Age and Ageing Advance Access originally published online on November 14, 2007
Age and Ageing 2008 37(2):217-220; doi:10.1093/ageing/afm152
The aluminium content of bone, and mortality risk
SIR—Even though aluminium is the commonest metal in the earth's crust, evolution has not conferred it with an essential biological function. The metal has been regarded as relatively biologically inert in the past. Aluminium is now considered to be a potentially toxic metal that might trigger apoptosis [1]. Aluminium poisoning may lead to three types of disorder: aluminium-induced bone disease, microcytic anaemia and encephalopathy, which is well known in patients with chronic renal failure [2–7]. Induction of progressive central nervous system diseases has also been suggested, e.g. amyotrophic lateral sclerosis, Parkinson's disease [9] and Alzheimer's dementia [10–12].Aluminium normally enters the body through the diet owing to its natural presence in many foods, and from leaching into food by aluminium-containing cooking utensils. The total dietary intake has been estimated at 4–9 mg Al/day [13–15], and 4% of the aluminium content of the diet is retained by intestinal absorption. This aluminium can partially be accumulated in bone—the main storage site of aluminium—for years under continuous intake conditions [16]. In the elderly, and especially in young patients with an Alzheimer-type pathology, the intestinal absorption of aluminium is increased [18], thus enhancing the putative bone-tissue accumulation.
Given that aluminium is exponentially accumulated in the body with ageing [19], that aluminium is associated with neurodegenerative diseases, and that aluminium is linked to processes in the cell that eventually lead to premature cell death, the hypothesis of considering whether aluminium plays a role in the ageing process and is associated with mortality risk is warranted. This study was therefore performed in order to examine whether the aluminium content in bone in humans was associated with mortality risk.
A total of 198 patients—132 women and 66 men—with a mean age of 73 years and a range of 16–98 years were included in this study, and all characteristics are shown in Table 1. They were treated at either of the two hospitals in the county of Uppsala, and admitted to the hospitals for either arthroplasty of the hip because of osteoarthritis (n = 50), shaft fractures of the femur (n = 9) or the tibia (n = 10), or hip fracture (n = 129). Of these hip-fractures cases, 62 had a diagnosis of dementia on admission to hospital, while none of the remaining 136 participants had this diagnosis. The Ethics Committee of the Medical Faculty of Uppsala University approved the study.
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During the operations on all cases, bone biopsies from the trabecular bone of the proximal femur or from the proximal tibia were taken using an aluminium-free instrument. The bone samples were immediately put in sealed polyethylene test tubes, frozen and stored at –20°C until analysis at a maximum of 6 months after the operation. Prior to analysis, after drying at 120°C for 48 h the bone samples were weighed. The bone samples were then decomposed using ultra-pure nitric acid in a quartz tube, and an internal standard (Indium), diluted with high-purity water (with a resistivity of over 18 M
-cm), was added. The samples were then introduced into an inductively coupled mass spectrometer (Perkin-Elmer Elan 6000) and measured for their content of aluminium (ng/g dry bone). All handling of the samples was carried out in a clean room. Quality control was assessed through use of a reference material (IAEA H-8 Animal bone) in every fifth sample, randomly distributed in the measurement series. The coefficient of variation (CV) was 4.7% for the method used [20]. Creatinine in serum was measured kinetically as a creatinine-picrate complex based on a modified Jaffe's reaction in a spectrophotometer. The CV was 2.1% at a level of 147 µmol/l, and the normal reference range was set to 60–106 µmol/l.
The aluminium levels of the bones displayed a skewed distribution. We, therefore, used aluminium values transformed into natural logarithms—values which in turn were normally distributed (Shapiro-Wilk test W = 0.99; P = 0.25). The estimated sex- and age-adjusted mean aluminium values among those who had died and among survivors were calculated using the general linear models (GLM) procedure in the SAS package (Version 9, SAS Institute, Cary, NC, USA). We used Cox's proportional hazard models (PHREG procedure of SAS) to assess the association between the aluminium content in bone, as either quartiles or as a continuous variable, and mortality. The results from an age-adjusted model and a multivariable model including age, serum creatinine (both continuous), sex and separate indicator variables for each disease status—demented hip-fracture cases, non-demented hip-fracture cases, patients with osteoarthritis and patients with a shaft fracture—are presented. The participants contributed person-time from the date of the first investigation, until the date of death or the end of the follow-up period (28 February 2007)—whichever came first. Dates of deaths were based on data from the continuously updated Swedish National Population Register. We checked the proportional hazard assumption of the models, that the association did not differ in length of follow-up time, using graphical methods and a Wald chi-square test (all P>0.5).
Descriptive characteristics of the participants are displayed in Table 1. The oldest subject at study entry among those who had died was 98 years, compared to 95 years among those who were alive at the end of the study. All samples contained aluminium ranging from 58 to 13,332 ng/g dry weight of bone. The crude average aluminium values were higher among those who had died, but if we considered the differences in age between deceased and survivors there remained no difference in log-transformed aluminium values between the groups (6.7; 95% CI 6.5–6.9 for those who had died and 6.8; 95% CI 6.6–7.0 for the survivors).
We found no association between the aluminium content in bone and mortality risk (Table 2). The multivariable hazard ratio (HR) per standard deviation increase in log-transformed aluminium was 1.00 (95% CI 0.80–1.26). This estimate remained identical if we restricted the analysis to only include participants older than 65 years of age (n = 153) at study entry (HR 1.00; 95% CI 0.79–1.25). The highest compared with the lowest quartile of aluminium conferred a multivariable HR of 0.87 (95% CI 0.45–1.68), despite a 10-fold higher median aluminium value in Quartile 4 (Table 2).
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Discussion
As far as we know, this study is the first clinical study to evaluate the aluminium content in bone and mortality risk. After age adjustment, we found no association with high aluminium values and increased mortality risk.
The hypothesis that aluminium slowly leaks into the cells and could actually be one of the fundamental ageing mechanisms, especially in long-lived post-mitotic cells such as nerve and muscle cells [1] of various kinds leading to degeneration of cells and eventually cell death, is thus not supported by our data of the aluminium accumulation (as measured in the bone). Nevertheless, several studies have identified aluminium in the brain, and further investigation has revealed that the metal is present in close relation with the nuclei and may produce changes in the DNA expressions that can cause cell damage [11, 21–23]. The suggested mechanisms that could cause these damages might be aluminium-induced apoptosis, proposed to be induced by a local intracellular increased oxidative stress and inflammation induced by aluminium [24–27].
A major strength of our study was our ability to directly measure, using a validated method, the aluminium content in bone biopsies extracted during an operation, since bone tissue is the body's main storage site for aluminium. Great efforts have been made to avoid false results when processing the samples: all biopsies were taken using an aluminium-free instrument, the samples were then stored in aluminium-free sealed polyethylene test tubes and all handling was carried out in a clean room. None of the selected patients refused participation, and the possibility of subject selection by the aluminium content of bone is not likely even though we only used orthopaedic patients, with the practical purpose of accessing bone biopsies. Additionally, we have previously shown that the aluminium content of the bone was similar in demented and non-demented hip fracture cases as in osteoarthritic patients as well as in subjects with high-energy trauma type of fractures [19]. This indicates that the aluminium content of the bone among our participants is presumably not different from the general population of our setting. We find it also unlikely that choosing only orthopaedic patients as participants in the study could have affected our internal validity—the range in aluminium exposure was extensive.
Even though our results do not indicate this, despite a considerable exposure span regarding aluminium values and despite any tendency towards an increased risk of mortality, we were not able to detect a more subtle association between aluminium in bone and mortality risk. Our confidence range indicates that we were able to detect an increase in mortality risk of approximately 25% or higher for each standard deviation increase in aluminium.
In conclusion, even though we accumulate aluminium in bone throughout our lives, and though there are experimental suggestions that aluminium induces premature cell death, the content of bodily aluminium does not seem to influence overall mortality risk.
- Aluminium is the commonest metal in the earth's crust, but no essential biological function is known.
- Aluminium is considered to be a potentially toxic metal that might trigger apoptosis.
- Aluminium normally enters the body through the diet, owing to its natural presence in many foods.
- Aluminium is exponentially accumulated in the body with ageing.
- The content of aluminium in the body does not seem to influence overall mortality risk.
The study was sponsored by the Swedish Alzheimer Foundation and the Swedish Research Council. Neither party had any role in the design, execution, analysis and interpretation of data or the writing of the study.
The authors' each declare no conflict of interest.
Acknowledgements
Sincere thanks are due to Lena Dalnert and Lotta Classon, group leaders on OR, for their untiring efforts. We also wish to thank Assistant Professor Ulf Lindh and PhD student Peter Frisk, for technical assistance.
1 Department of Orthopaedics, Uppsala University Hospital, S-751 85 Uppsala, Sweden
2 Department of Orthopaedics, Uppsala Clinical Research Centre (UCR), Uppsala University Hospital, S-751 85 Uppsala, Sweden
3 Västra Vallgatan 29, S-271 35 Ystad, Sweden
* To whom correspondence should be addressed Email: hans.olov.hellstrom{at}akademiska.se; hans-olov.hellstrom{at}bredband.net
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