Metformin Bone Health and Density Impact: What the Evidence Actually Shows

What the large metformin trials measured

Metformin's trial evidence on this page is built on glycemic and metabolic outcomes. The Diabetes Prevention Program assigned 3,234 adults with elevated fasting and post-load glucose to placebo, metformin 850 mg twice daily, or an intensive lifestyle program. Mean age was 51, mean BMI 34.0, and 68% were women. Over a mean 2.8 years, diabetes incidence was 11.0, 7.8 and 4.8 cases per 100 person-years respectively, a 31% reduction with metformin (95% CI 17 to 43%) and 58% with lifestyle [2].

The 15-year follow-up of 2,776 participants found diabetes incidence reduced 18% with metformin versus placebo (HR 0.82) and no overall difference in microvascular disease: 12.4% with placebo, 13.0% with metformin, 11.3% with lifestyle [3].

ADOPT randomized 4,360 patients to rosiglitazone, metformin or glyburide for a median 4.0 years, with time to monotherapy failure as the primary outcome. It reported glycemic durability, more weight gain and edema with rosiglitazone, and more gastrointestinal events with metformin than with rosiglitazone [4].

What the label and trials say about vitamin B12

The label's vitamin B12 warning comes with a schedule. In 29-week clinical trials, subnormal B12 levels developed in approximately 7% of patients whose levels had been normal; the decrease may be associated with anemia and appears rapidly reversible with discontinuation or B12 supplementation. The label directs measuring hematologic parameters annually and vitamin B12 at 2 to 3 year intervals, and managing any abnormalities [1].

A secondary analysis of the Diabetes Prevention Program gives longer-term numbers. Low B12 (203 pg/mL or less) occurred in 4.3% versus 2.3% at 5 years (p=0.02) but not significantly more at 13 years (7.4% versus 5.4%, p=0.12). Combined low and borderline-low B12 (298 pg/mL or less) was more common with metformin at 5 years (19.1% versus 9.5%) and at 13 years (20.3% versus 15.6%, p=0.02). Odds of deficiency rose 13% per year of metformin use (OR 1.13, 95% CI 1.06 to 1.20) [5].

What the label covers

Metformin is labeled as an adjunct to diet and exercise for glycemic control in type 2 diabetes: in adults, and in children 10 and older for the immediate-release tablets. Prediabetes, PCOS and weight loss are not labeled uses, and bone health is not a labeled use either [1].

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