Intensive Lifestyle Intervention, Metabolomics, and Risk of Frailty Fracture in Overweight or Obese Patients with Type 2 Diabetes - Weight loss is critical to overweight or obese patients with type 2 diabetes (T2D) for improving glycemic
control, cardiovascular risk factors, and quality of life. However, weight loss has been found to be associated
with increased bone loss and risk for fractures by many studies, including the Action for Health in Diabetes (Look
AHEAD) trial in which we observed an intensive lifestyle intervention (ILI) for weight loss was associated with
39% increased risk for frailty fracture (hip, pelvis, upper arm, or shoulder fractures) compared with diabetes
support and education (DSE) (control group) among overweight or obese patients with T2D. Frailty fractures are
devastating and represent a part of osteoporotic fracture types. We also observed the ILI was associated with
increased bone loss in a subgroup of Look AHEAD who also had dual-energy X-ray absorptiometry (DXA) scans.
However, the mechanisms linking the ILI and increased risk of fracture are still largely unknown but very
important for developing effective methods for protecting bone and preventing fracture during intentional weight
loss. The overall goal of this proposed study is to identify metabolomic changes which mediate the effect of ILI
on the increased risk for frailty fracture in the Look AHEAD trial using a state-of-the-art liquid chromatography-
mass spectrometry (LC-MS)-based metabolomics approach. In this study, we will include 4,659 Look AHEAD
participants (2,357 in ILI and 2,302 in DSE) who had blood samples collected at both baseline and the 1-year
visit and had a median follow-up of 11.3 years for fracture outcomes. Among those, 1,274 participants (642 in
ILI and 632 in DSE) also had DXA scans for bone mineral density (BMD) at both baseline and year 1. In this
study, we will further measure serum bone turnover markers (BTMs) and reanalyze DXA images to obtain the
trabecular bone score (TBS) to evaluate bone metabolism and bone microarchitecture (an indicator of bone
quality) in the DXA subgroup. A comprehensive two-stage metabolomics approach, including an
untargeted/global metabolomics analysis with relative quantification followed by chemical structure validation
and absolute quantification, will support the following Specific Aims: Aim 1) To examine the effects of ILI on
changes in metabolomic profiles from baseline to year 1; Aim 2) To examine whether 1-year changes in
metabolomic profiles are associated with and mediate the effect of ILI on the risk of frailty fracture; Aim 3) To
examine whether 1-year changes in metabolomic profiles are associated with changes in BTMs, BMD, and TBS;
and Aim 4) To examine whether baseline metabolomic profiles modify the effect of ILI on the risk of frailty fracture.
The proposed study will provide comprehensive insights into the biological mechanisms underlying the increased
risk of frailty fracture caused by the ILI. These findings will help discover molecular targets for blocking the
detrimental effect of intentional weight loss on bone health. The study will also provide novel biomarkers for
predicting the risk of frailty fracture and directing the personalization and optimization of lifestyle intervention for
weight loss among overweight and obese patients with T2D.
