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
Insulin	Anabolic	Increases fall risk[68]	No negative effect	Hip, 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 ↑
Metformin	Anabolic (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 apoptosis		In 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 ↓
Sulfonylurea	Negligible effect	Increases fall risk due to hypoglycemia	Negligible effect	A 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 ↔/↑
Pioglitazone	Proadipogenic. Inhibits osteoblast differentiation. Inhibits osteoclast differentiation[77]	None	The 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 inhibitors	Preclinical studies demonstrated antiresorptive evidence[80]	None	None	The 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 Analogues	Pro-osteoblast. Suppress sclerostin and increase osteocalcin[82]	By virtue of weight loss, they are supposed to cause a decrease in BMD	BMD 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 inhibitors	Preclinical data are conflicting	Weight loss causes BMD loss. Increased PTH due to phosphate reabsorption	A 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 surgery	No direct effect. Mechanical unloading, nutritional deficiencies and hormonal changes are catabolic to bone	Massive 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 procedures	Patients 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 ↑

AGB: Adjustable gastric banding; AMPK: AMP-activated protein kinas; BMD: Bone mineral density; CI: Confidence interval; CTX: C-terminal cross-linked telopeptide; DPP-4: Dipeptidyl-peptidase 4; GLP-1: Glucagon -like peptide-1; HR: Hazard ratio; OR: Odds ratio; PTH: Parathormone; QCT: Quantitative computed tomography; RCT: Randomized controlled trial; RYGB: Roux-en-Y gastric bypass; RR: Relative risk; SGLT-2: Sodium-glucose cotransporter 2; T2DM: Type 2 diabetes mellitus; TZD: Thiazolidinedione; ↑: Increase; ↓: Decrease; ↔: Unchanged; +ve: Positive; -ve: Negative.