Osteoporosis Int (1995) 5:30-34
© 1995 European Foundation for Osteoporosis
Original Article
Comparison of the Treatment Effects of Ossein-Hydroxyapatite
Compound and Calcium Carbonate in Osteoporotic Females
P. Rfiegsegger 1, A. Ketler 2, and M. A. D a m b a c h e r 3
1Institute for Biomedical Engineering, University and Federal Institute of Technology, Zurich; 2Osteoporosis Center, Liestal; and 3Research
Laboratory for Calcium Metabolism, Orthopaedic University Hospital, Zurich, Switzerland
Abstract. The aim of the study was to evaluate whether
ossein-hydroxyapatite (OHC) is more effective than
calcium carbonate (CC) in preventing luther bone loss
in postmenopausal osteoporosis. Forty osteoporotic
patients were monitored for 20 months. The patients
were randomly assigned to one of two groups and
treated in a double-masked manner with 1400 mg
calcium per day, in the form of either O H C or CC. OHC
consists of hydroxyapatite, collagens and non-collage-
nous proteins/peptides containing insulin-like growth
factor I (IGF-I; 1341 ng), insulin-like growth factor II
(IGF-II; 670 ng), transforming growth factor beta
(TFG-/3; 166 ng) and osteocalcin (47 #g). The bone
densities were evaluated at intervals of 4 months with
high-precision peripheral quantitative computed
tomography. After 20 months of treatment the loss of
trabecular bone was 0.8 + 0.5% in the OHC group and
1.8 + 0.7% in the CC group. The difference between
the O H C and CC groups was statistically significant.
This study shows that OHC is more effective than CC in
slowing peripheral trabecular bone loss in patients with
manifest osteoporosis.
Keywords: Bone densitometry; Computed tomo-
graphy; Ossein-hydroxyapatite compound; Postmeno-
pausal osteoporosis
Correspondence and offprint requests to: Dr Peter Rfiegsegger,
Institut fiJr biomedizinische Technik, ETH und Universitfit Zfirich,
Moussonstrasse 18, CH-8044 Ztirich, Switzerland.
Osteoporosis
International
Introduction
Calcium intake throughout life appears to be a key
factor determining whether or not osteoporosis may
develop. Women who consumed milk with every meal
during childhood and adolescence are reported to have
a higher bone density than women drinking milk less
frequently [1]. Adequate calcium intake until adulthood
may also be helpful in achieving a high peak bone mass
[2]. In the menopausal age range data are sparse,
however, and bone loss might be influenced by other
factors such as ovulatory disturbances [3]. In the first 5
years after menopause, bone loss and calcium intake are
probably no longer directly related [4], whereas healthy
older postmenopausal women may again profit from
calcium supplementation, especially if their daily
calcium intake is less than 400 mg/day [5]. A review of
36 papers on calcium intake and bone mass [6] con-
cluded that a calcium supplement of around 1000 mg/
day in postmenopausal women can prevent the loss of
approximately 1% of bone mass per year. It has been
suggested that the relationship between calcium intake
and bone mass displays a threshold effect, so that
beyond a certain intake additional calcium has no effect
[7]. This threshold is assumed to be below 800 mg/day.
Whilst the therapeutic effect of calcium supple-
mentation in older women with a low daily calcium
intake is no longer a controversial issue, the efficiency of
various calcium sources is. In general calcium citrate
malate is said to be better than calcium carbonate [8,9],
but others [10] state that all forms of calcium supple-
mentation have approximately the same bioavailability.
In a pilot study we evaluated the effect of O H C
(ossein-hydroxyapatite compound) on manifest osteo-
porosis using high-precision, low-dose peripheral
Ossein-HydroxyapatiteCompared with Calcium Carbonate in PostmenopausalOsteoporosis
quantitative computed tomography (pQCT). The
results indicated a positive effect of OHC treatment
[11]. The aim of the present study was to discover
whether O H C is superior to calcium carbonate (CC) in
preventing bone loss in postmenopausal osteoporosis.
To this end a double-masked, comparative study was
performed.
Methods
Experimental Subjects
Forty postmenopausal patients in the age range 58-78
years were treated for 20 months, Osteoporosis was
diagnosed on the basis of at least one crush fracture of
the spine without adequate trauma. No treatment with
estrogens,, calcium, vitamin D, or any other drug that
could have influenced bone had been given prior to
therapy. No history of an event known to influence bone
metabolism, such as alcoholism, nicotine abuse, steroid
administration or antiepileptic drugs, diabetes mellitus,
thyroid disease or hyperparathyroidism, was present.
The patients were randomly assigned to one of two
groups and treated in a double-masked manner with 8
film-coated tablets per day (breakfast 2, lunch 2, dinner
4). The film-coated tablets contained a total of 1400 mg
calcium in the form of either OHC or CC. Five drop-
outs occurred during the observation period of 20
months: 3 in the O H C group (1 fell ill, 1 refused the
drug, 1 changed to estrogens) and 2 in the CC group (1
fractured the radius at the measuring site, 1 changed to
estrogens). The complete data on 17 patients in the
OHC group (age 67.2 + 7.0 years) and 18 patients in the
CC group (age 65.6 + 5.4 years) were available for the
final analysis.
Medication
Ossein-hydroxyapatite compound (OHC), derived
from bone of bovine origin, contains an organic and an
inorganic component. The organic component, ossein,
consists of collagen and non-collagenous peptides/pro-
teins with growth factors and bone-specific proteins
insulin-like growth factors I and II (IGF-I and IGF-II),
transforming growth factor beta (TGF-B) and osteocal-
cin. These factors have been isolated and quantified by
Stepan et al. [12]. The inorganic part, hydroxyapatite,
supplies calcium and phosporous in a physiological ratio
of 2:1. O H C 6.64 g (1.4 g calcium) corresponds to 3.32 g
hydroxyapatite, 1.72 g collagen, 0.6 g non-collagenous
peptides/proteins with 1341 +_ 90 ng IGF-I, 670 _+ 70 ng
IGF-II, 166 + 10 ng TGF-/3 and 47 + 4/~g osteocalcin.
Bone Densitometry
Bone density measurements were performed at inter-
vals of 4 months using peripheral quantitative computed
31
tomography (pQCT). Measuring sites were the distal
tibia (a weight-bearing bone) and the distal radius (a
non-weight-bearing bone) for trabecular bone density
(TBD) examinations. The diaphysis of the radius was
used for the determination of a parameter describing
compact bone. The measuring and evaluation pro-
cedure has been described previously [13,14] and can be
characterized as follows:
The patient's arm (or leg) is positioned in a radiolu-
cent cast which enables comfortable immobilization
during the measuring process and allows reproducible
orientation of the bone axis relative to the measuring
plane. The measuring system - a special-purpose CT
instrument for low-dose bone densitometry- provides a
digital radiogram as a positioning aid for the examin-
ation site. The examination site in the ultradistal radius
(or tibia) is then covered with a stack of ten tomograms
(slice thickness i mm, interslice distance i mm). During
the 20 months of follow-up six such measurements are
made. After the sixth measurement the bone volume
common to all examinations of a patient is determined.
Then the bone density changes in this bone sample are
evaluated. This procedure enables a reproducibility in
routine patient examinations of 0.3 % at a radiation dose
of only 0.1 mSv per examination [15].
Statistical Analysis
The mean, SD and SEM for values at visits 1 to 6 were
calculated for all variates. The changes in bone densities
between the first visit (baseline) and all subsequent
visits were determined. Within groups these changes
were analyzed with a paired t-test. The differences
between the mean bone density over time and the
densities measured at the visits 1 to 6 were also calcu-
lated for each patient and an analysis of variance
performed.
Results
The baseline values are summarized in the Tables I and
2. For trabecular bone the baseline values of the two
treatment groups are the same (difference not statisti-
cally significant). They are approximately 30% below
the respective bone densities of healthy women at the
age of 50 years [14]. For cortical bone the baseline
values are different (p <0.05).
To analyse the effects of the two treatment modalities
on the bone densities we followed a two-step approach.
First, all bone density changes relative to the respective
baseline values were calculated and analyzed with a
paired t-test. From month 8 onwards the trabecular
bone loss (Table 1) in the CC group was significantly
different from baseline. In the OHC group this differ-
ence did not reach significance. In contrast, as regards
cortical bone loss the values in both groups differed
significantly from baseline (Table 2). In addition to the
relative values in Tables 1 and 2, absolute values are
32 P. Rtiegsegger et al.

Table 1. Trabecular bone density: initial values (baseline) and relative changes over 20 months

Group n Baseline values % change from baseline values

(g/cm3)

4 months 8 months 12 months 16 months 20 months

Radius
CC 18 0.150_+0.012 -0.3_+0.3 -0.9+0.5* -1.4_+0.6" -1.9+0.6" -1.8_+0.7"
OHC 17 0.158+0.015 +0.1 +0.4 -0.3+0.3 -0.5+0.4 -0.8_+0.5 -0.8_+0.5
Tibia
CC 18 0.171_+0.013 -0.0-+0.2 -0.5_+0.2* -0.7+0.3* -1.1+0.4" -1.3_+0.5"
OHC 17 0.171_+0.016 +0.2_+0.3 -0.7_+0.4 -0.2_+0.9 -0.3_+0.7 -0.5_+0.6

Values are the mean + SEM.

CC, calcium carbonate; OHC, ossein-hydroxyapatite compound.
*Significant changes from baseline: p <0.05.

Table 2. Cortical bone density: initial values (baseline) and relative changes over 20 months

Group n Baseline values % change from baseline values

(g/cm3)

4 months 8 months 12 months 16 months 20 months

Radius
CC 18 0.943+0.046 -0.6_+0.2* -1.0+0.3" -1.7+0.4" -2.4+0.6* -2.9+0.7*
OHC 17 1.068+0.056 -0.2+0.2 -1.0+0.3' -1.6+0.4" -2.0+0.5* -2.1+0.6"
Tibia
CC 18 0.698+0.030 -0.5_+0.2* -0.6+0.3* -1.0+0.3" -1.4_+0.3" -1.8+0.4"
OHC 17 0.818+0.043 -0.1+0.2 -0.5+0.3* -1.1+0.3" -1.3+0.4" -1.6+0.5"

Values are the mean + SEM.

CC, calcium carbonate; OHC, ossein-hydroxyapatite compound.
*Significant changes from baseline: p <0.05.

40

&
& 30

20

10

RADIUS TIBIA RADIUS TIBIA

~ OHC Group ~ OHC Group
a ~ CC Group ~ CC Group b
Fig. 1. a Loss of trabecular bone density in the distal radius and distal tibia during 20 months. Bone loss in the radius is significantly (p <0.05)
lower in the OHC-treated group than in the CC group. For comparison: untreated patients are reported [24] to lose approximately 5 mg/cm3
during the same time period, b Bone loss in the diaphyses of radius and tibia. The difference between OHC and CC is marginal and does not
reach statistical significance.
Ossein-Hydroxyapatite Compared with Calcium Carbonate in Postmenopausal Osteoporosis
& be the excellent bioavailability of OHC [23].
N
0
m of 3.7% in the radius and in the tibia. A comparison of
~I -1
-2
r~
z data on the habitual dietary calcium intake in the part of
0 5 10 15 20
TIME [months]
---I--- O H C Group
--|-- C C Group
Fig. 2. Temporal changes of the mean trabecular bone density of the
radius of patients with postmenopausal osteoporosis. The data of the
two treatment groups are given together with their regression lines.
The two slopes are different at p <0.05.
shown in Fig. 1. The mean density changes (in mg/cm3)
between the first and last visits are depicted for trabecu-
lar bone and cortical bone.
Secondly, for the most sensitive bone parameter -
the trabecular bone density of the distal radius - an
analysis of variance was performed. The differences
between mean bone density over time and the densities
measured at visits 1 to 6 were calculated. For both
groups the assumption of a linear bone loss with time
was tested and found to be true. Then the slopes were
calculated and their departure from zero tested. Re-
gression lines and the array means with their SEM are
plotted in Fig. 2. For both groups the slopes of the
regression lines were found to be negative (b -- -0.146
for CC and b = -0.080 for OHC and significantly
different from zero (2 <0.01). The analysis of the slopes
of the two treatment groups shows that the CC group
loses more bone than the OHC group, with a signifi-
cance of p <0.05.
Discussion
Previous studies have shown a positive effect of OHC on
different forms of osteopenic disease such as primary
and secondary osteoporosis [16], corticoid-induced
osteoporosis [17,18] and hepatogenous osteoporosis
[19,20]. It has also been reported that OHC restored to
normal the high bone turnover following oophorectomy
[21]. The present study shows that OHC is more
effective than CC in preventing further bone loss in
postmenopausal osteoporosis.
The better performance of OHC might be attributed
33
to the osteogenic effects of its organic component as
suggested by animal studies [22]. Another reason might
In a previous publication [24] we reported on the
bone loss of trabecular bone (cortical bone was not
measured) in untreated postmenopausal women with
osteoporosis. Over 20 months this groups showed a loss
this historical group with the present treatment groups
suggests that CC as well as OHC considerably reduces
the rate of trabecular bone loss in women with post-
menopausal osteoporosis: while CC halves the rate of
bone toss, OHC manages nearly to halt it.
Although diet was not recorded in this study we have
Switzerland from which the patients were recruited
(mean daily calcium intake between 400 and 600 mg in
the age range considered). This suggests that dietary
calcium did not bias the study conditions.
We conclude that OHC is more effective than CC in
slowing peripheral trabecular bone toss in patients with
manifest osteoporosis. In the absence of side-effects and
interactions it should allow long-term treatment for a
broad range of patients.
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Received for publication 5 August 1993
Accepted in revised form 22 April 1994