Diabetes pharmacotherapy and effects on the musculoskeletal system

Abstract

Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

“…Ex-4 and sitaglitin (DPP4 inhibitor) are known to improve kidney function by attenuating inflammation in chronic or diabetic kidney disease models. 17,72 Therefore, it is unclear whether the beneficial effect of Ex-4 is due to its role in improving kidney function, its direct effect on muscle, or both in the current study. Further studies are needed to clarify this.…”

“…Similar to the observations in Dex‐treated mice, Ex‐4 significantly increased total muscle mass, CSA of the TA muscle, and muscle function in CKD mice. Ex‐4 and sitaglitin (DPP4 inhibitor) are known to improve kidney function by attenuating inflammation in chronic or diabetic kidney disease models . Therefore, it is unclear whether the beneficial effect of Ex‐4 is due to its role in improving kidney function, its direct effect on muscle, or both in the current study.…”

“…Therefore, GLP‐1‐based drugs have been developed as an anti‐diabetic therapy. Although some studies have implicated the possible effects of GLP‐1‐based drugs on muscle mass, metabolism, and function, little is known about the precise mechanisms underlying its effects . Therefore, we investigated whether GLP‐1‐based drugs have a therapeutic effect in muscle wasting.…”

Canagliflozin should be prescribed with caution to individuals with type 2 diabetes and high risk of amputation

“…Research has demonstrated roles for magnesium, calcium and vitamin D in promoting wound healing, with clinical trial evidence of enhanced diabetic foot ulcer healing with both magnesium and vitamin D supplementation [27][28][29]. Canagliflozin administration led to an increase of urine calcium excretion and magnesium wasting in animal models, and a decrease in 1,25(OH) 2 -vitamin D in hospitalised patients [30]. Further research is needed in humans to determine whether these effects on calcium, magnesium and vitamin D metabolism are specific to canagliflozin or a general characteristic of SGLT2 inhibitors.…”

Effects of dapagliflozin on the serum levels of fibroblast growth factor 21 and myokines and muscle mass in Japanese patients with type 2 diabetes: A randomized, controlled trial

“…The prevalence of type 2 diabetes is increasing worldwide, and it is pathologically involved in accelerating the loss of muscle mass and strength. Muscle atrophy is a high‐risk factor for physical disability and mortality; therefore there is an urgent need to develop effective strategies to prevent and treat diabetes‐related muscle atrophy, including sarcopenia.…”