Review
Copyright ©The Author(s) 2021.
World J Diabetes. Jun 15, 2021; 12(6): 706-729
Published online Jun 15, 2021. doi: 10.4239/wjd.v12.i6.706
Table 2 The effect of diabetes therapies on skeletal parameters and fracture risk
Agents
Effect on bone metabolism
Additional effects on fracture risk
Effect on bone markers and BMD
Effect on fracture
Overall effect
InsulinAnabolic Increases fall risk[68]No negative effectHip, peripheral and osteoporotic fracture risk is magnified[69]. A propensity matched cohort analysis demonstrated adjusted sub hazard ratio of 1.38 (95%CI: 1.06-1.80) for major fractures with insulin use as compared with nonusers[70]. Females are more prone. No increased risk with glargine use[71]Effect on bone +ve. Fracture risk ↑
MetforminAnabolic (via AMPK). Skew the mesenchymal stem cells from the adipogenic to the osteogenic arm[72] and inhibit osteoclast differentiation[73]Reductions in oxidative stress and cell apoptosisIn a meta-analysis the use of metformin was associated with a reduced risk of fracture (RR 0.86, 95%CI: 0.75-0.99). It was mostly prescribed in the early stages of T2DM, and there was less hypoglycemia that might explain fewer fractures with metformin[74]Effect on bone +ve. Fracture risk ↓
SulfonylureaNegligible effectIncreases fall risk due to hypoglycemiaNegligible effectA recent meta-analysis including 11 studies involving 255644 individuals showed 14% increase in the risk of developing fracture[75]. Most of the fractures were attributable to increased fall due to hypoglycemia[76]Effect on bone-neutral. Fracture risk ↔/↑
PioglitazoneProadipogenic. Inhibits osteoblast differentiation. Inhibits osteoclast differentiation[77]NoneThe bone resorption marker(CTX) was elevated, while indicators of bone formation were reduced[78]. It was also associated with significant reduction in BMD among women at the lumbar spine as well in femoral neck. An updated meta-analysis including 24544 participants from 22 RCTS showed significantly increased incidence of fracture was found in women (OR=1.94; 95%CI: 1.60-2.35; P<0.001), but not in men (OR=1.02; 95%CI: 0.83-1.27; P=0.83). The fracture risk was independent of age, and there was no clear association with duration of TZD exposure[79]Effect on bone -ve. Fracture risk ↑
DPP-4 inhibitorsPreclinical studies demonstrated antiresorptive evidence[80]NoneNoneThe overall risk of fracture did not differ between patients exposed to DPP-4 inhibitors and controls (RR, 0.95; 95%CI: 0.83-1.10; P = 0.50) in a meta-analysis including 62 RCTs[81]Effect on bone- neutral. Fracture risk ↔
GLP-1 AnaloguesPro-osteoblast. Suppress sclerostin and increase osteocalcin[82]By virtue of weight loss, they are supposed to cause a decrease in BMDBMD did not significantly change after exenatide-induced weight loss (-3.5 ± 0.9 kg); suggesting that exenatide treatment attenuated BMD decrements after weight loss[83]The Bayesian network meta-analysis suggested that GLP-1 RAs had a decreased bone fracture risk compared to other antihyperglycemic drugs, and exenatide is the safest agent with regard to the risk of fracture[84]Effect on bone +ve. Fracture risk ↔
SGLT-2 inhibitorsPreclinical data are conflictingWeight loss causes BMD loss. Increased PTH due to phosphate reabsorptionA randomized controlled study (104 wk) found that canagliflozin induced reductions in hip BMD (−1.2% relative to placebo)[85]A recent meta-analysis including 30 RCTs demonstrated that the incidence of bone fractures was not significantly different between patients taking SGLT2 inhibitors and placebo[86]Effect on bone ↔. Fracture risk ↔
Metabolic surgeryNo direct effect. Mechanical unloading, nutritional deficiencies and hormonal changes are catabolic to boneMassive weight loss causes a reduction of BMD. The severity of bone outcomes seems to be related to the degree of malabsorption varies depending on different proceduresPatients undergoing gastric bypass surgery, BMD was 5%-7% lower at the spine and 6%–10% lower at the hip compared with nonsurgical controls, as assessed by QCT and dual-energy X-ray absorptiometry[87]In a large database from the United Kingdom. RYGB is associated with a 43% increased risk of nonvertebral fracture compared with AGB, with risk increasing >2 yr after surgery. The risk was highest after 5 yr of surgery (HR 3.91)[87]Effect on bone -ve. Fracture risk ↑