Pathophysiology and Management of Type 2 Diabetes Mellitus Bone Fragility

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,  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, ; 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 (, )
			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 (, 95% CI 0.17-0.87); however, exenatide treatment was associated with an elevated risk of incident bone fractures (, 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  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  yr), in Germany	The use of DPP-4 inhibitors was associated with a significant decrease in the risk of developing bone fractures (all patients , 95% CI 0.54-0.84; women , 95% CI 0.54-0.97; men , 95% CI 0.44-0.88)
	[90]	Meta-analysis based on 51 RCTs (; mean age  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; ) or when DPP-4 inhibitor was compared against an active comparator (OR; 1.59, 95% CI 0.91-2.80, )
			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,  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)