Group Title: BMC Endocrine Disorders
Title: Age-related increases in parathyroid hormone may be antecedent to both osteoporosis and dementia
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Title: Age-related increases in parathyroid hormone may be antecedent to both osteoporosis and dementia
Physical Description: Book
Language: English
Creator: Braverman, Eric
Chen, Thomas
Chen, Amanda
Arcuri, Vanessa
Kerner, Mallory
Bajaj, Anish
Carbajal, Javier
Braverman, Dasha
Downs, B. W.
Blum, Kenneth
Publisher: BMC Endocrine Disorders
Publication Date: 2009
 Notes
Abstract: BACKGROUND:Numerous studies have reported that age-induced increased parathyroid hormone plasma levels are associated with cognitive decline and dementia. Little is known about the correlation that may exist between neurological processing speed, cognition and bone density in cases of hyperparathyroidism. Thus, we decided to determine if parathyroid hormone levels correlate to processing speed and/or bone density.METHODS:The recruited subjects that met the inclusion criteria (n = 92, age-matched, age 18-90 years, mean = 58.85, SD = 15.47) were evaluated for plasma parathyroid hormone levels and these levels were statistically correlated with event-related P300 potentials. Groups were compared for age, bone density and P300 latency. One-tailed tests were used to ascertain the statistical significance of the correlations. The study groups were categorized and analyzed for differences of parathyroid hormone levels: parathyroid hormone levels 30 (n = 62, mean = 62.4 ± 28.3 SD, p = 02).RESULTS:Patients with parathyroid hormone levels 30, which demonstrated greater P300 latency (P300 = 345.7 ± 3.6 SE, p = .02). Participants with parathyroid hormone values 30 (n = 48, M = -1.85 ± .19 SE, p = .04).CONCLUSION:Our findings of a statistically lower bone density and prolonged P300 in patients with high parathyroid hormone levels may suggest that increased parathyroid hormone levels coupled with prolonged P300 latency may become putative biological markers of both dementia and osteoporosis and warrant intensive investigation.
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BMC Endocrine Disorders BioMedCentral


Research article


Age-related increases in parathyroid hormone may be antecedent
to both osteoporosis and dementia
Eric R Braverman18, Thomas JH Chen2, Amanda LC Chen3, Vanessa Arcuri4,
Mallory M Kerner4, Anish Bajaj4, Javier Carbajal4, Dasha Braverman4, B
William Downs5 and Kenneth Blum*4,5,6,7


Address: 'Department of Neurological Surgery, Weill Cornell College of Medicine, New York, New York, USA, 2Department of Health and
Occupational Safetly, Chang Jung Christian University, Taiwan, Republic Of China, 3Department of Engineering, Chang Jung Christian University,
Taiwan, Republic Of China, 4Department of Neurological Research, Path Research Foundation, New York, NY, USA, 5Department of Molecular
Nutrition & Nutrigenomics, LifeGen, Inc La Jolla, California, USA, 6Department of Physiology and Pharmacology, Wake Forest University School
of Medicine, Winston -Salem, NC, USA, 7Department of Psychiatry, School of Medicine, University of Florida, Gainesville, FL, USA and 8Path
Medical Research Foundation, 304 Park Ave South, 6th Floor, NY, NY 10010, USA
Email: Eric R Braverman pathmedical@aol.com; Thomas JH Chen tjhchen@yahoo.com.tw; Amanda LC Chen tjhchen@yahoo.com.tw;
Vanessa Arcuri vanessaarcuri@yahoo.com; Mallory M Kemer mallory.kemer@gmail.com; Anish Bajaj dranishbajaj@gmail.com;
Javier Carbajal javi64shoebox@aol.com; Dasha Braverman dasha@totalhealthnutrients.com; BWilliam Downs billdowns001@comcast.net;
Kenneth Blum* drd2gene@aol.com
* Corresponding author



Published: 13 October 2009 Received: 14 September 2008
BMC Endocrine Disorders 2009, 9:21 doi:10. 1186/1472-6823-9-21 Accepted: 13 October 2009
This article is available from: http://www.biomedcentral.com/1472-6823/9/21
2009 Braverman et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.ore/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



Abstract
Background: Numerous studies have reported that age-induced increased parathyroid hormone plasma levels
are associated with cognitive decline and dementia. Little is known about the correlation that may exist between
neurological processing speed, cognition and bone density in cases of hyperparathyroidism. Thus, we decided to
determine if parathyroid hormone levels correlate to processing speed and/or bone density.
Methods: The recruited subjects that met the inclusion criteria (n = 92, age-matched, age 18-90 years, mean =
58.85, SD = 15.47) were evaluated for plasma parathyroid hormone levels and these levels were statistically
correlated with event-related P300 potentials. Groups were compared for age, bone density and P300 latency.
One-tailed tests were used to ascertain the statistical significance of the correlations. The study groups were
categorized and analyzed for differences of parathyroid hormone levels: parathyroid hormone levels <30 (n = 30,
mean = 22.7 5.6 SD) and PTH levels >30 (n = 62, mean = 62.4 28.3 SD, p _< 02).
Results: Patients with parathyroid hormone levels <30 showed statistically significantly less P300 latency (P300
= 332.7 4.8 SE) relative to those with parathyroid hormone levels >30, which demonstrated greater P300
latency (P300 = 345.7 3.6 SE, p = .02). Participants with parathyroid hormone values <30 (n = 26) were found
to have statistically significantly higher bone density (M = -1.25 .31 SE) than those with parathyroid hormone
values >30 (n = 48, M = -1.85 .19 SE, p = .04).
Conclusion: Our findings of a statistically lower bone density and prolonged P300 in patients with high
parathyroid hormone levels may suggest that increased parathyroid hormone levels coupled with prolonged P300
latency may become putative biological markers of both dementia and osteoporosis and warrant intensive
investigation.




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Background
While numerous studies have reported that age-induced
increased parathyroid hormone (PTH) plasma levels are
associated with cognitive decline [1] and dementia [2,3],
little is known about the correlation that may exist
between neurological processing speed and bone density
in cases of hyperparathyroidism or elevated PTH. The
latency of the P300 auditory evoked potential (which
measures processing speed and has been shown to accu-
rately predict memory impairment [4]) has only been
studied with PTH levels in chronic renal failure, and the
last work on this topic, to our knowledge, was published
in 1983 [5].

PTH is anabolic in bone, but when secreted in excess it is
catabolic [6]. Its levels increase with age in both genders,
paralleling the incidence of osteopenia and osteopososis
[7]. Recombinant human PTH 1-34 (teriparatide) is now
being used as a treatment for osteoporosis, and its admin-
istration has been shown to stimulate bone formation
and increase bone mineral density [8]. Interestingly, it has
recently been discovered that intermittent administration
of teriparatide inhibits endogenous PTH production [9],
possibly via negative feedback. So far, there has not yet
been any published research on teriparatide administra-
tion for hyperparathyroidism-induced osteoporosis.

Our greater understanding of PTH has led to lowering of
the reference ranges. In 2003, the American Kidney Foun-
dation recommended that levels should be kept between
35 and 70 pg/ml [10] for stage 3 chronic kidney disease,
which is characterized by a glomerular filtration rate
(GFR) of 30-59 mL/min/1.73 m2, and that an estimated
7.7% of the population suffers [11]. Currently, the accept-
able reference range for parathyroid hormone (PTH) is
between 10 and 60 pg/mL. It has been suggested that,
where there is normal renal function and elevated serum
calcium, an intact PTH concentration of >50 pg/mL
strongly suggests primary hyperparathyroidism [12]. It is
well established that hyperparathyroidism is responsible
for changes in bone metabolism leading to a reduction in
bone mineral density [13], and the National Osteoporosis
Foundation lists hyperparathyroidism as a risk factor for
osteoporosis [14].

The P300 wave is an event related potential that can be
recorded via electroencephalograph (EEG) as a positive
deflection in voltage at a latency of roughly 300 + age mil-
liseconds [4]. The presence, magnitude, topography, and
time of this signal can measure and describe processing
speed. Prolonged P300 latency is an antecedent to mem-
ory loss and cognitive decline [4]. Since hyperparathy-
roidism has already been associated with cognitive
decline [ 1-3], and increased P300 latency is an early meas-
ure and a better predictor of preclinical dementia than


memory or mental status tests [4], we decided to deter-
mine if PTH levels correlate to processing speed and/or
bone density.

Methods
Participants
The sample consisted of 95 patients from PATH Medical,
an integrative care center and research foundation. Ages
ranged between 18 and 90 years, with a mean of M =
58.85, SD = 15.47. We started with age 18 because many
individuals enter adulthood with poor bone density. Fur-
thermore, osteoporosis is considered to be a childhood
disease, in that childhood and adolescence are the times
when peak bone mass is established [15,16 Missing data
reduced the sample size for P300 speed of processing
(P300SP) and P300 voltage (P300V) to 92. For Bone Min-
eral Density (BMD), missing data reduced the sample size
to 74. Forty (forty-two percent) were male and fifty-six
(fifty-eight percent) were female. All patients signed an
approved IRB consent form based on an approval from
the PATH Research Foundation IRB committee (registra-
tion # IRB00002334). Patients were made aware that their
results could be used in medical research and by signing
the informed consent, they volunteered to participate in
this study.

In this study, analysis was conducted only on patients
with complete data, (n = 92, age-matched, age 18-90
years, mean = 58.85, SD = 15.47), including measurement
of intact serum PTH levels (BioReference Laboratories)
between 9 AM and 3 PM, BMD, and neurological process-
ing speed as determined by P300 latency. The P300 wave
is an event-related potential that can be recorded via elec-
troencephalograph (EEG) as a positive deflection in volt-
age at a latency of roughly 300 msec. We have found in
previous research that the P300 wave is an accurate predic-
tor of cognitive decline [4], and the "reference" range for
P300 latency is roughly 300 + age msec. In this study,
groups were categorized by patients with: PTH levels <30
(n = 30, mean = 22.7 5.6 SD) and PTH levels >30 (n =
62, mean = 62.4 + 28.3 SD, p < .02). We used a Hologic
Dual-Energy X-Ray Absorptiometry (DEXA) machine to
measure BMD, focusing on the lumbar vertebrae and the
left hip for all participants. Groups were compared for age,
BMD and P300 latency.

Statistical Analysis
One-tailed tests were used to ascertain the statistical sig-
nificance of the correlations. The statistical analysis of the
data was conducted in four phases. First, the PTH measure
was dichotomized, with PTH values below 30 categorized
as 1 (low), and PTH values above 30 categorized as 2
(high). We used 30 as the cutoff since it is close to but
slightly lower than the midpoint of the current reference
range (35) [ 12], and since 30 is clearly well below the cur-


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rent risk range which is not yet well defined. This step was
taken to test the statistical significance of differences in
P300SP, P300V and BMD between low and high levels of
PTH. In addition, the BMD measure was dichotomized
using a median (Md) split procedure (Md = -1.88), with
BMD values equal to or lower than Md categorized as 1
(low), and values greater than Md categorized as 2 (high).
This step was taken to test the statistical significance of dif-
ferences in P300SP and P300V, between low and high lev-
els of BMD.

The second phase of the analysis of the data involved the
calculation of the q-test of normality for P300SP, P300V,
BMD and age. This test was conducted to determine
whether parametric or non-parametric tests of signifi-
cance should be used to examine differences between the
high and low levels of PTH on P300SP, P300V and BMD-
-and between the high and low levels of BMD on P300SP
and P300V. A test of normality was also conducted for
PTH.

The q-test is calculated by dividing the sample's standard
deviation by the sample's range. The obtained q statistic is
compared against a given range for the sample size at
hand, and a q value falling within this range, derived on
the basis of a .025 significance level [17] is interpreted as
indicative that the sample distribution does not depart
statistically significantly from normality. A table due to
Sachs (1984) [18] provides critical ranges of values for
varying sample sizes. For the present sample size of 95 for
age, the q span, ranged between 4.17 and 6.07; for the
P300SP and P300V sample size of 92, it ranged between
4.15 and 6.05; and for BMD's sample size of 74, it ranged
between 4 and 5.87.

The third phase of the analysis of the data involved the
calculation of the correlations among age, BMD, PTH,
P300SP, and P300V.

The fourth phase of the analysis of the data involved the
calculation of tests of statistical significance using the
dichotomized PTH measure as the independent variable
and P300SP, P300V, BMD, and age as dependent varia-
bles. Tests of statistical significance were also calculated
using the dichotomized BMD measure as the independent
variable and P300SP and P300V as the dependent varia-
bles. The effect sizes (ES) of the categorized PTH and BMD
measures were calculated to ascertain the strength of asso-
ciation between the categorized independent and the
dependent variables. Effect size is calculated as

ES = [(t2 /(t2 + df)]1/2.

An ES equal to or higher than .20 is considered empiri-
cally consequential.


Results
The following paragraphs describe the outcomes of the
tests of normality, the correlational analyses, and the anal-
yses of differences between the levels of the dichotomized
forms of PTH and BMD.

Tests of Normality
Figure 1 displays the distributions of P300SP, figure 2 dis-
plays the distributions of P300V, figure 3 displays the dis-
tributions of BMD, and figure 4 displays the distributions
of age. For P300SP, P300V, BMD and age, the distribu-
tions tended to approach symmetry, suggesting further,
more formal testing for normality by means of the q-test.

Table 1 displays the q-test outcomes. As shown in this
table, the q value of P300SP was 6.02, that for P300V was
5.23, and that for age was 5.04--all falling within the nor-
mality range for n = 92 of 4.15 to 6.05. For BMD, it was
5.54, falling within the normality range for n = 74 of 4 to
5.87. The q value for PTH was 6.38, falling outside the
4.17 to 6.07 normality range for n = 95. These outcomes
supported the assumption of normality required for the
use of parametric tests in the case of P300SP, P300V,
BMD, and age, and hence, the Pearson correlation coeffi-
cient was used to calculate the level of relation among the
variables in continuous form, and the t-test was used to
ascertain the statistical significance of the differences
between the two categories of PTH on P300SP, P300V,
BMD. Since the hypotheses were stated unidirectionally,
one-tailed tests were used; alpha (a) was set at the .05
level.

Pearson Correlation Coefficients
Table 2 displays the Pearson correlation coefficients. In
this table, BMD and PTH appear in both continuous and
dichotomized form. As evidenced by the outcomes shown
in this table, age proved to be statistically significantly cor-
related with PTH, P300SP, and P300V; BMD proved to be
statistically significantly correlated with PTH in dichot-
omized form; BMD in dichotomized form proved to be
statistically significantly correlated with P300V; PTH
proved to be statistically significantly correlated with
P300P; and P300SP proved to be statistically significantly
correlated with P300V.

The following tables depict the t-test outcomes. They
show the means, standard deviations and standard errors
of the dependent variables for each category of the inde-
pendent variables, and show the t-statistics, p- values, and
effects sizes.

Table 3 displays the t-test outcomes of P300SP by PTH in
categorized form. As shown in this table, the P300SP
mean of the low category of PTH (M = 332.66, SD = 6.39)
proved to be statistically significantly lower than that of


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Std. Deviation =28.07

Mean = 341.4

N = 92.00


280.0 300.0 320.0 340.0 360.0 380.0 400.0 420.0 440.0


the high PTH category (M = 345.68, SD = 28.08), t = -2.12,
df = 90, p = .02 (1-tail test). The effect size was ES = .22--
an effect which, being greater than .20, proved to have
practical significance according to criteria propounded by
Cohen [19] and Kirk [20].

These findings disclosed that level of PTH is positively
associated with level of P300P, and that the strength of the
association is of practical importance. The implications of
these findings are discussed below.

Table 4 displays the t-test outcomes of P300V by PTH in
categorized form. As shown in this table, the P300V mean
of the low category of PTH (M = 5.27, SD = 3.15) did not
differ statistically significantly from that of the high PTH
category (M = 5.28, SD = 2.39), t = -.028, df= 5.31, p = .49
(1-tail test). The effect size was ES = .03, showing a null
effect of PTH on P300V. These findings disclosed a lack of


association between PTH and P300V levels. The implica-
tions of these findings are also discussed below.

Table 5 displays the t-test outcomes of BMD by PTH in cat-
egorized form. As shown in this table, the mean BMD
score of participants in the low category of PTH (M = -
1.25, SD = 1.57) differed statistically significantly from
that of participants in the high PTH category (M = -1.85,
SD = 1.28), t = 1.77, df= 72, p = .04 (1-tail test). The effect
size was ES = .20, showing a substantive effect of PTH on
BMD in terms of criteria propounded by [19] and [20].
These findings disclosed an empirically important associ-
ation between levels of PTH and levels of BMD. The impli-
cations of these findings are also discussed below.

Table 6 displays the t-test outcomes for P300SP by BMD
in categorized form. As shown in this table, the mean age
of participants in the low category of BMD (M = 344.18,


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260.0


Figure I
P300 SP.


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30







20







10







0
1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0

Figure 2
P300 V.


SD = 30.40) did not differ statistically significantly from
that of participants in the high PTH category (M = 341.99,
SD = 21.48), t = .35, df= 70, p = .36 (1-tail test). The effect
size was ES = .04--an effect which, being lower than .20,
proved to have insubstantial practical significance accord-
ing to criteria propounded by [19] and [20]. This effect
was the same as the Pearson correlation coefficient of
P300SP with the original categorized BMD scores (r = -
.04, p > .05). The implications of these findings are also
discussed below.

Table 7 displays the t-test outcomes for P300V by BMD in
categorized form. As shown in this table, the mean age of
participants in the low category of BMD (M = 5.80, SD =
2.83) differed statistically significantly from that of partic-
ipants in the high BMD category (M = 4.38, SD = 13.66),
t = 2.46, df = 70, p = .005 (1-tail test). The effect size was
ES = .28--an effect which, being greater than .20, proved


10.0 11.0 12.0 13.0 14.0 15.0


to have practical significance. This effect was the same as
the Pearson correlation coefficient of P300SP with the
original categorized BMD scores (r = .-.28, p = .008). The
implications of these findings are also discussed below.

Finally, table 8 displays the means, standard deviations
and standard errors of the two PTH categories. As shown
in this table, the two categories' means differed substan-
tially: category 1 (low): M = 22.65; category 2 (high): 62.37.

Discussion
Our findings suggest that age dependent prolonged P300
latency, as well as age dependent increased PTH levels,
may interact. This is a timely discovery since there has
been a recent influx of research highlighting the connec-
tions between the brain and the bones, and a new field
has been birthed called neuropsychosteology [21,22].


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Std. Deviation = 30.01

Mean = 49.5

N = 95.00







10 20 30 40 50 60 70 80 90 100 110 110 120 130 140 150 160 170 180 190 200/














10 20 30 40 50 60 70 80 90 100 110 110 120 130 140 150 160 170 180 190 200


Figure 3
BMD.


Many studies have confirmed neuropsychiatric disease
increases with osteoporosis (OP) [23-25].

Our measurement of PTH did not take into account fac-
tors that could affect analysis: age, gender, menopausal
status, vitamin D and calcium supplementation, smoking,
alcohol consumption, steroid use, family history of oste-
oporosis, physical activity, drugs to control bone and cal-
cium metabolism, rheumatoid arthritis, other diseases
that cause secondary osteoporosis, levels of sex hormones,
etc. Further studies will be needed to clarify all of these
variables in relation to PTH's effects on the aging brain
and aging skeleton.

Based on our findings, we suggest that control of PTH lev-
els may be important for protecting against age-induced
dementia. PTH's potential involvement with dementia
may be explained in the following way: PTH has been


shown to cross the blood-brain barrier [26]. PTH has been
considered a candidate risk factor for senile dementia
because sustained high levels of PTH in the brain may
cause degeneration of specific brain regions due to Ca(2+)
overloading [27,28].

Moreover, OP is a genetic disease and as such the role of
1,25-dihydroxyvitamin D3-receptor gene polymorphisms,
known OP genetic antecedents [29] may contribute in
some way to the age-linked impairments in both parathy-
roid and neurological processing function. It is to be
noted that PTH tides are of short duration while Vitamin
D or calcitriol tides are of long duration. PTH quickly
mobilizes bone calcium, while calcitriol tends to more
slowly increase the absorption of dietary calcium. In the
case of low or no dietary calcium, calcitriol mobilizes
bone calcium together with PTH. Because of this, mixed
effects occur during Vitamin D deficiency, and pseudo- or


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Std. Deviation = 15.47

Mean = 58.9

N = 95.00


0
10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 55.0 60.0 65.0 70.0 75.0 80.0 85.0 90.0


Figure 4
Age.


secondary hyperparathyroid conditions occur. Further-
more, overnight fasting with reduced absorption of die-
tary calcium associated with age results in a regulatory set
point inducing an increase of PTH secretion with age[30].

It is apparent that PTH levels should be kept below 60 pg/
ml, and we believe based on our findings that these levels
may be lowered still. Further research should involve


P300 latency testing for a larger number of patients and
stratification by age, and correlating PTH levels and BMD.
This study provides the first potential indirect evidence
that may highlight the importance of processing speed as
an early electrophysiological marker of OP, which war-
rants further investigation.


Table 2: Correlation Matrix.


Table I: q-Tests for Normality of Distribution.


Variables 1. Age
2. BMD
Statistics P300SP P300V BMD PTH Age 3. BMD'
4. PTH
SD 28.07 2.66 1.41 30.01 15.47 5. PTH2
Range 169 13.93 7.82 191 78 6. P300SP
q 6.02 5.23 5.54 6.37 5.04 7. P300V


The q range for normality for a sample size of 93, as was the case for
P300SP, P300V, PTH, and Age, is 4.16 to 6.07 with a significance level
of .025. For a sample size of 74, as was the case for Bone density, the
q range is 4 to 5.87, also with a significance level of .025.


IDichotomized (I <= -1.88; 1.88; 2 > -t-Test Outcomes-1.88)
2Dichotomized (I < 30; 2 > 30)
P < 0.05
IDichotomized (I <= -* p < .05


I 2 3 4 5 6 7


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Table 3: t-Test of the Difference in P300SP Between the
Categories of PTH.


P300SP


t-Test


Table 5: t-Test of the Difference in BMD Between the Categories
of PTH.


BMD


t-Test


PTH N M


SD SE T Df p ES*


PTH N M SD SE T Df P ES*


I (< 30) 30 332.66 26.39 4.81

2 (> 30) 62 345.68 28.08 3.57
Total 92 341.44 28.07 2.93


-2.12 90 .02 .22


I (< 30) 26 -1.25 1.57 .31

2 (> 30) 48 -1.85 1.28 .19
Total 74 -1.64 1.41 .163


1.77 72 .04 .20


*Effect size


Increases in PTH levels with age are major factors respon-
sible for age-related increase in bone resorption, and con-
tribute to kidney stone formation as well [31]. PTH levels
need to be monitored in osteoporotic, memory-impaired
people and lowering the levels may be an important part
of the therapeutic process of teriparatide injections. At the
PATH Medical Clinic, PTH levels were reduced by teri-
paratide injections by an average of 20 points, possibly
due to a negative feedback mechanism. This is further sup-
ported by others [9]. Additional research has shown that
teriparatide therapy may need to be supplemented by GH
or GH-dependent factors in order for the anabolic
response of bone [32,33].

Finally, the findings of this study showing a significant
relationship between higher PTH plasma levels and pro-
longed P300 latency as well as a decrease in BMD suggest
that hyperparathyroidism and elevated PTH due in part to
age may lead to dementia and OP. The connection
between elevated PTH and cognitive decline is becoming
well studied. A recent study published in the Journal of
Clinical Endocrinology and Metabolism presented results
of various cognitive testing in postmenopausal women
with hyperparathyroidism, before and after parathyroid-
ectomy, with pre-surgical cognitive impairments improv-
ing after surgery [33]. Further studies are warranted to
confirm the value of increased PTH levels coupled with
increased P300 latency as putative biological markers of
both dementia and OP.


Table 4: t-Test of the Difference in P300V Between the
Categories of PTH.


P300V


*Effect size

Conclusion
Patients with PTH levels <30 showed statistically signifi-
cantly lesser P300 latency (P300 = 332.7 4.8 SE) relative
to those with high PTH levels (>30), who demonstrated
greater P300 latency (P300 = 345.7 + 3.6 SE, p = .02). In
addition, participants with PTH values < 30 (n = 26) were
found to have statistically significantly higher bone den-
sity (M = -1.25 + .31 SE) than those with PTH values > 30
(n = 48, M = -1.85 + .19 SE, p = .04)

The relevance of this research is more far reaching than
might be initially suspected. A healthy skeleton is more
important to overall health than for just lowering fracture
risk. Healthy bones are intimately involved as an endo-
crine organ performing many important functions includ-
ing the production of red blood cells, immune cells,
platelets, various growth factors, and cytokines [35]. Bone
cells and immune stem cells have a common origin and a
functional relationship called the "osteo-immune rela-
tionship [35-37]" Healthy bones also exert an endocrine
regulation of sugar homeostasis, fat storage, energy
metabolism, cognition and more [38]. These functional
relationships are the basis for the growing field of oste-
oimmunology [35]. Moreover, chronic immune system
overexertion is known to lead to bone loss, promote mus-
cle wasting [35] and increase fat storage [38-41].

This research supports the notion that a strong relation-
ship exists between bone health, brain health, neurologi-
cal competence, endocrine function, immune health, and
genetics, building potential therapeutic bridges across the

Table 6: t-Test of the Difference in P300SP Between the
Categories of BMD.


t-Test


P300SP


PTH N M SD SE T


df p ES*


BMD N M SD SE t df p ES*


I (< 30) 30 5.27 3.15 .58

2 (> 30) 62 5.28 2.39 .30
Total 92 5.29 2.66 .28


028 45.31 .49 .03


*Effect size


I (<=-1.88) 36 344.18 30.40 5.06

2 (>-1.88) 36 341.99 21.48 3.58
Total 92 341.44 28.07 2.93


.35 70 .36 .04


*Effect size


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http://www.biomedcentral.com/1472-6823/9/21


Table 7: t-Test of the Difference in P300V Between the
Categories of BMD.

P300V

BMD N M SD SE t df p

I (<=-1.88) 36 5.80 2.83 .47
2.46 70 .005
2 (>-1.88) 36 4.38 13.66 .33
Total 92 5.28 2.66 .28


realms of neuropsychosteology, osteoimmunology,
nutrigenomics.

Our findings of a statistically lower bone density and
longed P300 in patients with high PTH levels may su
that PTH levels coupled with delayed P300 latency
become putative biological markers of dementia and
oporosis, and further punctuate the importance of
relationships in the evaluation of overall mental
physical wellbeing. These conclusions support the n
that hyperparathyroidism, dysregulation of bone met


lism, osteopenia, ost
dents have a more
implicating the opp
therapeutic intervene
related and potential
further confirmation

Competing inter
Thomas JH Chen, Ar
lory Kerner, Anish B
any competing inter
flict of interest. Eric
PATH Medical, where
for diagnostic purpo
tific director of the
paid consultant, an
LifeGen, which gran
This study received fi
donor, Rein Narma.

Authors' contribi
ERB developed th
provided editorial c
project; TJHC-signifi


Table 8: Means and Sta
PTH categories.

Category

I (< 30)
2 (> 30)
Total


ments; ALCC provided editorial comments and litera-
ture check for accuracy; VA- editorial and clinical
assistance involving data collection, initiation of the first
draft of the paper; MK provided data collection, work on
ES* the first draft, editorial contribution, significant additions
to the references and background research; AB -provided
patient assessment and data collection; JC provided
.28 patient assessment and data collection; DB patient coor-
dination, editorial comments, and obtained patient con-
sent and regulatory involvement; BWD responsible for
final editorial comments; KB major co -principle investi-
and gator responsible for write -up of manuscript and statisti-
cal analysis direction and paper correspondent. All
authors read and approved the final manuscript.
pro-
ggest Acknowledgements
may The authors would like to thank Path Research Foundation, New York, NY,
oste- and LifeGen, Inc. for their financial support. We want to thank the entire
these staff of PATH Medical and especially acknowledge the grant support of Rein
and Narma. The authors appreciate the work of Dr. Emanuel Martinez Pons of
Brooklyn College, NYC, for his statistical expertise. Dr. Pons was a paid
consultant on the project.
tabo-


teoporosis, and its sub-clinical prece- References
systemic impact on overall health, 1. Dotzenrath CM, Kaetsch AK, Pfingsten H, Cupisti K, Weyerbrock N,
ortunity for expanding the scope of Vossough A, Verde PE, Ohmann C: Neuropsychiatric and cogni-
on to augment treatment for other tive changes after surgery for primary hyperparathyroidism.
tion to augment treatment for other World Surg 2006, 30(5):680-5.
ly serious disorders as well. We await 2. Flicker L, Ames D: Metabolic and endocrinological causes of
of this preliminary study. dementia. Int Psychogeriatr 2005, 17(Suppl I):S79-92.
3. Washimi Y: Dementia in parathyroid disease. Nippon Rinsho
2004, 62(Suppl):349-52.
tests 4. Braverman ER, Blum K: P300 (latency) event-related potential:
manda LC Chen, Vanessa Arcuri, Mal- an accurate predictor of memory impairment. Clin Electroen-
cephalogr 2003, 34(3):124-39.
ajaj, and Javier Carbajal do not have 5. Cohen SN, Syndulko K, Rever B, Kraut J, Coburn J, Tourtellotte
tests. We declare that we have no con- WW: Visual evoked potentials and long latency event-related
potentials in chronic renal failure. Neurology 1983,
R. Braverman MD, is the director of 33(9):1219-22.
e he utilizes both the P300 and TOVA 6. Silver J, Bushinsky D: Harnessing the parathyroids to create
ses. Kenneth Blum, PhD is the scien- stronger bones. Curr Opi Nephrol Hypertens 2004, 13(4):471-6.
7. DeGroot LJ, Jameson JL: Endocrinology. Volume 2. Fifth edition.
PATH Research Foundation and is a Elsevier, Philadelphia; 2006:1534-1538.
1 also the chief scientific advisor for 8. Rubin MR, Bilezikian JP: Parathyroid hormone as an anabolic
skeletal therapy. Drugs 2005, 65(17):2481-98.
ted financial support to this research. 9. Anastasilakis AD, Polyzos SA, Goulis DG, Slavakis A, Efstathiadou Z,
ending through a grant from a private Kita M, Koukoulis G, Avramidis A: Endogenous intact PTH is sup-
pressed during Teriparitide (rhPTH 1-34) administration in
postmenopausal women with established osteoporosis.
Endocr] 2008, 55(3):613-6.
itions 10. National Kidney Foundation: K/DOQI clinical practice guide-
e experimental concept and design, lines for bone metabolism and disease in chronic kidney dis-
ease. Am J Kid Dis 2003, 42(Suppl 3):SI.
contributions, was clinical director of I I. Coresh J, Selvin E, Stevens LA, Manzi J, Krusek JW, Eggers P, Van
cant editorial contributions and com- Lente F, Levey AS: Prevalence of chronic kidney disease in the
United States. JAMA 2007, 298(17):2038-47.
12. Gomella LG, Haist SA: "Chapter 4. Laboratory Diagnosis:
ndard Deviations of PTH by the Two Chemistry, Immunology, Serology" (Chapter). Clinician's
Pocket Reference: The Scut Monkey, I le [http://www.accessmedi
cine.com/content.aspx?alD=2699454].
13. Mazzaglia PJ, Berber E, Kovach A, Milas M, Esselstyn C, Siperstein AE:
N M SD SE The changing presentation of hyperparathyroidism over 3
decades. Arch Surg 2008, 143(3):260-6.
30 22.65 5.62 1.03 14. National Osteoporosis Foundation: Physicians Guide to Preven-
65 62.37 28.33 3.51 tion and Treatment of Osteoporosis. Washington DC: National
Osteoporosis Foundation; 2003.
95 46.82 30.01 3.08 15. Hightower L: Osteoporosis: pediatric disease with geriatric
consequences. Orthop Nurs 2000, 19(5):59-62.


Page 9 of 10
(page number not for citation purposes)


BMC Endocrine Disorders 2009, 9:21








BMC Endocrine Disorders 2009, 9:21


16. Chesnut CH 3rd: Is osteoporosis a pediatric disease? Peak
bone mass attainment in the adolescent female. Public Health
Rep 1989, 104(Suppl):50-4.
17. Kanji G: 100 Statistical Tests. London, Newbury Park, California:
Sage Publications; 1993.
18. Sachs L: Applied Statistics: A Handbook of Techniques. 2nd
edition. Springer-Verlag, Berlin, Germany; 1984.
19. Cohen J: Statistical Power Analysis for Behavioral Sciences.
2nd edition. Eribaum Associates, Hillsdale, NJ; 1988.
20. Kirk RE: Statistics: an Introduction 4th edition. Harcourt Brace College
Publishers, Fort Worth; 1999.
21. Yirmiya R, Goshen I, Bajayo A, Kreisel T, Feldman S, Tarn J, Trembov-
ler V, Csernus V, Shohami E, Bab I: Depression induces bone loss
through stimulation of the sympathetic nervous system. Proc
Natl Acad Sci USA 2006, 103(45):16876-81.
22. Kahl KG, et al.: Bone mineral density, bone turnover, and oste-
oprotegerin in personality disorder. Psychosom Med 2006,
68:669-74.
23. Milliken LA, Wilhelmyj, Martin CJ, Finkenthal N, Cussler E, Metcalfe
L, Guido TA, Going SB, Lohman TG: Depressive symptoms and
changes in body weight exert independent and site-specific
effects on bone in postmenopausal women exercising for I
year. J Gerontol A Biol Sci Med Sci 2006, 61 (5):488-94.
24. Ilias I, Alesci S, Gold PW, Chrousos GP: Depression and oste-
oporosis in men: association or causal link? Hormones (Athens)
2006, 5(1):9-16.
25. Halbreich U, Palter S: Accelerated osteoporosis in psychiatric
patients: possible pathophysiological processes. Schizophr Bull
1996, 22(3):447-54.
26. Khudaverdyan DN, Asratyan AA: Effect of the parathyroid hor-
mone-Calcium system on functional activity of the hypotha-
lamus-neurohypophysis complex. Bulletin of Experimental Biology
and Medicine 1996, 122(5): 1069-71.
27. Cermik TF, Kaya M, Ugur-Altun B, Bedel D, Berkarda S, Yigitbasi ON:
Regional cerebral blood flow abnormalities in patients with
primary hyperparathyroidism. Newroradiology 2007,
49(4):379-85.
28. Margolin D, Hammerstad J, Orwoll E, McClung M, Calhoun D:
Intracranial calcification in hyperparathyroidism associated
with gait apraxia and parkinsonism. Neurology 1980,
30(9):1005-7.
29. Ohtera K, Ishii S, Matsuyama T: Influence of Vitamin D Receptor
Alleles on Human Osteoblast-Like Cells. j Born joint Surg Br
2000, 83:134-138.
30. Kurbel S, Radi R, Kotromanovic Z, Puseljic Z, Kratofil BA: calcium
homeostasis model: orchestration of fast acting PTH and
calcitonin with slow calcitriol Med. Hypotheses 2003,
61(3):346-50.
31. Scillitani A, Guarnieri V, Battista C, De Geronimo S, Muscarella LA,
Chiodini I, Cignarelli M, Minisola S, Bertoldo F, Francucci CM, Mala-
volta N, Piovesan A, Mascia ML, Muscarella S, Hendy GN, D'Agruma
L, Cole DE: Primary hyperparathyroidism and the presence of
kidney stones are associated with different haplotypes of the
calcium-sensing receptor. J Clin Endocrinol Metabi 2007,
92(1):277-83.
32. HockJM, Fonsecaj: Anabolic effect of human synthetic parath-
yroid hormone-(l-34) depends on growth hormone. Endo-
crinology 1990, 127(4): 1804-10.
33. White HD, Ahmad AM, Durham BH, Patwala A, Whittingham P, Fra-
ser WD, Vora JP: Growth hormone replacement is important
for the restoration of parathyroid hormone sensitivity and
improvement in bone metabolism in older adult growth hor-
mone-deficient patients. j Clin Endocrinol Metab 2005,
90(6):3371-80.
34. Walker MD, McMahon DJ, Inabnet WB, azar RM, Brown I, Vardy S,
Cosman F, Silverberg S: Neuropsychological Features in Pri-
mary Hyperparathyroidism: A Prospective Study. j Clin Endo-
crinol Metab 2009, 94(6): 195 1-1958.
35. Boyce BF, Yao Z, Zhang 0, Guo R, Lu Y, Schwarz EM, Xing L: New
roles for osteoclasts in bone. Ann N Y Acad Sci 2007,
I 116:245-254.
36. McCormick RK: Osteoporosis: integrating biomarkers and
other diagnostic correlates into the management of bone
fragility. Altern Med Rev 2007, 12(2): 13-145.


http://www.biomedcentral.com/1472-6823/9/21


37. Ostrowski K, Rohde T, Zacho M, Asp S, Pedersen BK: Evidence
that interleukin-6 is produced in human skeletal muscle dur-
ing prolonged running. j Physiol 1998, 508:949-953.
38. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin
R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F,
Ducy P, Karsenty G: Endocrine regulation of energy metabo-
lism by the skeleton. Cell 2007, 130(3):456-469.
39. Keys A, Brozekj, Henschel A, Mickelsen 0, Taylor HL: The Biology
of Human Starvation. Minneapolis University of Minnesota Press;
1950.
40. Dulloo A,Jacquetj: Adaptive reduction in basal metabolic rate
in response to food deprivation in humans: a role for feed-
back signals from fat stores. Am Clin Nutr 1998, 68:599-606.
41. Dulloo AG, Girardier L: Adaptive changes in energy expendi-
ture during refeeding following low-calorie intake: evidence
for a specific metabolic component favoring fat storage. Am
J Clin Nutr 1990, 52:415-20.

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