Bone disease and diabetes mellitus

Abstract

Diabetes Mellitus (DM) and Osteoporosis (OP) frequently co-exist with advanced age and imply large health challenges worldwide. The last decades there has been a growing interest regarding fracture risk in DM. Currently used screening methods (Dual Energy X-ray Absorptiometry (DXA) and FRAX) underestimate fracture risk in diabetes patients. New methods for risk assessment are needed. In my thesis, we have studied the significance of neuropathy, the IGF-system and metabolic control in relation to bone mineral density and fracture risk in DM, both in a rat-model and in humans.

Study I: In an epidemiological register study of 24 605 patients, 12 551 men and 12054 women with T1DM the cumulative incidence of hip fractures was analyzed. Conclusion. Both men and women with TIDM have a several folds increased risk for hip fracture with higher risk in those with peripheral neuropathy.

Study II: Diabetic osteopathy and the IGF-system were analyzed in an animal model of mild T2DM, the Goto-Kakizaki rat, to assess the systemic as well as local bone and joint status. Conclusion. Bone mineral density (BMD) was lower in peripheral bone in diabetic compared to control rats and there were both systemic and local disturbances of the IGF-system.

Study III: Bone and joint neuropathy were studied in the same diabetic rats and compared to controls to explore and define abnormalities of the peripheral nervous system in diabetic osteopathy according to nerve conduction velocity and neuropeptide expression in bone and joints. Conclusion. Rats with mild T2DM and neuropathy exhibited neuropeptidergic changes in the periphery, especially autonomic nerve deficits, which we suggest is an important factor underlying the development of regional osteopenia.

Study IV: In a prospective clinical study 66 subjects with T1DM or T2DM with peripheral poly-neuropathy (PNP) were followed for a mean of 11 years in T1DM and 8 years in T2DM to investigate fracture incidence and risk factors. Quantitative ultrasound (QUS) of calcaneus but not DXA spine or femur neck predicted future fractures. Fracture incidence was high in this cohort of poorly controlled diabetes subjects with the mean age of 58 years at inclusion. DXA spine T score was normal in both T1DM and T2DM, while T score DXA femoral neck and QUS of calcaneus were low, which correlated well. QUS of calcaneus and low levels IGFBP-5 predicted future fracture of the hip and foot. There was an inverse correlation between the incidence of any fracture and baseline levels of serum IGF-I. There were no gender differences or difference between type of diabetes in the incidence of fractures or risk factors.

In summary, the results of our studies show that peripheral local osteopenia occurs in diabetes associated with impaired IGF availability/activity and PNP independent of type of diabetes or gender and leads to an increased incidence of peripheral fractures. The pathogenesis behind fractures in DM is multifactorial. Neuropathy, microangiopathy and metabolic factors including the IGF system influence the development of peripheral osteopenia and fracture risk. This indicates that assessment of fracture risk should be follow in diabetes patients besides microangiopathy and neuropathy. QUS of calcaneus, serum levels of IGF-I and IGFBP-5 could be complementary screening methods for fracture risk assessment in subjects with diabetes and PNP.