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The effect of lead in bone densitometry
Nuclear Instruments and Methods in Physics Research B 213 (2004) 599–602 www.elsevier.com/locate/nimb
The effect of lead in bone densitometry Marija Popovic *, Fiona E. McNeill, Colin E. Webber, David R. Chettle Department of Physics and Astronomy, McMaster University, 1280 Main Street West, Hamilton, Ont., Canada L8S 4K1
Abstract Dual energy X-ray absorptiometry (DXA) is presently considered the standard technique for diagnosis of osteoporosis. It has been suggested that the presence of lead interferes with the accurate measurement of bone mineral density (BMD) by DXA because of the increased attenuation and that an accurate measurement of BMD cannot be determined unless the patientÕs bone lead content of patients is known. We performed DXA measurements on plaster of Paris phantoms and a Hologic Spine phantom in combination with polyester resin doped with various concentrations of lead. At lead levels which correspond to bone concentrations in occupationally exposed individuals, the suggested increase in densitometric BMD was not detected. Numerical calculations show that the effect of the lead depends upon the two energies of the X-ray beam of a particular device. The discrepancy between the actual and the densitometric BMD increases linearly and is about 0.3% at 100 ppm. Such change cannot be detected by the Hologic QDR 4500A, the device used for this experiment. Ó 2003 Elsevier B.V. All rights reserved. PACS: 87.19.Xx; 87.50.Gi; 87.59.Ls; 87.66.Xa Keywords: Lead; Dual energy X-ray absorptiometry
1. Introduction Over the past three decades the scientific community has compiled evidence that links lead to a wide range of ill effects in humans. Subclinical lead toxicity is observed in numerous epidemiological studies at low to moderate blood lead levels (10–25 lg/dl) [1–3]. Lead in blood is the most commonly used biological marker of lead dose. With a mean biological life of 30 days, lead in blood reflects current exposure to lead and the endogenous release of lead from the skeleton. Autopsy studies
*
Corresponding author. E-mail address: [email protected] (M. Popovic).
reveal that 70–95% of bodyÕs lead burden is stored in the skeleton [4]. The metal is stored in long-lived compartments of the bone where the mean lead elimination time is measured in decades. For this reason, bone lead levels are proven to be a measure of cumulative lead exposure. Human skeleton is continuously resorbed and rebuilt by the action of osteoclast and osteoblast bone cells, at an annual rate of 1–8% [5]. Lead inhibits osteoclastic bone resorption and osteoblastic bone formation. There is evidence that the effect is more pronounced in osteoblasts than in osteoclasts, and that the imbalance in the dual process of bone formation and bone resorption ultimately results in bone loss and bone tissue deterioration, both characteristic of osteoporosis.
0168-583X/$ - see front matter Ó 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0168-583X(03)01677-X
600
M. Popovic et al. / Nucl. Instr. and Meth. in Phys. Res. B 213 (2004) 599–602
The definition of osteoporosis is based on the measurements of bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA). Proximal femur BMD of an individual is compared to that of a young adult and, according to the World Health Organization criteria, a T-score of less than )2.5 is taken to be a sign of osteoporosis [6]. The association between lead and osteoporosis in humans remains a controversial topic. The reason may very well be the obvious difficulty in conducting a controlled study with a sufficiently large population. Osteoporosis takes decades to develop and, especially in females, may be triggered by sudden changes in bone metabolism and rapid bone turnover during physiological changes, such as lactation and menopause. Experiments in vitro provide evidence at the cellular level that lead exposure may cause osteoporosis as a result of an imbalance between bone formation and bone resorption [7]. Animal studies provide substantial evidence that dietary lead intake is related to negative changes in bone mass and bone volume. Solid evidence that lead in bone induces osteoporosis and significantly lower BMD in humans does not yet exist and there are two opposing opinions for why this may be the case. Lead is incorporated into the hydroxyapatite crystals during calcification. The first argument suggests that, due to similar chemical properties of the two ions, relatively heavy lead ions replace calcium ions in the bone matrix. The result is an increase in bone density, while lead exerts its toxic effect on the skeleton [8]. Contrary to this argument it has been suggested by Puzas [9] that any increase in BMD is a pure artifact of DXA produced by enhanced attenuation of photons by the presence of high atomic number lead atoms in bone. Their studies reveal a logarithmic dependence of BMD on bone lead content. The experiments by Puzas show a 5% increase in BMD at lead concentrations of 10 lg/g of bovine bone [9]. Proving that the artifact of DXA exists would imply that the BMD cannot be correctly determined by DXA without measuring the bone lead content of the individual. The latter argument provided motivation for our current study, the results of which are presented below.
2. Numerical investigation The DXA algorithm is based on a two-component model limiting itself to differentiating between bone and soft tissue. Assuming a monoenergetic X-ray beam, the following argument holds. Two X-rays, one with high energy (h) and one with low energy (l) pass through a thickness (t) of soft tissue (s) and bone (b). The intensities of the two X-ray beams upon reentering air are governed by the following photon attenuation equations in two media, " !# l l l l l l I ¼ I0 exp ts þ tb ; q s q b " ð1Þ h h !# l l ts þ tb ; I h ¼ I0h exp q s q b where ðl=qÞ represents the attenuation coefficient of X-rays in the given medium. Attenuation coefficients of compounds depend linearly on the relative amount of each element in the compound by weight. In the presence of lead (Pb), Eq. (1) takes the following form: l l I l ln 0l ¼ ts q s I " l # l l l þ ð1 xÞ þ x tb ; q b q Pb ð2Þ h h I0 l ln h ¼ ts q s I " h # h l l þ ð1 xÞ þ x tb ; q b q Pb where x represents the amount of lead in grams per unit mass of bone. The X-ray beam of the QDR 4500A is not monoenergetic. It is estimated that the lower energy peak is at approximately 40 keV and that the peak of the higher-energy beam does not exceed 100 keV. Eq. (1) may be solved simultaneously for tb , h l l h I0 I0 l l ln ln l q q I Ih s s tb ¼ h l h l : ð3Þ l l l l q q q q s
b
b
s
M. Popovic et al. / Nucl. Instr. and Meth. in Phys. Res. B 213 (2004) 599–602
3.1. Materials and methods Measurements were performed with two sets of lead-doped phantoms. Polyester phantoms were made by adding 1005 mg/ml lead atomic absorption standard solution to polyester resin. The resin, to the best of our knowledge, contains no lead and is often used as a model for biological tissue. Special care was taken to ensure that the lead solution was uniformly distributed throughout the volume of the mould. The phantoms were cut into various shapes to provide a range of lead concentrations when placed over a spine phantom. The lumbar spine QC phantom is an anthropomorphic model with an accepted BMD of 1.018 g/ cm2 . The fact that the lead doped polyester phantom is positioned over the spine phantom does not influence the analysis of the two-dimensional image by DXA, provided that the projected region of the spine phantom completely encompasses the region of the polyester phantom. Plaster of Paris phantoms are bone lead XRF calibration standards with known amounts of lead used in previous studies of bone lead. To account for the presence of the soft tissue around the phantom, all measurements were also performed
4. Results For the scan option used, the precision, given as the standard deviation (SD), is 0.00806 g/cm2 . Therefore, the minimum difference in BMD between two scans which cannot be attributed to measurement error with 95% confidence is 0.023 g/ cm2 . Such a difference has not been noted between any two measurements performed on polyester phantoms or plaster of Paris phantoms alone or in the presence of water. The variance of the measurements was within the scope of statistical fluctuations. The results of the experiments are shown graphically in Figs. 1 and 2. Error bars represent SD from the mean where the same measurement was repeated multiple times. All plaster of Paris 1.03 1.025 2
3. Experimental
with the phantom centrally positioned in a water bath. DXA scans were performed with a fan beam QDR 4500A densitometer (Hologic, Inc., Bedford, MA) calibrated daily according to the manufacturerÕs recommendations. The spine array mode of the scan protocol was used (point resolution 0.0901 cm). The phantoms were placed with the aid of a laser beam to assure a high positioning reproducibility during all measurements. All DXA measurements were performed by the same investigator. After manually positioning the bone and the laser beam that marks the start of the scan, the measurements were performed in a fully automated manner.
BMD (g/cm )
The parameters lnðI0l =I l Þ and lnðI0h =I h Þ are calculated from Eq. (2) using arbitrary values of tb and ts at a range of X-ray energies. The calculated parameters represent the function of intensities as seen by the detector ignoring the presence of lead. Eq. (3) is then used to obtain the artificial value of BMD, and percentage difference is calculated between the artificial BMD and the starting value as given above. The exact values of tb and ts are irrelevant when calculating the absolute difference in these parameters. The attenuation coefficients ðl=qÞs;b are calculated for ICRU-44 soft tissue and bone [10]. The results show a linear increase in absolute difference between measured and actual BMD. The difference is dependent on dual X-ray energies used, and at 100 ppm the maximum calculated difference is about 0.3%.
601
1.02 1.015 1.01 1.005 1 0.995 0
10
20
30
40
50
60
lead concentration (ppm)
Fig. 1. Polyester phantoms. The dependence of BMD on concentration of lead as measured by DXA.
602
M. Popovic et al. / Nucl. Instr. and Meth. in Phys. Res. B 213 (2004) 599–602 0.013
density/mass
0.0125
0.012
0.0115
0.011
0.0105 0
50
100
150
200
250
lead (ppm)
Fig. 2. Plaster of Paris phantoms. The effect of lead on BMD as measured by DXA. The results have been normalized with respect to density.
phantoms had the same volume and were weighed to correct for slight differences in mass introduced with the small amount of air present in the volume. BMD results were hence normalized with respect to mass. Plaster of Paris phantoms measured in water show consistently higher BMD (results not shown). This is purely the result of a different medium used to mimic soft tissue (water versus air), and the discrepancy is constant at all concentrations of lead investigated. The results of linear regression in the case of plaster of Paris phantoms do not show a significant correlation between BMD and lead concentrations. In the case of polyester phantoms, linear regression results in a slight decrease in BMD (0:00130 0:00006 ðg=cm2 =ppmPbÞ, p < 0:05).
5. Conclusion The current findings using polyester and plaster of Paris phantoms demonstrate that lead does not interfere with DXA measurements of BMD using a Hologic QDR 4500A densitometer. The measurements performed on three sets of lead doped phantoms do not confirm the results of the study done by Puzas which suggests that at low concentrations of lead, BMD measured by DXA increases by 5%. The difference between any two measurements performed on a single set of phan-
toms does not exceed the value of 0.023 g/cm2 and, therefore, all variation in measurements is less than the precision of the QDR 4500A device used. The calculations based on the attenuation of Xrays in two media show that the small predicted increase in BMD was not detectable. The relationship between the two parameters is linear and its magnitude farther depends upon the two X-ray energies used for measurement. However, the maximum absolute difference between the actual and the artificially increased BMD is about 0.3% at 100 ppm. The reasons for the obvious disagreement in the results of the current study and that conducted by Puzas are not clear. The findings presented here suggest that higher than expected BMD in lead exposed individuals are not likely to be attributed to the artifact produced by DXA device.
Acknowledgements This work is supported by Natural Sciences and Engineering Research Council of Canada (NSERC) and the Eugene G. Bolotkin Scholarship.
References [1] D. Faust, J. Brown, Pediatrics 80 (1987) 623. [2] H.L. Needleman, G. Gatsonis, J. Am. Med. Assoc. 263 (1993) 673. [3] H. Hu, M. Rabinowitz, D. Smith, Environ. Health Perspect 106 (1998) 1. [4] P.S.I. Barry, Br. J. Indust. Med. 32 (1975) 119. [5] International Commission on Radiological Protection Publication 23, Report on the task group on reference man, Pergamon Press, Oxford, 1973. [6] J.A. Kanis, L.J. Melton III, C. Chrisiansen, C.C. Johnston, N. Khaltev, J. Bone Miner. Res. 9 (1994) 1137. [7] D.G. Hicks, R.J. OÕKeefe, K.J. Reynolds, D.A. CorySlechta, J.E. Puzes, A. Judkins, R.N. Rosier, Toxicol. Appl. Pharmacol. 140 (1996) 164. [8] E. Escribano, M. Revilla, E.R. Hernandez, C. Seco, J. Gonzales-Riola, L.F. Villa, H. Rico, Calcif. Tissue Int. 60 (1997) 200. [9] J.E. Puzas, Personal communication. [10] National Institute of Standards and Technology website. http://physics.nist.gov/cgi-bin/Xcom/xcom3_1.
The effect of lead in bone densitometry Marija Popovic *, Fiona E. McNeill, Colin E. Webber, David R. Chettle Department of Physics and Astronomy, McMaster University, 1280 Main Street West, Hamilton, Ont., Canada L8S 4K1
Abstract Dual energy X-ray absorptiometry (DXA) is presently considered the standard technique for diagnosis of osteoporosis. It has been suggested that the presence of lead interferes with the accurate measurement of bone mineral density (BMD) by DXA because of the increased attenuation and that an accurate measurement of BMD cannot be determined unless the patientÕs bone lead content of patients is known. We performed DXA measurements on plaster of Paris phantoms and a Hologic Spine phantom in combination with polyester resin doped with various concentrations of lead. At lead levels which correspond to bone concentrations in occupationally exposed individuals, the suggested increase in densitometric BMD was not detected. Numerical calculations show that the effect of the lead depends upon the two energies of the X-ray beam of a particular device. The discrepancy between the actual and the densitometric BMD increases linearly and is about 0.3% at 100 ppm. Such change cannot be detected by the Hologic QDR 4500A, the device used for this experiment. Ó 2003 Elsevier B.V. All rights reserved. PACS: 87.19.Xx; 87.50.Gi; 87.59.Ls; 87.66.Xa Keywords: Lead; Dual energy X-ray absorptiometry
1. Introduction Over the past three decades the scientific community has compiled evidence that links lead to a wide range of ill effects in humans. Subclinical lead toxicity is observed in numerous epidemiological studies at low to moderate blood lead levels (10–25 lg/dl) [1–3]. Lead in blood is the most commonly used biological marker of lead dose. With a mean biological life of 30 days, lead in blood reflects current exposure to lead and the endogenous release of lead from the skeleton. Autopsy studies
*
Corresponding author. E-mail address: [email protected] (M. Popovic).
reveal that 70–95% of bodyÕs lead burden is stored in the skeleton [4]. The metal is stored in long-lived compartments of the bone where the mean lead elimination time is measured in decades. For this reason, bone lead levels are proven to be a measure of cumulative lead exposure. Human skeleton is continuously resorbed and rebuilt by the action of osteoclast and osteoblast bone cells, at an annual rate of 1–8% [5]. Lead inhibits osteoclastic bone resorption and osteoblastic bone formation. There is evidence that the effect is more pronounced in osteoblasts than in osteoclasts, and that the imbalance in the dual process of bone formation and bone resorption ultimately results in bone loss and bone tissue deterioration, both characteristic of osteoporosis.
0168-583X/$ - see front matter Ó 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0168-583X(03)01677-X
600
M. Popovic et al. / Nucl. Instr. and Meth. in Phys. Res. B 213 (2004) 599–602
The definition of osteoporosis is based on the measurements of bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA). Proximal femur BMD of an individual is compared to that of a young adult and, according to the World Health Organization criteria, a T-score of less than )2.5 is taken to be a sign of osteoporosis [6]. The association between lead and osteoporosis in humans remains a controversial topic. The reason may very well be the obvious difficulty in conducting a controlled study with a sufficiently large population. Osteoporosis takes decades to develop and, especially in females, may be triggered by sudden changes in bone metabolism and rapid bone turnover during physiological changes, such as lactation and menopause. Experiments in vitro provide evidence at the cellular level that lead exposure may cause osteoporosis as a result of an imbalance between bone formation and bone resorption [7]. Animal studies provide substantial evidence that dietary lead intake is related to negative changes in bone mass and bone volume. Solid evidence that lead in bone induces osteoporosis and significantly lower BMD in humans does not yet exist and there are two opposing opinions for why this may be the case. Lead is incorporated into the hydroxyapatite crystals during calcification. The first argument suggests that, due to similar chemical properties of the two ions, relatively heavy lead ions replace calcium ions in the bone matrix. The result is an increase in bone density, while lead exerts its toxic effect on the skeleton [8]. Contrary to this argument it has been suggested by Puzas [9] that any increase in BMD is a pure artifact of DXA produced by enhanced attenuation of photons by the presence of high atomic number lead atoms in bone. Their studies reveal a logarithmic dependence of BMD on bone lead content. The experiments by Puzas show a 5% increase in BMD at lead concentrations of 10 lg/g of bovine bone [9]. Proving that the artifact of DXA exists would imply that the BMD cannot be correctly determined by DXA without measuring the bone lead content of the individual. The latter argument provided motivation for our current study, the results of which are presented below.
2. Numerical investigation The DXA algorithm is based on a two-component model limiting itself to differentiating between bone and soft tissue. Assuming a monoenergetic X-ray beam, the following argument holds. Two X-rays, one with high energy (h) and one with low energy (l) pass through a thickness (t) of soft tissue (s) and bone (b). The intensities of the two X-ray beams upon reentering air are governed by the following photon attenuation equations in two media, " !# l l l l l l I ¼ I0 exp ts þ tb ; q s q b " ð1Þ h h !# l l ts þ tb ; I h ¼ I0h exp q s q b where ðl=qÞ represents the attenuation coefficient of X-rays in the given medium. Attenuation coefficients of compounds depend linearly on the relative amount of each element in the compound by weight. In the presence of lead (Pb), Eq. (1) takes the following form: l l I l ln 0l ¼ ts q s I " l # l l l þ ð1 xÞ þ x tb ; q b q Pb ð2Þ h h I0 l ln h ¼ ts q s I " h # h l l þ ð1 xÞ þ x tb ; q b q Pb where x represents the amount of lead in grams per unit mass of bone. The X-ray beam of the QDR 4500A is not monoenergetic. It is estimated that the lower energy peak is at approximately 40 keV and that the peak of the higher-energy beam does not exceed 100 keV. Eq. (1) may be solved simultaneously for tb , h l l h I0 I0 l l ln ln l q q I Ih s s tb ¼ h l h l : ð3Þ l l l l q q q q s
b
b
s
M. Popovic et al. / Nucl. Instr. and Meth. in Phys. Res. B 213 (2004) 599–602
3.1. Materials and methods Measurements were performed with two sets of lead-doped phantoms. Polyester phantoms were made by adding 1005 mg/ml lead atomic absorption standard solution to polyester resin. The resin, to the best of our knowledge, contains no lead and is often used as a model for biological tissue. Special care was taken to ensure that the lead solution was uniformly distributed throughout the volume of the mould. The phantoms were cut into various shapes to provide a range of lead concentrations when placed over a spine phantom. The lumbar spine QC phantom is an anthropomorphic model with an accepted BMD of 1.018 g/ cm2 . The fact that the lead doped polyester phantom is positioned over the spine phantom does not influence the analysis of the two-dimensional image by DXA, provided that the projected region of the spine phantom completely encompasses the region of the polyester phantom. Plaster of Paris phantoms are bone lead XRF calibration standards with known amounts of lead used in previous studies of bone lead. To account for the presence of the soft tissue around the phantom, all measurements were also performed
4. Results For the scan option used, the precision, given as the standard deviation (SD), is 0.00806 g/cm2 . Therefore, the minimum difference in BMD between two scans which cannot be attributed to measurement error with 95% confidence is 0.023 g/ cm2 . Such a difference has not been noted between any two measurements performed on polyester phantoms or plaster of Paris phantoms alone or in the presence of water. The variance of the measurements was within the scope of statistical fluctuations. The results of the experiments are shown graphically in Figs. 1 and 2. Error bars represent SD from the mean where the same measurement was repeated multiple times. All plaster of Paris 1.03 1.025 2
3. Experimental
with the phantom centrally positioned in a water bath. DXA scans were performed with a fan beam QDR 4500A densitometer (Hologic, Inc., Bedford, MA) calibrated daily according to the manufacturerÕs recommendations. The spine array mode of the scan protocol was used (point resolution 0.0901 cm). The phantoms were placed with the aid of a laser beam to assure a high positioning reproducibility during all measurements. All DXA measurements were performed by the same investigator. After manually positioning the bone and the laser beam that marks the start of the scan, the measurements were performed in a fully automated manner.
BMD (g/cm )
The parameters lnðI0l =I l Þ and lnðI0h =I h Þ are calculated from Eq. (2) using arbitrary values of tb and ts at a range of X-ray energies. The calculated parameters represent the function of intensities as seen by the detector ignoring the presence of lead. Eq. (3) is then used to obtain the artificial value of BMD, and percentage difference is calculated between the artificial BMD and the starting value as given above. The exact values of tb and ts are irrelevant when calculating the absolute difference in these parameters. The attenuation coefficients ðl=qÞs;b are calculated for ICRU-44 soft tissue and bone [10]. The results show a linear increase in absolute difference between measured and actual BMD. The difference is dependent on dual X-ray energies used, and at 100 ppm the maximum calculated difference is about 0.3%.
601
1.02 1.015 1.01 1.005 1 0.995 0
10
20
30
40
50
60
lead concentration (ppm)
Fig. 1. Polyester phantoms. The dependence of BMD on concentration of lead as measured by DXA.
602
M. Popovic et al. / Nucl. Instr. and Meth. in Phys. Res. B 213 (2004) 599–602 0.013
density/mass
0.0125
0.012
0.0115
0.011
0.0105 0
50
100
150
200
250
lead (ppm)
Fig. 2. Plaster of Paris phantoms. The effect of lead on BMD as measured by DXA. The results have been normalized with respect to density.
phantoms had the same volume and were weighed to correct for slight differences in mass introduced with the small amount of air present in the volume. BMD results were hence normalized with respect to mass. Plaster of Paris phantoms measured in water show consistently higher BMD (results not shown). This is purely the result of a different medium used to mimic soft tissue (water versus air), and the discrepancy is constant at all concentrations of lead investigated. The results of linear regression in the case of plaster of Paris phantoms do not show a significant correlation between BMD and lead concentrations. In the case of polyester phantoms, linear regression results in a slight decrease in BMD (0:00130 0:00006 ðg=cm2 =ppmPbÞ, p < 0:05).
5. Conclusion The current findings using polyester and plaster of Paris phantoms demonstrate that lead does not interfere with DXA measurements of BMD using a Hologic QDR 4500A densitometer. The measurements performed on three sets of lead doped phantoms do not confirm the results of the study done by Puzas which suggests that at low concentrations of lead, BMD measured by DXA increases by 5%. The difference between any two measurements performed on a single set of phan-
toms does not exceed the value of 0.023 g/cm2 and, therefore, all variation in measurements is less than the precision of the QDR 4500A device used. The calculations based on the attenuation of Xrays in two media show that the small predicted increase in BMD was not detectable. The relationship between the two parameters is linear and its magnitude farther depends upon the two X-ray energies used for measurement. However, the maximum absolute difference between the actual and the artificially increased BMD is about 0.3% at 100 ppm. The reasons for the obvious disagreement in the results of the current study and that conducted by Puzas are not clear. The findings presented here suggest that higher than expected BMD in lead exposed individuals are not likely to be attributed to the artifact produced by DXA device.
Acknowledgements This work is supported by Natural Sciences and Engineering Research Council of Canada (NSERC) and the Eugene G. Bolotkin Scholarship.
References [1] D. Faust, J. Brown, Pediatrics 80 (1987) 623. [2] H.L. Needleman, G. Gatsonis, J. Am. Med. Assoc. 263 (1993) 673. [3] H. Hu, M. Rabinowitz, D. Smith, Environ. Health Perspect 106 (1998) 1. [4] P.S.I. Barry, Br. J. Indust. Med. 32 (1975) 119. [5] International Commission on Radiological Protection Publication 23, Report on the task group on reference man, Pergamon Press, Oxford, 1973. [6] J.A. Kanis, L.J. Melton III, C. Chrisiansen, C.C. Johnston, N. Khaltev, J. Bone Miner. Res. 9 (1994) 1137. [7] D.G. Hicks, R.J. OÕKeefe, K.J. Reynolds, D.A. CorySlechta, J.E. Puzes, A. Judkins, R.N. Rosier, Toxicol. Appl. Pharmacol. 140 (1996) 164. [8] E. Escribano, M. Revilla, E.R. Hernandez, C. Seco, J. Gonzales-Riola, L.F. Villa, H. Rico, Calcif. Tissue Int. 60 (1997) 200. [9] J.E. Puzas, Personal communication. [10] National Institute of Standards and Technology website. http://physics.nist.gov/cgi-bin/Xcom/xcom3_1.