Daily Endocrinology Research Analysis
Three impactful endocrinology-related studies stood out today: a UK Biobank cohort links both type 1 and type 2 diabetes to higher osteoporotic fracture risk with clear dose–responses by disease duration and microvascular complications; an RCT from the STAMPEDE platform shows metformin does not improve overall survival in metastatic hormone-sensitive prostate cancer but mitigates ADT-related metabolic adverse effects; and a mechanistic JEM study reveals neutrophil egress from bone marrow sustain
Summary
Three impactful endocrinology-related studies stood out today: a UK Biobank cohort links both type 1 and type 2 diabetes to higher osteoporotic fracture risk with clear dose–responses by disease duration and microvascular complications; an RCT from the STAMPEDE platform shows metformin does not improve overall survival in metastatic hormone-sensitive prostate cancer but mitigates ADT-related metabolic adverse effects; and a mechanistic JEM study reveals neutrophil egress from bone marrow sustains myelopoiesis and inflammation in obesity despite weight loss.
Research Themes
- Diabetes and skeletal health risk stratification
- Endocrine-oncology: ADT metabolic toxicity and metformin repurposing
- Immunometabolism of obesity and persistent inflammation after weight loss
Selected Articles
1. Type 1 and 2 diabetes mellitus: comprehensive fracture risk relationships in UK Biobank.
In a prospective UK Biobank analysis (n≈499,000), both type 1 (IRR 2.93) and type 2 diabetes (IRR 1.25) were associated with higher incident osteoporotic fracture risk independent of traditional risk factors, adiposity, eBMD, and CRP. Risk in type 2 diabetes increased with disease duration, and microvascular complications approximately doubled the risk.
Impact: This very large, well-adjusted prospective cohort provides robust, quantifiable fracture risk estimates in diabetes, highlighting disease duration and microvascular complications as dose-dependent risk factors beyond BMD.
Clinical Implications: Incorporate diabetes type, duration, and microvascular complications into fracture risk assessment and management. Consider earlier DXA screening, fall prevention, and possibly tailored anti-osteoporotic therapy in diabetes, even when eBMD is preserved.
Key Findings
- Type 1 diabetes associated with nearly threefold higher fracture risk (IRR 2.93, 95% CI 2.37–3.62).
- Type 2 diabetes associated with modestly higher fracture risk (IRR 1.25, 95% CI 1.14–1.38), with risk increasing by disease duration.
- Greater number of microvascular complications doubled fracture risk (any vs none, IRR 2.03, 95% CI 1.57–2.62).
- Associations were partly independent of traditional risk factors, adiposity, eBMD by heel ultrasound, and CRP.
Methodological Strengths
- Very large prospective cohort (n≈498,949) with sex-stratified analyses.
- Robust multivariable Poisson regression adjusting for eBMD, adiposity, and CRP; evaluation of disease duration and microvascular complications.
Limitations
- Observational design; residual confounding cannot be excluded.
- Bone density estimated by heel ultrasound (eBMD) rather than DXA; fracture ascertainment details not elaborated in abstract.
Future Directions: Develop diabetes-specific fracture risk tools incorporating duration and microvascular complications; test targeted anti-osteoporotic strategies in randomized trials for people with diabetes.
2. Metformin for patients with metastatic prostate cancer starting androgen deprivation therapy: a randomised phase 3 trial of the STAMPEDE platform protocol.
Among 1,874 non-diabetic patients with metastatic hormone-sensitive prostate cancer, adding metformin to standard of care did not significantly improve overall survival (HR 0.91; p=0.15). Grade ≥3 adverse events were similar overall with more gastrointestinal events in the metformin arm, but ADT-related metabolic adverse effects were significantly reduced with metformin.
Impact: A large, pragmatic phase 3 platform RCT provides definitive evidence against routine metformin addition for survival benefit, while informing supportive care by reducing ADT metabolic toxicity.
Clinical Implications: Do not add metformin solely to improve survival in metastatic hormone-sensitive prostate cancer without diabetes. Consider metformin to mitigate ADT-related metabolic complications in selected patients, with attention to gastrointestinal tolerance.
Key Findings
- Overall survival not significantly improved with metformin (median 67.4 vs 61.8 months; HR 0.91, 95% CI 0.80–1.03; p=0.15).
- Grade ≥3 adverse events occurred in 57% (metformin) vs 52% (SOC), with more gastrointestinal events in the metformin arm.
- Adverse metabolic side-effects of ADT were significantly reduced in the metformin group compared with standard care.
- Most patients received ADT plus docetaxel (82%); median follow-up 60 months.
Methodological Strengths
- Randomised, phase 3, platform trial with large sample and long median follow-up.
- Clinically relevant endpoints and contemporary standard-of-care backbone.
Limitations
- No overall survival benefit; trial not blinded; small proportion received modern AR pathway inhibitors.
- Increased gastrointestinal adverse events with metformin may limit tolerability in some patients.
Future Directions: Define subgroups with potential benefit (e.g., metabolic responders), prospectively assess cardio-metabolic endpoints and quality of life, and explore combinations with AR pathway inhibitors.
3. Bone marrow neutrophil density regulates myelopoiesis during obesity and weight loss.
In mice, obesogenic signals drive adipose macrophage-mediated recruitment of bone marrow neutrophils, activating hematopoietic stem cells and sustaining myelopoiesis; weight loss does not resolve this axis. Blocking neutrophil egress reduced bone marrow myelopoiesis, adipose inflammation, and improved glucose tolerance. In humans with obesity, plasma neutrophil chemokines were elevated, correlated with insulin resistance, and did not fall after weight loss.
Impact: This study uncovers a persistent neutrophil-driven hematopoietic circuit linking bone marrow and adipose tissue that sustains inflammation in obesity despite weight loss, revealing a therapeutic target for immunometabolic disease.
Clinical Implications: Weight loss alone may not normalize obesity-related inflammation; targeting neutrophil recruitment/egress (e.g., chemokine/CXCR axes) could enhance metabolic improvements post-weight loss.
Key Findings
- Obesogenic stimuli drive adipose tissue macrophages to recruit neutrophils from bone marrow, activating HSCs and sustaining myelopoiesis.
- Neutrophil recruitment persists despite weight loss, maintaining systemic myeloid inflammation.
- Pharmacologic inhibition of neutrophil egress reduced bone marrow myelopoiesis, decreased adipose inflammation, and improved glucose tolerance in mice.
- In humans with obesity, plasma neutrophil chemokines were elevated, correlated with insulin resistance, and did not decrease with weight loss.
Methodological Strengths
- Mechanistic multi-system approach with in vivo mouse models and human correlational plasma chemokine data.
- Interventional blockade of neutrophil egress demonstrating causal links to myelopoiesis and metabolic outcomes.
Limitations
- Translational gap: primary evidence from mouse models; human data are correlative.
- Specific pharmacologic targets and safety in humans remain to be defined.
Future Directions: Longitudinal human studies (e.g., post-bariatric surgery) linking neutrophil chemokine dynamics to metabolic trajectories; early-phase trials targeting CXCR/chemokine pathways in obesity.