Bidirectional association between haematopoiesis and bone metabolism : an integrated Mendelian randomization and pharmacoepidemiology analysis

Abstract

The intricate interplay between the haematopoietic, immune, and skeletal systems has been extensively explored in the field of osteoimmunology. Preclinical studies have been conducted in recent decades to elucidate the complex interaction within these systems. Despite the wealth of knowledge gained from these preclinical investigations, research involving human evidence has been limited. Moreover, the majority of the reported human observational studies were cross-sectional in nature, which inherently limits their ability to establish causal relationships.

To address this knowledge gap, the present thesis aimed to investigate the causal association between haematopoiesis and bone metabolism by leveraging both human genetic data and real-world evidence. Specifically, this thesis employed Mendelian randomization (MR) analyses to explore the causal relationships between these two systems using genetic data. Subsequently, a nested case-control study and a retrospective cohort study were conducted to further substantiate the observations derived from the genetic data. These complementary studies aimed to evaluate whether the causal relationship identified through genetic analyses could be corroborated by real-world evidence.

To evaluate the effects of haematopoiesis on bone metabolism, an MR analysis using publicly available genetic data was conducted to determine whether there was any causal relationship between blood cell traits and bone mineral density (BMD). Results showed that red blood cell (RBC) traits were positively associated with BMD while white blood cell traits were inversely associated with BMD. Findings suggested that haematopoiesis might play an essential role in bone metabolism.

To further investigate the relationship of RBC traits with bone metabolism in human, a real-world study among chronic kidney disease patients was conducted to evaluate the relationship between erythropoiesis-stimulating agents (ESA) and osteoporotic fracture. The nested case-control study found that prolonged ESA treatment and ESA-responder were associated with an increased risk of osteoporotic fracture, suggesting the regulation of RBC might influence bone metabolism.

Contrarily, bone metabolism may also have a role in haematopoiesis. An MR analysis in the reverse direction was conducted to assess the impact of bone metabolism on haematopoiesis. The results indicated that BMD was positively correlated with immature RBC but inversely correlated with mature RBC. Therefore, genetic evidence suggested that bone metabolism is a regulator of erythropoiesis.

To further explore the effects of bone on erythropoiesis, a retrospective cohort analysis on hip fracture patients was conducted to evaluate if there was any difference in the risk of anaemia among patients using bisphosphonate, a class of anti-osteoporosis medication. Patients using zoledronate, a more potent anti-resorptive agent, were associated with an increased risk of anaemia compared to alendronate, a less potent anti-resorptive agent. Findings from real-world data aligned with MR findings, indicating that bone metabolism might be associated with erythropoiesis.

By integrating genetic data and real-world evidence, this thesis suggested the bidirectional causal associations between haematopoiesis and bone metabolism. The findings from this research have the potential to shed light on the underlying mechanisms governing the interplay between these systems, potentially paving the way for novel therapeutic interventions and improved clinical management strategies.