Periodic Reporting for period 4 - MULT2D (Multiscale Mechanics of Bone Fragility in Type-2 Diabetes)
Reporting period: 2023-08-01 to 2025-01-31
The MULT2D project tackled the critical issue of skeletal fragility in individuals with long-term Type 2 Diabetes (T2D). Despite appearing normal in scans, bones in people with T2D are more likely to fracture. Understanding why this happens is essential for improving patient outcomes and reducing the growing healthcare burden.
The project aimed to uncover the biological and mechanical changes in diabetic bone using a combination of animal studies, human tissue analysis, and advanced computer modelling.
One major achievement came from a 46-week animal study using diabetic rats. The team observed early and progressive deterioration in bone size, strength, and mineral development. Importantly, this fragility was not primarily due to AGE (Advanced Glycation End-products) accumulation, as widely assumed, but rather linked to impaired bone turnover and delayed mineral maturation. These findings, published in high-impact journals, earned awards such as the Engineers Ireland Medal.
MULT2D also developed cutting-edge multiscale models to study bone mechanics at the molecular level. Simulations revealed that non-collagenous proteins like osteocalcin and osteopontin play vital roles in helping bone resist damage by dissipating energy. The balance between intra- and extra-fibrillar mineralisation was shown to determine whether bone behaves as brittle or tough—insights with important implications for understanding diabetic bone weakness.
In parallel, the team analysed human bone tissue from T2D patients. Surprisingly, AGE accumulation was not linked to weaker bones; in some cases, it coincided with better resistance to certain types of loading. Mechanical testing and high-resolution imaging showed that bone composition was altered, but these changes didn’t always reduce performance—highlighting the complex interplay of remodeling, mineralisation, and protein function in diabetic bone.
Beyond scientific insights, MULT2D delivered technical innovations, including:
-A multiscale modelling platform linking protein interactions to whole-bone mechanics.
-Novel algorithms to simulate complex trabecular bone structures.
-A phase-field model to predict bone fracture initiation and propagation.
These tools now support further research into bone disease, biomaterials, and implant design. The project trained early-career researchers, established new research directions, and positioned the team for continued impact in biomedical engineering. By shifting the understanding of diabetic bone fragility away from AGEs and toward deeper biological mechanisms, MULT2D opens new doors for diagnostics and treatment strategies in skeletal health.
The project aimed to uncover the biological and mechanical changes in diabetic bone using a combination of animal studies, human tissue analysis, and advanced computer modelling.
One major achievement came from a 46-week animal study using diabetic rats. The team observed early and progressive deterioration in bone size, strength, and mineral development. Importantly, this fragility was not primarily due to AGE (Advanced Glycation End-products) accumulation, as widely assumed, but rather linked to impaired bone turnover and delayed mineral maturation. These findings, published in high-impact journals, earned awards such as the Engineers Ireland Medal.
MULT2D also developed cutting-edge multiscale models to study bone mechanics at the molecular level. Simulations revealed that non-collagenous proteins like osteocalcin and osteopontin play vital roles in helping bone resist damage by dissipating energy. The balance between intra- and extra-fibrillar mineralisation was shown to determine whether bone behaves as brittle or tough—insights with important implications for understanding diabetic bone weakness.
In parallel, the team analysed human bone tissue from T2D patients. Surprisingly, AGE accumulation was not linked to weaker bones; in some cases, it coincided with better resistance to certain types of loading. Mechanical testing and high-resolution imaging showed that bone composition was altered, but these changes didn’t always reduce performance—highlighting the complex interplay of remodeling, mineralisation, and protein function in diabetic bone.
Beyond scientific insights, MULT2D delivered technical innovations, including:
-A multiscale modelling platform linking protein interactions to whole-bone mechanics.
-Novel algorithms to simulate complex trabecular bone structures.
-A phase-field model to predict bone fracture initiation and propagation.
These tools now support further research into bone disease, biomaterials, and implant design. The project trained early-career researchers, established new research directions, and positioned the team for continued impact in biomedical engineering. By shifting the understanding of diabetic bone fragility away from AGEs and toward deeper biological mechanisms, MULT2D opens new doors for diagnostics and treatment strategies in skeletal health.
he MULT2D project, conducted over 72 months, followed an interdisciplinary approach to uncover the causes of bone fragility in Type 2 Diabetes (T2D). Research was structured across three main Work Packages (WPs), combining animal studies, computational modelling, and human tissue research to investigate diabetic bone fragility from the molecular to whole-organ level.
WP1: Experimental Evaluation in Preclinical Models
Using the Zucker Diabetic Fatty (ZDF) rat model, the team examined how T2D affects bone over time. Animals were assessed at 12, 26, and 46 weeks for changes in bone structure and strength using imaging, biochemical assays, and mechanical testing.
Key results included:
-Early and progressive bone growth impairments in diabetic rats.
-Reduced bone size and fracture resistance, especially in older animals.
-Evidence that impaired bone turnover and delayed mineral maturation, rather than AGE accumulation, were key contributors to fragility.
-Elevated bone resorption and inflammatory markers in diabetic animals.
WP2: Multiscale Computational Modelling
This work package developed multiscale computational tools to simulate bone mechanics across scales—from proteins to tissues—using molecular dynamics (MD), coarse-grain modelling, and finite element analysis.
Key results included:
-Demonstration that osteocalcin and other non-collagenous proteins (NCPs) enhance fracture resistance via energy-dissipating mechanisms.
-Identification of extra-fibrillar mineral as a key determinant of stiffness, with intra-fibrillar mineral contributing to toughness.
-Development of a novel phase-field model to simulate bone fracture evolution.
-Creation of an integrated multiscale framework for predicting diabetic bone fragility.
WP3: Human Bone Tissue Analysis
This workpackage focused on analyzing bone samples from T2D patients, including testing under fall-like conditions and detailed imaging. Early pandemic delays led to initial use of animal tissue substitutes.
Key results included:
-AGE accumulation did not reduce bone strength; in some cases, mechanical properties improved.
-No significant mechanical deterioration was observed in trabecular bone under standard or cyclic loading.
-Structural and compositional changes were present but insufficient to explain fragility, reinforcing the role of remodeling impairments.
-Development of models to explore fracture risk based on trabecular architecture.
WP1: Experimental Evaluation in Preclinical Models
Using the Zucker Diabetic Fatty (ZDF) rat model, the team examined how T2D affects bone over time. Animals were assessed at 12, 26, and 46 weeks for changes in bone structure and strength using imaging, biochemical assays, and mechanical testing.
Key results included:
-Early and progressive bone growth impairments in diabetic rats.
-Reduced bone size and fracture resistance, especially in older animals.
-Evidence that impaired bone turnover and delayed mineral maturation, rather than AGE accumulation, were key contributors to fragility.
-Elevated bone resorption and inflammatory markers in diabetic animals.
WP2: Multiscale Computational Modelling
This work package developed multiscale computational tools to simulate bone mechanics across scales—from proteins to tissues—using molecular dynamics (MD), coarse-grain modelling, and finite element analysis.
Key results included:
-Demonstration that osteocalcin and other non-collagenous proteins (NCPs) enhance fracture resistance via energy-dissipating mechanisms.
-Identification of extra-fibrillar mineral as a key determinant of stiffness, with intra-fibrillar mineral contributing to toughness.
-Development of a novel phase-field model to simulate bone fracture evolution.
-Creation of an integrated multiscale framework for predicting diabetic bone fragility.
WP3: Human Bone Tissue Analysis
This workpackage focused on analyzing bone samples from T2D patients, including testing under fall-like conditions and detailed imaging. Early pandemic delays led to initial use of animal tissue substitutes.
Key results included:
-AGE accumulation did not reduce bone strength; in some cases, mechanical properties improved.
-No significant mechanical deterioration was observed in trabecular bone under standard or cyclic loading.
-Structural and compositional changes were present but insufficient to explain fragility, reinforcing the role of remodeling impairments.
-Development of models to explore fracture risk based on trabecular architecture.
The MULT2D project has made significant advances beyond the state of the art in bone biomechanics, diabetic bone disease, and multiscale computational modelling. At the outset, the prevailing belief was that bone fragility in Type 2 Diabetes (T2D) was mainly due to the accumulation of sugar-related molecules called Advanced Glycation End-products (AGEs), which were thought to stiffen bone and impair its mechanical function. MULT2D directly challenged this view.
By integrating long-term animal studies, high-resolution human tissue testing, and cutting-edge molecular simulations, the project revealed that AGE accumulation is not the primary driver of fragility. Instead, impaired bone turnover, disrupted protein-mineral interactions, and delayed mineral maturation were identified as the key contributors. This represents a fundamental shift in understanding and opens new directions for diagnostics and therapy.
Key Advances Beyond the State of the Art
Reframing the role of AGEs: Research showed that AGE accumulation did not consistently impair bone performance, contradicting long-held assumptions and highlighting the need to focus on remodeling and tissue renewal dysfunction in T2D.
First long-term diabetic bone model: A unique 46-week animal study showed strong links between diabetes progression, reduced mineral quality, inflammation, and declining bone strength.
Multiscale models of bone fragility: The project developed a new coarse-grained molecular dynamics and phase-field modelling framework to simulate how mineral and protein architecture affects fracture mechanics. This provided previously unseen insights into micro-to-macro scale bone mechanics.
Highlighting the role of NCPs: Proteins such as osteocalcin and osteopontin were shown to be key to energy dissipation and damage resistance in bone, reshaping how protein function is viewed in bone health.
Novel modelling tools: MULT2D introduced advanced algorithms for simulating trabecular bone structures, offering tools to inform future biomaterials and implant design.
Expected and Achieved Results
By project completion, MULT2D had:
-Established a new paradigm for understanding diabetic bone fragility.
-Delivered validated computational models for both research and clinical application.
-Widely disseminated its findings through journals, conferences, and international collaborations.
By integrating long-term animal studies, high-resolution human tissue testing, and cutting-edge molecular simulations, the project revealed that AGE accumulation is not the primary driver of fragility. Instead, impaired bone turnover, disrupted protein-mineral interactions, and delayed mineral maturation were identified as the key contributors. This represents a fundamental shift in understanding and opens new directions for diagnostics and therapy.
Key Advances Beyond the State of the Art
Reframing the role of AGEs: Research showed that AGE accumulation did not consistently impair bone performance, contradicting long-held assumptions and highlighting the need to focus on remodeling and tissue renewal dysfunction in T2D.
First long-term diabetic bone model: A unique 46-week animal study showed strong links between diabetes progression, reduced mineral quality, inflammation, and declining bone strength.
Multiscale models of bone fragility: The project developed a new coarse-grained molecular dynamics and phase-field modelling framework to simulate how mineral and protein architecture affects fracture mechanics. This provided previously unseen insights into micro-to-macro scale bone mechanics.
Highlighting the role of NCPs: Proteins such as osteocalcin and osteopontin were shown to be key to energy dissipation and damage resistance in bone, reshaping how protein function is viewed in bone health.
Novel modelling tools: MULT2D introduced advanced algorithms for simulating trabecular bone structures, offering tools to inform future biomaterials and implant design.
Expected and Achieved Results
By project completion, MULT2D had:
-Established a new paradigm for understanding diabetic bone fragility.
-Delivered validated computational models for both research and clinical application.
-Widely disseminated its findings through journals, conferences, and international collaborations.