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©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
Published online Jun 15, 2021. doi: 10.4239/wjd.v12.i6.706
Table 1 Summary of meta-analyses evaluating risk of fracture in patients with type 2 diabetes mellitus
| Ref. | Fracture site | Risk effect (95%CI) | P value | Risk factors (site) |
| Vilaca et al[39], 2020 | Hip | RR 1.33 (1.19-1.49) | S | Younger age, female gender, insulin use, longer duration of diabetes (hip) |
| Nonvertebral | RR 1.19 (1.11-1.28) | S | ||
| Koromani et al[43], 2020 | Vertebral (incident) | OR 1.35(1.27-1.44) | S | |
| Vertebral (prevalent) | OR 0.84 (0.74-0.95) | S | ||
| Wang et al[36], 2019 | All | RR 1.22 (1.13-1.31) | S | |
| Hip | RR 1.27 (1.16-1.39) | S | ||
| Distal forearm | RR 0.97 (0.66-1.09) | NS | ||
| Upper arm | RR 1.54 (1.19-1.99) | S | ||
| Ankle | RR 1.15 (1.01-1.31) | S | ||
| Vertebrae | RR 1.74 (0.96-3.16) | NS | ||
| Liu et al[44], 2018 | Limb | RR 1.18 (1.02-1.35) | S | Female gender (leg/ankle) |
| Leg/Ankle | RR 1.80 (1.13-2.87) | S | ||
| Humerus | RR 1.27 (0.60-2.68) | NS | ||
| Wrist/hand/foot | RR 1.26 (0.94-1.71) | NS | ||
| Forearm | RR 0.98 (0.78-1.23) | NS | ||
| Vilaca et al[45], 20191 | Ankle | RR 1.30 (1.15-1.48) | S | |
| Wrist | RR 0.85 (0.77-0.95) | S | ||
| Moayeri et al[37], 2017 | All | RR 1.05 (1.04-1.06) | S | Older age, male gender, duration of diabetes. Insulin use, Corticosteroid use (overall) |
| Hip | RR 1.20 (1.17-1.23) | S | ||
| Vertebral | RR 1.16 (1.05-1.28) | S | ||
| Foot | RR 1.37 (1.21-1.54) | S | ||
| Wrist | RR 0.98 (0.88-1.07) | NS | ||
| Proximal humerus | RR 1.09 (0.86-1.31) | NS | ||
| Ankle | RR 1.13 (0.95-1.32) | NS | ||
| Jia et al[38], 20172 | All | IRR 1.23 (1.12-1.35) | S | |
| Hip | IRR 1.08 (1.02-1.15) | S | ||
| Vertebrae | IRR 1.21 (0.98-1.48) | NS | ||
| Ni and Fan[42], 2017 | All LBMF | RR 1.24 (1.09-1.41) | S | Female gender |
| Dytfeld and Michalak[40], 20173 | Hip | OR 1.30 (1.07-1.57) | S | Cohort studies, Studies conducted in Asia (hip) |
| Vertebral | OR 1.13 (0.94-1.37) | NS | ||
| Fan et al[41], 2016 | Hip | RR 1.34 (1.19-1.51) | S | |
| Vestergaard[16], 2007 | Hip | RR 1.38 (1.25-1.53) | S | |
| Wrist | RR 1.19 (1.01-1.41) | S | ||
| Vertebrae | RR 0.93 (0.63-1.37) | NS | ||
| All | RR 0.96 (0.57-1.61) | NS | ||
| Janghorbani et al[14], 2007 | Hip | RR 1.7 (1.3-2.2) | S |
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 ↑ |
Table 3 Effects of osteoporosis medications in patients with type 2 diabetes mellitus
| Medication | Effect on glucose metabolism | BMD | Risk of fracture |
| Alendronate | Reduction in the risk of diabetes | Increase | NA/unchanged |
| Risedronate | Reduction in the risk of diabetes | Increase | NA |
| Etidronate | NA | NA | Unchanged |
| Denosumab | No effect on blood glucoselevels | Increase | Decrease |
| Raloxifene | Improves insulin sensitivity | NA | Decrease/unchanged |
| Teriparatide | No effect blood glucose levels | Increase | Unchanged |
- Citation: Palui R, Pramanik S, Mondal S, Ray S. Critical review of bone health, fracture risk and management of bone fragility in diabetes mellitus. World J Diabetes 2021; 12(6): 706-729
- URL: https://www.wjgnet.com/1948-9358/full/v12/i6/706.htm
- DOI: https://dx.doi.org/10.4239/wjd.v12.i6.706