Severe Cortical and TrabecularOsteopenia in SecondaryHyperparathyroidism

Diego Brancaccio1, Claudio Di Leo2, Alberto Bestetti2,Paola Carpani1, Luca Tagliabue2, Mario Cozzolino1,Andrea Galassi1, Gian Luigi Tarolo2, Maurizio Gallieni1

1Department of Nephrology and Dialysis, 2NuclearMedicine Department, Ospedale San Paolo, School ofMedicine, University of Milano, Milano, Italy.

Background: Peripheral quantitative computed tomo-

graphy (pQCT) provides real volumetric bone density

values, not only of the total, but also of trabecular and

cortical bone, separately. In addition, it provides data on

bone geometry that can be related to the risk of fracture.

Methods: Total, cortical, and trabecular volumetric bone

mineral densities (BMD), as well as the main geometric para-

meters (cross-sectional area, cortical area, trabecular area,

and cortical thickness) were assessed by pQCT at the distal

radius in 24 hemodialysis patients affected by severe secondary

hyperparathyroidism (PTH, mean�SD: 1444� 695 pg/mL).

The strength-strain index (SSI), a biomechanical par-

ameter describing bone fragility, was also determined.

Results: Compared with a control group of 64 healthy age-

matched subjects, volumetric BMD (mg/cm3) was signifi-

cantly reduced in all patients (total BMD: 243� 87 vs.

405� 138, cortical BMD: 605� 218 vs. 856� 204, trab-

ecular BMD: 95� 51 vs. 182� 75). Cortical area and

cortical thickness showed significant modifications, while

cross-sectional area did not. SSI was significantly reduced

(547� 125 vs. 927� 306 mm3). PTH levels showed a sig-

nificant inverse correlation with cortical BMD (r¼�0.56),

cortical thickness (r¼�0.46), cortical area (r¼�0.61),

and SSI (r¼�0.54). Quantitative analysis of bone

demonstrated cortical porosity.

Conclusions: In dialysis patients with severe secondary

hyperparathyroidism, pQCT showed a significant cortical

osteopenia, associated with geometric and mechanical bone

impairment. Interestingly, we also found a comparable

deficit of trabecular bone, which may be related to the very

high PTH levels. Generalized cortical thinning, intracortical

porosity and cortical-endosteal resorption (‘‘trabecular-

ization’’ of the cortical bone) are major determinants of

reduced bone strength, which may be quantitated by pQCT.

Hemodial Int. 2003; 7(2):122–129.

Key words

Bone mineral density, renal osteodystrophy, secondary

hyperparathyroidism, peripheral quantitative computed

tomography (pQCT), dialysis, parathyroid hormone

Introduction

In patients on maintenance hemodialysis, bone disease is

a major cause of morbidity and osteitis fibrosa, charac-

terized by excessive osteoclastic bone resorption and sub-periosteal erosions, representing the main bone

abnormality of secondary hyperparathyroidism [1].

At the onset of dialysis therapy, bone density is often

lower than that of healthy, age-matched controls [2], and

loss of bone mineral content continues throughout the

course of maintenance dialysis. In recent years, several

noninvasive approaches for measuring bone mineral con-

tent (BMC) and bone mineral density (BMD) have beendeveloped, such as single-photon absorptiometry (SPA),

dual-photon absorptiometry (DPA), and dual-energy

X-ray absorptiometry (DXA). The usefulness of these

methods for detection and follow-up of post-menopausal

and senile osteoporosis is well established, and BMD

measurements are now recognized as accurate predictors

of the risk of osteoporotic fractures [3]. These technolo-

gies may also be used to evaluate loss of bone densitycaused by other disease processes, including end-stage

renal disease (ESRD) [4].

Common densitometric approaches (i.e., DXA, SPA,

DPA) are not able to distinguish the cortical from the

trabecular component, and measure only the overall

quantity of bone, usually defined as bone mineral con-

tent. No information on the quality and architectural

design of bone is provided [5]. Another disadvantage ofthe conventional posterior-anterior scan is the error

related to spinal degenerative changes and aortic calci-

fication, which artificially enhance bone mineral density

assessed at the lumbar spine. On the contrary, peripheral

quantitative computed tomography (pQCT) allows a

selective assessment of true volumetric cortical and trab-

ecular bone mineral density, with minimal impact from

degenerative changes. Moreover, this technology pro-vides several biomechanical parameters describing bone

strength. These include the cross-sectional moment of

Correspondence to:

Professor Diego Brancaccio,

Renal Unit – Ospedale San Paolo, Via A. di Rudinı, 8 – 20142

Milano, Italy. email: diego.brancaccio@tiscalinet.it

122

inertia, which reflects the geometry of bone and the

flexural and torsional strength of diaphyseal bone [6],

and the elastic modulus describing the characteristicsof bone material, an indicator of the load/deformation

ratio [7].

In the attempt to noninvasively predict bone fracture

risk, Ferretti and coworkers proposed the bone strength

index (BSI) as a parameter that combines information

about material properties (volumetric cortical BMD) and

geometrical shape (cross-sectional moment of inertia),

and that closely correlates with fracture load (r¼ 0.89)[8]. In addition, they proposed another more sophisti-

cated biomechanical index, the strength-strain index

(SSI), which correlates with anaerobic muscle exercise,

reflecting the ability of bone to respond to changes in the

loading pattern through remodeling [8]. The strength-

strain index is therefore a biomechanical parameter

describing bone fragility.

The main purpose of this study was to use pQCTto investigate the effects of long-term PTH excess on

1) trabecular and cortical bone mineral density, and on

2) geometry and resistance of the appendicular skeleton

in patients affected by severe secondary hyperpara-

thyroidism.

Subjects and methods

Subjects

We studied 24 uremic patients on thrice weekly mainte-

nance hemodialysis. All patients were affected by severe

secondary hyperparathyroidism; they were selected for

this study if they had an indication for parathyroidectomy,

based on the presence of persistently elevated intact PTH

(>500 pg/mL) and calcium-phosphorus product levels

(>70 mg2/dL2) in serum.The control group consisted of 64 healthy age-

matched subjects recruited among hospital personnel.

Table I summarizes age, height, weight, and body mass

index of patients and controls. The control group was

also comparable for gender, time since menopause, use of

estrogen, and use of drugs for osteoporosis. All subjects

gave their written informed consent.

Laboratory determinations

Serum intact PTH levels were determined by radio-

immunoassay (Nichols Institute Diagnostics, San Juan

Capistrano, CA, USA); the most recent reference intervalis: 17–76 pg/mL. Serum calcium (normal: 8.1–10.4 mg/dL),

phosphorus (normal: 2.4–4.1 mg/dL), and alkaline phos-

phatase (normal: 98–279 U/L) were measured by routine

automated methods. The calcium-phosphorus product in

serum (Ca�PO4) was also calculated. Ca�PO4 levels in

normal subjects range from 28–45 mg2/dL2; in dialysis

patients levels <60 have been recommended, although it

has not been determined if levels between 45 and 60 aresafe or if extraskeletal calcifications occur.

Peripheral quantitative computed tomography (pQCT)

Volumetric bone density was measured by peripheral

quantitative computed tomography (L’CAN, Tomo-

gamma Laboratori Scientifici, Cerro Maggiore, Milano,

Italy), on the non-dominant forearm at the 4% proximal

point to the distal end of the radius, in a transversal scan

1.5 mm thick. A scout view of the distal forearm was

carried out to position the scanner. An x-ray source of40 kV was used; the effective dose equivalent, measured

using an anthropometric phantom and an ionization

probe, was very low (<2 mSv) [9]. Cortical and trabecular

regions of interest were recognized by an automatic algo-

rithm. Bone mineral density measurements were

expressed as exact values in milligrams per cubic centi-

meter (mg/cm3) and as Z-scores, which represent the

BMD value normalized for age and sex-matched mean,or as T-scores that refer to the young adult reference

mean calculated from the manufacturer’s database.

Cortical thickness (CThk) was calculated automatically,

assuming a circular ring model for the radius, using the

following formula:

CThk ¼ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiTotal Area=�

p�

ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiTrabecular Area=�

p

The short-term precision errors (CV), measured over

a 3-day period, were 0.5% for trabecular BMD, 0.8% for

cortical BMD in vivo, and 0.3% in vitro (on a polyethyl-

ene phantom). The long-term precision in vitro, assessed

by daily measurements of a 4-month period on the stand-

ard phantom, was 0.8%.

The strength-strain index (SSI) was calculated auto-

matically using the following formula [8,10]:

SSIðmm3Þ ¼ �a � d2

d max� CD

CD max

where a¼ area of one voxel of the cortex (mm2),

d¼ distance of one voxel to the center of gravity of thecortical area (mm), d max¼maximum distance (eccen-

tricity) of one voxel to the center of gravity (mm),

TABLE I Anthropometric measurements of uremic patients and controls.

Abbreviations: BMI ¼ body mass index.

Total

population n

Age

(years)

Weight

(kg)

Height

(cm)

BMI

(kg/m2)

Patients 24 52 60 163 23

SD �14 �13 �11 �5

Controls 64 52 65 165 24

SD �13 �11 �8 �4

p values n.s. 0.04 n.s. n.s.

Hemodialysis International, Vol. 7, No. 2, 2003 pQCT in Severe Secondary Hyperparathyroidism

123

CD¼ cortical density (g/cm3), and CD max¼maximum

cortical density (1.2 g/cm3) [11].

The sum over all voxels of the product (a� d2) rep-resents the cross-sectional moment of inertia. Division by

(d max) yields the section modulus. The ratio of CD and

CD max acts as an estimator of the modulus of elasticity [11].

Quantitative bone analysis

Automated quantitative bone analysis is based on a para-

bolic fitting function (f¼ ax2þ c). This mathematical

function represents the distribution of bone mineral den-

sity (f) along the distance (x) from the edge to the bary-

center of the radius (Figures 1 and 2). The coefficient (a)

represents the initial slope of the curve, mainly influenced

by bone mineral abnormalities at the cortical site, while

the coefficient (c) represents the tail of the curve, corres-ponding to the barycenter of the radius. Furthermore, the

tridimensional display (3-D) of this parabolic function

was obtained using an iterative reconstruction algorithm.

Statistical analysis

Data are reported as mean values� standard deviation

(SD) and as a range. The correlation between parameters

was carried out using Pearson’s analysis. The normality

of the two groups was excluded by the Kolmogorov-

Smirnov test, and then the Mann-Whitney non-parametric test was used to compare intergroup differences.

The criterion for statistical significance was p< 0.05.

The precision error of the measurements was expressed

as coefficient of variation [CVs¼ (SD/mean)� 100].

Results

Clinical and biochemical characteristics of uremic

patients are summarized in Table II. The comparison ofdensitometric data between patients and control subjects

is shown in Table III. Total, cortical, and trabecular

volumetric bone densities were reduced in the uremic

patients in comparison with their controls (total BMD:

243 mg/cm3 vs. control 405, �40%, p< 0.000001; cortical

BMD: 605 mg/cm3 vs. 856, �29%, p< 0.000001; trab-

ecular BMD: 95 mg/cm3 vs. 182, �48%, p< 0.000001).

The absolute amount of bone lost per unit of surface wasgreater in the cortical compartment.

Similarly, among geometric parameters, cortical area

(0.7 cm2 vs. control 0.8, p< 0.001) and cortical thickness

(1.4 mm vs. control 1.7, p< 0.00005) were significantly

FIGURE 1 Bone quantitative analysis performed automatically on peripheral quantitative computed tomography slices in a normal subject and in

a representative uremic patient. The bone density profile (parabolic curve) of the uremic patient appears flatter than normal, indicating cortical

osteopenia.

Brancaccio et al. Hemodialysis International, Vol. 7, No. 2, 2003

124

lower, while cross-sectional (total) area and trabecular

area were not significantly different (Table IV). Strength-strain index was significantly reduced in all patients (SSI:

547 mm3 vs. control 927, p< 0.000001).

The relationships of serum PTH levels and duration

of dialysis with densitometric measurements, and geo-

metric and biomechanical parameters were also evalu-

ated (Table V). Serum PTH levels were inversely

correlated with cortical density, cortical area, cortical

thickness, and strength-strain index. Total and trabecularbone densities also appeared inversely correlated with

serum PTH, but not significantly.

Length of time on dialysis treatment showed a nega-

tive but not significant correlation with trabecular(r¼�0.27), cortical (r¼�0.32), and total (r¼�0.43)

volumetric bone mineral densities, as well as with cortical

thickness (r¼�0.23) and strength-strain index

(r¼�0.23). In patients, age was negatively correlated

only with trabecular density (r¼�0.61, p< 0.001).

Automated bone quantitative analysis (Figure 1) and

its three-dimensional (3-D) representation using the

paraboloid of revolution model (Figure 2), demonstratedthe existence of an endosteal resorption process, mainly

regarding the cortical component (‘‘trabecularization’’ of

FIGURE 2 Three-dimensional representation of mineral density distribution from the center of gravity (trabecular site) to the periphery (cortical site) of the

radius by the paraboloid model of revolution (see text). The slope of the paraboloid model allows a better evaluation of cortical osteopenia and

‘‘trabecularization’’ of the cortex. PTH¼ parathyroid hormone.

TABLE II Clinical and biochemical characteristic of uremic patients. Abbreviations: sPTH¼ serum parathyroid hormone; P¼ serum phosphate; Ca¼ total

serum calcium; Ca � P ¼ calcium-phosphate product.

n¼24 Dialysis duration (months) sPTH (pg/mL) Alkaline phosphatase (U/L) P (mg/dL) Ca (mg/dL) Ca�P (mg2/dL2)

Mean 144 1444 811 7.4 10.9 87

SD �88 �695 �543 �2.1 �1.2 �32

Range 12–328 810–3250 221–2017 4.6–12.2 10.6–13.7 51–166

Normal 17–76 98–279 2.4–4.1 8.1–10.4 25–45

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125

the cortex). In Figure 2 an example of 3-D representation

is illustrated. Data from a normal subject and a patient

with severe secondary hyperparathyroidism are pre-

sented. The scout view is already clearly different, withreduced cortical density in the patient radius. After con-

tour regularization, the final paraboloid model is pro-

vided by the software and allows a clinical evaluation of

the amount of cortical bone loss by visual analysis of the

paraboloid slope, which is clearly abnormal in the

patient.

The finding of trabecularization of the cortex

is further supported by a clear direct correlation ofserum PTH levels and the ratio trabecular/cortical area

(Table V), reflecting a relative progressive endocortical

expansion of trabecular bone as PTH levels increase.

Discussion

Our results demonstrate a significant reduction in volu-

metric bone mineral density at trabecular and cortical

sites in hemodialysis patients with severe secondary

hyperparathyroidism. We defined the severity of second-

ary hyperparathyroidism based on levels determined by a

first generation intact PTH assay. It is now known thatsuch an assay is not a measurement of 1–84 PTH exclu-

sively, but a measurement of 1–84 PTH and 7–84 PTH,

which has been demonstrated to have inverse biological

activities of 1–84 PTH [12]. Experience with second-

generation assays showed that the actual 1–84 PTH levels

are 30 to 40% less than first generation. However, within

the range of PTH levels in our patient population (810 to

3250 pg/mL), it is very unlikely that the bone histological

finding would be different from high-turnover bone dis-ease due to secondary hyperparathyroidism.

Among the geometric and biomechanical parameters,

cortical area, cortical thickness, and strength-strain index

values were significantly reduced in all patients, com-

pared with age-matched controls. Serum PTH levels

showed a significant negative correlation with cortical

bone mineral density, cortical area, cortical thickness,

and strength-strain index.Our results confirm the existence of a direct correl-

ation between serum PTH and bone mineral loss [13].

Indeed, previous studies demonstrated that a chronic

increase in PTH secretion causes loss of appendicular

cortical bone [14,15] and is associated with a reduction

of total body and skull bone density in dialysis patients

[16–18]. Similar findings were reported in patients with

chronic renal failure [2,19]. Russo et al., who studiedhemodialysis patients by pQCT [20], also found a reduc-

tion in volumetric cortical density, but no significant

changes of trabecular bone. However, their patient popu-

lation was different from ours, because secondary hyper-

parathyroidism was not present in all their patients.

Our data on the status of cortical bone are consistent

with the findings of bone biopsy-based studies [21,22].

Schober et al. suggested that the major structuralabnormality in the skeleton of dialysis patients is general-

ized thinning of cortical bone due to increased endo-

cortical resorption, the most characteristic effect of

hyperparathyroidism on bone structure [21]. In this

study, mineralized cortical bone volume at the ileum

was reduced by approximately 45% [21]. We confirmed

this finding non-invasively in the radius, a site of pre-

dominantly cortical bone. In particular, the geometricchanges observed in our patients, which were closely

related to serum PTH levels, could reflect a loss in bone

mechanical competence due to subperiosteal and endo-

cortical erosions, but especially to increased intracortical

remodeling, ‘‘trabecularization’’ of cortical bone, and

cortical thinning [22]. This hypothesis is further sup-

ported by the evidence of a significant decrease of the

non-invasive index of bone strength (SSI), closely related

TABLE III Volumetric bone mineral densities assessed using peripheral

quantitative computed tomography in uremic patients with severe

secondary hyperparathyroidism and in age-matched healthy controls.

BMD ¼ bone mineral density.

Trabecular Cortical Total

Population BMD (mg/cm3) BMD (mg/cm3) BMD (mg/cm3)

Patients (n¼ 24) 95 605 243

SD �51 �218 �87

Controls (n¼ 64) 182 856 405

SD �75 �204 �138

Variation (%) –48 –29 –40

p values <0.000001 <0.000001 <0.000001

TABLE IV Geometric and biomechanical parameters of the ultradistal radius.

Bone area

Total Trabecular Cortical

Total population (cm2) (cm2) (cm2) Trabecular/cortical area Cortical thickness (mm) Strength strain index (mm3)

Patients (24) 2.6 1.9 0.7 2.7 1.4 547

SD �0.7 �0.6 �0.1 �1.0 �0.2 �125

Controls (64) 2.6 1.9 0.8 2.4 1.7 927

SD �0.6 �0.5 �0.2 �1.0 �0.3 �306

p values n.s. n.s. <0.001 <0.008 <0.00005 <0.000001

Brancaccio et al. Hemodialysis International, Vol. 7, No. 2, 2003

126

to the architectural and mineral characteristics of the

cortex. The stress strain index could be used to identify

asymptomatic patients who are most in need of prevent-

ing or aggressively treating secondary hyperparathyroid-ism and its deleterious consequences on cortical bone.

Although measurement of bone mineral density is not

diagnostic of the type of metabolic bone disease affecting

a specific dialysis patient, it may be useful to quantitate

the severity of the disease process. The more precise

quantitative and qualitative data obtained by pQCT

measurement are particularly useful in the clinical assess-

ment of bones in dialysis patients.Although cortical bone loss is predominant, we

observed that both cortical and trabecular bone densities

are reduced. This is somewhat surprising, and in contrast

to numerous previous findings starting in the 1960s with

the seminal contribution of Kaye and co-workers [23],

who found osteosclerosis, which has also been defined as

‘‘rugger-jersey spine’’ [24], in secondary hyperparathy-

roidism. Indeed, it is generally assumed that PTH has anegative effect on cortical bone and anabolic effects on

trabecular bone [25]. For this reason, PTH has been

advocated for the treatment of spinal osteoporosis. We

showed that very high PTH levels might be detrimental

to trabecular bone as well. Karantanas et al. also found

low trabecular BMD values in a subset of 16 hemodia-

lysis patients with osteopenic spinal fractures studied by

quantitative computed tomography [26], although PTHlevels were not specified. In 18 women with primary

hyperparathyroidism, Hesp et al. also detected a mean

deficit of 40% in trabecular bone density at the distal

radius by pQCT [27]. The bone anabolic effects of PTH

may therefore be evident only in mild forms of hyperpar-

athyroidism, while more severe degrees of the disease

seem to be associated with both cortical and trabecular

destruction of bone. Thus, the association of reducedcortical and trabecular density with decreased cortical

thickness and cortical area may result in a reduction in

the ability of bone to absorb energy, leading to a higher

risk for Colles’ fractures.

The deficit of both cortical and trabecular bone

implies a negative bone calcium balance, despite a prob-

able total positive calcium balance [28], considering that

most of our patients have been treated for many years

with calcium salts, vitamin D preparations. and a dia-

lysate calcium of at least 1.5 mMol/L. The most plausible

explanation for this paradox is a shift of calcium frombone to extra-skeletal calcifications. We recently showed

that such a process is at least, in part, reversible [29].

Dual x-ray absorptiometry (DXA) is the most popu-

lar method for measuring bone density in the general

population, because it gives very precise measurements

at clinically relevant sites with minimal radiation. Periph-

eral DXA is inexpensive, fast, and widely available, but

pQCT offers several important clinical advantages,which counterbalance its higher cost and longer acqui-

sition time, especially in patients with renal osteodys-

trophy who show marked abnormalities of bone

mineralization. Indeed, it has the potential to become

the standard method for bone densitometry in the future.

DXA methods are able to evaluate the bone mineral

content (BMC; mg/cm) and the areal density (BMD;

mg/cm2), but only quantitative computed tomography(QCT) can measure the true volumetric bone density in

the sense of mass per unit volume (mg/cm3). In addition,

DXA measurements do not discriminate between trab-

ecular and cortical bone, and quantitative computed

tomography has the best capacity to predict fractures in

osteoporotic patients [30,31]. Louis et al. demonstrated

on human cadavers by pQCT the existence of a direct

correlation between compressive strength of the radiusand cortical density and thickness [32]. Although at pre-

sent, pQCT is not widely available, it offers better quan-

titative and qualitative information, and it might become

a more reliable standard for assessment of bone status in

dialysis patients, who are more difficult to study with

traditional DXA techniques because of the presence of

diffuse extra-skeletal calcifications and other osteoarti-

cular pathologies, such as dialysis amyloidosis.A major unresolved issue is the relationship between

bone mineral density and the risk of fracture in dialysis

patients. The quality of bone is probably as important as

the density of bone, as suggested by the finding of an

increased risk of fractures in adynamic bone [33].

Larger studies are needed to assess differences in

trabecular and cortical bone mineral densities, as well

TABLE V Relationships of serum PTH levels and dialysis duration with bone densitometric measurements, geometric and biomechanical parameters.

Abbreviations: PTH ¼ parathyroid hormone; R ¼ correlation coefficient; DD ¼ dialysis duration; BMD ¼ bone mineral density; SSI ¼ strength strain

index.

BMD Bone area

Trabecular Cortical Total Trabecular Cortical Total Trabecular/Cortical Cortical Thickness SSI

PTH-R �0.21 �0.56 �0.31 0.26 �0.61 0.28 0.67 �0.46 �0.54

p values n.s. <0.0001 n.s n.s. <0.001 n.s. <0.001 0:02 <0.009

DD-R �0.27 �0.32 �0.43 0.07 0.02 0.04 0.1 �0.23 �0.23

p values n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.

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as differences in bone geometric properties, between

sexes in secondary hyperparathyroidism. These analyses

could not be performed due to the limited number ofpatients enrolled in this study. Maybe for the same rea-

son, in our patient population the dialytic age was not

significantly correlated with bone mineral density meas-

urements. This finding can also be explained by the fact

that time spent on dialysis may not accurately reflect the

duration of renal bone disease, as the onset of chronic

renal failure is often unknown.

In conclusion, in severe secondary hyperparathyroid-ism, long-term PTH excess plays a major pathogenic

role, responsible for 1) cortical osteopenia (intracortical

porosity), 2) cortical thinning (cortical-endosteal resorp-

tion), and 3) geometric and mechanical bone impairment

with resultant increased fragility and consequent higher

risk for fracture. Cortical porosity can be further studied

by a rapid, fully automated and easy-to-interpret bone

quantitative analysis and three-dimensional repre-sentation by the paraboloid of revolution model. The use

of peripheral QCT seems to be an attractive technique in

bone monitoring of hemodialysis patients, due to the low

radiation exposure, the ability to assess volumetric den-

sity of cortical and trabecular sites separately, and the

ability to evaluate non-invasively the geometric and bio-

mechanical properties of the distal radius. Due to limit-

ations of cost and unavailability of pQCT, its wide clinicaluse cannot be considered now; the technique remains a

research tool, but it may represent the reference method

of bone densitometry in the future.

Acknowledgement

We thank Dr. Wolfgang Froelich (L’ACN Laboratori

Scientifici, Cerro Maggiore, Milano, Italy) for technical

assistance.

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