Anemia is common among older people and the prevalence increases with advancing age.[3
] Both clinical and epidemiologic research has suggested that anemia is a significant risk factor for morbidity and mortality particularly among older persons. Anemia may be a clinical indicator of disease pathology or may present as a co-morbid condition which increases the severity of existing health conditions.[5
The WHI, with its large sample size and diverse race/ethnic sample, presents a great opportunity to prospectively assess the relationship between anemia and fracture risk in post-menopausal women from different racial and ethnic backgrounds. Our analysis provides direct evidence of a significant increase in risk for hip fracture among U.S. postmenopausal women who present with anemia. The results also suggest elevated spinal and all fracture risks associated with anemia. The increased fracture risk could not be completely explained by co-morbidity, falls, or other life-style factors. The increased fracture risk associated with anemia in our study ranged from 7% to 38% across fracture sites, after including multiple covariates. Our study cannot determine whether the association between anemia and fracture is a causal relationship, but these results highlight the importance of further understanding the underlying mechanisms of this association.
No prior study has prospectively evaluated the relationship between anemia and fracture risk. However, our study results are consistent with the results from the InCHIANTI study in Italy, which showed that anemia was associated with lower bone density, an association that was most significant in older women as compared to older men. Interestingly, anemia-related bone loss was mostly associated with cortical bone loss rather than trabecular bone loss in the InCHIANTI study.[7
] In contrast, our study found increased fracture risk at both high trabecular and high cortical composition bone sites, such as spine and hip. In this same Italian cohort, hemoglobin levels were also found to be related to skeletal muscle properties: lower hemoglobin concentrations were correlated with lower skeletal muscle mass and strength.[5
] Reduced skeletal muscle mass and strength may have direct impacts on bone density since bone is responsive to mechanical stimulation. Low skeletal muscle mass may also increase the risk of falling. Indeed, findings have unequivocally pointed to a significant association between anemia and falls in older adults. [8
] However, in our study, falls did not contribute significantly to the observed association between anemia and fracture risk.
The prevalence of anemia increases with age. In NHANES III one-fifth of women 85 or older presented with anemia. Specifically, the rates of anemia in older women doubled from 10% to 20% when comparing prevalence among 75 to 84 year olds to those over 85 years of age.[3
] Our findings are in agreement with previous studies showing an increased prevalence rate of anemia with aging. In addition, we have found that the anemia-associated prevalence rate for hip fracture and all fractures was significantly higher in the 70–79 year old group in comparison to the younger age groups. A similar trend was observed for spinal fractures but the result did not reach the level of statistical significant at the p-value of 0.05. These results suggest that the absolute fracture risk and the difference of absolute risk were greatest within the oldest group of women in our study. The reason for this differential risk relationship between fractures and anemia by age group cannot be determined in this study.
We demonstrated significant race/ethnic differences in the prevalence of anemia in this population supporting the findings from other reports. In NHANES III, the lowest overall prevalence in persons over age 65 was seen in Non-Hispanic whites (9.0%). Mexican Americans (10.4%) had a slightly higher rate, but African Americans (27.8%) had a rate 3 times higher than non-Hispanic whites when the same WHO criteria for anemia was applied.[3
] In spite of the strikingly high prevalence of anemia in African Americans, one study has suggested that older African Americans, classified as anemic by WHO criteria, were not at risk for higher mortality and disability; however, an increased risk of death and disability was found in whites with anemia from the same cohort study.[30
] Their results suggest racial differences in the association between WHO defined anemia and adverse health events, thus lending support for different anemia cutoff points by race/ethnicity. We did not find race/ethnic differences in the association between anemia and risk for all fractures. However, smaller numbers of fractures in some minority groups have limited our ability to make a conclusive statement.
The underlying mechanisms of the relationship between anemia and fractures are most likely to be complicated and heterogeneous. The association we observed here may be the reflection of direct, indirect or a combination of direct and indirect effects of anemia on fracture risk. Many known risk factors of anemia in older adults, such as androgen insufficiency, chronic inflammation, age-associated renal insufficiency, stem cell aging,[31
] and nutrient deficiency including iron, cobalamin (B12) and folate deficiencies, [32
] are also known risk factors for osteoporosis and fractures. Thalassemia patients are at higher risk for bone diseases, including severe osteoporosis and fractures,[34
] but we do not have information on thalassemia in this current study. Sickle cell disease predisposes an individual to low bone density[35
] and hence increases the person's risk for future fractures. It is unlikely that the increased risk of fracture in our study was mainly due to sickle cell disease since only two participants reported having the disease in the baseline questionnaire. In addition to these possible indirect links for the association between anemia and fracture risk, low hemoglobin levels may directly affect precursors of bone cells.[36
] In future investigations, bone density, geometric structures and bone metabolic markers may be used to help understand the underlying mechanisms related to this increased fracture risk among older anemic women.
Anemia has been considered a modifiable risk factor for adverse health consequence.[39
] Although anemia is associated with an increased risk of fractures in our study, whether improving hemoglobin concentration in anemic women can reduce risk for fractures remains to be studied. One prior study[41
] showed that after hip fractures women who had hemoglobin levels less than 12 g/dL stayed longer in the hospital and more likely died from the fracture than those with normal hemoglobin levels at the time of hospital admission. Our analysis indicates anemia is associated with higher risk for fractures, but does not provide evidence as to whether a pre-existing anemic condition contributes to longer-term health outcomes of fractures.
In this study only hip fractures were adjudicated. Non-hip fractures were self-reported so they are subject to reporting error. Although the agreement between self-report of fractures and medical record confirmed diagnosis of fractures is estimated to be 70% in this cohort, there was a range of variation in the accuracy of the self-reported fractures by fracture anatomical site,[42
] which may have prevented us from accurately assessing the associations between non-hip fractures and anemia. In the current study, spine fractures referred to clinical spinal fractures only, so under-reporting for undiagnosed spinal fractures might have also occurred. It is unknown if these information biases differ by anemia status; hence, their impact on the study findings is difficult to assess. It has been suggested that only anemia linked with renal disease or chronic inflammation are associated with a higher mortality rate.[43
] A case-control study in the WHI has suggested that poor renal function, as measured by cystatin, is associated with increased hip fracture risk.[44
] Lack of renal function measurements is a limitation of this current study and needs to be addressed in future investigations. Anemia was defined using a single baseline measurement of hemoglobin and may not reflect persistent anemia. No information on inflammation status was collected during the study. Previous studies have shown that one third of the anemia cases in older populations are due to nutrient deficiency; one third to renal insufficiency and chronic inflammation; and one third related to factors that are less understood and difficult to detect in clinical settings.[33
] The contributing causes for anemia could not be determined in our study. Whether different subtypes of anemia are associated with fracture risk differently is impossible to be addressed in this study, but remains an interesting research topic for future investigation.
WHI is the largest health study ever undertaken among postmenopausal women in the United States. The racially and ethnically diverse cohort makes this study unique in understanding possible differential associations between anemia and fracture risk across racial and ethnic sub-groups. Over the course of the study, 20,006 fractures were diagnosed between January 1999 and September, 2006, making WHI the largest number of reported fractures in post-menopausal women. Hence the study results have provided first hand evidence on the association between anemia and fracture risk in postmenopausal women.