‘My Osteoporosis Went Away But My Diabetes Got Worse…’

A 74-year-old female with type 2 diabetes of 20 years duration and osteoporosis diagnosed 8 years prior presented in April 2012 for initial endocrine consultation. Her diabetes was well controlled with a recent HbA1c of 6.5% on a three-drug regimen of oral antihyperglycemic therapy, including metformin 850 mg three times daily, glipizide 10 mg twice daily and pioglitazone 45 mg daily. 

Background

The patient underwent DXA scanning of the hip and lumbar spine in July 2012. Results revealed a lumbar spine density (L2-L4) of 1.506 gm/cm² (T-score, 2.49) and femoral neck density of 0.644 gm/cm² (T-score, –2.93), consistent with osteoporosis. 

Given the potential deleterious effects on bone mineral density (BMD) reported with thiazolidinediones (TZDs), we decided to discontinue the pioglitazone in July 2012. However, somewhat expectedly, discontinuation of the TZD resulted in elevation in her HbA1c over the ensuing months. Canagliflozin was ultimately added to the same dose of metformin and glipizide to attain reasonable glycemic control.

In November 2014, she underwent repeat DXA scanning on the same DXA machine in the same location, performed and interpreted by the same clinical densitometrist and physician. Remarkably, lumbar spine density (L2-L4) was now 1.678 gm/cm² (T-score, 3.56) and femoral neck density was 0.961 gm/cm² (T-score, –0.22), which signified an 11.4% increase in lumbar spine density and a rather remarkable 49.3% increase in femoral neck BMD.

Case Discussion

What is the explanation for this dramatic improvement in BMD?

TZDs are associated with weight gain and fat redistribution. Could excess body weight potentially explain the increase in her lumbar spine BMD noted between the two DXA scans?

Our patient had lost 13 kg in the time period between the two scans. The only change in her medications during this time period had been the addition of canagliflozin (a few months prior) and the discontinuation of the pioglitazone 27 months prior. Levels of 25-hydroxyvitamin D were unchanged at 45 ng/mL in April 2012 and 37 ng/mL in August 2014, without any change in her vitamin D intake or any current or prior antiresorptive medications

See the Norland DXA image below for a comparison of femoral neck BMD images in July 2012 and November 2014.

We cannot be sure of the exact explanation for this dramatic improvement in BMD, given the numerous factors involved in bone mineral metabolism. However, the potential role of TZD discontinuation is intriguing and certainly worth careful consideration, after weighing the current state of the evidence.

There are epidemiological data supporting a modest increase in fracture risk in individuals with type 2 diabetes, without clear mechanistic explanations for the increased skeletal fragility. Preclinical, observational studies and meta-analyses of clinical trials suggest that TZDs may reduce BMD and increase fracture risk.

There is fairly rigorous evidence to support an increased incidence of peripheral appendicular skeletal fractures in postmenopausal women with type 2 diabetes. Much of the evidence has been derived from studies of rosiglitazone — which is now rarely prescribed in the United States. Direct randomized skeletal comparison data between rosiglitazone and pioglitazone are not available.

Very few studies have been designed to assess fracture risk as a primary endpoint. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation by TZDs stimulates differentiation of mesenchymal stem cells to favor adipogenesis at the expense of osteoblast formation in basic and animal models. However, there have been inconsistent reports on the deleterious effects on cortical bone structure with TZD use. Increased fracture risk in men and younger women is not well established.

In addition, the mechanism by which TZDs increase skeletal fragility are still unclear. More recent, prospective, placebo-controlled clinical trial data with both TZDs suggest negligible decreases in BMD over 12 to 18 months (pioglitazone 30 mg daily vs. placebo for 1 year in type 2 diabetes and pioglitazone 30 mg  to 45 mg daily vs. placebo for 18 months in impaired glucose tolerance or type 2 diabetes).

These recent data do not support a causal relationship between pioglitazone and increased fracture risk, although the short duration of these studies may miss subsequent bone loss, which has been reported to become apparent during later years of TZD treatment.^1,2

How then should we proceed with our patients with type 2 diabetes and osteoporosis, given the current state of the evidence?³

Fracture risk and skeletal health should be considered in all patients with type 2 diabetes for whom TZD therapy is being considered. Postmenopausal women with type 2 diabetes are at higher risk than men or younger premenopausal women. Those who are deemed to be at higher risk should have a frank conversation about risks and benefits of ongoing therapy.  In TZD-naïve high risk patients, consideration of alternative therapies still seems prudent.

References

1. Grey A et al. The skeletal effects of pioglitazone in type 2 diabetes or impaired glucose tolerance: a randomized controlled trial. Eur J Endocrinol. 2013;170(2):255-62.
2. Bone HG et al. Effects of pioglitazone on bone in postmenopausal women with impaired fasting glucose or impaired glucose tolerance: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2013;98(12):4691-4701.
3. Grey A. Diabetes medications and bone. Curr Osteoporos Rep. 2015;13(1):35-40.