Distinct effects of pioglitazone and metformin on circulating sclerostin and biochemical markers of bone turnover in men with type 2 diabetes mellitus

Lierop, Antoon H van; Hamdy, Neveen A. T.; Meer, R.W. van der; Jonker, Jacqueline T.; Lamb, Hildo J.; Rijzewijk, Luuk J.; Diamant, Michaëla; Romijn, Johannes A.; Smit, Johannes W. A.; Papapoulos, Socrates E.

doi:10.1530/eje-11-1061

Cited by 72 publications

(48 citation statements)

References 42 publications

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“…In patients with T2DM, the increase of serum sclerostin is associated with a significant decrease in the b-catenin serum concentration, suggesting, indeed, that sclerostin signaling is modulated in diabetes (31). On one hand, this gives support to the hypothesis that bone, which produces almost all the available sclerostin, may play a role also in glucose metabolism and insulin resistance (8,32,35). On the other hand, it can be speculated that anti-sclerostin antibody treatment, which is a promising option for severe osteoporosis and surgical implant fixation, might have a role in T2DM treatment (36).…”

Section: Discussionmentioning

confidence: 64%

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

et al. 2015

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OBJECTIVEA gene mutation of the Wnt/b-catenin signaling cascade is present in rare patients with the insulin resistance syndrome. Sclerostin is a circulating peptide inhibiting Wnt/b-catenin signaling. Our aims were to evaluate serum sclerostin in subjects with prediabetes and to analyze its relationship with insulin resistance and b-cell function. RESEARCH DESIGN AND METHODSWe performed a cross-sectional study including 43 healthy normal glucose-tolerant (NGT) individuals and 79 individuals with impaired glucose regulation (IGR), which included subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG-IGT, undergoing oral glucose tolerance test (OGTT) and dual-energy X-ray absorptiometry. A subgroup of 18 with NGT and 30 with IGR also underwent a euglycemic-hyperinsulinemic clamp with tracer. RESULTSSclerostin levels were higher in IGR compared with NGT (50.8 6 2.4 vs. 38.7 6 2.3 pmol/L; P = 0.01), positively correlated with HOMA-insulin resistance (IR) (r = 0.62; P < 0.001), and negatively correlated with insulin-mediated total body glucose disposal (r = 20.40; P < 0.001). Fasting endogenous glucose production (EGP) and hepatic and adipose tissue insulin resistance indexes were positively correlated with sclerostin levels (r = 0.48, r = 0.62, and r = 0.61, respectively; P < 0.001). Fasting and OGTT insulin clearance were inversely correlated with sclerostin serum levels (r = 20.52 and r = 20.44, respectively; both P < 0.001). Sclerostin levels were not correlated with b-cell function parameters. In multiple linear regression analysis, the addition of sclerostin levels to the traditional risk factors for insulin resistance improved the r 2 associated with HOMA-IR (r 2 change: 0.055; F change: 28.893; P = 0.001) and insulin-mediated total body glucose disposal (r 2 change: 0.059; F change: 4.938; P = 0.033). CONCLUSIONSSclerostin levels are increased in individuals with prediabetes and correlated with insulin resistance in skeletal muscle, liver, and adipose tissue. The correlation between sclerostin and insulin clearance at fasting state and during OGTT is novel; thus, studies are needed to explore the potential causal relationship.

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Section: Discussionmentioning

confidence: 64%

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

et al. 2015

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“…Of the five studies reporting on bsALP, one reported a significant increase with TZDs [12] and no effect was seen in four [13,17,25,28]. Of the 11 studies reporting on PINP, three reported significant increases with TZDs [12,18,33], two showed significant decreases [27,31] and six found no effect [13-15, 17, 25, 28]. Of the six studies that reported on osteocalcin, one demonstrated a significant decrease with TZDs [14] and five showed no effect [21,23,25,28,31].…”

Section: Study Characteristicsmentioning

confidence: 95%

“…Figure 3 shows that there were no statistically significant differences in percentage change in BMD between the TZD group and controls following treatment withdrawal. 10 studies reporting on CTX, five reported significant increases with TZDs [12,17,18,28,33] and five showed no effect [13-15, 25, 31]. Of the five studies reporting on bsALP, one reported a significant increase with TZDs [12] and no effect was seen in four [13,17,25,28].…”

Section: Study Characteristicsmentioning

confidence: 99%

The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis

2015

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Aims/hypothesis Thiazolidinediones (TZDs) are associated with an increased risk of fracture but the mechanism is unclear. We sought to determine the effect of TZDs on bone mineral density (BMD) and bone turnover markers. Methods PubMed, EMBASE and Cochrane CENTRAL databases were searched from inception until January 2015 for randomised controlled trials comparing TZDs with metformin, sulfonylureas or placebo, and those reporting changes in BMD and/or bone turnover markers. The primary outcome was percentage change in BMD from baseline and results were pooled with random effects meta-analyses. Results In all, 18 trials were included in the primary analyses and another two were included in the sensitivity analyses (n=3,743, 50% women, mean age 56 years, median trial duration 48 weeks). TZDs decreased BMD at the lumbar spine (difference −1.1% [95% CI −1.6, −0.7]; p<0.0001), total hip (−1.0% [−1.4, −0.6]; p<0.0001) and forearm (−0.9% [−1.6, −0.3]; p=0.007). There were statistically non-significant decreases in BMD at the femoral neck (−0.7% [−1.4, 0.0]; p=0.06) and total body (−0.3% [−0.5, 0.0]; p=0.08). Five trials (n=450) showed no statistically significant difference in percentage change in BMD between the TZD group and controls up to 1 year following TZD withdrawal. In 14 trials, the effect of TZD treatment on turnover markers varied considerably between individual studies. Conclusions/interpretation Treatment with TZDs results in modest bone loss that may not be reversed 1 year after cessation of treatment.

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“…Other mechanisms, beside the alteration of adipocyte and osteoblast differentiation, could be involved in the detrimental action of thiazolidinediones on bone metabolism. An increase of markers of bone turnover has been reported with both pioglitazone and rosiglitazone, compared with either metformin or placebo in randomized trials (12,13), although some studies disagree (14). It is possible that the reduction in bone density is partly due to increased bone reabsorption, as suggested by the higher number of circulating osteoclast precursors in women treated with thiazolidinediones (15).…”

Section: Mini-reviewmentioning

confidence: 99%

Drugs for type 2 diabetes: role in the regulation of bone metabolism

Mannucci

Dicembrini

2015

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SummaryUntil a few years ago, the possibility that glucose-lowering drugs affect glucose metabolism and fracture risk was not even considered. The increased incidence of fractures with thiazolidinediones in women was a causal finding. This phenomenon, which has been demonstrated by large-scale clinical trials, is associated with a reduction in bone density. Thiazolidinediones stimulate adipocyte differentiation, and inhibit osteoblast differentiation, from bone marrow stromal cells; other mechanisms could also be involved in the thiazolidinedione-induced reduction of bone density. Insulin has an anabolic effect on the bone, but it is nonetheless associated with an increased incidence of fractures in observational studies. Although this finding could be partly due to unaccounted confounders, it is likely that insulin-induced hypoglycemia, and consequent falls, produce a higher risk for fractures, at least in the elderly. Among older drugs, metformin and sulfonylureas do not appear to produce any beneficial or detrimental effects on the bone. Of newer agents, DPP4 inhibitors have been associated with a possible protective effect in earlier trials, but this result has not been confirmed in larger scale studies on patients with a higher level of comorbidities. Considering that the increase in active incretin levels determined by DPP4 inhibitors could theoretically improve bone density, further clinical studies are needed to assess more clearly the effect of this class of drugs. GLP-1 receptor agonists also increase bone density in experimental models, but human data are still insufficient to draw any conclusion.

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Distinct effects of pioglitazone and metformin on circulating sclerostin and biochemical markers of bone turnover in men with type 2 diabetes mellitus

Cited by 72 publications

References 42 publications

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis

Drugs for type 2 diabetes: role in the regulation of bone metabolism

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