Metformin revisited: Does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy

Table 1 Role of AMP-activated protein kinase activation on cell metabolism in different organs

Organ	Effect	Mechanism of action	Ref.
Liver	Inhibition of anabolic pathways	Inhibition of fatty acid synthesis	[27]
		Inhibition of gluconeogenesis
	Stimulation of ATP synthesis	Stimulation of Mitochondrial oxidative phosphorylation	[27]
Skeletal muscle	Regulation of energy expenditure during exercise	Favours the transition from glycolitic to oxidative skeletal muscle fibers	[28]
		Regulation of myocitic uptake and oxidation of fatty acids	[21]
		Enhanced glucose uptake via an increase in GLUT4 expression	[21]
	Increase in skeletal muscle regeneration	Regulation of post-injury inflammatory response	[29]
		Stem cell reprogramming: Induction of proliferation, differentiation and self-renewal	[21]
Bone	Increase in osteoblastogenesis	Increases MSC differentiation towards the osteoblastic lineage favouring Runx2 expression	[30,37]
		Decreases PPARγ expression diminishing MSC differentiation towards the adipocytic phenotype	[36,37]
	Decrease in osteoclastogenesis	Negative regulation of RANKL expression by osteoblasts	[35]

MSC: Mesenchymal stem cells; ATP: Adenosine triphosphate; GLUT4: Glucose transporter type 4; RANKL: Receptor activator for nuclear factor κB ligand.

Table 2 Clinical evidences of metformin effects on bone

Study design	Study population	n	Outcome	Ref.
Case control study	All subjects with bone fracture in Denmark (year 2000), vs 3-fold controls	124655 fracture patients 373962 control	Fracture risk = 0.81 (95%CI: 0.70-0.93)1 (for metformin)	[59]
Cohort Study	Rochester residents first meeting Diabetes glycaemic criteria (1970-1994)	1964 diabetic patients	Fracture risk = 0.7 (95%CI: 0.6-0.96)2 (for metformin)	[6]
Case control study	A study nested within a cohort of 1945 diabetic Tuscany outpatients (1998-2004)	83 fracture patients 249 control	Fracture risk = 0.60 (95%CI: 0.34-1.08)3 (for metformin)	[60]
Double-blind, randomized, controlled clinical trial	Recently diagnosed, drug-naïve patients with type 2 diabetes, treated for a median of 4 yr with rosiglitazone, metformin, or glyburide	Rosiglitazone: n = 1456; Metformin: n = 1454; Glyburide: n = 1441	Nº Fractures (%): Rosiglitazone 60 (9.30) Metformin 30 (5.08)4 Glyburide 21 (3.47)4	[12]
Double-blind, randomized, controlled clinical trial	Recently diagnosed, drug-naïve patients with type 2 diabetes, treated for a median of 4 yr with RSG, MET, or GLY	Paired baseline and 12-mo stored serum samples from 1605 patients	In women, CTX increased by 6.1% with RSG, decreased by 1.3% with MET (P = 0.03) In men, CTX was unchanged on RSG (-1.0%) and fell with MET -12.7% (P = 0.001)	[61]
Randomized, parallel group, double-blind, multicentre study	Drug naïve, male and female patients who had an established clinical diagnosis of type 2 diabetes mellitus	688 patients equally randomized to RSG/MET or MET	BMD at week 80: Lumbar = (-2.2) (95%CI: -3.5, -0.9) Total hip = (-1.5) (95%CI: -2.3, -0.7)5	[62]
Prospective randomized study with active comparator study	Forty postmenopausal diabetic women recruited from Tanta University Hospitals	20 patients on metformin and 20 on sitagliptin, for 12 wk	BMD was unchanged in both groups at week 12 Bone turnover markers remained unchanged from baseline in MET	[63]
Prospective randomized double-blind, double-dummy with active comparator	Men with uncomplicated type 2 diabetes mellitus, aged 45-65 yr	71 men were randomized to PIO once daily or MET twice daily	Sclerostin levels at week 24 increased by 11% in PIO-treated patients and decreased by 1.8% in MET-treated patients (P = 0.018)	[64]

¹Relative risk of any fracture interpreted as OR with 95%CI for several variables in the population of Denmark (National Health Registry, year 2000);

²Multivariate HR for the development of any new fracture among 1964 Rochester, MN, United States residents after recognition of diabetes mellitus in 1970-1994;

³Exposure for at least 36 mo to hypoglycemic treatments in case subjects and matched control subjects, interpreted as OR with 95%CI;

⁴P < 0.01 for comparison of fracture risk in women with rosiglitazone (unadjusted, contingency χ² test);

⁵Percentage of change in BMD at week 80, comparing RSG/MET vs MET. RSG: Rosiglitazone; MET: Metformi; GLY: Glyburide; PIO: Pioglitazone; BMD: Bone mineral density; OR: Odds ratio; HR: Hazard ratios.