Table 1.
| Metformin | |||
| Preclinical | Ref. | Effect | |
| [2, 63] | ↑ Bone mass and bone strength ↓ AGE accumulation ↓ ROS formation ↓ Osteoblast apoptosis |
||
| Clinical | Ref. | Characteristics | Fracture risk |
| [46] | Prospective cohort study among 1964 Rochester residents who first met glycemic criteria for diabetes in 1970-1994 (mean age, 61.7 ± 14.0 yr; 51% men) | The risk was decreased among users of biguanides (HR, 0.7; 95% CI, 0.6-0.96) | |
| [64] | Prospective cohort study, based on data from the Osteoporotic Fractures in Men (MrOS) study that enrolled 5,994 men (aged ≥65 years) | Metformin did not increase the risk of nonvertebral fracture | |
| [65] | Case-control study based on 498,617 subjects in Denmark | Decreased risk of fractures | |
| [66] | Population based study among 206,672 individuals | There was no association of hip fracture with cumulative exposure to metformin | |
| Overall: ↓ = fracture risk | |||
|
| |||
| Sulfonylureas | |||
| Preclinical | Ref. | Effect | |
| [2, 61, 63] | ↑ Osteoblast proliferation and differentiation | ||
| Clinical | Ref. | Characteristics | Fracture risk |
| [46] | Prospective cohort study among 1964 Rochester residents who first met glycemic criteria for diabetes in 1970-1994 (mean age, 61.7 ± 14.0 yr; 51% men) | No significant influence on fracture risk was seen with sulfonylurea | |
| [65] | Case-control study based on 498,617 subjects in Denmark | Use of sulfonylureas was associated with a decreased risk of any fracture | |
| [66] | Population-based study among 206,672 individuals | There was no association of hip fracture with cumulative exposure to sulfonylureas | |
| [67] | Retrospective observational study on 361,210 patients with type 2 diabetes | ICD-9-CM-coded outpatient hypoglycemic events were independently associated with an increased risk of fall-related fractures | |
| [69] | Cross-sectional study on 838 Japanese patients with T2DM | Decreased risk of vertebral fractures in postmenopausal women (OR = 0.48, P = 0.018) | |
| Overall: ↓ = fracture risk, ↑ fall risk due to hypoglycemia | |||
|
| |||
| Thiazolidinediones | |||
| Preclinical | Ref. | Effect | |
| [2, 63] | ↑ Osteoclastogenesis ↑ Osteocytes apoptosis |
||
| [70–72] | ↑ Bone marrow adipogenesis ↓ Osteoblastogenesis |
||
| Clinical | Ref. | Design | Fracture risk |
| [73] | Longitudinal study on ADOPT data from 1,840 women and 2,511 men with T2DM | The increase in fractures with rosiglitazone representing hazard ratios (95% CI) of 1.81 (1.17-2.80) and 2.13 (1.30-3.51) for rosiglitazone compared with metformin and glyburide occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs | |
| [76] | Nested case-control study based on data of 32,466 T2DM from the Longitudinal Health Insurance Database 2000 (LHID2000) and the catastrophic illness patient registry (CIPR) in Taiwan | Increased risks for fracture in patients who used TDZs, especially in female patients younger than 64 years old, for whom the risk was elevated from a 1.74- to a 2.58-fold odds ratio | |
| Overall: ↑ fracture risk (peripheral fractures) | |||
|
| |||
| Incretins | |||
| Preclinical | Ref. | Effect | |
| [2, 63] | DPP-4 inhibitors ↓ Bone resorption; ↑ trabecular and cortical bone volume |
||
| [82, 83] | GLP1-RA ↑ Proliferation of bone marrow mesenchymal stem cells; ↓ differentiation adipocytes; ↓ sclerostin expression |
||
| Clinical | Ref. | Design | Fracture risk |
| [85] | Meta-analysis including 16 RCTs and a total of 11,206 patients to study the risk of bone fractures associated with liraglutide or exenatide, compared to placebo or other active drugs | Liraglutide treatment was associated with a significant reduced risk of incident bone fractures (MH − OR = 0.38, 95% CI 0.17-0.87); however, exenatide treatment was associated with an elevated risk of incident bone fractures (MH − OR = 2.09, 95% CI 1.03-4.21) | |
| [86] | Meta-analysis including 7 RCTs to assess GLP-1Ra-related fracture risk compared with other antidiabetic drugs | Use of GLP-1Ra does not modify the risk of bone fracture in T2DM compared with the use of other antidiabetic medications | |
| [88] | A case-control study nested within a cohort of 1,945 diabetic outpatients with a follow-up of 4.1 ± 2.3 yr | No significant association was observed between bone fractures and medications | |
| [89] | A retrospective analysis of real-world data that matched 4160 DPP4i ever users to never users in metformin-treated T2DM patients (mean age 61 ± 11 yr), in Germany | The use of DPP-4 inhibitors was associated with a significant decrease in the risk of developing bone fractures (all patients HR = 0.67, 95% CI 0.54-0.84; women HR = 0.72, 95% CI 0.54-0.97; men HR = 0.62, 95% CI 0.44-0.88) | |
| [90] | Meta-analysis based on 51 RCTs (N = 36,402; mean age 57 ± 5 yr), to assess fractures in T2DM, comparing DPP-4 inhibitors with either an active agent or a placebo | No association of fracture events with the use of DPP-4 inhibitor when compared with placebo (OR; 0.82, 95% CI 0.57-1.16; P = 0.9) or when DPP-4 inhibitor was compared against an active comparator (OR; 1.59, 95% CI 0.91-2.80, P = 0.9) | |
| Overall: ↓ fracture risk with liraglutide; =↓ fracture risk with DPP-4 inhibitors | |||
|
| |||
| SGLT-2 inhibitors | |||
| Preclinical | Ref. | Effect | |
| [94] | ↑ Urinary calcium ↓ Serum PTH levels |
||
| Clinical | Ref. | Design | Fracture risk |
| [92] | Meta-analysis on 20 studies including 8,286 patients treated with SGLT-2 compared with placebo | Not increased fracture risk; pooled risk ratio of bone fracture in patients receiving SGLT2 inhibitors versus placebo was 0.67 (95% confidence interval, 0.42-1.07) | |
| [93] | Cumulative meta-analysis of 38 RCTs (10 canagliflozin, 15 dapagliflozin, and 13 empagliflozin) involving 30,384 patients | Compared with placebo, canagliflozin (OR 1.15; 95% CI 0.71-1.88), dapagliflozin (OR 0.68; 95% CI 0.37-1.25), and empagliflozin (OR 0.93; 95% CI 0.74-1.18) were not significantly associated with an increased risk of fracture | |
| [96] | Randomized phase 3 study on 10,194 T2DM patients to describe the effects of canagliflozin on bone fracture risk | Fracture risk was increased with canagliflozin treatment and may be mediated by falls | |
| Overall: = fracture rate or ↑ by canagliflozin | |||
|
| |||
| Insulin | |||
| Preclinical | Ref. | Effect | |
| [97–99] | ↑ Bone anabolism; ↓ bone resorption ↑ BMD |
||
| Clinical | Ref. | Design | Fracture risk |
| [46] | Prospective cohort study among 1964 Rochester residents who first met glycemic criteria for diabetes in 1970-1994 (mean age, 61.7 ± 14.0 yr; 51% men) | Increased fracture risk in patients on insulin (HR, 1.3; 95% CI, 1.1–1.5) | |
| [64] | Prospective cohort study, based on data from the Osteoporotic Fractures in Men (MrOS) study that enrolled 5,994 men (aged ≥65 years) | The risk of nonvertebral fracture increased only among men with T2DM who were using insulin (HR 1.74, 95% CI 1.13, 2.69) | |
| [43] | Prospective study on 3,654 older Australians | Insulin treatment was associated with increased fracture risk (adjusted RR 5.9, 95% CI 2.6-13.5) | |
| [101] | Prospective cohort study based on data from 9654 women, aged >65 yr in the Study of Osteoporotic Fractures | Insulin-treated diabetics had more than double the risk of foot (multivariate adjusted RR, 2.66; 95% CI, 1.18-6.02) fractures compared with nondiabetics | |
| Overall: ↑ fracture risk (especially nonvertebral fracture) | |||