Full text of DOI:10.1359/jbmr.2001.16.1.113

JOURNAL OF BONE AND MINERAL RESEARCH
Volume 16, Number 1, 2001
© 2001 American Society for Bone and Mineral Research
Effects of Oral Alendronate in Elderly Patients with
Osteoporosis and Mild Primary Hyperparathyroidism
MAURIZIO ROSSINI,1 DAVIDE GATTI,1 GIANCARLO ISAIA,2 LEONARDO SARTORI,3
VANIA BRAGA,1 and SILVANO ADAMI1
ABSTRACT
In a large proportion of the patients with primary hyperparathyroidism (PHPT), a variable degree of
osteopenia is the only relevant manifestation of the disease. Low bone mineral density (BMD) in patients with
PHPT is an indication for surgical intervention because successful parathyroidectomy results in a dramatic
increase in BMD. However, low BMD values are almost an invariable finding in elderly women with PHPT,
who are often either unwilling or considered unfit for surgery. Bisphosphonates are capable of suppressing
parathyroid hormone (PTH)–mediated bone resorption and are useful for the prevention and treatment of
postmenopausal osteoporosis. In this pilot-controlled study, we investigated the effects of oral treatment with
alendronate on BMD and biochemical markers of calcium and bone metabolism in elderly women presenting
osteoporosis and mild PHPT. Twenty-six elderly patients aged 67–81 years were randomized for treatment
with either oral 10 mg alendronate on alternate-day treatment or no treatment for 2 years. In the control
untreated patients a slight significant decrease was observed for total body and femoral neck BMD, without
significant changes in biochemical markers of calcium and bone metabolism during the 2 years of observation.
Urine deoxypyridinoline (Dpyr) excretion significantly fell within the first month of treatment with alendro-
nate, while serum markers of bone formation alkaline phosphatase and osteocalcin fell more gradually and the
decrease became significant only after 3 months of treatment; thereafter all bone turnover markers remained
consistently suppressed during alendronate treatment. After 2 years in this group we observed statistically
significant increases in BMD at lumbar spine, total hip, and total body (؉8.6 ؎ 3.0%, ؉4.8 ؎ 3.9%, and
؉1.2 ؎ 1.4% changes vs. baseline mean ؎ SD) versus both baseline and control patients. Serum calcium,
serum phosphate, and urinary calcium excretion significantly decreased during the first 3–6 months but rose
back to the baseline values afterward. Increase in serum PTH level was statistically significant during the first
year of treatment. These preliminary results may make alendronate a candidate as a supportive therapy in
patients with mild PHPT who are unwilling or are unsuitable for surgery, and for whom osteoporosis is a
reason of concern. (J Bone Miner Res 2001;16:113–119)
Key words: primary hyperparathyroidism, alendronate, osteoporosis, bisphosphonates
vestigators have reported an increased risk for osteoporotic
fractures.(1–3) Successful parathyroidectomy results in dra-
matic increases in both lumbar spine and femoral neck bone
INTRODUCTION
N POSTMENOPAUSAL women osteoporosis and primary hy-
I
perparathyroidism (PHPT) are two common disorders. mineral density (BMD).(4–10) These recent findings tend to
PHPT is associated with cortical osteopenia and some in- broaden the indications for surgery, and low BMD, in
1Riabilitazione Reumatologica, Ospedale di Valeggio, Universita` di Verona, Verona, Italy.
2Dipartimento di Medicina Interna, University of Turin, Turin, Italy.
3Istituto di Medicina Interna, University of Padua, Padua, Italy.
113

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ROSSINI ET AL.
TABLE 1. BASELINE CLINICAL CHARACTERISTICS AND BMDS IN THE TWO PROSPECTIVE GROUPS AND IN THE RETROSPECTIVE
SURGICALLY TREATED PATIENTS (MEAN AND SD)
Alendronate group
Control group
Surgical group
Characteristics
Age (years)
(n ϭ 13)
(n ϭ 13)
(n ϭ 13)
72 (5)
23 (7)
24.7 (3.5)
74 (4)
24 (8)
23.8 (3.2)
61 (4)
13 (6)
23.9 (2.6)
Time since menopause (years)
Body mass index (kg/m2)
BMDs
Femoral neck (g/cm2)
T score femoral neck (SD)
Z score femoral neck (SD)
Trochanter (g/cm2)
0.577 (0.057)
Ϫ3.2 (0.6)
Ϫ0.7 (0.6)
0.459 (0.062)
0.390 (0.076)
0.607 (0.069)
0.700 (0.090)
0.820 (0.062)
0.554 (0.038)
Ϫ3.5 (0.4)
Ϫ0.8 (0.5)
0.440 (0.071)
0.377 (0.106)
0.566 (0.078)
0.728 (0.070)
0.815 (0.098)
Ward triangle (g/cm2)
Total hip (g/cm2)
Lumbar spine (g/cm2)
Total body (g/cm2)
0.738 (0.093)
patients with otherwise asymptomatic PHPT, has become or cardiovascular problems. Baseline characteristics and
an indication for surgical intervention.(11) Low BMD values BMDs are shown in Table 1. Exclusion criteria were con-
are almost invariably found in elderly women with PHPT current systemic illness, thyroid disease, hepatic or renal
and in a large proportion of them osteopenia is the only dysfunction (serum creatinine Ͼ1.9 mg/dl), and other dis-
relevant manifestation of the disease. However, a large orders known to influence bone mass. The patients with
proportion of these patients with mild PHPT have complex
medical problems and are either unwilling or considered
unfit for parathyroid surgery. This makes a medical ap-
proach oriented at the recovery and conservation of bone
mass somewhat attractive. Hormone-replacement therapy
(HRT) significantly increases BMD and reduces urinary
calcium excretion and bone turnover in postmenopausal
women with mild PHPT.(12–18) However, in elderly patients
HRT is associated with problems of compliance or even
safety.
Bisphosphonates are capable of suppressing parathyroid
hormone (PTH)–mediated bone resorption in hyperparathy-
roidism and can be used as an adjunct for the acute medical
control of severe hypercalcemia.(19–25) Moreover, bisphos-
phonates are useful for the prevention and treatment of
postmenopausal osteoporosis and, recently, it has been
shown that oral alendronate(26–29) and risedronate(30) have
the capacity to reduce the incidence of osteoporotic frac-
tures.
active gastroduodenal ulcer or disturbances in the esopha-
geal transit also were excluded as advised by the alendro-
nate warning label. No patient had received estrogens,
bisphosphonates, or other drugs interfering with bone or
mineral metabolism for the last 18 months. The patients
were randomized for treatment with either 10 mg of alen-
dronate taken orally on alternate days (alendronate group)
or no treatment (control group). In the original protocol, the
chosen dose was 5 mg/day but this formulation was with-
drawn from the Italian market and substituted with the
10-mg formulation exactly when we initiated the study. All
patients were maintained on a controlled diet with a calcium
intake of 800-1200 mg/day.
During the recruitment of the 26 patients for the treatment
trial, 13 additional PHPT patients came under our observa-
tion. They were comparable to the patients recruited for the
study for severity of disease but were somewhat younger
(61 Ϯ 4 years) and had the parathyroid tumor surgically
removed (Table 1 and 2). In this group of patients the spine
BMD was obtained before and 12 months after surgery.
The overall 39 patients were recruited within 12 months
in the three centers equipped with either QDR1000 or -2000
(Hologic, Inc., Waltham, MA, USA). Each patient had the
entire follow-up done in the same center. Informed consent
was obtained from all the patients and the study was ap-
proved by a local ethics committee.
In this study we investigate the effects of oral treatment
with alendronate on BMD and biochemical markers of
calcium and bone metabolism in elderly women presenting
osteoporosis and mild PHPT.
MATERIALS AND METHODS
Patients
Twenty-six elderly women aged 67–81 years presenting
osteoporosis (defined as a lumbar and/or femoral neck BMD
over 2.5 SD below the young normal reference range) and
Clinical evaluation
Lateral spine radiography was obtained at study entry,
mild PHPT, as defined by the Consensus Development and 3 patients (1 in the control group and 2 in the alendro-
Conference on the management of PHPT,(11) were enrolled nate group) with severe osteoarthritis and scoliosis were
in three centers of northern Italy. All patients were unwill- excluded from subsequent spine density analysis. None of
ing or considered unfit for surgery because of advanced age the patients had radiological evidence of thoracic or lumbar

ALENDRONATE TREATMENT OF PRIMARY HYPERPARATHYROIDISM
115
TABLE 2. BASELINE BIOCHEMICAL VALUES (MEAN AND SD) IN THE TWO PROSPECTIVE GROUPS AND IN THE
RETROSPECTIVE SURGICALLY TREATED PATIENTS
Reference
range
Alendronate
group
Control
group
Surgical
group
Parameters
s-Calciuma (mg/dl)
s-Phosphate (mg/dl)
s-PTH (pg/ml)
s-Bone-alkaline phosphatase (U/liter)
s-Osteocalcin (nmol/liter)
u-Calcium/creatinine (mmol/mmol)
u-D-Pyridinoline/creatinine (nmol/mmol)
8.4–10.4
2.6–4.6
10–65
11.0 (0.4)
2.9 (0.6)
144 (52)
42 (12)
4.1 (1.3)
0.59 (0.24)
9.8 (3.6)
10.9 (0.3)
2.6 (0.5)
155 (28)
43 (9)
3.6 (1.6)
0.60 (0.19)
11.2 (3.3)
11.1 (0.5)
2.6 (0.5)
150 (66)
45 (9)
3.7 (1.2)
0.64 (0.11)
10.1 (2.3)
10–35
0.6–2.5
0.06–0.54
3.0–8.0
a Serum calcium levels were adjusted for albumin levels.
vertebral fracture and/or variant femur anatomy that could bles 1 and 2). The patients who underwent successful par-
affect the accuracy of bone density evaluation.
athyroidectomy were significantly younger (mean age, 61 Ϯ
4 years; data not shown) than the patients in the other
groups. All patients completed the first 6 months of follow-
up. Three patients in the alendronate group dropped out
during the first year either for gastric intolerance to the drug
or for the discovery of breast cancer or for the necessity to
introduce diuretic therapy. One patient of the control group
was lost to follow-up during the second year for “in situ”
endometrial cancer. In Table 3 the percent changes from
baseline in biochemical parameters (mean Ϯ SD) during the
study are shown. Serum calcium, serum phosphate, and
urinary calcium excretion remained fairly stable in the con-
trol group. In the alendronate-treated patients the biochem-
ical variables significantly decreased during the first 3–6
months but rose back to the baseline values afterward. The
decreases in serum calcium were associated with increases
in serum PTH levels, which remained significantly in-
creased over baseline during the first year of treatment. The
mean percent changes from baseline in biochemical markers
of bone turnover are shown in Fig. 1. Urine Dpyr excretion
significantly fell within the first month of treatment in the
alendronate group and remained suppressed at all times
relative to baseline. The serum markers of bone formation
alkaline phosphatase and osteocalcin fell more gradually
and the decrease became significant after 3 months of treat-
ment.
The BMD percent changes at all relevant skeletal sites in
the two groups are shown in Fig. 2. A significant increase
versus baseline was observed at all studied sites in the
patients on alendronate. The changes already were statisti-
cally significant within the first 6 months of treatment in the
“trabecular” sites (lumbar spine, trochanter, and Ward’s
triangle). A significant positive correlation was found be-
tween the changes in total body BMD at the first year and
both baseline bone alkaline phosphatase and serum osteo-
calcin levels (correlation coefficients 0.84 and 0.64, respec-
tively; p Ͻ 0.05, data not shown) in alendronate-treated
patients. During the second year of treatment, a continuous
trend to increase was observed at all skeletal sites. In the
untreated patients BMD decreased at most skeletal sites but
the changes were statistically significant only for total body
Fasting blood samples were obtained at entry and after 1,
3, 6, 12, and 24 months for measurement of serum calcium,
phosphate, creatinine (standard multichannel autoanalyz-
ers), and bone alkaline phosphatase (precipitation procedure
with wheat-germ lectin; Boehringer Mannheim, Ingelheim,
Germany). Serum calcium was corrected for albumin con-
centration. Urine samples also were obtained at the same
time points for the determination of calcium and creatinine
(standard multichannel autoanalyzers). Aliquots of serum
and urine were kept at Ϫ80°C until analyzed for serum
osteocalcin (radioimmunoassay [RIA] kit; Incstar Corp.,
Stillwater, MN, USA), intact PTH (Diagnostic Systems
Laboratories, Nichols, CA, USA), and free deoxypyridino-
line (Dpyr)/creatinine ratio (Metra Biosystems, Nichols,
CA, USA).
BMD was measured using dual-energy X-ray absorpti-
ometry (DXA; QDR1000 or -2000). Scans of whole body,
lumbar spine (vertebrae L2–L4), and proximal femur sub-
regions were obtained every 6 months and were analyzed
using the manufacturer’s software. In our laboratories, the
precision of these measurements of BMD are 0.4% for
the total body, 0.9–1.0% for the lumbar spine, 1.3–1.4% for
the femoral neck, 2.7–2.9% for the Ward triangle, 1.6–1.7%
for the trochanter, and 1.1–1.2% for the total hip.
Statistical methods
The significance of the percent changes in biochemical
parameters and in BMD from baseline was evaluated by
Student’s t-test for paired observation. The comparison of
the changes between treated and control patients was eval-
uated by analysis of variance (ANOVA) for repeated mea-
sures and then by Student’s t-test for unpaired observation.
Correlation was carried out using Spearman rank correlation
(SPSS 8.0; SPSS, Inc., Chicago, IL, USA).
RESULTS
At study entry, the patients’ clinical characteristics,
BMDs, and biochemical values did not differ significantly
between the two groups that had a medical follow-up (Ta- and femoral neck after 2 years of observation. A significant

116
ROSSINI ET AL.
FIG. 1. Percent changes in serum bone alkaline phospha-
tase, serum osteocalcin, and Dpyr urinary excretion in the
control (dotted line) and alendronate-treated (continuous
line) primary hyperparathyroid patients. The significance
(p Ͻ 0.05) of the differences also is shown. ؠ, versus
baseline; ء, between groups.
negative correlation was found between the changes in total
body BMD and baseline serum bone alkaline phosphatase
(correlation coefficient Ϫ0.69; p Ͻ 0.05). The correlation
coefficients of the relationships between bone alkaline phos-
phatase and BMD changes in both treated and control
patients did not change after adjusting for age or baseline
BMD values. The differences between alendronate-treated
patients and control patients were significant at all sites after
2 years of observation.
In the surgically treated patients, spine BMD increased by
6.7 Ϯ 6.5% within a year (data not shown). This increase
was superimposable (ϩ7.0%) to that observed after 1 year
of alendronate therapy. None of the patients complained of

ALENDRONATE TREATMENT OF PRIMARY HYPERPARATHYROIDISM
117
dose of alendronate is comparable with that observed after
estrogen-replacement therapy.(16–18) Bone density increases
are somewhat more superior than those obtained with an
equivalent dose (5 mg/day) of alendronate in osteoporotic
patients,(26–28,32,33) and this might be related to the in-
creased bone turnover of PHPT patients, which is known to
be related to the densitometric increases during treatment
with inhibitors of bone resorption.(34,35) In fact, the bone
turnover markers were above the normal range in 45–62%
of the patients. This hypothesis also is supported by the
correlation we found between baseline serum osteocalcin
and alkaline phosphatase and the BMD changes obtained
after alendronate therapy. Recently, it also has been ob-
served that the biochemical markers and the histomorpho-
metric indices of bone turnover are significantly correlated
with the bone densitometric gains achieved after successful
surgical treatment of PHPT patients.(8) In our study the
surgically treated patients were younger then those treated
with alendronate, but even though they were not matched by
design, the severity of bone involvement and baseline bone
markers were similar and the order of BMD changes at
trabecular sites in the alendronate-treated patients are sim-
ilar to those consequent to the surgical correction of PHPT,
as observed in this and in other studies.(4–9) The increases in
femoral neck BMD after 2 years of alendronate therapy are
lower than those (ϩ6%) observed by Silverberg et al.(7)
after parathyroidectomy but similar to those reported in
other studies.(6,9)
FIG. 2. Percent changes in BMD at the lumbar spine, total
body, and hip sites in the control (dotted line) and
alendronate-treated (continuous line) primary hyperparathy-
roid patients. The significance (p Ͻ 0.05) of the differences
also is shown. ؠ, versus baseline; ء, between groups.
The clinical relevance of the bone mass changes observed
with alendronate therapy is uncertain and it is unknown
whether changes of this magnitude would be of clinical
importance for later fracture risk. Our study is far from
being powered to detect changes in fracture rate and the risk
of fracture in these patients with mild PHPT is still
disputed.(1–3,36–40)
Alendronate therapy rapidly decreased the biochemical
marker of bone resorption. The nadir was achieved by the
sixth month and a 50% decrease has maintained all through-
out the treatment period. The markers of bone formation
decreased at a slower rate with a nadir around the twelfth
month of alendronate therapy. The uncoupling between the
clinical vertebral or nonvertebral fracture during the period
of observation.
DISCUSSION
We found that in patients with mild PHPT, the treatment markers of bone resorption and bone formation, particularly
with low oral doses of alendronate (10 mg on alternative within the first 3 months, most likely was associated with
days) was able to increase BMD at all the skeletal sites intense positive bone balance, which explains the transient
explored, independent of the structural prevalence of corti- fall in serum calcium and urinary calcium excretion and the
cal or trabecular bone tissue. The 5-mg daily dose initially transient significant increase in serum PTH. The biochem-
was chosen because this was the only dose recommended ical changes observed here are similar to those we obtained
for the treatment of postmenopausal osteoporosis in Italy at in an early study with oral clodronate in mild PHPT pa-
the time when the study was submitted to the Ethical Com- tients(23) and resemble those occurring after parathyroidec-
mittee and it is the daily dose recommended now for osteo- tomy. It is then confirmed that at least in patients with mild
porosis prevention in United States. The assumption that 10 PHPT the serum calcium-PTH feedback is preserved and
mg alendronate on alternate days are equipotent to 5 mg/day that the decrease in serum calcium is transient and of little
made when the 5 mg of alendronate was withdrawn from clinical relevance in these patients in whom hypercalcemia
the Italian market seems acceptable in light of the recent is not a major concern. The consequences of the transient
observation that 70 mg once weekly and 10 mg daily are PTH changes on bone metabolism remain uncertain, being
therapeutically equivalent in the treatment of postmeno- potentially either positive or negative.
pausal osteoporosis.(31) The observed increases in total body
In the control patients of this study the biochemical
calcium indicate that the remarkable changes in the more markers of disease activity remained stable over the period
trabecular sites did not come at the expense of cortical bone. of observation, but the BMD values slowly declined at the
The order of changes we observed with this relatively low cortical sites (femoral neck and total body), and these de-

118
ROSSINI ET AL.
10. Christiansen P, Steiniche T, Brixen K, Hessov I, Melsen F,
Heickendorff L, Mosekilde L 1999 Primary hyperparathyroid-
ism: Whole-body bone mineral density in surgically treated
Danish patients: A three-year follow-up study. Bone 25:597–
602.
11. Consensus Development National Institutes of Health (NIH)
Conference Panel 1991 Diagnosis and management of asymp-
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12. Marcus R, Madvig P, Crim M, Pont A, Kosek J 1984 Conju-
gated estrogens in the treatment of postmenopausal women
with hyperparathyroidism. Ann Intern Med 100:633–640.
13. Marcus R 1991 Estrogens and progestins in the management
of primary hyperparathyroidism. J Bone Miner Res 6(Suppl
1):S125–S129.
14. Selby PL, Peacock M 1986 Ethinyl estradiol and norethin-
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observation. These results are similar to those observed in
other longitudinal studies including postmenopausal women
with PHPT(17,18) but in contrast with other published longi-
tudinal data on BMD in untreated PHPT patients.(7,41–43)
However, at variance with these latter studies, our patients
were considerably older and the majority of them had some
degree of physical disability associated with low physical
activity.
In our study the correlation observed between baseline
serum levels of bone alkaline phosphatase and the percent
decline in total body BMD seems to indicate that the pa-
tients with the highest bone turnover were those loosing
more bone. Similar correlation was reported by Guo et
al.(18) using urinary cross-linked N-terminal telopeptide of
type I collagen as bone turnover marker.
In conclusion, the results of this pilot study indicate that
in postmenopausal women 10 mg of alendronate taken on
alternate days significantly increases BMD at the most
clinically relevant skeletal sites. The order of changes ob-
served after 2 years of therapy are very close to those
obtained within a few months after surgical correction of the
disease. This result makes alendronate a good candidate as
a supportive therapy in patients with mild PHPT who are
unwilling or unsuitable for surgery, in whom osteoporosis is
a reason of concern.
18. Guo CY, Thomas WE, al-Dehaimi AW, Assiri AMA, Eastell
R 1996 Longitudinal changes in bone mineral density and
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Address reprint requests to:
Prof. Silvano Adami
Ospedale
37067 Valeggio, Verona, Italy
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Received in original form January 10, 2000; in revised form
August 2, 2000; accepted August 22, 2000.