Effect of sitagliptin vs. placebo on bone mineralization in women with type 2 diabetes: the SLowDOWN (SitagLiptin in Diabetes for Osteoporosis in WomeN) randomized clinical trial

1. In women with type 2 diabetes (T2D), treatment with sitagliptin was associated with preservation of the total femur T score compared to treatment with placebo, indicating a protective effect on bone health in such patients. 

Evidence Rating Level: 1 (Excellent)

Study Rundown: The SLowDOWN randomized, double-blind, placebo-controlled trial included 132 women with T2D on metformin and 52 weeks of sitagliptin 100 mg daily with the aim of investigating the effect of sitagliptin on bone outcomes in women with T2D. They found that treatment with sitagliptin was associated with a preserved total hip T score compared with placebo (between-group difference +0.11; 95% CI 0.03–0.19; p=0.0063), while other skeletal sites (femoral neck, lumbar spine) and trabecular bone score showed no significant between-group differences. Bone turnover markers and vitamin D were unchanged, whereas sitagliptin significantly lowered circulating DPP-4 activity (24 and 52 weeks) and several inflammatory mediators at 24 weeks. Glycemic control remained comparable between groups, and treatment was well tolerated without serious adverse events. These data suggest a modest, site-specific preservation of hip bone status with sitagliptin beyond glycemic effects in women with T2D who are not osteoporotic. Confirmation in longer-term studies—including higher-risk populations and fracture endpoints—is needed to establish clinical relevance and delineate mechanisms.

Click to read the study in BMC Medicine

Relevant Reading: Glycated Hemoglobin Level and Risk of Hip Fracture in Older People with Type 2 Diabetes: A Competing Risk Analysis of Taiwan Diabetes Cohort Study

In-Depth [Randomized Controlled Trial]: 

Women with type 2 diabetes (T2D) experience higher fracture risk than nondiabetic peers, a discrepancy not fully explained by bone mineral density (BMD) alone. Advanced glycation end products, low-grade inflammation, neuropathy, and certain glucose-lowering drugs may impair bone quality. Dipeptidyl peptidase-4 inhibitors (DPP-4i) have been hypothesized to benefit bone via effects on incretins and osteo-immune pathways, but high-quality randomized evidence with skeletal outcomes has been limited. The SLowDOWN trial tested whether sitagliptin preserves skeletal status while controlling for glycemic change in women with well-controlled T2D.

SLowDOWN was a multicenter, phase III, double-blind, randomized, placebo-controlled trial conducted at outpatient diabetes clinics in Rome, Italy. Investigators enrolled 132 adult women with T2D receiving stable metformin monotherapy and with stable glycemic control. Participants were randomized to sitagliptin 100 mg daily or matching placebo for 52 weeks. The primary skeletal outcomes were the change in dual-energy X-ray absorptiometry (DXA) measures of BMD and T-scores at the lumbar spine and proximal femur (total hip and femoral neck). Trabecular bone score (TBS) was derived from lumbar images. Prespecified secondary outcomes included serum DPP-4 concentration and activity, standard bone-turnover markers (e.g., P1NP, CTX, osteocalcin), osteo-regulatory proteins (e.g., OPG, sclerostin), 25-hydroxyvitamin D, glycemic indices, and a multiplex panel of inflammatory mediators relevant to bone remodelling. Analyses followed an intention-to-treat framework, with a per-protocol sensitivity analysis.

Baseline characteristics were well balanced, and medication adherence was high. Over 52 weeks, sitagliptin preserved the total hip (total femur) T-score, whereas placebo showed a statistically significant decline. The within-group estimate for sitagliptin was −0.02 T-score units (95% CI −0.07 to 0.03; p=0.46) compared with −0.13 (95% CI −0.19 to −0.07; p<0.0001) for placebo, yielding a between-group difference of +0.11 (95% CI 0.03 to 0.19; p=0.0063). At the femoral neck, trends favored sitagliptin, but the between-group difference was not significant. At the lumbar spine, neither BMD nor T-score differed between groups, and TBS was similarly unchanged.

Biomarker data confirmed on-target pharmacology. Sitagliptin significantly reduced circulating DPP-4 activity at 24 and 52 weeks. Inflammatory mediators implicated in bone turnover—including CXCL10, eotaxin, GM-CSF, IL-1α, IL-7, MIP-1β, PDGF-BB, and VEGF—were lower with sitagliptin at 24 weeks, suggesting an anti-inflammatory signal. In contrast, classical bone-turnover markers (P1NP, CTX, osteocalcin), OPG, sclerostin, and 25-hydroxyvitamin D showed no meaningful between-group differences over time. Glycemic indices (fasting glucose and HbA1c) and lipids remained similar between arms, indicating that skeletal findings were unlikely to be driven by differential metabolic control.

Safety was favorable. Five non-serious adverse events occurred across both groups, and no serious adverse events or deaths were reported.

Overall, in women with T2D on metformin and without baseline osteoporosis, one year of sitagliptin produced a modest, site-specific preservation of total hip T-score relative to placebo, without significant effects on absolute BMD, lumbar spine measures, TBS, or bone-turnover markers. The accompanying reductions in DPP-4 activity and select inflammatory mediators are biologically plausible contributors but remain exploratory. Limitations include the modest effect size confined to a single skeletal site, the 52-week duration, and the restricted population (women, metformin monotherapy, good glycemic control), which limits generalizability to men or higher-risk patients and precludes inference about fracture outcomes. These findings are hypothesis-generating and support longer, adequately powered trials in higher-risk populations with fracture endpoints to determine clinical relevance.

Image: PD

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