Complete Blood Count Parameters and Bone Health: Clinical and Experimental Evidence.

INTRODUCTION

Osteoporotic fractures are a major global health concern, particularly in the aging population [ 1 ]. As life expectancy increases, the prevalence of osteoporosis and hematological disorders also rises [ 2 , 3 ]. These fractures considerably contribute to morbidity and mortality, leading to functional decline, reduced quality of life, and increased healthcare costs. In Korea, hip fractures are associated with poor prognosis, with 1-year post-hospitalization mortality rates of approximately 21% in men and 14% in women, which increase with age [ 4 ]. Given these implications, identifying modifiable risk factors for fracture susceptibility is crucial for enhancing patient outcomes and alleviating healthcare burden.

Hematopoiesis occurs in the bone marrow, where hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) coexist within a shared regulatory microenvironment [ 5 , 6 ]. This spatial and functional proximity enables bidirectional crosstalk between bone and blood cells [ 5 ]. Hematopoietic cell signals influence osteoblast and osteoclast activity, while bone-derived factors help maintain HSC function and support hematopoiesis [ 7 , 8 ]. These interactions support the concept that alterations in hematological parameters may reflect or impact skeletal health [ 7 ].

Complete blood count (CBC), a widely used diagnostic test, provides key insights into red blood cells (RBCs), white blood cells (WBCs), and platelets, all of which have been implicated in bone metabolism and homeostasis. Although anemia has been relatively well studied in relation to osteoporosis and fractures [ 9 - 11 ], additional CBC parameters, including red cell distribution width (RDW), leukocyte differential counts, and platelet indices, may also contribute to bone fragility and fracture risk [ 12 - 15 ].

Anemia, characterized by a reduced RBC count, hemoglobin level, or hematocrit, is associated with impaired oxygen delivery to musculoskeletal tissues, compromised bone remodeling, diminished muscle strength, and increased susceptibility to falls and fractures [ 16 , 17 ]. Additionally, the RDW, a marker of erythrocyte heterogeneity, is linked to oxidative stress and metabolic instability, which can contribute to skeletal fragility [ 12 , 18 ]. Chronic inflammation, indicated by elevated WBC count and neutrophil-to-lymphocyte ratio (NLR), accelerates osteoclast-mediated bone resorption [ 14 ], whereas platelet-related abnormalities may influence bone remodeling and fracture healing [ 19 , 20 ].

This review synthesizes clinical evidence linking CBC parameters to fracture susceptibility. It also examines the physiological and pathophysiological mechanisms underlying these associations, highlights key clinical and epidemiological findings, and identifies gaps in current knowledge to guide future research. By integrating existing evidence, this review aims to clarify the clinical relevance of CBC parameters in fracture risk assessment and to support the development of more effective screening and prevention strategies for osteoporosis-related fractures.

CBC PARAMETERS AND BONE HEALTH: BIOLOGICAL MECHANISMS AND CLINICAL EVIDENCE

Hematopoiesis and osteogenesis are tightly coupled processes that occur within the shared bone marrow microenvironment, where HSCs and MSCs coexist and interact via common regulatory pathways [ 7 ]. MSCs give rise to osteoprogenitors and bone-forming osteoblasts, and their differentiation is tightly regulated by signaling pathways including bone morphogenetic proteins (BMPs), Wnt, transforming growth factor-beta (TGF-β), parathyroid hormone, Hedgehog, and insulin-like growth factor [ 21 ]. BMPs, Wnt signaling factors, and osteoblast-derived cytokines such as osteopontin, angiopoietin-1, and stem cell factor, also contribute to maintaining HSC function in addition to promoting osteoblast differentiation [ 22 ]. Disruption of hematopoiesis, as seen in anemia, myelodysplastic syndromes, and leukemia, may impair MSC osteogenic differentiation, ultimately reducing bone formation and increasing susceptibility to fractures [ 23 ].

CBC is a widely used diagnostic test that provides essential information on key hematologic components, including RBCs, WBCs, hemoglobin, hematocrit, and platelets. While traditionally employed in the assessment of systemic and hematologic disorders, emerging evidence highlights the relevance of CBC parameters in bone health and fracture risk. These indices influence bone metabolism through diverse mechanisms such as oxygen transport, immune modulation, and cytokine-mediated cellular signaling ( Fig. 1 ).

The following sections present both mechanistic insights and clinical evidence related to the role of RBCs, WBCs, and platelets in bone metabolism and fragility. Each component is introduced with its physiological relevance, followed by a synthesis of clinical findings examining their associations with bone mineral density (BMD) and fracture outcomes.

RBCs and bone metabolism

RBCs play a fundamental role in bone metabolism by supporting oxygen transport, which is essential for osteoblast activity and bone remodeling [ 24 ]. Hypoxic conditions impair osteoblast proliferation, differentiation, and matrix production [ 25 - 27 ], while also enhancing osteoclastogenesis via activation of hypoxia-inducible factor-1α (HIF-1α) [ 28 ]. Consequently, anemia may disrupt these oxygen-dependent processes, contributing to impaired bone formation and increased bone resorption.

Among the various subtypes of anemia, iron deficiency anemia has been most extensively studied in relation to bone health. Iron is essential for collagen synthesis, osteoblast differentiation, and vitamin D metabolism [ 24 , 29 ]. Chronic iron deficiency has been shown to induce oxidative stress and mitochondrial dysfunction in osteoblasts [ 30 ], and to promote osteoclastogenesis through hypoxia-related mechanisms [ 31 ]. Conversely, iron overload, as observed in hereditary hemochromatosis and transfusion-dependent anemias, is also detrimental to skeletal integrity. Excess iron increases oxidative stress, stimulates osteoclast activity, and suppresses osteoblast function [ 16 ]. Furthermore, iron overload disrupts hydroxyapatite formation [ 32 ] and alters MSC differentiation, favoring adipogenesis over osteogenesis [ 33 ]. Elevated serum ferritin levels, a biomarker of iron overload, have been correlated with increased bone turnover, bone loss, and fracture risk [ 34 , 35 ]. Other forms of anemia, including aplastic anemia and pernicious anemia, may impair bone metabolism by disrupting hematopoiesis and DNA synthesis, respectively [ 36 , 37 ]. Pernicious anemia is also associated with peripheral neuropathy, which can increase the risk of falls through impaired proprioception and sensory deficits [ 37 ]. In addition, anemia-induced microvascular dysfunction may reduce bone perfusion, thereby impairing the delivery of oxygen and nutrients required for skeletal homeostasis [ 24 , 38 , 39 ]. Reduced hematocrit may contribute to localized hypoxia and stimulate proliferation of osteoclast precursors [ 40 ]. Although transient blood loss may initially enhance osteoblast activity, sustained bone resorption may ultimately disrupt remodeling cycles and compromise bone formation [ 40 ].

RDW, a measure of variability in RBC size, has emerged as a potential hematologic marker reflecting systemic inflammation and oxidative stress [ 41 - 43 ]. Elevated RDW levels have been linked to increased concentrations of proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), which promote osteoclast differentiation and bone resorption [ 44 , 45 ]. Clinical studies have reported that higher RDW is associated with an increased risk of hip fracture, supporting its potential utility as a biomarker of skeletal fragility [ 12 ].

Oxidative stress plays a critical role in bone remodeling by modulating both osteoblast and osteoclast activity [ 46 , 47 ]. Elevated RDW correlates with higher levels of reactive oxygen species (ROS), which impair osteoblast differentiation and enhance osteoclast-mediated bone resorption [ 48 , 49 ]. Persistent oxidative stress disrupts the bone microenvironment by causing mitochondrial dysfunction, impairing collagen synthesis, and increasing bone turnover [ 50 , 51 ]. These effects are further amplified under chronic inflammatory conditions, where elevated WBC counts and associated cytokines, such as IL-1β and TNF-α–drive ROS production, forming a self-perpetuating cycle of bone degradation [ 52 ].

Clinically, anemia has been consistently associated with reduced BMD and increased fracture risk. A prospective cohort study reported that older men with anemia had more than a 50% increased risk of non-spinal fractures [ 11 ]. Similarly, the Women’s Health Initiative demonstrated that postmenopausal women with lower hemoglobin levels exhibited significantly higher hip fracture rates over a 10-year follow-up period [ 53 ]. Meta-analyses have further confirmed significant associations between anemia and both vertebral and non-vertebral fractures, independent of age, sex, and frailty status [ 9 ]. In men, anemia may also serve as a surrogate marker for hypogonadism, which independently contributes to reduced BMD and impaired erythropoiesis [ 54 , 55 ].

Hematocrit, which reflects the proportion of blood volume occupied by RBCs, has also been examined in this context. However, low hematocrit is frequently a consequence of hematologic disorders such as leukemia, multiple myeloma, and myelodysplastic syndromes, making it difficult to delineate its independent effects on bone health. In contrast, elevated hematocrit levels, as seen in polycythemia, may impair bone repair due to microvascular dysfunction [ 56 ]. Nevertheless, large-scale studies investigating the association between hematocrit and skeletal outcomes remain limited.

Collectively, these findings suggest that RBC-related indices, including hemoglobin, hematocrit, and RDW, may serve as clinically relevant biomarkers for assessing fracture risk. Further research is warranted to elucidate underlying mechanisms, define prognostic thresholds, and determine whether correction of hematological abnormalities can improve skeletal outcomes and reduce fracture incidence.

WBCs and bone remodeling

WBCs are central mediators of immune responses and inflammatory signaling pathways that play a critical role in bone remodeling [ 36 ]. Chronic systemic inflammation, reflected by elevated total WBC count or NLR, has been associated with increased osteoclast activity and suppression of osteoblast function. Proinflammatory cytokines, including TNF-α, IL-6, and receptor activator of nuclear factor-kappa B ligand (RANKL), are key drivers of osteoclastogenesis and bone resorption, contributing to decreased bone mass and increased fracture risk [ 44 , 57 , 58 ].

Among WBC subsets, neutrophils and lymphocytes appear to exert divergent effects on bone homeostasis. Neutrophils have been shown to promote bone resorption through proinflammatory signaling and upregulation of RANKL expression. In contrast, lymphocyte subtypes have context-dependent roles: regulatory T cells suppress osteoclast differentiation and promote osteoblast activity, while helper T cells may enhance osteoclastogenesis [ 59 - 61 ]. Lymphocytopenia, which reflects immune dysregulation, has been linked to impaired osteoblast function and reduced bone formation, thereby increasing osteoporosis risk. Alterations in these immune cell populations may therefore disrupt the balance of bone remodeling in favor of resorption [ 62 ].

Recent clinical data support these mechanistic observations. One study reported that men with accelerated bone loss had higher neutrophil counts and lower lymphocyte counts, often accompanied by anemia, suggesting a possible link between bone metabolism and hematopoietic dysfunction [ 63 ]. Another cohort study found a modest positive association between total WBC count and lumbar spine BMD in women [ 64 ]. These findings indicate that the effects of WBC parameters on bone may vary by sex, population, and comorbid conditions. Further evidence highlights that different WBC subtypes may influence skeletal outcomes independently. In older adults, elevated NLR has been associated with increased risk of vertebral fractures [ 65 , 66 ]. Moreover, immune dysregulation in osteoporosis involves altered B and T cell function and cytokine expression. B lymphocytes support skeletal homeostasis via production of osteoprotegerin, a decoy receptor for RANKL, but aberrant B and T cell interactions may exacerbate bone loss in osteoporotic states [ 61 , 67 , 68 ].

Despite growing evidence, the mechanistic links between WBC-derived inflammatory pathways and skeletal fragility remain incompletely understood. Further studies are warranted to clarify these relationships and to evaluate the utility of WBC indices, including NLR and differential counts, as biomarkers of bone health and fracture susceptibility.

Platelets in skeletal biology

Platelets are primarily involved in hemostasis and wound healing, but accumulating evidence suggests they also play an active role in bone repair and regeneration. Through the release of growth factors such as platelet-derived growth factor, TGF-β, and vascular endothelial growth factor, platelets facilitate osteoblast proliferation, angiogenesis, and extracellular matrix deposition, all of which are essential for bone remodeling [ 69 - 73 ]. Given the critical role of microvascular circulation in delivering nutrients and signaling molecules, changes in platelet count and function may significantly influence skeletal homeostasis [ 71 ].

Experimental studies indicate that thrombocytopenia impairs fracture healing and bone regeneration due to insufficient delivery of osteogenic mediators [ 72 , 74 ]. Platelets contribute to the early stages of bone repair by forming fibrin clots, releasing pro-regenerative cytokines, and recruiting MSCs for osteoblastic differentiation. Reduced platelet count may also compromise bone perfusion and nutrient delivery, further hindering the regenerative process. Conversely, excessive platelet activation has been linked to a proinflammatory state, promoting osteoclast activity and bone loss [ 15 ]. Activated platelets secrete inflammatory mediators such as prostaglandins and RANKL, which enhance osteoclastogenesis [ 75 ]. Platelets also serve as a major peripheral source of serotonin, a bioactive amine that inhibits osteoblast function when present in excess [ 76 , 77 ]. In vitro studies further support these findings, demonstrating that activated platelets promote osteoclast differentiation via RANKL-dependent mechanisms [ 59 ]. While megakaryocytes, the precursors of platelets, have been shown to support osteoblast proliferation and inhibit osteoclastogenesis [ 75 ], excessive platelet activation may disrupt this regulatory balance.

Clinical data align with these mechanistic insights. Both thrombocytopenia and thrombocytosis have been associated with alterations in bone remodeling and fracture risk [ 78 ]. Population-based studies of patients with immune thrombocytopenia suggest an increased fracture risk compared to the general population, although this association may be confounded by corticosteroid use [ 79 ]. Data directly linking thrombocytopenia to BMD, however, remain limited.

Thrombocytosis has also been implicated in reduced bone quality, potentially via inflammatory pathways. Elevated platelet counts may reflect or exacerbate systemic inflammation, a known contributor to bone resorption. This is particularly evident in chronic inflammatory diseases such as rheumatoid arthritis, where reactive thrombocytosis is often present and osteoporosis is a common comorbidity [ 80 ]. Increased platelet activation has been associated with excessive cytokine release [ 81 ], altered bone homeostasis, and accelerated bone loss.

Epidemiologic evidence supports these observations. A large Korean study found that higher platelet counts, even within the normal range, were significantly associated with lower BMD and increased risk of osteopenia and osteoporosis in middle-aged and older adults [ 82 ]. Similarly, National Health and Nutrition Examination Survey data from 2011 to 2018 demonstrated a negative correlation between platelet count and BMD, particularly in men [ 83 ]. Other studies in older men and postmenopausal women have shown associations between low mean platelet volume and decreased BMD [ 15 , 84 ]. In contrast, a study in Chinese women reported a positive association between platelet count and BMD, suggesting possible population-specific variations that warrant further investigation [ 85 ].

Although current findings suggest a role for platelets in skeletal integrity, the underlying mechanisms remain incompletely defined. Additional research is needed to clarify these pathways and to determine whether platelet indices can serve as reliable biomarkers of bone health. Investigating therapeutic strategies that modulate platelet function, such as platelet rich plasma therapy, may offer new opportunities to enhance bone regeneration and reduce fracture risk. A more comprehensive understanding of platelet biology in the skeletal context may help inform novel approaches to osteoporosis prevention and treatment.

In conclusion, CBC parameters provide valuable insights into bone metabolism and fracture risk. RBCs support osteoblast activity through oxygen delivery, while anemia is linked to impaired bone formation, delayed healing, and lower bone density. RDW, reflecting oxidative stress and inflammation, is associated with increased osteoclast activity and skeletal fragility. WBCs contribute to bone remodeling via immune-mediated pathways. Elevated WBC count and NLR are markers of chronic inflammation and have been associated with increased bone resorption. Platelets support bone repair by releasing growth factors, and abnormalities in platelet count have been linked to disrupted bone remodeling. These findings suggest that CBC-derived markers may serve as accessible indicators of skeletal health. Key clinical studies supporting these associations are summarized in Table 1 . Further studies are needed to clarify the underlying mechanisms and assess whether correcting hematological abnormalities can improve bone outcomes.

CLINICAL IMPLICATIONS AND FUTURE PERSPECTIVES

Accumulating evidence indicates that CBC parameters may offer additional insights into bone health and fracture risk. These hematological markers can complement traditional assessment tools for osteoporosis and fracture prevention. Although current models rely primarily on BMD and clinical risk factors, CBC-derived indices may improve risk stratification. Nevertheless, further studies are needed to validate their clinical utility and define how best to integrate these parameters into existing risk assessment frameworks.

Potential clinical utility of CBC parameters in osteoporosis evaluation

CBC testing is widely available, cost-effective, and routinely performed in clinical settings. Recent studies suggest that specific CBC indices, including anemia, RDW, WBC count, NLR, and platelet levels, may be associated with skeletal fragility. Among these, anemia has shown a relatively consistent association with increased fracture susceptibility, while inflammatory markers such as elevated WBC count and NLR may reflect ongoing bone resorption.

Unlike BMD testing, which requires specialized equipment and is typically limited to high-risk populations, CBC is often included in routine health evaluations. This accessibility offers a potential opportunity to identify individuals at risk for compromised bone health. Hematological abnormalities, including anemia, platelet count changes, and WBC-related inflammatory markers, may serve as indicators of skeletal deterioration.

While these associations are promising, further research is needed to clarify the underlying mechanisms, determine clinically relevant thresholds, and assess whether modifying CBC abnormalities can lead to improved skeletal outcomes. At this stage, CBC may be considered a supportive marker in the clinical evaluation of osteoporosis, particularly in individuals with systemic comorbidities or limited access to imaging.

Gaps in current knowledge and directions for future research

Despite increasing evidence linking CBC parameters to bone health, several critical knowledge gaps must be addressed before these hematological markers can be reliably incorporated into clinical practice. First, the biological mechanisms underlying the relationship between the CBC indices and bone metabolism have yet to be clearly defined. Although anemia, inflammation, and oxidative stress have been implicated in skeletal fragility, the causal pathways are not fully understood. Longitudinal studies are required to determine whether temporal changes in CBC parameters can independently predict fracture risk beyond the traditional risk factors. Although abnormal CBC parameters such as anemia or elevated inflammatory markers have been associated with increased fracture risk, it remains uncertain whether clinically meaningful thresholds can be established. These parameters are influenced by various physiological and pathological factors and are therefore unlikely to function as independent predictors. Nevertheless, their incorporation into multivariable risk models may be useful, particularly in older adults with multiple comorbidities. Finally, interventional studies are needed to evaluate whether correcting hematological abnormalities leads to improved skeletal outcomes. Although treatments for anemia and inflammation have shown benefits in other disease contexts, their effects on bone health remain unclear. Well-designed randomized controlled trials are essential to assess whether targeting CBC abnormalities can translate into a meaningful reduction in fracture risk.

CONCLUSIONS

CBC parameters are promising, accessible, and cost-effective biomarkers that may provide additional insights during the clinical evaluation of osteoporosis. RBC indices, WBC counts, and platelet markers have been associated with skeletal fragility through mechanisms involving oxygen transport, inflammation, and bone remodeling. While these associations highlight the potential relevance of CBC in identifying individuals with compromised bone health, further research is needed to clarify underlying biological mechanisms and determine whether correcting hematological abnormalities can improve skeletal outcomes. Addressing these gaps may help refine osteoporosis assessment strategies and support identification of individuals at increased risk.

Footnotes

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

This review was written during Jeonghoon Ha’s tenure as a visiting scholar in the Stanford University Division of Endocrinology (August 2024–July 2025) under Professor Joy Wu’s mentorship.

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