although increased visceral fat appears to be the major culprit, possibly through its elaboration of toxic cytokines that not only damage blood vessels but likely inhibit bone formation and increase bone resorption.

Third, the pharmacology of newer anti-diabetic drugs is coming into greater focus. The clinical trials with the TZDs made us acutely aware of the adverse skeletal effects when PPARG is activated by agents such as rosi- and pio-glitazone. These agents work by uncoupling bone remodeling, particularly by enhancing bone resorption, leading not only to bone loss, but to a greater risk of limb fractures, particularly in those individuals with peripheral neuropathy. Newer drugs that have been approved for the treatment of T2D and enhance insulin secretion, such as the insulin secretagogues (e.g. GLP1 analogs, DPP4 inhibitors) may actually protect the skeleton by inhibiting bone resorption and/or stimulating bone formation. On the other hand, agents in clinical development that increase energy expenditure, reduce body fat mass and improve insulin sensitivity, such as FGF-21, may have an adverse effect on the skeleton including greater marrow adiposity and increased bone resorption(7).

In summary, much has changed in the skeletal landscape of diabetes over the last half decade as both basic and clinical studies have demonstrated. Future directions include the development of more powerful insulin sensitizers that can enhance bone mass and protect individuals from the devastating effects of fracture. Improved imaging techniques may help us understand the role of the microvasculature in diabetic bone disease and the effects of chronic neuropathic disease on skeletal remodeling. More bench to bedside studies will likely provide the impetus to make diabetic bone disease a thing of the past.
 

References

  1. Rosen CJ: Sugar and Bone: A Not so Sweet Story. J Bone Min Res 2008: 23; 1881-1883.Sealand R, Razavi C and Adler RA. Diabetes Mellitus and Osteoporosis. Curr Diab Rep 2013; March 8 E pub ahead of print
  2. Leslie WD, Rubin MR, Scwartz AV, Kanis JA. T2D and bone. J Bone Min Res 2012; 27: 2231-7.
  3. Petit MA, Paudel ML, Taylor BC, Hughes JM, Strotmeyer ES, Schwartz AV, Cauley JA, Zmuda JM, Hoffman AR, Ensrud KE; Osteoporotic Fractures in Men (MrOs) Study Group. Bone mass and strength in older men with T2D: the Osteoporotic Fractures in Men Study Group. J Bone Min Res 2010 25:285-291.
  4. Patsch JM, burghardt AJ, Yap SP, Baum T, Schwartz AV, Joseph GB, Link TM. Increased cortical porosity in T2D postmenopausal women with fragility fractures. J Bone Min Res 2013; 28: 213-24.
  5. Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, Faugere MC, Aja S, Hussain MA, Brüning JC, Clemens TL. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 2010 142 309-319.
  6. Wei W, Dutchak PA, Wang X, Ding X, Wang X, Bookout AL, Goetz R, Mohammadi M, Gerard RD, Dechow PC, Mangelsdorf DJ, Kliewer SA, Wan Y. FGF-21 promotes bone loss by potentiating the effects of PPARG. Proc Nat Acad Sci USA 2012: 109:3143-3148.