Osteoporosis: Evaluation and Treatment continued....
P-236
PERFORMANCE OF A REAL-TIME IMAGING QUS SYSTEM USING AN ENHANCED COUPLING
AGENT
G. F. Mitchelmore, W. K. Wacker, R. F. Morris, K. L. Morris, K. G.
Faulkner*
GE Medical Systems Lunar, Madison, WI, USA
Ultrasonometry of the os calcis is increasingly accepted
as an effective low-cost method to assess osteoporotic fracture risk. The Lunar Achilles
InSight (GE Medical Systems) is a fourth-generation system incorporating a 2-D solid-state
receiving array. It eliminates 'blind' measurement by displaying a real-time heel image
prior to and during measurement. A Region-of-Measurement circle on the image shows the
measurement location. Historically, ultrasonometers have used water, ultrasound gel or
mineral oil as the coupling medium to transfer the ultrasound signal from the transducers
through the heel. Oil-based agents create difficulties in clean up and staining of
clothes. Gel is water-soluble but must be cleaned from the transducers and heel. We
evaluated a new coupling agent, isopropyl alcohol (70%) that was selected for its
recognized safety in external application.
In vivo performance was compared between the Achilles
InSight and the Achilles Express (GE Medical Systems), a previous generation
ultrasonometer. Volunteers (n=29, including 22 older women) with a wide range of heel
densities were measured on two days, using gel one day and alcohol the other. The combined
data were subjected to regression (alcohol on gel values) and paired t-test analysis.
Stiffness Index was highly correlated between alcohol and gel (r=0.983). Slope was almost
identical to 1 while offset equaled 1.5, not significantly different from zero (alpha =
0.05).
Measurement convergence time of Stiffness Index was
evaluated on 22 subjects who were measured with gel and isopropyl alcohol using a fixed
acquisition time of 3 minutes. Alcohol-coupled signals converged more rapidly and BUA and
SOS values stabilized faster as compared to gel.
Precision (%CV) was calculated for alcohol and gel
measurements made on the same foot on separate days. Ten subjects were measured fifteen
times in succession with repositioning between measurements. Alcohol had better repeat
precision (lower variance). Results were highly significant (p<0.001) by F-test for
Stiffness Index (CV of 1.95% Vs. 2.55%), BUA and SOS.
Isopropyl alcohol as a coupling agent gives Stiffness
Index results nearly identical to coupling gel. Alcohol provides significantly shorter
measurement time, superior stability and improved precision while eliminating the problems
of messy oils or gels.
[Programme]
P-237
THE EFFECTS OF MENATETRENONE ON THE BONE AND SERUM LEVELS OF VITAMIN K2
(MENAQUINONE DERIVATIVES) IN OSTEOPENIA INDUCED BY PHENYTOIN IN GROWING RATS
K. Onodera1*, A. Takahashi2, H. Wakabayashi3,
J. Kamei4, N. Sogawa1, C. Sogawa1, S. Kitayama1,
H. Mayanagi2, H. Shinoda5
1Division of Dental Pharmacology, Okayama University Graduate
School of Medicine and Dentistry, Okayama, Japan
2Clinics of Dentistry for the Disabled, Tohoku University
Dental Hospital, Sendai, Japan
3Department of Clinical Pharmacotherapy, Faculty of
Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences,
Niigata, Japan
4Department of Pathophysiology & Therapeutics, Faculty of
Pharmaceutical Sciences, Hoshi University, Tokyo, Japan
5Division of Pharmacology, Tohoku University Graduate School
of Dentistry, Sendai, Japan
We reported that long-term treatment of phenytoin induced
osteopenia and co- administration of vitamin K2(menatetrenone) prevented such
bone loss. In this study, we investigated the effect of phenytoin and/or vitamin K2(menatetrenone)
on bone mineral density (BMD) and the changes in the levels of menaquinone derivatives
(MK-n) in the serum. The levels of menaquinone derivatives in the femur were measured
using high-performance liquid chromatography with an electrochemical detector. In this
study, we found that he values of BMD were significantly decreased in all parts of the
femoral bones measured in the phenytoin-treated group. When the bone and the serum levels
of MK-6 were decreased by phenytoin administration, we could observed bone loss in rats.
Conversely, when bone loss was prevented by combined administration of menatetrenone with
phenytoin, the bone levels of MK-6 were increased up to the levels of vehicle-treated
rats. Accordingly, in this study, we
suggest that long-termed phenytoin exposure may inhibit
bone formation concomitantly with insufficient of vitamin K, which, at least in part,
contributed to bone loss in rats.
[Programme]
P-238
EFFECTS OF MENATETRENONE AND/OR ALENDRONATE ON BONE MINERAL DENSITY OF
TIBIAE IN PHENYTOIN TREATED RATS
A. Takahashi1*, K. Onodera2, T. Saito1,
H. Shinoda3, H. Mayanagi1
1Clinics of Dentistry for the Disabled, Tohoku University
Dental Hospital, Sendai, Japan
2Division of Dental Pharmacology, Okayama University Graduate
School of Medicine and Dentistry, Okayama, Japan
3Division of Pharmacology, Tohoku University Graduate School
of Dentistry, Sendai, Japan
Antiepileptic drugs have been shown to induce
hypocalcemia that is associated with osteomalacia and osteoporosis in clinical practice.
Among the antiepileptic drugs, diphenylhydantoine (phenytoin,
5,5-diphenyl-2,4-imidazolidinedione) is one of the most commonly used for the therapy of
patients with various types of seizures. Recently, we reported that long-term
administration of phenytoin induces osteopenia in growing rats, moreover, daily intake of
menatetrenone showed preventive effects against such phenytoin-induced osteopenia. In this
study, we investigated the effects of menatetrenone and/or alendronate on bone mineral
density in phenytoin-treated rats. A long-termed administration of phenytoin (20 mg/kg per
day for 5 weeks) produced bone loss in the tibiae of growing rats. The values of bone
mineral density (BMD) were significantly decreased in the tibial diaphysis and metaphysis
in the phenytoin-treated group. Combined administration of menatetrenone or alendronate
with phenytoin did not decrease BMD in the tibiae. Treatment of menatetrenone with
phenytoin maintained BMD as same as control, however, treatment of alendronate with
phenytoin increased BMD more than control. Administration of menatetrenone and alendronate
with phenytoin showed additional effect on BMD. Thus, we conclude that combined treatment
with menatetrenone plus alendoronate was more effective than therapy with menatetrenone
alone on antiepileptics-induced bone loss.
[Programme]
P-239
INTRAVENOUS INTERMITTENT NERIDRONATE IN THE TREATMENT OF POSTMENOPAUSAL
OSTEOPOROSIS
V. Braga*, D. Gatti, J. Bakri, F. Colapietro, E. Battaglia, R. Prizzi, M.
Rossini, S. Adami
Rheumatological Rehabilitation, University Hospital Valeggio S/M, Italy
Bisphosphonates have been used with success in the
treatment of osteoporosis, but oral therapy often lacks compliance. Here we report the
results of a clinical trial with the aminobisphosphonate neridronate administered
intravenously (IV).
The study included 78 postmenopausal women with spine
bone mineral density (BMD) at least -2.5 SD below peak. Patients were randomized to
receive for two years either 50 mg IV neridronate bimonthly and 500 mg calcium plus 400 U
vitamin D supplements daily (n. 39) or calcium vitamin D supplements alone (control group,
n. 39). Treatment was continued over 2 years with an additional 1 year follow-up of
calcium-vitamin D supplements alone in both groups.
Neridronate was well tolerated with the appearance of
typical clinical signs of an acute phase reaction in 5 of the patients and only after the
first infusion.
In the control group no significant changes in BMD or
bone markers were observed. In the neridronate group BMD rose progressively at the spine
up to 7.4%, 6.1% (SD) and at the femoral neck up to 5.8%, 8.2% (SD) at the end of the
second year. In the succeeding follow-up months these gains were maintained at both
skeletal sites. Serum bone alkaline phosphatase (bone AP) and serum type I collagen C-
telopeptide (CTX) significantly decreased within 2 months. The bone AP values reached a
-30% plateau after 6 months, while CTX attained the lowest mean value (- 47%) only by the
end of the treatment with neridronate. Both bone markers returned almost to baseline
values 1 year after treatment discontinuation.
Treatment of postmenopausal osteoporosis with 50 mg IV
neridronate bimonthly results in clinically relevant increases in BMD amongst the largest
so far observed with any other bisphosphonate.
[Programme]
P-240
ESTIMATION OF GLUCOCORTICOID EFFECTS ON BONE METABOLISM MARKER AND BONE
MINERAL DENSITY IN RATS
F. Moradi1*, A. Sobhani1, M. Naraghi1,
M. Moghadsi2, M. Ansari3, A. Ghasemzadeh1
1Dept. Anatomy, Faculty of Med.,Tehran Univ. of Med. Sci.
Tehran, Iran
2Dept. Rheumatology, Faculty of Med.Tehran Univ. of Med. Sci.
Tehran, Iran
3Dept. Biochemistry, Faculty of Med.Tehran Univ. of Med. Sci.
Tehran, Iran
Abstract:
Introduction: Glucocorticoid induced osteoporosis was
characterized by decreased of osteoblast numbers and a marked impairment of new bone
formation. The present study evaluated the effect of methylprednisolone Acetate on
metabolism and bone mineral density of rats.
Methods and Material: Total duration of the experiment
was four weeks. Eighteen male Sprague Dawley rats (8 week old and 180 gr weight) were
randomly divided into three groups: Group A (n=6), was a base line control or normal
animal. Group B (n=6), get only normal saline (0.9%) and group C (n=6), get
methylprednisolne acetate (0.2 mg/kg) subcutaneously 3 times for 4 weeks. For evaluation
on Biochemical agents changed in the serum calcium, Acid phosphatas and osteocalcine were
measured before and after treatment. Also, bone mineral density (BMD) of lumber vertebrae
was measured by dual energy x-ray absorptiometry (DEXA).
Results: The results showed that, the serum calcium level
unaffected (p<0.05) by methylprednisolone acetate, but the serum Acid phosphatase level
was significantly (p<0.05) increased after 4 weeks treatment. Also, the serum
osteocalcine level and bone mineral density of lumbar vertebrae were significantly
(p<0.05) decreased by methylprednisolone acetate treatment compared with the other
groups.
Conclusions: The findings indicate that by administration
of methylprednisolne actate bone formation lumber vertebrae was decreased and bone
resorption in lumber vertebrae was increased.
Key words: Glucocorticoid, osteoporosis, Bone Markers
Metabolism, BMD and rat.
[Programme]
P-241
BONE DENSITOMETRY AND OSTEOPOROSIS DIAGNOSTIC THRESHOLD
Z. Killinger*, J. Payer, P. Hrśzikovį, E. Stenovį
1st Internal Clinic,University Hospital, Bratislava, Slovakia
Dual-energy X-ray absorptiometry /DXA/ is regarded as the
best method for use in clinical practice for the diagnosis of osteoporosis. It still
remains debate on, how the results obtained should be used to make decision about
treatment. In routine practice T score below -2,5 SD is the most important factor for
initiating an antiresorptive treatment. In most centres only one region is routinely
measured. Presence of osteophytes, calcifications, vertebral deformities and different
speed of bone loss after the menopause in individual regions may cause a discrepancy in
BMD results. The type of DXA and used normative data contribute to the discrepancies. The
diagnosis of osteoporosis may be missed if only one site is measured. In our centre we
have performed since 1993 more than 30 000 scans of lumbar spine and femoral neck in each
patient using Norland XR 36. We found relative high discrepancies between both measured
sites.
We present the results of a retrospective analysis of
1018 women divided in 5 age groups. We found in 38% the difference between femoral neck
and lumbar spine T score more than 1 SD and in 7,5% of patients more than 2 SD. If
screened only at femoral neck 13,5% (mean) patients with osteopenia and 6% (mean) of
patients with osteoporosis would be misdiagnosed as normal. Relative high differences were
found in all age groups. In contrast with published data we found higher sensitivity of
lumbar spine measurement also in older patients over 70y. in spite of occurrence of
osteoproductive changes in this region. Consistent exclusion of lumbar vertebrae with
anatomical changes will still increase the sensitivity of spine measurement. Selection of
measured region, type of DXA device and used normative data should be taken in account
/except of quality of the scan due to anatomic changes/ if the diagnosis of osteoporosis
is the endpoint. Precise diagnosis and extrapolation of diagnostic criteria to
intervention thresholds is a key issue in clinical decision making about antiresorptive
treatment.
[Programme]
P-242
DEVELOPMENT OF MUSCLE STRENGHT, BONE MINERAL DENSITY, PHYSICAL FUNCTION,
JOINT DAMAGE AND CLINICAL DISEASE ACTIVITY IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS.
IMPACT OF PHYSICAL TRAINING. A 5-YEAR PROSPECTIVE STUDY
A. Häkkinen1, T. Sokka2,3, H. Kautiainen4,
A. Kotaniemi4, P. Hannonen2*
1Department of Physical Medicine and Rehabilitation, Central
Hospital, Jyväskylä, Finland
2Department of Medicine, central Hospital, Jyväskylä,
Finland
3Division of Rheumatology, Vanderbilt University, Nashville,
US
4Rheumatism Foundation Hospital, Heinola, Finland
Objective: To investigate the long-term effects of a
2-year home-based strength training on muscle strenght, bone mineral density (BMD), joint
damage, disease activity and physical function in patients with early rheumatoid arthritis
(RA) after a subsequent 3-year follow-up.
Methods: Seventy patients with early RA were randomly
assigned to perform either strength training (EG) or range of motion exercises (CG).
Maximal strength of various muscle groups were recorded with dynamometers, BMD was
measured at the femoral neck and at the lumbar spine by dual x-ray densitometry. Disease
activity was assessed by disease activity score (DAS), the extent of joint damage by
Larsen`s score and physical function by the self report Health Assessment Questionnaire
(HAQ).
Results: The respective mean maximum muscle strength
index increases during the 2-year training period were 32% and 18% in EG and in CG and
they remained at the reached level throughout the subsequent 3-year follow-up period. The
BMD values between the study groups at both measured sites were comparable at baseline and
at all subsequent measurements. The EC patients remained better physical function in
comparison to the CG cases, while the development of joint erosions and DAs indices were
comparable between groups throughout the study.
Conclusion: Individually tailored and regularly conducted
physical exercises including strength training improves muscle strength and physical
function and maintains BMD in patients with early RA. Further, it does not accelerate the
development of radiographic joint damage or increase clinical disease activity.
[Programme]
P-243
ALENDRONATE (ALN) TAKING IN POSTMENOPAUSAL OSTEOPOROSIS (PMO) AT
DIFFERENT TIMES IN THE COURSE OF THE DAY
B. H. Hoene*, H. J. H. Heberling, J. S. Steindorf, T. M. Mühlberg, A. S.
Sawistowsky, S. N. Neumann, S. G. Gerstenberger
Community Hospital Leipzig, Germany
Bisphosphonates are world-wide accepted as one of the
most important treatment schedules of PMO. They are associated with stringent dosing
recommendations due to their poor gastrointestinal absorption and upper gastrointestinal
side effects. This facts may cause problems of compliance.
The aim of our clinical trial was to investigate the
effects of taking ALN in the morning on the empty stomach and on the other hand in the
evening.
We studied the effects of the two treatment groups on
bone mineral density and bone turnover in 36 postmenopausal women with diminished BMD (at
least minus 2.5 SD of peak bone mass). All patients were supplemented with calcium and
vitamin D. BMD of lumbar spine and femur was measured using DEXA at different time
intervals. Bone turnover markers were assessed at baseline,3, 6 and 12 months.
Results: Morning and evening taking of 10 mg ALN
increased lumbar spine BMD by 4.5% and respectively 3.5% in relation to baseline. BMD
gains were also seen at the femoral neck (Ward triangle) by 5.3% in the morning group and
3.8% in evening taking group. Even so was seen a significant suppression of the bone
resoption markers in both doses regimes. The same percentage of withdrawals following an
adverse effect was observed for patients receiving 10 mg in the morning and for those
receiving 10 mg in the evening.
Conclusion:This small clinical trial demonstrates that
ALN (10 mg) is efficacious in different taking regimes. The evening taking is an effective
alternative in patients with problems in taking ALN on empty stomach.
[Programme]
P-244
EFFECT OF EGGSHELL CALCIUM AND COMBINATION THERAPY WITH ALENDRONATE ON
THE OVARIECTOMIZED RATS
K. Svik*, M. Stancikova, R. Istok, R. Stancik
National Institute of Rheumatic Diseases, Piestany, Slovakia
Objective. The effects of eggshell calcium in the form of
biopreparation Biomin H as a source of calcium and its combination with sodium alendronate
on ovariectomy (OVX) induced bone loss were studied in a long-term prophylactic treatment
regime in rats.
Methods. Adult female Sprague Dawley rats (250±10g) were
subjected to bilateral ovariectomy and sham operation (SHAM). Forty nine animals were
divided into 7 groups of seven: (1) sham; (2) OVX controls; OVX rats treated: (3) with
alendronate 250 µg/kg (ALN-1); (4) with alendronate 500 µg/kg (ALN-2); (5) with Biomin H
8 mg/kg (BIO-1); (6) with Biomin H 16 mg/kg (BIO-2); and (7) Biomin H 8 mg/kg plus
alendronate 250 µg/kg (ALN-1+BIO-1). For a period of 9 weeks the animals were on a
calculated diet containing 7.5 g Ca/kg, 6.5 g P/kg and 1000 IU vitamin D3/kg diet. Sodium
alendronate and Biomin H were applied orally daily. Both pyridinoline (Pyr) and
deoxypyridinoline (Dpyr) were determined in the urine by HPLC method. Bone mineral density
(BMD) and bone mineral content (BMC) of the whole body and femur were detected using DEXA.
Results. All densitometric parameters except BMC of the
whole body were markedly decreased in OVX rats in comparison with SHAM controls. Both
urinary Pyr and Dpyr were significantly lower in SHAM, ALN-1, ALN-2, BIO-2 and ALN-
1+BIO-1 groups compared to the OVX control. The beneficial protective effect of these
agents were observed on BMD and BMC of the whole body and femur after 9 weeks of
ovariectomy. BIO-1 alone did not change significantly these parameters in OVX rats, but
its combination with ALN-1 had similar effect as ALN-2.
Conclusion. Our data show the significant preventive
effect of alendronate and Biomin H 16 mg/kg in the treatment of OVX rats and the
beneficial effect of the combination of low dose eggshell calcium (Biomin H) with low dose
alendronate, which may be cost saving due to reduce dose of alendronate.
[Programme]
P-245
VALUE OF BONE SCINTIGRAPHY FOR THE DETECTION AND AGEING OF VERTEBRAL
FRACTURES IN PATIENTS WITH SEVERE OSTEOPOROSIS
E. Kucukalic*, A. Begic, I. Gavrankapetanovic, F. Gavrankapetanovic, J.
Dizdarevic, S. Sokolovic, B. Hadzihasanovic, D. Avdic, I. Hizar
Clinical Center, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
Bone scintigraphy is used to detect sceletal lesions a
the earliest possible time, to monitor the course of skeletal disease and evaluate the
metabolic activity of skeletal lesions.In osteoporosis it is useful for detection of age
of fractures, particularly of the vertebrae. Acute vertebral colapse is associated with a
characteristic pattern of intensive linear uptake corresponding to the site of fracture.
Activity fades over the ensuing 6-18 months, which allows intensity of uptake to enable
assessment of the age of fracture.
Aim: The aim of this study was to determine, by using the
bone scan, age of veretebral fractures in patients with severe osteoporosis.
Materials and Methods: 24 female patients were studied
with bone scintigraphy after BMD and radiographic examination. BMD was measured with DEXA
HologicQDR 4500 Elite system. BMD showed T-score under -2.5 SD. The patients were divided
into two groups according to the clinical simptoms: groupI: Patients with acute low back
pain (onset at last 1-2 months); groupII: Patients with chronical back pain.
Scintigraphy was performed using double-head camera
equiped with low energy high resolotion collimator 3 hours after i.v. injection of 740 MBq
Tc-99m MDP.
MDP uptake was assessed visually and graded as 1.miled;
2.moderate; 3.intensive.
Results:
Gruop I : Intensive linear uptake of MDP was confirmed in
12 patients (100%)
Group II: Intensive linear uptake of radiofarmaceutical
was confirmed in 1 patient (8.3%)
Moderate linear uptake of MDP we have found in 3 patients
(25%)
Miled uptake of MDP was confirmed in 8 (66.7%)
Intensive uptake of radiofarmaceutical we have found in
patients with acute low back pain.
Conclusion: Intensity of uptake of Tc-99m MDP is good
parametar for assesssment of the age of fracture.
The present study confirms that Tc-99m MDP scintigraphy
is an accurate method for the
detection of the ageing of fractures cousing
osteoporosis.
[Programme]
P-246
CORRELATION BETWEEN BONE SCINTIGRAPY AND MINERAL BONE DENSITY IN PATIENTS
WITH OSTEOPOROSIS AND OSTEOPENIA
A. Begic*, E. Kucukalic, I. Gavrankapetanovic, F. Gavrankapetanovic, J.
Dizdarevic, S. Sokolovic, B. Hadzihasanovic, D. Avdic, I. Hizar, S. N. Begovic S, Beslic N
Clinical Center, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
Aim: The aim of this study was to evaluate the role of
Tc-99m MDP bone scintigraphy and compare with MBD measurment.
Materials and methods: This study included two groups of
female patients: 13 postmenopausal women with established osteoporosis, and 5 women with
osteopenia. BMD was measured wit DEXA Hologic QDR 4500 Elite system.
Scintigraphic examination were performed according to
standard protocol, 3 hours after i.v. injection of 740 MBq Tc-99m MDP. All images were
visually analysed by three nuclear medicine physicians.
Results: In the first group, all 13 scans showed an
intensive linear uptake of MDP in the lumbar spine. In the same group, asymptomatic sites
of increased tracer uptake were identified in femur of 1 patient, in humerus of 1 patient,
and 1 scan revealed focal increased uptake in the ribs. In the second group (patients with
osteopenia) WBS were found normal in 4 patients, and 1 patients had mild increased uptake
of radiotracer in the region of lumbar spine.
Conclusion: WBS is in positive correlation with MBD, and
can revealed all fractures sites in patients with osteoporosis. In patients with
osteopenia WBS is not diagnostic procedure of choice.
[Programme]
P-247
MINIMIZING ADVERSE SIDE EFFECTS DURING OSTEOPOROSIS INDUCTION IN SHEEP BY
MODULATION OF CORTICOSTEROID ADMINISTRATION
R. Holz1,2*, C. Eckhardt1, E. Schneider1,
C. A. Lill1,3
1AO Research Institute Davos
2Department of Traumatology, University of Regensburg
3Department of Orthopaedic Surgery, University of Heidelberg
Recent studies developed a large animal model for
osteoporosis to investigate new fixation devices and fracture healing in osteoporotic bone
with a combination of ovariectomy (OVX), calcium and vitamin D3 restricted
diet, and application of
Methylprednisolone (MP). Due to the immunodepression
effect of MP 31 % of the animals developed abscesses of the skin and internal organs. The
aim of this project was to reduce the adverse side effects due to corticosteroid
administration without compromising the desired bone loss, with combined treatment of OVX,
diet and i.m. administration of an uniform total dose of 1800 mg MP. Four groups with
different administration schedules were compared during a follow up of 4 months.
Thirty-six female white alpine sheep (6.5 ±0.6 years)
included in this study. Bone mineral density (BMD) measurements in the distal tibia and
radius were performed before and monthly during induction by peripheral quantitative CT
(pQCT). Bone structure from biopsies of the iliac crest taken before and after
osteoporosis induction and from necropsies of the femoral head and lumbar vertebral body
(L4, L5) was determined using Micro-CT. The Health condition of the animals was documented
weekly and postmortem examination of abdominal organs and subcutaneous tissue from the
injection areas was performed.
Cancellous BMD in the radius diminished 30 % in group 1,
30 % in group 2, 31 % in group 3 and 22 % in group 4. The BMD of the tibia decreased 37 %
in group 1, 34 % in group 2, 43 % in group 3 and 34 % in group 4.
In the iliac crest trabecular number was reduced 18 % in
group 1, 18 % in group 2, 14% in group 3 and 9 % in group 4. Trabecular separation
increased 34 % in group 1, 31 % in group 2, 28 % in group 2 and 16 % in group 4.
Except in group 3 adverse side effects like disseminated
alopecia, local or systemic infections due to drug administration were seen.
It seems to be possible to induce osteoporosis in sheep
without causing severe adverse side effects by reducing the number of steroid injections
and increasing the single dose simultaneously.
[Programme]
P-248
EACH HERBAL EXTRACT OF SOPHORAE FLAVESCENTIS RADIX AND SOPHORAE FLOS
(LEGUMINOSAE) PREVENTS BONE LOSS IN OVARIECTOMIZED (OVX) RATS
H. Ha1, C. Kim1*, K. Y. Song2
1Drug Research and Development, Korea Institute of Oriental
Medicine, Seoul, Korea
2College of Medicine, Chung-Ang University, Seoul, Korea
Aging and estrogen deficiency after menopause induces
bone loss and results in osteoporosis. Estrogen replacement therapy is indeed effective in
preventing bone loss caused by menopause, but it is also accompanied by some adverse
effects, such as uterus bleeding and breast cancer. This study was focused on development
of new drug from herbal extract of Sophorae Flavescentis Radix (SR) or Sophorae Flos (SF),
to prevent and treat osteoporosis after menopause without any side effects. The
proliferation of osteoblast like cell (Saos-2) induced by each herbal extract was analyzed
using a tetrazolim salt (MTT) and alkaline phosphatase (ALP) activity. Adult OVX SD rats
(10 weeks old) were divided into five groups; sham, control, 17beta-estradiol (E2; 1
microg/kg/day), SR (5 g/kg/day), and SF (5 g/kg/day). Animals in each group were
administrated daily dosage for 9 weeks. After complete blood cells counts and bioche
trabecular bone areas (TBAs) of tibia and lumbar were measured by bone histomorphometry.
In results, both SR and SF extracts induced cell proliferation on Saos-2 mical analysis in
plasma as biomarkers, tibia and lumbar were isolated and then (117% and 119% of control).
The ALP activities of the extracts on Saos-2 were 257% and 189% of control. The TBAs of
tibia in SR and SF groups were increased 169% and 163% of control (p<0.01), better than
that in E2 group (147% of control, P<0.05). SR and SF increased TBA of lumbar 141%
(P<0.01) and 127% (P<0.05) of control (P<0.01), better than or similar to that in
E2 (124% of control, P<0.05). Each herbal extract of SR and SF did not induce
estrogenic side effects in uterus. In conclusion, both SR and SF extracts prevent
OVX-induced cancellous bone loss for 9 weeks in OVX rats. (Supported partially by a grant
from KIOM, Korea)
[Programme]
P-249
HIGH INCIDENCE OF BONE TURNOVER DISTURBANCES WITH INCREASING AGE
D. Ivan1,2*, I. Zosin1, D. David1, M.
Vlad1, P. Bottermann2
1Clinic of Endocrinology, University of Medicine and Pharmacy,
Timisoara, Romania
22nd Medical Clinic, Technical University Munich, Germany
Introduction: Biochemical and hormonal markers of bone
metabolism can offer useful information about the dynamics of bone turnover and type of
bone loss. The aim of this study was to evaluate this information in an homogenous group
of elderly people.
Material and Methods: 74 clinically healthy residents of
a senior's home (56 women, 18 men, aged 56-95). Venous serum samples were drawn (in the
middle of June) for determination of serum calcium and phosphorus, alkaline bone
phosphatase, creatinine, urea-N, PTH, 25-OH-D3 and 1,25-(OH)2-D3 and the morning
spot-urine was collected for measurement of deoxypyridinoline(DPD)-excretion.
Results: Subjects were divided in four age subgroups:
56-65 years (18 cases), 66- 75 years (27 cases), 76-85 years (21 cases) and 86-95 years (8
cases). All of them had normal renal function (creatinine<1.2 milig/dl, urea-N<22
milig/dl). 25-OH-D3 levels (mean ± SEM) were below the normal range in all four groups;
serum calcium levels (mean ± SEM) decreased gradually but remained within the normal
range and PTH levels increased gradually with age (mean ±SEM: 40.97 ±18.23, 45.96
±18.30, 69.75 ±40.59, 101.74 ±64.81pico/ml) as well as the DPD-excretion (mean ±SEM of
DPD/Creatinine ratio: 3.90 ±1.31, 5.02 ±1.69, 6.55 ±2.93, 8.82 ±4.72). In spite of low
25-OH-D3 levels, the serum levels of 1,25-(OH)2-D3 remained within the normal range.
Conclusions: 1.) The incidence of vitamin D deficiency is
also in younger age groups very high and reaches with increasing age even 100%. 2.) The
progressive decrease of serum calcium levels, even within normal range, leads to a
secondary hyperparathyroidism with increased bone degradation (elevated DPD-excretion).
3.) Assessment of bone turnover in elderly persons has to take into account all the
parameters, biochemical as well as hormonal (PTH and vitamin D); the information offered
needs to be judged for each person separately. 4.) There is evidence that even at advanced
age the kidney preserves its ability to synthesize normal amounts of 1,25- (OH)2-D3.
[Programme]
P-250
ONE-MONTH SALMON CALCITONIN EFFECT ON FRACTURE HEALING IN NORMAL AND
ORCHIDECTOMISED MALE RATS
I. C. Koulouris*, I. Paspati, I. Dontas, P. Raptou, E. Kataxaki, G. P.
Lyritis
Laboratory for the Research of Musculoskeletal Interactions, KAT
Hospital, Medical School, University of Athens, Greece
Aim: The aim of this study is to investigate the
volumetric changes in the callus after experimental osteotomy of the femur in normal male
Wistar rats, normal rats treated with sCalcitonin (sCT), orchidectomised rats and
orchidectomised rats treated with sCT.
Material & Methods: We used 112 male Wistar rats
divided into 8 groups of 14 each. The 56 rats were orchidectomised at the age of 2 months
and all the animals were undertaken hemiosteotomy (OT) in the middle of their right femur
at the age of 3 months. The animals were divided in 8 groups as follows:
Group a, sacrificed at 2 weeks,normal
Group b, sacrifised at 2 weeks,normal+sCT
Group c, sacrificed at 2 weeks, orchidectomised
Group d, sacrificed at 2 weeks, orchidectomised + sCT
Group A, sacrificed at 4 weeks, normal
Group B, sacrificed at 4 weeks, normal +sCT
Group C, sacrificed at 4 weeks, orchidectomised
Group D, sacrificed at 4 weeks, orchidectomised + sCT
The animals of b, B, d and D groups immediately after the
OT were given 5 IU of sCT subcutaneous daily. After the sacrifice of the animals we
studied the total bone content, the total bone density and the total bone area of the
callus by pQCT (STRATEC XCT 960).
Results were as follows:
For Total BMC (mg/cm2):
A compared to a: increase of 0.91%, ns
C compared to c: increase of 3.97%, ns
B compared to b: increase of 6.60%, ns
D compared to D: increase of 7.08%, p<0.0005
For Total BMD (mg/cm2):
A compared to a: decrease of 1.26%, ns
C compared to c: decrease of 0.69%, ns
B compared to b: increase of 6.84%, P=0.02
D compared to d: increase of 5.69%, p=0.02
For Total area (cm2)
A compared to a:increase of 3.3%, ns
C compared to c:increase of 4.85% , p=0.02
B compared to b: no change
D compared to d: increase of 10.94%, p=0.01
Conclusion: The volumetric parameters of the callus
studied by pQCT in normal rats without treatment and normal rats given sCT do not
demonstrate statistically significant changes, with the exception of total BMD. In
orchidectomised rats treated with sCT these parameters demonstrate statistically
significant increase between two and four weeks, thus suggesting a possible positive
effect on salmon calcitonin on modeling phase during fracture healing in the
orchidectomised animals.
[Programme]
P-251
EVALUATION OF BMD MEASUREMENTS ACCORDING TO THE LEAST DENSE VERTEBRA:
IMPLICATIONS FOR CLINICAL DENSITOMETRY
D. Hadjidakis*, A. Mylonakis, P. Katsavochristos, S. A. Raptis
2nd Department of Internal Medicine-Propaedeutic, Research Institute and
Diabetes Center, 'Evangelismos' and 'Evgenidion' Hospitals, Athens University, Greece
The evaluation of L2-L4 bone mineral density (BMD)
measurements is sometimes hintered by existing lesions which may result in major
variations between individual vertebrae's BMD values Aim: To investigate the diagnostic
value of one individual vertebra among L2-L4 presenting a remarkable difference of BMD
value. Methods: In 1327 women with natural menopause (NMP), 331 women with premature
natural menopause (EMP) and 510 women with surgical menopause (SUMP), BMD measurements
were performed at L2-L4 vertebrae and femoral neck (FN) by DEXA.
All women were less than 66 years old and didn't suffer
from any disease or receive any medication affecting bone metabolism. Those with obvious
degenerative lesions on x-rays were excluded. Women whose vertebral measurements detected
one vertebra with a BMD value less than 90% from the immediate denser one (LDV), comprised
3 subgroups [269 NMP aged 56.1 ±4.3 years (mean ±1SD), 43 EMP aged 53.7 ±7.4 and 60
SUMP aged 52 ±7.7]. Percentages of osteopenic (OPE) and osteoporotic (OPO) women based on
L2-L4, LDV or FN BMD values were estimated (WHO criteria). Results: A LDV was detected in
20.3% of total NMP, 13% of EMP and 11.8% of SUMP women (NMP vs EMP, SUMP: p<0.001). The
distribution of LDV didn't differ significantly between the subgroups with the L4 vertebra
accounting for 70-77% of total LDV, the L2 for 18-26% and the L3 for 3-7%. In all
subgroups percentages of OPE, OPO based on LDV BMD values were significantly higher
compared to L2-L4 or FN respective ones (p<0.001). Only in NMP subgroup there was a
significant correlation between either L2-L4 or LDV and FN BMD values (r=0.38 and 0.58
respectively, p<0.001). In the other subgroups LDV was always stronger correlated to FN
BMD value, though not significantly. Conclusions: NMP women present significantly greater
proportion of LTV compared to either EMP or SUMP. Most frequently L4 appears as the LDV.
This LDV seems to be stronger correlated to femoral neck BMD values compared to mean
L2-L4. The evaluation of a detected LDV seems to be necessary since it can ameliorate
factors which interfere to vertebral DEXA measurements.
[Programme]
P-252
RISEDRONATE THERAPY FOR PREVENTION OF BONE LOSS IN MEN WITH IDIOPATHIC
OSTEOPOROSIS: A 1-YEAR STUDY
B. Gerbert1*, H. Heinze1, A. Oehme1, U.
Nawroth2, J. Schulze1
1Clinic of Internal Medicine, Technical University of Dresden,
Dresden, Germany
2Practice of Orthopaedics, Radebeul, Germany
The objective of this prospective study was to assess the
efficiency of a therapy with 5 mg risedronate daily on bone mineral density and vertebral
and non-vertebral fractures in men suffering from idiopathic osteoporosis. Subjects
consisted of 93 men (age 57,2 ± 11,5 years) with idiopathic osteoporosis (T-score
<-2,5 at lumbar spine or neck). The primary clinical symptom was back pain. At
enrollment 16 of them had one or more vertebral fracture and 16 a non-vertebral fracture,
altogether 38 vertebral and 24 non-vertebral fractures.
On baseline both serum levels of vitamin D3,
testosterone, TSH, parathyroid hormone, osteocalcin, calcium, phosphate, alkaline
phosphatase and 24h-urine levels of cross links, N-telopeptides, calcium, phosphate were
normal. We repeated all measurements after 3, 6 and 12 months of therapy. X-ray films of
thoracic and lumbar spine and dual-energy X-ray absorptiometry (DXA) at various skeletal
sites (hip, spine) were performed at enrollment and after one year of the therapy with
risedronate. Additionally, subjects received 1000 mg calcium and 800 IE colecalciferol
daily.
After one year of therapy we found serum level of PTH,
calcium, osteocalcin, bone specific and alkaline phosphatase as well as urine levels of
pyridinolin-, deoxypyridinolin-crosslinks and N-telopeptides to have decreased
significantly, whereas a significant increase of phosphate in urine was measured. Urine
level of calcium diminished not significantly.
We measured a significant increase of bone mineral
density in the lumbar spine (p<0,01) by +4,7% (L1 +4,0%, L2 +4,0%, L3 4,1%, L4 +5,6%)
and by +1,3 % in the neck ( p< 0,05). In comparison 9 patients were treated only with
calcium and vitamin D and in this patients an increase of bone mineral density of + 2,2 %
in the lumbar spine and of + 1,9 % in the neck was measured.
5 new vertebral (3 patients) and no new non-vertebral
fractures were recorded in the course of the study. That means 12 % of the patients
suffering from a prevalent vertebral fracture get a new fracture within the first year of
therapy.
Conclusion: Therapy with 5 mg risedronate is efficient
for male patients suffering from idiopathic osteoporosis. The study will be continued.
[Programme]
P-253
FEMORAL QCT, BUT NOT PERIPHERAL QCT AND QUANTITATIVE ULRASOUND, IMPROVE
THE PREDICTION OF FEMORAL FAILURE VERSUS IN SITU DXA
E-M. Lochmüller1*, V. Kuhn1, F. Eckstein2
1Gynaecology Hospital I, LMU München, Germay
2Institute of Anatomy, LMU München, Germany
Femoral fractures have the most substantial personal and
socioeconomic impact in osteoporosis, and bone densitometry is currently clinically used
to predict mechanical strength for estimating fracture risk. In this study we test the
hypothesis that femoral strength prediction with DXA (bone mass) can be improved a) by
geometric parameters obtained at the proximal femur itself using femoral QCT, and b) by
geometric and ultrasound parameters obtained in the peripheral skeleton (distal radius and
calcaneus, respectively).
89 specimens were investigated at an age of 80 ± 10
years. In situ DXA was performed on the left femur, and ex situ QCT on the same femur
after degassing. One set of slices (2 mm) was acquired in the axial plane, and one set
perpendicular to the neck (1 mm), and proprietory software was used for digital
postprocessing. In situ pQCT was applied to the distal radius, and ex situ quantitative
ultrasound to the calcaneus. Pairs of femora were tested to failure, one in side impact
and one in vertical loading.
With the side impact, in situ DXA displayed a correlation
of r = 0.72 with failure laods, whereas femoral density from QCT showed a correlation of
0.77 and femoral bone content (QCT) of 0.80. In a multiple regression model, a correlation
of 0.87 was achieved when using femoral content and trabecular cross sectional area of the
neck. In vertical loading, DXA displayed a correlation of 0.69 with failure loads, femoral
content (QCT) of 0.80, and a multiple regression model with femoral content and the
section modulus of the neck 0.82. The multiple regression models provided signficantly
higher correlations (p < 0.05) than femoral DXA for both side impact and vertical
loading. pQCT and QUS only displayed moderate correlations (0.34 to 0.64) and did not add
significant information to DXA in muliple regression models.
Prediction of femoral strength can be effectively
improved versus in situ DXA when determining densitometric and geometric variables with
QCT. Peripheral measurements with pQCT and QUS, in contrast, add no significant
information to DXA. Analysis of geometric properties may improve the prediction of
fracture risk but should be performed at the site of interest.
[Programme]
P-254
DIFFERENTIAL PREDICTION OF EARLY POSTMENOPAUSAL FRACTURES BY FRACTURE
HISTORY
R. J. Honkanen1,4*, H. Kroger2,4, M. Tuppurainen3,4,
E. Alhava2,4
1Research Institute of Public Health, University of Kuopio,
Kuopioi, Finland
2Department of Surgery, Kuopio University Hospital, Kuopio,
Finland
3Department of Gynecology, Kuopio University Hospital, Kuopio,
Finland
4Bone and Cartilage Research Unit, University of Kuopio,
Kuopio, Finland
We have shown retrospectively that former wrist fracture
is strongly associated with later wrist fracture but not with later non-wrist fracture,
whereas former non- wrist fracture is associated with both later wrist and non-wrist
fracture (CTI 1997:60:327-31). Now we studied if the same pattern can be seen
prospectively.
The study population consisted of those OSTPRE cohort
(13100 women born in 1932-41) women who responded to postal enquiries in May 1989
(baseline), May 1994 and May 1999 (N=11074) and who had fracture history information at
baseline (N=10277). At baseline 1865 of these women reported a fracture and 559 women a
wrist fracture since the age of 15. During the 10-year follow-up1915 women reported a
fracture and 736 women a wrist fracture. These follow-up fractures were validated by
patient record perusal.
History of fracture predicted follow-up fracture with an
odds ratio (OR) of 1.9 (95%CI 1.7-2.2). Old wrist fracture predicted new wrist fracture
with an OR of 2.6 (2.1-3.4) and other fractures with an OR of 1.5 (1.2-1.9), whereas old
non-wrist fracture predicted new wrist fracture with an OR of 1.3 (1.1-1.6) and new
non-wrist fracture with an OR of 1.7 (1.4-2.0). After excluding women who had sustained
more than one fracture before or after baseline, 9624 women with 1415 (393 wrist) old and
1370 (496 wrist) new fractures were left for sub-analyses with following ORs: wrist to
wrist 3.0 (2.2-4.1), wrist to non-wrist 1.3 (0.95-1.8), non-wrist to wrist 1.1 (0.8-1.5)
and non-wrist to non-wrist 1.6 (1.3-1.9).
The strong wrist to wrist fracture prediction may be due
to low bone density and quite uniform trauma mechanism (fall), whereas the weaker
non-wrist to non-wrist fracture prediction may reflect both the more diversified nature of
fracture and trauma mechanism as well as weaker bone density dependency. Interestingly, no
clear predictions crossing over the fracture categories were found.
[Programme]
P-255
RISEDRONATE EFFECTS ON BONE LOSS AND ARCHITECTURAL DISTURBANCES IN A RAT
MODEL WITH A MASSIVE BONE LOSS. A DENSITOMETRIC, HISTOMORPHOMETRIC AND MICROTOMOGRAPHIC
STUDY
S. Blouin1, H. Libouban1, M. F. Moreau1,
S. Horlait2, M. Audran1, D. Chappard1*
1GEROM-LHEA Faculty of Medicine, Angers, France
2Procter and Gamble Pharmaceuticals, France
Risk factors for osteoporosis include deficiency of
sexual steroids and disuse. The orchidectomized (ORX) rat is a suitable model for
hypogonadism-induced osteoporosis. An IM injection of botulinum (BTX) neurotoxin produces
a paralysis and induces a localized bone loss. ORX and BTX models were combined to see if
bone loss could be prevented by risedronate.
36 aged male rats were randomized into 3 groups. Animals
were either SHAM operated; ORX and paralyzed with BTX (one hindlimb); ORX+BTX+risedronate
(5µg/kg/d). ORX and BTX were done the same day; risedronate therapy began on the day of
surgery. Animals were euthanazied after one month. DXA was used to measure total and
regional BMC on both hindlimbs and on excised right vs. left tibia and femur.
Histomorphometry was done on the tibia to measure BV/TV and trabecular characteristics
(Tb.Th, Tb.N, Tb.Sp). Microarchitecture was analyzed by X-ray microtomography; volume
fraction, 3D trabecular thickness and Structure Modeling Index (SMI) were measured.
Whole body BMC was decreased after ORX; this was
abolished by risedronate. Effects of ORX and BTX on bone loss were cumulative: a -30% BMC
was observed in the isolated tibia of ORX+BTX animals on the paralyzed side. BV/TV and
Tb.N decreased significantly after ORX whereas Tb.Sp increased significantly. Tb.Th did
not decrease significantly on the non-paralyzed side and was significantly lower on the
paralyzed side. Effects of ORX+BTX on bone loss were cumulative because significant
differences were observed for BV/TV, Tb.N, Tb.Sp between two side. After risedronate
therapy, BV/TV and Tb.Sp remained at the SHAM levels and Tb.N became significantly higher
than SHAM value. Microtomography results confirmed these observations: SMI increased
significantly in ORX+BTX confirming increased conversion of plates into pillars.
Risedronate limited the 3D alterations and appeared to have early effects on the massive
and acute bone loss induced by the combination of factors.
[Programme]
P-256
PREDICTORS OF EARLY FAILURE OF BISPHOSPHONATE THERAPY IN PATIENTS
REGISTERED IN THE CANADIAN DATABASE OF OSTEOPOROSIS AND OSTEOPENIA (CANDOO)
R. G. Josse1*, A. M. Sawka2, G. Ioannidis2,
T. M. Murray1, R. J. Sebaldt2, D. A. Hanley3, J. P. Brown4,
C. H. Goldsmith2, A. Papaioannou2, W. P. Olszynski5, A.
Petrie2, J. D. Adachi1
1University of Toronto, Toronto, Ontario, Canada
2McMaster University, Hamilton, Ontario, Canada
3University of Calgary, Calgary, Alberta, Canada
4Laval University, Ste-Foy, Quebec, Canada
5University of Saskatchewan, Saskatoon, Saskatchewan, Canada
Factors predicting early failure of bisphosphonate
therapy are not well- characterized. Thus, our aim was to determine predictive
characteristics of patients who experienced early failure of bisphosphonate therapy as
defined by incident clinical fracture within 2 years of starting therapy ('early
fracture') or loss of 3% or more of hip or spine bone mineral density from baseline to
months 13 to 24 of therapy ('early densitometric failure'), using data from CANDOO. We
studied 1588 patients (163 men and 1425 women) over the age of 50 years who were started
on cyclic etidronate (n=1119) or daily alendronate (n=469) therapy following enrollment in
CANDOO. The alendronate treated patients were subdivided into those taking alendronate
with no previous history of etidronate use (n=209), and those with previous history of
etidronate use (n=260). Several baseline variables including anthropometric and life style
factors were examined. Multivariable logistic regression analysis using a backwards
conditional approach was utilized to determine the association between these variables
with early treatment failure. Odds ratios (OD) and 95% confidence intervals (CI) were
calculated. Results indicated that 31 patients experienced an incident fracture within 2
years of starting bisphosphonate therapy. Seven sustained a clinical vertebral fracture,
22 a non-vertebral fracture and 2 had both clinical vertebral and non-vertebral fractures.
Incident fracture within 2 years of starting therapy was most strongly independently
predicted by a previous history of non-vertebral fracture (2.98; 95% CI: 1.30, 6.83).
Ninety-eight patients lost >3% bone mass at the hip or spine from baseline to 13-24
months with bisphosphonate treatment (early densitometric failure). Early densitometric
failure was most strongly independently predicted by treatment group. Alendronate
treatment with no previous etidronate use (0.23; 95% CI: 0.09, 0.59) and with previous
etidronate use (0.24; CI: 0.11, 0.51) was protective compared with current etidronate
therapy. In addition, increased femoral neck bone density was also protective (1.36; 95%
CI: 1.10-1.68: for each 0.1 gm/cm2 increase). In conclusion, in patients treated with
bisphosphonates, the strongest predictor of early incident fracture is previous history of
fracture, whereas early bone loss is predicted by the potency of the prescribed
bisphosphonate and the baseline femoral neck bone density.
[Programme]
P-257
PREDICTIVE VALUE OF WHOLE BODY BISPHOSPHONATE RETENTION ON LUMBAR BMD
AFTER A TWO YEARS PERIOD OF BISPHOSPHONATE THERAPY
A. Nzeusseu1, G. Depresseux1, F. Jamar2,
J. P. Devogelaer1*
1Department of Rheumatology, Saint-Luc University Hospital,
Belgium
2Department of Nuclear Medicine
Rationale
Nowadays, it is well established that bone fragility
depends on both bone mineral density (BMD) and bone remodelling. Higher bone remodelling
and lower BMD lead to an increased propensity to fracture. Therefore, we assessed whether
bone turnover as measured by the whole body bisphosphonate (BP) retention (WBR) could
predict BMD response to bisphosphonate therapy in patients suffering from osteoporosis
(OP).
Methods
Out of 173 patients referred for BP-WBR, 154 patients
were followed during an average of 26.9 ± 12.6 (SD) months. 19 patients were excluded
owing to impaired renal function. All 154 patients had undergone at least two BMD and
BP-WBR measurements during the period of follow-up. The patients were divided in two
groups according to their BP-WBR, with a cut-off for high level of remodelling settled at
34 %. 22 patients were in the normal or low-turnover (LT) group (BP-WBR < 34 %), while
132 patients with a WBR > 34 % were considered high-turnover (HT) group.
Results
There was a strong negative correlation between L-BMD and
BP-WBR measurements in the whole group (r = - 0.28; p = 0.0006). The L-BMD after a mean
period of 26.9 months slightly but not significantly increased in the whole LT group
(0.761 ± 0.143 g/cm2) as compared to baseline (0.743 ± 0.147 g/cm2). During the same
period, L-BMD of the HT group significantly increased from 0.770 ± 0.143 g/cm2 to 0.797
± 0.149 g/cm2 (p < 0.0001). Moreover, in the LT group, the L-BMDs in the 11 patients
on BP therapy increased from 0.749 ± 0.164 g/cm2 to 0.780 ± 0.158 g/cm2 (p< 0.032),
whereas in the HT group, the L-BMDs of the 87 BP-treated patients significantly and
dramatically increased from 0.768 ± 0.142 g/cm2 to 0.800 ± 0.148 g/cm2 (p < 0.0001).
At the total hip (TH-BMD), there was no statistically
significant change during the follow-up in either groups.
Conclusion
First, higher the BP-WBR, lower the L-BMD; Second, bone
turnover as assessed by BP-WBR has some predictive value for response to BP therapy after
two years. This could help to encourage patients to improve their compliance to therapy.
[Programme]
P-258
ADHERENCE TO BISPHOSPHONATES AND HORMONE REPLACEMENT THERAPY IN A
TERTIARY CARE SETTING OF PATIENTS IN THE CANADIAN DATABASE OF OSTEOPOROSIS AND OSTEOPENIA
(CANDOO)
A. Papaioannou1*, G. Ioannidis1, R. J. Sebaldt1,
J. P. Brown2, C. H. Goldsmith1, D. A. Hanley3, W. P.
Olszynski4, A. Petrie1, R. G. Josse5, T. M. Murray5,
P. Boulos1, N. Ferko1, J. D. Adachi1
1McMaster University, Hamilton, Ontario, Canada
2Laval University, Ste-Foy, Quebec, Canada
3University of Calgary, Calgary, Alberta, Canada
4University of Saskatchewan, Saskatoon, Saskatchewan, Canada
5University of Toronto, Toronto, Ontario, Canada
There is a growing number of available therapies that may
be used in the treatment and prevention of osteoporosis and fragility fractures. However,
therapies for osteoporosis must be taken long-term to be effective. The purpose of this
study was to determine the difference in adherence to etidronate, alendronate and hormone
replacement therapy in a group of patients seen at our tertiary care centres. CANDOO, a
prospective observational database designed to capture clinical data, was searched for
patients who started therapy following entry into CANDOO. A total of 1967 individuals met
the inclusion criteria. Of these individuals, 1196, 477, and 294 men and women with a mean
age (standard deviation) of 67.0 (8.6), 66.3 (8.4), 60.1 (7.5) years initiated etidronate,
alendronate, or hormone replacement therapy respectively. Of the total sample, 441 (22.4%)
individuals had a prevalent vertebral fracture, and 877 (44.5%) had a prevalent
non-vertebral fracture at baseline. At one year, 85.7% of patients were still taking any
one of the three therapies. This value decreased to 77.2% at 2 years and to 69.6% at 3
years. A Cox proportional hazards regression model was used to assess differences between
treatment groups in the time to discontinuation of therapy (days). Several potential
covariates such as anthropometry, medications, illnesses, fractures and lifestyle factors
were entered into the model. A forward selection technique was used to generate the final
model. Hazard ratios and 95% confidence intervals (CI) were calculated. Adjusted results
indicated that alendronate- treated patients were more likely to discontinue therapy as
compared with etidronate- treated patients (1.404; 95% CI: 1.15, 1.714). No statistically
significant differences were found between hormone replacement therapy and etidronate
users (0.971; 95% CI: 0.862, 1.093) and hormone replacement therapy and alendronate users
(0.824;
95% CI: 0.624, 1.088) after controlling for a number of
variables. Increasing age and presence of incident non-vertebral fractures were found to
be independent predictors of adherence. In conclusion, alendronate users were 40.4% more
likely to discontinue therapy than etidronate users over the follow-up period. Potential
barriers to long-term patient adherence to osteoporosis therapies need to be evaluated.
[Programme]
P-259
RELATIONSHIP OF VARIOUS PARAMETERS OF BONE RESORPTION (TRAP, COLLAGEN
CROSSLINKS) WITH SERUM MARKERS OF BONE FORMATION AND HISTOMORPHOMETRIC BONE PARAMETERS
T. Eidner*, G. Lehmann, A. Müller, G. Hein
Rheumatology & Osteology, Dpt. of Internal Medicine IV,
Friedrich-Schiller- University of Jena, Germany
Introduction: Tartrat-resistant acid phosphatase and
urinary excretion of collagen crosslinks are common markers of bone resorption. We
investigated the relations between these parameters and typical biochemical serum markers
of bone formation or osteoblast activity as well as histomorphometric bone parameters for
a group of patients with osteoporosis.
Materials and Methods: In 51 patients (31 women, mean age
57,2 ± 14 y., 20 men, mean age 49,3 ± 12 y.) with osteoporosis, who had undergone an
iliac crest biopsy, we determined the serum parameters osteocalcin (OC, ng/ml), bone
alkaline phosphatase (BAP, microg/l), tartrat-resistant acid phosphatase (TRAP) as well as
the urinary excretion of pyridinoline (PYD) and desoxypyridinoline (DPD) by HPLC
(nmol/mmol crea). Included histomorphometric parameters were: osteoid surface (OS),
osteoblast-covered surface (Ob.S), erosion surface (ES), osteoclast-covered surface
(Oc.S), number of osteoclasts (N.Oc) as well as mineralizing (tetracycline- labeled)
surface (MS), mineral apposition rate (MAR) und bone formation rate (BFR).
Results: Serum and urinary parameters of bone resorption
(TRAP vs PYD and TRAP vs DPD) did not correlate with each other (Spearman correlation
coefficient r=0,14, p>0,3). On the other hand, we found close correlations with
biochemical parameters of bone formation: TRAP related to OC (r=0,42, p=0,002), less
strong to BAP (r=0,34, p=0,03); collagen crosslinks related to BAP (r=0,48 for PYD, r=0,57
for DPD, p=0,001), DPD also to OC (r=0,38, p=0,06). Neither TRAP nor collagen crosslinks
correlated with the above histomorphometric parameters. Likewise, there were no
significant relations between serum parameters of formation and histomorphometry.
Conclusions: 1. The missing correlation between TRAP and
collagen crosslinks was not expected. Obviously, the two parameters characterize different
aspects of bone resorption. 2. The close correlations between the biochemical parameters
of bone resorption on the one hand and the parameters of bone resorption on the other hand
suggest a sustained coupling between bone formation and resorption in most cases. 3.
Significant relations between histomorphometric parameters (of trabecular iliac crest) and
biochemical markers of turnover (of complete skeleton) were not detectable. Therefore,
systemic bone turnover cannot be inferred from the histomorphometric results and vice
versa.
[Programme]
P-260
THE DECREASE IN STRENGTH OF THE FEMUR AND TIBIA ASSOCIATED WITH
OVARIECTOMY OF ADULT RATS, IS PREVENTED BY LOW INTENSITY, HIGH FREQUENCY VIBRATION.
B. S. Oxlund, G. Ųrtoft, T. T. Andreassen, H. Oxlund*
Dept of Connective Tissue Biology, Inst of Anatomy, University of Aarhus,
Aarhus, Denmark
The effect of low intensity, high frequency vibration on
bone mass, bone strength and skeletal muscle mass was studied in an adult ovariectomized
(OVX) rat model. One-year-old female rats were allocated randomly to the following groups:
start control, sham OVX, OVX without vibration, OVX with vibration at 17 Hz (0.5xg), OVX
with vibration at 30 Hz (1.5xg), OVX with vibration at 45 Hz (3.0xg). Vibrations were
given 30 min/day for 90 days. During vibration each group of rats was placed in a box on
top of the vibration motor. The amplitude of the vibration motor was 1.0 mm. The animals
were labeled with calcein at day 63 and with tetracycline at day 84. The tibia
mid-diaphysis was studied by mechanical testing and dynamic histomorphometry, the femur
distal metaphysis by mechanical compression. OVX without vibration increased the
periosteal bone formation rate and increased the medullary cross-sectional area i.e.
increased the endocortical resorption and outward antero-medial and lateral drifts of
cortical bone at the tibia mid-diaphysis. OVX also resulted in a reduced maximum bending
stress of the tibia diaphysis and a reduced compressive stress of the femur distal
metaphysis. Vibration at the highest intensity i.e. 45 Hz of OVX rats induced a further
increase in periosteal bone formation rate and inhibited the endocortical resorption seen
in OVX rats. Furthermore, vibration at 45 Hz inhibited the decline in maximum bending
stress and compressive stress induced by OVX. Neither OVX nor OVX with vibration
influenced skeletal muscle mass significantly. In conclusion, the results support the idea
of a possible beneficial effect of passive physical loading on the preservation of bone in
OVX animals.
[Programme]
P-261
ROCQ: RECOGNIZING OSTEOPOROSIS AND ITS CONSEQUENCES IN QUÉBEC (ROCQ), A
PATIENT HEALTH MANAGEMENT PROGRAMME
J. P. Brown1*, L. Bessette1, M. Beaulieu2,
L. Lafortune3, S. Jean1, E. Morarescu1, L- G. Ste-Marie4
1Laval University, Québec, Canada
2Merck Frosst Canada, Montréal, Canada
3Aventis Pharma, Montréal, Canada and Procter & Gamble
Pharmaceuticals, Toronto, Canada
4University of Montreal, Montréal, Canada
Background: It has been estimated that only 20-25% of
women presenting with fragility fractures are subsequently investigated for osteoporosis,
and only half of these receive treatment (Hajcsar EE, et al. CMAJ 2000; 163:819-822).
Objective: To improve the use of evidence-based
diagnostic and treatment strategies for women 50 years and over, who have suffered a
fragility fracture.
Hypotheses: ROCQ's interventions would: 1) double the
baseline number of patients investigated for osteoporosis; 2) initiate pharmacological
treatment in 70% of those identified with osteoporosis; 3) aim to reduce fragility
fractures incidence by 12.5%, if applied on a long-term basis.
Methods: The ROCQ programme is a prospective cohort study
using a randomized control design. At phase 1, women will sign a consent form and complete
a questionnaire regarding the circumstances of their fracture (traumatic or non-
traumatic). At phase 2 (6-8 months later), patients will be contacted by a non-health
professional interviewer to complete a telephone questionnaire on osteoporosis
(demographics, risk factors, co-morbidities, status of diagnosis and treatment), health
utility index and health care resources utilization. The study coordinator will inform the
patients by mail one week later, about the results of their randomization to one of 3
interventions: 1) to participate in a 2-hour learning programme held by their local
community health centre and to receive additional written educational material directed at
the patient and their family physician 2) to only receive written educational material by
mail or, 3) no specific intervention other than the interest raised by the questionnaires.
The educational material is based on the 2002 Clinical Practice Guidelines for the
Diagnosis and Management of Osteoporosis in Canada (Brown JP, et al. CMAJ 2002;
167:S1-S36). At phase 3 (6 months +2 after phase 2), patients with fragility fractures
will complete similar questionnaires. Responses to these two questionnaires (phase 2 and
3) will be compared and differences between the two, will measure the effectiveness of
ROCQ's interventions in improving diagnosis and treatment of osteoporosis. To test and
improve recruitment strategies as well as the feasibility of ROCQ's interventions, a pilot
study will take place during the first 18 months of the programme.
[Programme]
P-262
EFFECTIVENESS OF ETIDRONATE AND ALENDRONATE IN THE TREATMENT OF
OSTEOPOROSIS IN MEN REGISTERED IN THE CANADIAN DATABASE OF OSTEOPOROSIS AND OSTEOPENIA
(CANDOO)
W. P. Olszynski1*, G. Ioannidis2, R. J. Sebaldt2,
D. A. Hanley3, A. Petrie2, J. P. Brown4, R. G. Josse5,
T. M. Murray5, C. H. Goldsmith2, A. Papaioannou2, J. D.
Adachi2
1University of Saskatchewan, Saskatoon, Saskatchewan, Canada
2McMaster University, Hamilton, Ontario, Canada
3University of Calgary, Calgary, Alberta, Canada
4Laval University, Ste-Foy, Quebec, Canada
5University of Toronto, Toronto, Ontario, Canada
Although osteoporosis is regarded as a disease of women,
this condition is associated with disability and death in men. Thus, the purpose of our
prospective one year cohort study was to determine the effectiveness of etidronate and
alendronate to increase bone mineral density in men who were registered in CANDOO, a
multi- centre prospective clinical database of tertiary care of osteoporosis paitents. The
database was searched for men receiving daily etidronate (ETD), alendronate (ALD) or
calcium and vitamin D (CON) therapy. Patients were excluded if they did not start
osteoporosis therapy on or after their first clinical visit and did not have at least one
follow-up bone density visit after initiating therapy. Furthermore, patients were excluded
if they had been treated with calcitonin, fluoride or another bisphosphonate at any point
during the two years preceding the study. A total of 269 men meet the inclusion criteria
of the study. Of these men, 101, 42 and 125 were taking daily ETD, ALD, and CON therapy.
Our primary outcome measures were differences between treatment groups in the percent
change in lumbar spine and femoral neck bone mineral density (BMD) from baseline to one
year follow-up. Multivariable regression analysis was conducted. Regression coefficient
parameter estimates as well as 95% confidence intervals were calculated while controlling
for possible confounding effects of the other variables. The coefficient estimates
represent percent differences between groups in bone mineral density. Multiple imputation
was used to impute missing data. Results are shown in table.
Differences between the CON and the bisphosphonate groups
were observed at the lumbar spine but not at the femoral neck. There appears to be a trend
towards a greater increase in BMD with alendronate therapy. In conclusion, ETD and ALD
therapy appear to be effective in the treatment of osteoporosis in men.
Location |
ETD vs. CON* |
ALD vs. CON* |
ETD vs. ALD* |
Lumbar spine |
2.26(0.67, 3.85) |
5.23 (2.98, 7.47) |
-1.94 (-3.91, 0.02) |
Femoral neck |
0.68 (-1.17, 2.53) |
2.19(-0.53, 4.92) |
-1.21 (-3.82, 1.39) |
* reference group |
[Programme]
P-263
PARTICIPANT CHARACTERISTICS THAT PREDICT 3-YEAR INCIDENT CLINICALLY
RECOGNIZED VERTEBRAL DEFORMITY IN MENOPAUSAL WOMEN ENROLLED THE CANADIAN MULTICENTRE
OSTEOPOROSIS STUDY (CAMOS)
W. P. Olszynski1*, G. Ioannidis2, C. Berger3,
A. Papaioannou2, J. C. Prior4, L. Joseph3, D. A. Hanley5,
L. Pickard2, T. M. Murray6, J. P. Brown7, A. Tenenhouse3,
T. Anastassiades8, W. Hopman8, S. Kirkland9, C. Joyce10,
S. Poliquin3, N. Kreiger6, J. D. Adachi2 and the CaMos
Research Group
1University of Saskatchewan, Saskatoon, Saskatchewan, Canada
2McMaster University, Hamilton, Ontario, Canada
3McGill University, Montreal, Quebec, Canada
4University of British Columbia, Vancouver, British Columbia,
Canada
5University of Calgary, Calgary, Alberta, Canada
6University of Toronto, Toronto, Ontario, Canada
7Laval University, Ste-Foy, Quebec, Canada
8Queen's University, Kingston, Ontario, Canada
9Dalhousie University, Halifax, Nova Scotia, Canada
10Memorial University, St. John's, Newfoundland, Canada
Osteoporosis is a silent disease, until the first
fracture occurs. Given that bone densitometry screening of all women will not identify all
individuals who will suffer a fracture, other characteristics are required to estimate
fracture risk. Utilizing participants from CaMos, a nation-wide, random sample of the
population, we performed a three-year prospective cohort study in community dwelling
menopausal women to examine the association among various participant characteristics and
clinically recognized incident vertebral deformities as reported on the yearly follow- up
questionnaire (confirmed by x-ray or medical report). Participants were classified into
two groups according to incident fracture status: those without incident fractures during
the study period (n=4829), and those with an incident vertebral deformity (n=34).
Fractures due to minimal trauma were included in our analysis. Follow-up was calculated as
the time from baseline examination to the date of the incident deformity or three years.
Characteristics examined in the Cox multivariate survival analysis included age, prevalent
vertebral deformity status, change in height, current height, change in weight, current
weight, body mass index, SF-36 physical component summary score, and baseline lumbar spine
and femoral neck bone mineral density (BMD). Relative risk and 95% confidence intervals
(CI) were calculated. The mean (standard deviation) age, height and weight of participants
was 66 (10) years 159 (6) cm and 69 (14) kg for those without incident fractures and 74
(10) years, 156 (7) cm and 59 (11) kg for those with an incident vertebral deformity. The
relative risk of sustaining an incident vertebral fracture was associated with the SF-36
physical component summary score (0.959; 95% CI: 0.924, 0.996) and femoral neck BMD
(0.002; 95% CI: 0.00, 0.506). A prevalent vertebral deformity (2.337; 95% CI: 0.897,
6.088) and a loss of height (1.075; 95% CI: 0.970, 1.193) tended to be associated with
incident fracture status but further evidence will need to be collected to verify these
findings. Women with lower physical quality of life measures and femoral neck BMD were at
higher risk for sustaining an incident vertebral deformity. The identification of
high-risk women is essential to effectively use the growing number of available
osteoporosis therapies.
[Programme]
P-264
RISK FACTORS THAT PREDICT THREE YEAR INCIDENT NON- VERTEBRAL FRAGILITY
FRACTURE IN MENOPAUSAL WOMEN IN THE CANADIAN MULTICENTRE OSTEOPOROSIS STUDY (CAMOS)
J. P. Brown1*, G. Ioannidis2, C. Berger3,
D. A. Hanley4, J. C. Prior5, L. Joseph3, W. P.
Olszynski6, A. Papaioannou2, L. Pickard2,
T. M. Murray7, A. Tenenhouse3, T.
Anastassiades8, W. Hopman8, S. Kirkland9,
C. Joyce10, S. Poliquin3, N. Kreiger6,
J. D. Adachi2 and the CaMos Research Group
1Laval University, Ste-Foy, Quebec, Canada
2McMaster University, Hamilton, Ontario, Canada
3McGill University, Montreal, Quebec, Canada
4University of Calgary, Calgary, Alberta, Canada
5University of British Columbia, Vancouver, British Columbia,
Canada
6University of Saskatchewan, Saskatoon, Saskatchewan, Canada
7University of Toronto, Toronto, Ontario, Canada
8Queen's University, Kingston, Ontario, Canada
9Dalhousie University, Halifax, Nova Scotia, Canada
10Memorial University, St. John's, Newfoundland, Canada
A number of factors have been found to be associated with
previous non-vertebral fragility fractures; they include advanced age, height, existing
fracture, and propensity to falls. However, our understanding of risk factors related to
incident non-vertebral fractures is still inadequate. Thus, the purpose of this study was
to examine the association among various potential risk factors and incident non-vertebral
fractures in a three-year prospective cohort study of menopausal women who were enrolled
in CaMos. CaMos is a nation-wide, randomly selected sample of the Canadian population with
a baseline bone mineral density, weight and height as well as extensive questionnaires and
yearly fracture questionnaire follow-up. Fractures were confirmed by x-ray or medical
report. Participants were classified into two groups according to incident fracture
status: those without incident fractures during the study period (n=4829), and those with
an incident non-vertebral fracture at the wrist, hip, humerus, pelvis or ribs (n=163).
Only incident fractures resulting from minimal trauma were included in the analysis.
Follow-up was calculated as time from baseline examination to the date of incident
fracture or three years. Potential risk factors included in the Cox multivariate survival
analysis were anthropometric, fracture history and family history of osteoporosis, current
medications use, comorbid conditions, caffeine and alcohol intake, leisure and
occupational physical activity levels; tobacco use, bone density and quality of life
measures. Relative risk and 95% confidence intervals (CI) were calculated. The mean
(standard deviation) age of the participants was 66 (10) and 71 (10) years for those
without and with incident non- vertebral fractures. Results indicated that important risk
factors that modified relative risk include previous minimal trauma forearm fracture after
the age of 50 years (3.626; 95% CI: 1.876, 7.008), and other minimal trauma fractures
(1.957; 95% CI: 1.082, 3.540), SF-36 physical component summary score (0.965; 95% CI:
0.939, 0.991), femoral neck bone density (0.036; 95% CI: 0.001, 0.937) and inflammatory
bowel disease (2.207; 95% CI: 1.091, 4.465). In conclusion, this three-year analysis of an
ongoing prospective study shows that several important historical and medical factors are
associated with incident non-vertebral fractures. These should be assessed in osteoporosis
management.
[Programme]
P-265
THE IMPACT OF FRACTURE SEVERITY ON HEALTH RELATED QUALITY OF LIFE IN A
POPULATION BASED SAMPLE: RESULTS FROM THE OPUS STUDY
M. Glueer1*, D. M. Reid2, D. Felsenberg3,
T. Blemk3, R. Eastell4, C. Roux5, C. Glueer1
1University Clinic Kiel, Germany
2Aberdeen Royal Infirmary, UK
3Benjamin Franklin Hospital Berlin, Germany
4University of Sheffield, UK
5Hopital Cochin, Paris, France
It is known that fracture severity plays an important
role for the context of pain and limitations in everyday life (ADL) (Ettinger 1992).
Nevertheless, it remains unclear if fracture severity also has an impact on other aspects
of disease specific or generic Health related Quality of Life (HRQoL).
In a population based study (OPUS) with centers in
Germany, Britain and France 2375 women (mean age: 67, range 55 to 79) underwent a
broadrange of diagnostic examinations. Specifically, reduction in vertebral height was
determined by vertebral morphometry on spinal radiographs. Measurements were performed by
an experienced radiologist (T.B.) and the maximum vertebral height reduction was
calculated for each participant. For HRQoL we employed the SF12 with the subscores
physical and mental function and two overall scores of Health and QoL, symptoms (OQLQ),
fears (OPTQoL), and the QualEFFO with the subscales pain, ADL, social function, health
perception, and mood. All analyses were age-adjusted and regression models were employed.
Of the 2375 women 379 had fractures with more than 20%
height reduction. Maximum vertebral height reduction in women with fractures ranged from
0,20 to 0,92. With increasing fracture severity, the probability of deterioration of HRQoL
increased independent of age for physical SF12 (p<0,001), global health perception
(p<0,027), symptoms (OQLQ, p<0,006), pain (QualEFFO, p<0,022) , ADL (QualEFFO,
0,003), and health (QualEFFO, p<0,046). Moreover, age turned out to be a significant
covariate for all subscales except for the SF12-mental score and for the pain and social
QualEFFO domains (p<0,04 to 0,001). Further analyses showed that investigated HRQoL
aspects were also impaired in women with fractures, as compared to those without.
Our data shows that HRQoL is impaired in women with
vertebral fractures when compared to the general population, independent of their age.
Greater vertebral deformity is associated with worse generic and disease specific quality
of life, especially their physical aspects.
[Programme]
P-266
EFFECTS OF GROWTH AND OVARIECTOMY IN THE TIBIA OF INDIVIDUAL RATS: AN
IN-VIVO MICRO-CT STUDY
J. H. Waarsing1*, A. Leemans2, J. Day1,
A. G. H. Ederveen4, D. Van Dyck2, E. Buelens3, N. De
Clerck2, A. Sasov3, H. Weinans1
1Dept. of Orthopaedics, Erasmus Medical Centre, Rotterdam, The
Netherlands
2Visielab & Microtomography, RUCA, Antwerp, Belgium
3Skyscan B.V.B.A, Antwerp, Belgium
4Dept of Pharmacology, Organon, Oss, The Netherlands
The purpose of this study was to develop, test and
evaluate in-vivo micro-CT for the follow up study of bone architecture in small animals
like the rat.
An in-vivo micro-CT scanner (Skyscan 1076) was developed
in which the tibia of a rat, that is lying on a bed under gas-narcosis, can be scanned in
20 minutes, receiving a low radiation dose of 0.4 Gy. For this study, two female Wistar
rats were scanned: a sham operated and an ovariectomised rat. The animals were scanned at
week 0, just before surgery, at week 4 and at week 14. Architectural changes over time
were detected by overlaying two data sets, using an automatic algorithm that searches for
optimal matching. The scans were segmented into binary data sets using a local threshold
algorithm. Trabecular thickness was calculated using a model independent (3D) method.
The ovariectomised rat showed trabecular bone loss (70%
at week 4 + 5% at week 14) in the metaphysis vs. no bone loss in the sham operated rat.
After 14 weeks the epiphysial bone of the ovariectomised rat showed 25% bone loss, due to
thinning of trabeculae. We could see growth at the growth plate of the ovariectomised rat
(80 microns at week 4 + 80 microns at week 14). At the lateral cortex, periostial bone was
resorbed and endostial bone was appositioned (about 200 microns), resulting in a slight
change in shape of the bone. No growth could be seen in the sham operated rat.
Matching of two data sets allows detection of local
changes in bone, like growth and disappearance of trabeculae and thickness changes of
remaining trabeculae. These new developments of in-vivo micro-CT scanning make it possible
to perform longitudinal small animal studies and will greatly contribute to experimental
rat/mouse studies on pharmacological intervention and transgenic models.
[Programme]
P-267
THE RELATIONSHIP AMONG OSTEOPOROTIC FRACTURES AND HEALTH RELATED QUALITY
OF LIFE (HRQL) AS MEASURED BY THE HEALTH UTILITIES INDEX MARK II AND MARK III SYSTEMS
G. Ioannidis1*, E. A. Papadimitropoulos2, C. Berger3,
A. Papaioannou1, J. P. Brown4, L. Joseph3, D. A. Hanley5,
W.P. Olszynski6, J.C. Prior7, L. Pickard1 T.M. Murray8,
A. Tenenhouse3, T. Anastassiades9, W. Hopman9, S.
Kirkland10, C. Joyce11, S. Poliquin3, N. Kreiger6,
J.D. Adachi1 and the CaMos Research Group
1McMaster University, Hamilton, Ontario, Canada
2Eli Lilly and Company, Toronto, Ontario, Canada
3McGill University, Montreal, Quebec, Canada
4Laval University, Ste-Foy, Quebec, Canada
5University of Calgary, Calgary, Alberta, Canada
6University of Saskatchewan, Saskatoon, Saskatchewan, Canada
7University of British Columbia, Vancouver, British Columbia,
Canada
8University of Toronto, Toronto, Ontario, Canada
9Queen's University, Kingston, Ontario, Canada
10Dalhousie University, Halifax, Nova Scotia, Canada
11Memorial University, St. John's, Newfoundland, Canada
A total of 3394 women and 1122 men 50 years of age and
older participating in the baseline assessment for the Canadian Multicentre Osteoporosis
Study (CaMos) were evaluated in this cross-sectional population-based study. Lifetime
fracture occurrences were classified into seven categories including hip, pelvis, spine,
lower body (defined as upper and lower leg, knee, ankle and foot), upper body (defined as
arm, elbow, sternum, shoulder and clavicle), wrist and hand (defined as forearm, hand or
finger), and ribs. Given that two thirds of vertebral fractures are not recognized by the
individual, participants with subclinical vertebral deformities were also examined. Spinal
radiographs were used to confirm the existence of vertebral deformities for all
participants. The Health Utilities Index (HUI) Mark II and III systems were used to assess
HRQL. The Mark II and III systems assess current HRQL across six and eight attributes
respectively. Multivariate linear regression analyses were performed to determine the
association between various osteoporotic fracture types and HRQL, adjusting for possible
confounders. We calculated regression coefficient estimates and 95% confidence intervals
(CI) for all parameters. The regression coefficients for the fracture (yes/no for each
fracture type) terms represent adjusted differences in HRQL scores between participants
with and without fractures. Results indicated that the multi-attribute scores for the Mark
II system were negatively related to hip (-0.05; 95% CI: -0.09, -0.01), lower body (-0.02;
95% CI: -0.03, -0.000) and subclinical vertebral fractures (-0.02; 95% CI: -0.03,-0.00)
for women. The multi-attribute scores for the Mark III system in women were also
negatively related to hip (-0.09; 95% CI: - 0.14, -0.03) and rib fractures (-0.06; 95% CI:
-0.11, -0.00), in men for rib fractures (- 0.06; 95% CI: -0.12, -0.00). Duration (years)
since last fracture was not strongly associated with the HUI attributes. For the most
part, the largest differences in HRQL were observed between the 0-1 year and 10+ years
categories. In conclusion, this study demonstrates a negative association between past
osteoporotic fractures and HRQL in both women and men. Moreover, this study shows that the
association between minimal trauma fractures and quality of life depends on fracture type
and gender.
[Programme]
P-268
BARIUM SULFATE VS. POLYMETHYLMETHACRYLATE: DIFFERENCES IN BONE MINERAL
DENSITY?
M. O. Cachizumba, S. B. Gonēalves, F. C. Pérez Manghi, V. E.
Montangero, F. R. Spivacow, F. Massari*, J. R. Zanchetta
Instituto de Investigaciones Metabólicas, Universidad del Salvador,
Buenos Aires, Argentina
Percutaneous vertebroplasty is a procedure in which bone
cement is injected into a vertebral body to treat painful osteoporotic compression
fractures, due to the restoration of stiffness and strength that induces. The more common
cement used is the polymethylmethacrylate (PMMA), and although in the last years, barium
sulfate (BaSO4) is added to increase its visibility under fluoroscopy, which is a well
known cause of fake increased bone mineral density (BMD) using dual energy x-ray
absorptiometry (DEXA), there is still very common to find patients with vertebroplasty
with PMMA alone.
Objective: To evaluate in vitro, the potential changes in
bone density induced by PMMA alone or associated to BaSO4.
Material and Methods: We performed 10 density scans
(Hologic Delphi A) on 7 glass tubes with several materials: air; water; PMMA; PMMA +
BaSO4, ground vertebral trabecular bone (VTB), VTB + PMMA, and VTB + PMMA + BaSO4.
The best monomer-to-powder ratio recommended (0.53ml/g)
was used to maintain the greatest material properties of PMMA. The 20% by weight BaSO4 was
used to maintain proportions of the solution, and the relationship 60 % VTB/ 40 % cement
was used in vitro as is used in the practical setting.
Results: As expected, higher density values in all tubes
using BaSO4 were found. PMMA density was similar to air tube (given by glass), and VTB +
PMMA present 23 % lower density than VTB alone (0.551 vs. 0.712 grs/cm2 p: < 0.0001).
In this model, the addition of PMMA + BaSO4 to VTB, induced an increase of density of 2.8
times (2.004 vs. 0.712 grs/cm2 p:< 0.0001).
Conclusions: The lower bone density induced by the PMMA
alone or the increase induced by PMMA + BaSO4, could generate misinterpretation of lumbar
spine DEXA's studies in vivo, and this could by clinically significant.
[Programme]
P-269
THE EFFECT OF PERIODICAL STRAIN ADAPTATION ON THE STOCHASTIC REMODELLING
OF CANCELLOUS BONE STRUCTURES: AN ANABOLIC SIMULATION STUDY
C. A. Dobson1*, G. Sisias2, R. Phillips3,
C. M. Langton4, M. J. Fagan1
11School of Engineering, University of Hull, UK
2Department of Computer Science, University of Bradford, UK
3Department of Computer Science, University of Hull, UK
4Centre for Metabolic Bone Disease, Hull, UK
A stochastic simulation of cancellous bone remodelling
has previously been described [1] and applied to simple 2D lattice structures to simulate
the effect of anabolic therapies on depleted bone structures [2]. The density and
stiffness values of the structures showed a hysteresis effect, with a significant amount
of rebuilding beyond the original density required to regain the intact stiffness value.
The simulation has now been extended to model actual bone sections constructed from
micro-CT scan data, with the incorporation of strain adaptation to produce a realistic
simulation of anabolic treatment for osteoporosis after a period of bone resorption.
The chosen bone structure was subjected to a complex
loading, chosen to encourage the structure to equilibrate to a realistic structure when
subjected to iterative strain remodelling. The resulting stable structure was used as the
original on which subsequent remodelling was applied. This procedure (equilibration) was
repeated at various stages of the simulation runs studied.
The original equilibrium structure was stochastically
depleted by 5% or 10% of its density and then rebuilt in one of three ways. Either a)
stochastically, b) equilibrated at initial depletion and then stochastically rebuilt, or
c) equilibrated after original depletion and also after being rebuilt to original density.
Density and x- and y-stiffness values of the structures were evaluated at each step.
The effect of the equilibration of the structure will be
presented, examining the effect of amount of initial depletion, original alignment of the
structure and x and y stiffness, and the potential relationships to the histomorphometry
of the structures.
[Programme]
P-270
EFFECT OF RALOXIFENE ON BONE MINERAL DENSITY AND MARKERS OF BONE
REMODELING FOLLOWING ALENDRONATE THERAPY
D. Michalska1*, J. Stepan1, M. Terova2,
D. Masanauskaite3, I. Pavo3
1Faculty of Medicine, Charles University, Prague, Czech
Republic
2Eli Lilly, Prague, Czech Republic
3Lilly Area Medical Center, Vienna, Austria
Background: Alendronate (ALN) and raloxifene (RLX)
increases bone mineral density (BMD) and decreases fracture incidence over 4 years in
postmenopausal women with osteoporosis.
Aim: To compare the effect of one-year treatment with RLX
or placebo (PLB) following ALN therapy versus continuous treatment with ALN.
Methods: 99 women with postmenopausal osteoporosis (age,
65 ± 7 yr, femoral neck NHANES T-score, -2.8 ± 0.8) who were treated with ALN (10 mg/d)
for 43 ± 7 months were randomized to double-blinded RLX 60mg/day (N=33), PLB (N=33) or
continuing open label ALN (N=33) for another 12 months. All patients received calcium (500
mg/day) and vitamin D (800 IU/day). BMD was assessed by Hologic Delphi A. Serum
aminoterminal propeptide of type I collagen (PINP) was measured by a radioimmunoassay
(Orion Diagnostica). Serum type 1 collagen cross?linked C?telopeptide (CTX) was measured
using the Elecsys (Roche).
Results: No baseline differences were observed between
the groups in age, weight, height, BMD and duration of previous ALN treatment. BMD data
are summarized in the Table. Bone markers remained unchanged on ALN. CTX increased by 7.0
± 7.8% in the PLB group, and by 5.1 ± 10.8% in the RLX group. PINP increased by 19.7 ±
10.8 % in the PLB group, and by 22.1 ± 16.9 % in the RLX group.
Conclusion: RLX is superior to PLB in increasing BMD in
the total body after long-term ALN treatment. Continuing ALN or switching to RLX results
in similar BMD changes. Bone remodeling markers in the PLB and RLX group increased only
moderately and remained suppressed as compared with those prior the original ALN
treatment.
Delta |
% Spine |
% Femur |
% Neck |
% Total body |
ALN |
-0.5 ± 3.9 |
1.6 ± 2.7 |
2.0 ± 4.2 |
2.1 ± 1.5 |
PLB |
-2.7 ± 2.7 a |
0.3 ± 2.1 |
1.1 ± 3.4 |
0.7 ± 1.6 b |
RLX |
-0.7 ± 3.2 |
1.4 ± 2.8 |
2.3 ± 3.0 |
2.0 ± 2.0 |
P < 0.05 a PLB vs. ALN, b PLB vs. ALN and
RLX, ANOVA, mean ± SD |
[Programme]
P-271
BALANCE DISORDERS ARE GREATER IN INDIVIDUALS WITH OSTEOPOROSIS AND
KYPHOSIS
M. Sinaki1*, R. Brey2, C. Hughes3, K.
Kaufman3
1Department of Physical Medicine and Rehabilitation, Mayo
Clinic, Rochester, MN USA
2Vestibular and Balance Laboratory, Mayo Clinic, Rochester, MN
USA
3Motion Analysis Laboratory, Mayo Clinic, Rochester, MN USA
Imbalance and posture sway are two important risk factors
for falls. This study was designed to investigate the influence of kyphosis on postural
sway, gait unsteadiness and falls in elderly individuals.
Methods: Osteoporotic individuals with thoracic
hyperkyphosis (Cobb angle 50 to 65 degrees) were enrolled in the study along with healthy,
age-matched controls. The age of the study subjects ranged from 66 to 83, average age
75.8; and controls ranged from 62 to 83, average age 71.1. Thoracic kyphosis was assessed
from spinal radiographs. Prior to each test session all subjects were given the Dizziness
Handicapped Inventory (DHI) that assesses the individual's perception of their balance
impairment. Balance was also objectively assessed using Computerized Dynamic Posturography
(Neurocom, Clackamas, Oregon). This test consists of two components, the Sensory
Organization Test (SOT), and the Motor Control Test (MCT). The SOT consists of 6
conditions. A composite score is calculated made up of the mean of trials 1 and 2, and all
scores for conditions 3-6 or for a total of 14 scores.
Results: The total DHI was significantly different
between groups (osteoporotic mean 14.1; controls mean 0.18; p = 0.003). The osteoporotic
individuals with hyperkyphosis also had statistically significantly greater balance
abnormalities compared to the controls. The composite posturography score was
significantly different between the groups (osteoporotic, mean 60.4; control, mean 73.8; p
= 0.0006).
Conclusion: Osteoporotic/kyphotic individuals perceive
themselves to have a greater balance handicap than controls. This was confirmed by
objective balance assessment which demonstrated that osteoporotic/kyphotic individuals
have significantly poorer balance than healthy controls.
[Programme]
P-272
3D STEREOLITHOGRAPHY MODELS OF CANCELLOUS BONE STRUCTURES FROM MICRO-CT
DATA: PRODUCTION, TESTING AND VALIDATION OF FINITE ELEMENT RESULTS
C. A. Dobson1*, G. Sisias2, R. Phillips3,
C. M. Langton4, M. J. Fagan1
1School of Engineering, University of Hull, UK
2Department of Computer Science, University of Bradford, UK
3Department of Computer Science, University of Hull, UK
4Centre for Metabolic Bone Disease, Hull, UK
A stochastic simulation of cancellous bone resorption
that is integrated with a finite element package has been previously described [1], and
the mesh density, model size and remodelling parameters validated [2]. The simulation was
initially applied to two- dimensional idealised cancellous bone structures in a simulation
of osteoporosis, and the finite element results were validated by the mechanical testing
of stereolithography (STL) models of the depleted structures. This stereolithography
validation method has proved to be promising and been extended into three- dimensions.
This current paper will describe the extension of the method to realistic bone structures
in three-dimensions, using micro-CT scan data from histological samples of human
cancellous bone, and the subsequent testing of the stereolithography models.
Three-dimensional micro-CT datasets were obtained for
human cancellous bone from the iliac crest, femoral head, calcaneus, and two lumbar spine
locations. The highly complex structure of the cancellous bone samples caused the
triangulation of the surface (necessary for compatibility with the manufacturing
equipment) to result in file sizes in excess of the workable limits of the
stereolithography machine. Sophisticated tessellation algorithms were developed to enable
the datasets to be in a suitable form for stereolithography production whilst also
minimising memory requirements [3]. Five models of each of the samples were produced and
are in the process of being tested in compression to compare the stiffness with finite
element results for the structures. Preliminary test results have been gathered and show
the tests to be repeatable. The ratios of the directional properties of the models will be
compared with those predicted by the finite element results.
The potential use of stereolithography as a validation
tool is being investigated, with increasingly complex models being produced. It is
believed that the finite element results and stereolithography models of the bone will
allow us to fully explore the relationship between the stiffness and strength of the bone
and its physical and geometric properties.
[Programme]
P-273
BONE HISTOMORPHOMETRIC EVALUATION OF DAILY AND INTERMITTENT ORAL
IBANDRONATE IN POSTMENOPAUSAL OSTEOPOROSIS
P. J. Meunier1*, R. R. Recker2, R. S. Weinstein3,
C. H. Chesnut Iii4, B. Bonvoisin5, P. Mahoney5
1Hōpital Edouard Herriot, Lyon Cedex, France
2Creighton University, Omaha, Nebraska, USA
3University of Arkansas for Medical Sciences, Little Rock,
Arkansas, USA
4Deaconess Research Institute, Billings, Montana, USA
5F. Hoffmann-La Roche Ltd, Basel, Switzerland / Welwyn, UK
Recent results from a multinational, double-blind
fracture-prevention study conducted in women with postmenopausal osteoporosis demonstrated
that daily and intermittent regimens of oral ibandronate, a potent nitrogen-containing
bisphosphonate, significantly reduce vertebral fractures by 62% and 50%, respectively,
after 3 years (BONE: iBandronate Osteoporosis Trial in North America and Europe; Delmas et
al. 2002). The objective of this analysis was to evaluate the effects of daily and
intermittent ibandronate regimens on the quality of newly formed bone and on the bone
remodelling process. In the phase III fracture-prevention study, patients were randomised
to one of three groups: placebo; oral daily ibandronate (2.5mg/day); intermittent oral
ibandronate (20mg every other day for 12 doses every 3 months). A total of 110 patients
from this study were randomly assigned to undergo one transiliac crest bone biopsy at
either month 22 or 34 of treatment. Two doses of tetracycline were administered prior to
biopsy. According to qualitative histological assessment, newly formed bone was of normal
quality following treatment with ibandronate. In addition, no evidence of osteomalacia,
marrow fibrosis or cellular toxicity was observed. Quantitative histomorphometric analysis
demonstrated no impairment in mineralisation of bone matrix. Osteoid thickness (primary
safety parameter) and volume were reduced with active treatment compared with placebo (see
Table). Furthermore, mineralising surfaces and activation frequency were only moderately
decreased by ibandronate versus placebo, and hence excessive inhibition of bone turnover
was not observed. In summary, this histomorphometric analysis confirms that normal-quality
newly formed bone is produced after long-term treatment with oral ibandronate, even when
administered with an extended between- dose interval. These results support the excellent
safety profile of ibandronate.
Reference: Delmas PD, et al. Osteoporos Int 2002;13:S15
|
22 months |
34 months |
Treatment |
Placebo |
2.5mg daily |
20mg intermittent |
Placebo |
2.5mg
daily |
20mg
intermittent |
Osteoid thickness (µm) |
4.9 |
3.9** |
4.6 |
4.8 |
4.3* |
5.0 |
Osteoid volume (%) |
0.9 |
0.2** |
0.4 |
0.6 |
0.4* |
0.7 |
Mineralisin g surface (%) |
3.6 |
0.7* |
2.2 |
3.1 |
2.0 |
2.1* |
Activation frequency (per year) |
0.2 |
0.1* |
0.1 |
0.2 |
0.1 |
0.1 |
Osteoclast number (per mm2) |
0.1 |
0.1 |
0.1 |
0.1 |
0.1 |
0.0 |
Bone formation rate (µm3/µm2/d) |
0.02 |
0.01* |
0.01 |
0.02 |
0.01 |
0.01 |
Trabecular thickness (µm) |
131 |
110* |
117 |
116 |
124 |
126 |
Trabecular number (µm) |
1.1 |
1.3 |
1.3 |
1.1 |
1.2 |
1.3 |
Trabecular separation (µm) |
872 |
742 |
792 |
895 |
805 |
732 |
* p<0.05 (derived from non-parametric
Wilcoxon test: active group vs placebo). Note that as paired biopsies were not carried
out, it is impossible to compare the findings at 22 and 34 months. |
[Programme]
P-274
FEASIBILITY OF A STANDARDIZATION OF CALCANEUS QUS VARIABLES - RESULTS
FROM THE OPUS STUDY
R. Barkmann1*, R. Eastell2, D. M. Reid3,
C. Roux4, D. Felsenberg5, C. Glueer1
1University Clinic Kiel, Germany
2University of Sheffield, UK
3University of Aberdeen, UK
4Rene Descartes University, Paris, France
5Benjamin Franklin Hospital Berlin, Germany
Several Quantitative Ultrasound (QUS) devices are used
for the assessment of osteoporosis. However, results cannot be compared directly between
different machines. On the other hand standardization of DXA has proved very useful. We
tested whether calcaneus QUS variables can be standardized across devices from different
manufacturers.
In the Osteoporosis and Ultrasound (OPUS) study, 2837
women age 20-80 were recruited from random population samples at 5 centers in Aberdeen,
Berlin, Kiel, Paris, and Sheffield. A subgroup of 1765 women had complete results on 4 QUS
heel devices (Lunar Achilles+, Osteometer DTU-one, Quidel/Metra QUS-2, and DMS UBIS 5000).
We tested if SOS resp. BUA on these devices could be standardized against each other.
Regression formulas were calculated for BUA and SOS
separately for all combinations of devices and used for the standardization of the
variables of the single devices against each other. We tested the validity of this
approach by comparing the standardized residuals, after adjustment for the population
standard deviation for the measurements in a young population.
All correlations were significant at p<0.001.
Correlation coefficients ranged from R=0.69 to 0.80 for BUA and from R=0.84 to 0.89 for
SOS. Relative residual errors of the standardized variables ranged from 0.65 SD to 0.76 SD
for BUA and from 0.49 SD to 0.57 SD for BUA.
These data are higher than residual errors of the
standardization of DXA BMD of spine and hip (0.3 SD to 0.4 SD, literature data). However,
the performance for SOS approaches that of central DXA.
[Programme]
P-275
SUSTAINED EFFECT OF RISEDRONATE: A 7-YEAR STUDY IN POSTMENOPAUSAL WOMEN
O. Sorensen1*, S. Goemare2, D. Wenderoth3,
A. Chines3, C. Roux4
1Osteoporosis Research Clinic, Hvidore, Denmark
2Ghent University Hospital, Unit for Osteoporosis &
Metabolic Bone Disease, Belgium
3Procter & Gamble Pharmaceuticals, Mason, Ohio, USA
4Hopital Cochin, Paris, France
In a multinational, double blind, placebo controlled
study in women with established osteoporosis risedronate (RIS) significantly decreased the
incidence of vertebral fractures over 3 years.
In a 2 year extension of this study, RIS demonstrated a
sustained antifracture effect. At the end of the 5 years, 164 women participated in a
further 2 year extension in which all patients were given RIS 5 mg daily. We now report
the results for these women who either continued another 2 years on RIS (7 yr RIS, n=83)
or just initiated RIS (5 year PLBO/2 year RIS, n= 81). Throughout the 7 years of the
study, all patients received 1000 mg/d calcium and if baseline levels were low, up to 500
IU/day of vitamin D.
Over 7 years, lumbar spine (LS) BMD increased from
baseline by 11.5% in the 7 yr RIS group and 6.1% in the 5 yr PLBO/2 year RIS group. At the
total hip, BMD increased by 3.9% and -1.0% in the respective groups. During years 6-7,
increases in LS and total hip BMD were observed in both groups, with greater increases in
the 5 yr PLBO/2 year RIS group, as expected. The annualized incidence of new vertebral
fractures for this cohort is reported below. The cumulative incidence of osteoporosis-
related nonvertebral fractures over 7 years was 25.9% and 15.7% in the 5 yr PLBO/2 yr RIS
and 7 yr RIS groups, respectively. Overall adverse event profile was similar between the
two groups, including the incidence of upper gastrointestinal adverse events.
Treatment with risedronate over 7 years demonstrated
continued BMD increases. The results of this extension study strongly suggest sustained
effects of risedronate on vertebral fractures.
|
Anualized incidence of new vertebral
fractures |
|
5 yr PLBO/2yr RIS |
7 yr RIS |
Year 0-3 |
7.6 |
4.7 |
Year 4-5 |
12.3 |
5.2 |
Year 6-7 |
3.8 |
3.8 |
[Programme]
P-276
ACUTE EFFECTS OF ORAL STABLE STRONTIUM LOAD ON BONE AND MINERAL
METABOLISM IN HYPERCALCIURIC SUBJECTS
A. Rubinacci1*, M. Sirtori1, I. Villa1,
R. Daverio2, A. Soldarini2, C. Bianchin3, G. Vezzoli3
1Bone Metabolic Unit, Scientific Institute H San Raffaele,
Milano, Italy
2Dept of Clinical Chemistry, Scientific Institute H San
Raffaele, Milano, Italy
3Division of Nephrology, Dialysis and Hypertension, Scientific
Institute H San Raffaele, Milano, Italy
Recent observations raised the possibility that strontium
as well as other divalent and trivalent cations (aluminum, gadolinium, etc.) might be
involved in a complex cation sensing system interacting with bone remodeling and its
hormonal regulators via calcium sensing receptors. We have therefore analyzed the short
term (4 hours) effect on bone and mineral metabolism of an oral strontium load
(30.2micromol/kg body weight of SrCl2in water solution to a final concentratio
of 11.4 micromol/L) in hypercalciuric (under normocalcic (1g) and sodium (100mmol)
restricted diet > 0.11mg/dL glomerular filtrate) subjects (n=22, 9 females and 13
males).
The results indicate that oral stable Sr load induced a
significant (P<0.01) change in the level of plasma Sr. The higher mean plasma Sr
concentration during the test was achieved at T180, i.e.180 minutes after the load
(0.058mmol/L). AUC increased significantly (P<0.001) between T60 and T180 . After oral
stable Sr load, PTH concentration in plasma decreased significantly (P<0.001) between
T0 and T60, whereas no changes were observed in the control group. No significant changes
in serum calcium, BGP and CT were observed. The urinary excretion of mean total Dpd did
not change significantly and its variation throughout the experimental time did not differ
from the control group. Serum beta-CTx decreased significantly (P<0.001) over time in
Sr taking subjects whereas it did not change significantly in the control group not taking
Sr.
This study suggest that strontium interacts with mineral
metabolism by inhibiting PTH secretion. The possibility that this transient decrease
mediates the Sr effect on bone is unlikely as PTH returned to basal level at three hours
after Sr load, when strontium concentration was maximal and osteoclast activity inhibition
was significant.
[Programme]
P-277
RISEDRONATE SIGNIFICANTLY REDUCES THE RISK OF VERTEBRAL FRACTURES IN
ELDERLY POSTMENOPAUSAL WOMEN WITHIN 1 YEAR
S. Boonen1*, R. Eastell2, I. Barton3, M.
R. Mcclung4, C. H. Chesnut5
1Center for Metabolic Bone Disease, Universitaire
Ziekenhuizen, Leuven, Belgium
2Human Metabolism and Clinical Biochemistry, University of
Sheffield, Sheffield, UK
3Procter & Gamble Pharmaceuticals, Geneva, Switzerland
4Oregon Osteoporosis Center, Portland, Oregon, USA
5Osteoporosis Research Group, University of Washington,
Seattle, Washington, USA
Data are currently limited in determining the efficacy of
anti-resorptive agents in elderly patients.The effects of risedronate (RIS) have been
evaluated for the prevention and treatment of postmenopausal osteoporosis in women with
ages spanning several decades. The objective of this analysis was to determine the
efficacy of risedronate in reducing vertebral fracture risk in osteoporotic women aged
> 75 years.
The analysis included elderly osteoporotic women (aged
> 75 years) in the placebo (n=1507) and RIS 5 mg/day (n=1531) groups from the 3-year
Hip Intervention Program (HIP) and Vertebral Fracture Efficacy with Risedronate (VERT-MN
and VERT-NA) studies. Patients included those with a femoral neck BMD T-score <- 2.5SD
and/or at least one prevalent vertebral fracture. All patients received 1000 mg/d calcium
and up to 500 IU/d vitamin D, if baseline levels were low. Vertebral radiographs were
taken at baseline and at yearly intervals to determine prevalent and incident vertebral
fractures.
At baseline the mean femoral neck T-scores were -3.0SD
and -2.9SD in the placebo and RIS 5 mg groups, respectively. Three quarters of the
patients had at least one prevalent vertebral fracture. Compared with placebo, RIS
significantly reduced the risk of new vertebral fractures by 65% at one year (95%CI:
46-77%, p<0.001). This early onset was consistent within each of the three studies. RIS
significantly reduced the risk of both new vertebral and osteoporosis-related
non-vertebral fractures over 3 years. RIS was well tolerated with a safety profile
comparable to the placebo group.
In elderly postmenopausal women with osteoporosis,
increased rates of bone resorption continue to be associated with bone loss. In these
patients, risedronate provides rapid vertebral fracture risk reduction and long-term
efficacy over 3 years for vertebral and non-vertebral fractures.
[Programme]
P-278
RISEDRONATE TREATMENT OF ESTABLISHED PRIMARY AND SECONDARY OSTEOPOROSIS
IN MEN: 1-YEAR RESULTS FROM 218 PATIENTS
J. D. Ringe*, A. Dorst, H. Faber, K. Ibach
Medizinische Klinik IV, Klinikum Leverkusen, Leverkusen, Germany
Risedronate sodium has been shown to significantly
increase bone mineral density (BMD) and to significantly reduce the risk of morphometric
vertebral fractures in one year in postmenopausal osteoporosis. In the current three-year
study, we examine the effects of risedronate treatment in men with primary and secondary
osteoporosis.
In the single center, open label, randomized prospective
clinical study we enrolled 218 male patients with T-score of lower than -2.0 SD at lumbar
spine (LS) or femoral neck (FN) or lower than -1.0 SD at either site in the presence of an
osteoporotic fracture. The patients were allocated in pair-wise fashion into two treatment
groups. Patients in Group A (n=109) received risedronate 5 mg plus calcium 1000 mg and 800
IU Vit. D daily. In this group 56 patients had prevalent vertebral fractures (vert.fx) and
53 did not. There were a total of 109 patients in Group B. Those with a prevalent vert- fx
(Subgroup B1 n=54) were treated with alfacalcidol 1 mg plus calcium 500 mg daily, whereas
patients without prevalent vert.-fx (Subgroup B2, n=55) were treated with calcium 1000 mg
plus 800 IU plain vitamin D daily. In group A 40 of 109 patients (37%) and in group B 43
of 109 patients (39%) had secondary osteoporosis. BMD measurements were performed at
baseline and every 12 months thereafter.
After the first year of treatment men receiving
risedronate showed a mean LS BMD increase of 4.5% compared with a mean increase of 0.7% in
Group B patients (p<.0001). The mean change of total hip BMD was +2.5% and 0.2% for
Groups A and B, respectively (p<.0001). Corresponding changes at the FN were 1.6% and
0.01% for the respective groups (p=0.001). Both therapies were well tolerated.
We conclude that 1 year of risedronate therapy produces
favorable effects on BMD in men consistent with the results in women from phase 3 studies
in postmenopausal osteoporosis. The average increase rates of BMD at the 3 measured sites
were significantly higher than with alfacalcidol or vitamin D suggesting that risedronate
is superior in the treatment of men with primary or secondary osteoporosis.
[Programme]
P-279
COST EFFECTIVENESS OF RALOXIFENE: AN ECONOMIC EVALUATION IN A UK SETTING
F. Borgström3, O. Johnell2, B. Jönsson1,
D. Sykes5*, A. Oden4, J. Kanis1
1Centre for Health Economics, Stockholm School of Economics,
Box 6501, S-113 81 Stockholm, Sweden
2Department of Orthopaedics, Malmö General Hospital, S-214 01
Malmö, Sweden
3WHO Collaborating Centre for Metabolic Bone Diseases,
University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
4Independent Consulting Statistician, Göteborg, Sweden
5Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey
GU20 6PH, UK
The aim of this study was to examine the
cost-effectiveness of treatment with raloxifene in women at an increased risk of vertebral
fractures compared to no intervention. Risk functions for vertebral fracture and breast
cancer were based on epidemiological data from the UK, as were the data on costs following
different types of events. The simulations used an annual intervention cost of GBP 369
(cost of raloxifene plus monitoring), given for 5 years. A risk reduction of 50% for
vertebral fracture and 72% for breast cancer was assumed in the base case, in line with
available outcome data. A utility loss of 0.26 for the first year and 0.05 for second and
following years were assumed for spine fracture in line with new data.
Results are presented as cost per quality-adjusted life
year gained from the intervention for from a health care perspective with direct costs
only. Sensitivity analysis included variations in age, effectiveness, discount rates and
baseline risk of vertebral fracture.
Cost-effectiveness of intervention in postmenopausal
women with a relative risk (RR) for vertebral fracture of 2.0 was 19 900, 18 300 and 15
400 GBP/QALY at 60, 70 and 80 years of age respectively. The benefits of intervention
increase with age for vertebral fracture and decreases for breast cancer, which explains
the rather constant cost-effectiveness ratio. The cost-effectiveness ratio decreased with
higher relative risk of fracture.
We conclude that raloxifene can be targeted
cost-effectively to postmenopausal women at increased risk of vertebral fracture.
[Programme]
P-280
MODELLING THE EFFECTS OF PLACEBO AND CALCIUM/VITAMIN D SUPPLEMENTATION ON
THE TIME COURSE OF BIOMARKERS OF BONE TURNOVER IN OSTEOPOROTIC POSTMENOPAUSAL WOMEN
R. Gieschke1*, N. Hayashi1, P. Vis2, P.
Jacqmin2
1Pharma Development, F. Hoffmann-La Roche, Basel, Switzerland
2Exprimo Consulting LLP, Berenlaan 4, B-2340 Beerse, Belgium
Oral and intravenous (iv) formulations of ibandronate
(IBN), a potent nitrogen- containing bisphosphonate, are currently under development for
both the treatment and prevention of postmenopausal osteoporosis (OP) [1]. Bisphosphonates
exert their action through inhibition of osteoclast-mediated bone resorption. IBN has
demonstrated higher in-vivo potency compared with other currently licensed bisphosphonates
in osteoporosis.
The objectives of the current investigations were: (a) to
develop a mathematical model to describe the time course of both degradation markers of
bone turnover (such as CTX, a collagen breakdown product indicative of changes in
osteoclast activity) and formation markers of bone turnover (such as osteocalcin,
indicative of changes in osteoblast activity) following treatment with placebo,
calcium/vitamin D and IBN in osteoporotic postmenopausal females and (b) to explore the
effects of covariates (age, weight, time since menopause, baseline values for markers of
bone turnover and bone mineral density) on model parameters.
The effects of placebo (i.e. disease progression),
calcium/vitamin D and IBN on the time course of biomarkers of bone turnover were described
by direct and indirect response models by considering drug effects elicited through a dose
rate rather than drug concentrations (K-PD model approach [2]). These models were applied
to three studies comprising more than 700 patients who had received iv or oral treatment
regimens. Validation of this model on other studies supported its credibility.
Modelling the effects of placebo and calcium/vitamin D is
a prerequisite for modelling the overall effects on markers of bone turnover in response
to bisphosphonates such as IBN. Such models will enable simulation of clinical trials to
identify dosing regimens (iv and oral) that have the greatest probability of sustained
long-term clinical efficacy.
References:
[1] Delmas PD, et al. Oral ibandronate significantly
reduces fracture risk in postmenopausal osteoporosis when administered daily or with a
unique drug-free interval: results from a pivotal phase III study. Osteoporos Int 2002;13
(Suppl. 1):S15 (Abstract O37).
[2] Jacqmin P, et al. Modeling drug induced changes in
biomarkers without using drug concentrations: Introducing the K-PD Model. PAGE 2001 10th
Meeting, 7-8 June 2001, Basel, Switzerland.
[Programme]
P-281
ONCE WEEKLY ALENDRONATE PRODUCES A GREATER INCREASE IN BONE MINERAL
DENSITY THAN DAILY RISEDRONATE
D. Hosking1*, S. Adami2, D. Felsenberg3,
J-Y. Reginster4, J. Cannata5, M. Valimaki6, A.
Santora7, C. Yacik7, L. Zaru7
1Nottingham City Hospital, Nottingham, UK
2Ospedale Valeggio, Verona, Italy
3University Hospital, Berlin, Germany
4Chu de Liege, Liege, Belgium
5Hospital Central de Asturias, Asturias, Spain
6Helsinki University Central Hospital, Helsinki, Finland
7Merck Research Labs, Rahway, NJ
We report the 12-month Bone Mineral Density results of
the first head-to-head trial designed to compare the efficacy of alendronate and
risedronate for the treatment of osteoporosis. The 3-month, randomized, double-blind,
multicenter international study with double-blind extensions for an additional 9 months
(12 months in total), enrolled 549 postmenopausal women. Patients were 60-90 years old
(mean, 69), with osteoporosis defined by low BMD T-score (either lumbar spine or total
hip/femoral neck less than or equal to -2.5, or less than or equal to -2.0 at both sites).
Patients maintained a calcium intake of at least 1000 mg daily through food and/or calcium
supplements. Patients were randomized into three treatment groups: alendronate 70mg* once
weekly using standard am dosing; risedronate 5mg daily dosed 2 hours after a meal and at
least 2 hr before the next; or matching placebo for each. Results are based on a modified
intention-to-treat approach of lumbar spine and hip BMD at month 12.
In this study, alendronate 70 mg once weekly produced
significantly greater BMD increases over 12 months than did risedronate 5 mg daily, at the
spine and all hip sites. These differences may be due to the superior anti-resorptive
efficacy of alendronate 70 mg once weekly, reduced bioavailability of risedronate
resulting from post-meal dosing, or both.
*Manufactured by Merck & Co., Inc., Whitehouse
Station, NJ
[Programme]
P-282
PROSPECTIVE EVALUATION OF HIP-FRACTURE RISK IN INSTITUTIONALIZED ELDERLY
USING RADIAL-, PHALANGEAL- AND CALCANEAL BONE ULTRASOUND MEASUREMENTS
H. Dobnig*, A. Fahrleitner, C. J. Piswanger-Sölkner, M. Roth, B.
Obermayer-Pietsch, G. Leb
Div of Endocrinology, Karl Franzens University Graz, Austria
Fractures constitute a major clinical problem in
institutionalized elderly. Here, annual incidence rates for hip fractures usually range
between 3% to 5%. We sought to investigate whether bone ultrasound measurements would help
to characterize patients at very high risk for hip fractures.
A total of 1859 institutionalized female patients above
70 years of age who lived in 95 homes for elderly in the southern and eastern part of
Austria were followed for an average of 2 years. We excluded patients with hypercalcemia,
malignancies, hepatic and renal dysfunction (s.creatinine >1.8 mg/dL). Baseline
measurements for speed of sound (SOS) were performed at the distal radius (RAD), at the
proximal phalanx (PLX) of the third finger (Sunlight Omnisense device), or at the
calcaneal (CALC) site (including 'BUA' and 'stiffness'; Achilles Plus, Lunar).
A total of 118 hip fractures have occurred in these 2
years. Over the 8th, 9th and 10th decade there was a significant decrease in mean SOS
values of 0.84 SD (RAD), 0.60 SD (PLX) and 0.65 SD (CALC). RAD- and PLX-SOS values
correlated more closely with each other (r=0.45, p<0.001) than with CALC
SOS-measurements (0.25 and 0.18, p<0.0001). Using Cox-regression analyses and adjusting
the data for age and BMI we found an increase in the RR of hip fracture for each SD
decrease in SOS of 1.12 (0.92-1.4) for the RAD,1.09 (0.89-1.3) for the PLX, 1.42
(1.02-2.0) for BUA CALC, 1.37 (0.97-1.9) for the SOS CALC and 1.30 (1.05-1.6) for the CALC
'stiffness' measurements. ROC-analyses was significant for CALC BUA and 'stiffness'
parameters with resulting AUC of 0.59 (0.51-0.67) and 0.59 (0.52-0.66).
We conclude that mean bone ultrasound parameters are
grossly decreased at all measurement sites in institutionalized female patients and
further significant decreases occur over the 7th to 9th decade. The largest differences
between hip fracture- and non-hip fracture cases was found for calcaneal 'stiffness'
measurements (-0.39 SD, p=0.009). Together with the results of the ROC analyses our data
seem, however, not to justify the introduction of bone ultrasound measurements as a
screening tool for selection of institutionalized patients at very high risk of hip
fractures.
[Programme]
P-283
VERTEBRAL X-RAYS IN THE RECORDING AND PREDICTION OF FRACTURE; WHEN SHOULD
THEY BE ORDERED?
S. Kaptoge1*, M. Lunt2, D. Felsenberg3,
T. W. O'Neill2, J. Reeve1, E. P. O. S. Epos Study Group1
1Department of Medicine & Institute of Public Health,
University of Cambridge, Cambridge, UK
2ARC Epidemiology Unit, University of Manchester, Manchester,
UK
3Department of Radiology, Frei University B Franklin, Berlin,
Germany
Previous vertebral fracture increases risk of future
vertebral and hip fractures by 2.6-8 fold independently of BMD. British data suggest that
only 5-10% of subjects with a spine fracture are identified in primary care which impedes
rational treatment. Our objective was to develop algorithms for predicting a spine
fracture in men and women over 50 years of age if an X-ray is performed.
Data was analysed from 5,578 out of nearly 7,000 men and
women over 50 in the European Prospective Osteoporosis Study (EPOS). Prevalent deformities
were defined using the McCloskey-Kanis method. We modeled the risk of prevalent fracture
as a function of age, statural height loss since age 25, gender and fracture history
including limb fractures in the last 3 years using negative binomial regression modelling.
Receiver operating characteristic curves (ROC) were used to compare predictive ability of
models.
Risk of prevalent vertebral fracture significantly
increased with age [RR 1.04, 95% CI (1.03, 1.05) per year], height loss [1.07, (1.05,
1.09) per cm decrease], history of vertebral fracture [7.08, (5.64, 8.88)], forearm
fracture [1.54, (1.25, 1.89)], rib fracture [1.54, (1.16, 2.04)] and with incident lower
limb fracture [2.04, (1.33, 3.14)]. Male gender was associated with increased risk of
prevalent fracture [1.82, (1.53, 2.17)] and increasing body weight was associated with
lower risk [0.98 (0.98, 0.99) per 1kg increase]. The ROC curve generated by the optimal
model showed that at a sensitivity of 50% for identifying cases of at least one vertebral
deformity (or 58% for at least 2), specificity was increased from 50 to 75% compared to a
random allocation of X-rays. At a sensitivity of 75% the specificity was also improved by
the same amount. In women, history of hip fracture [RR 4.61, CI (2.43, 8.74)] substituted
for history of rib fracture and longer fertile period (age at menopause minus age at
menarche) was associated with lower risk of vertebral fracture [RR 0.97, CI (0,94, 0.99)
per year].
Decisions on whom to treat often depend on whether there
is a pre-existing spine fracture. Whom should have a spine X-ray to identify spine
fractures in primary care can be usefully guided by algorithms based on clinical history,
height and weight.
[Programme]
P-284
MODELLING THE EFFECTS OF IBANDRONATE TREATMENT ON THE TIME COURSE OF BONE
MINERAL DENSITY IN OSTEOPOROTIC POSTMENOPAUSAL WOMEN
R. Gieschke1*, N. Hayashi1, P. Vis2, P.
Jacqmin2
1Pharma Development, F. Hoffmann-La Roche, Basel, Switzerland
2Exprimo Consulting LLP, Berenlaan 4, B-2340 Beerse, Belgium
Ibandronate (IBN), a potent nitrogen-containing
bisphosphonate, is under investigation as oral and intravenous (iv) formulations for the
treatment and prevention of postmenopausal osteoporosis (OP) [1]. Drug action is exerted
by inhibition of osteoclast-mediated bone resorption, with higher potency compared with
other currently licensed bisphosphonates in osteoporosis.
The objectives of the current investigations were to
develop a pharmacologically realistic mathematical model for IBN using selected Phase I,
II and III data in order to describe the relationship between iv and/or oral dose, the
resulting plasma concentration exposure, the effect on markers of bone turnover and,
finally, the effect on bone mineral density (BMD).
A three-compartment model adequately described the PK
data and yielded estimates for bioavailability of IBN. Estimates for IBN bioavailability
were low and confirmed previous results obtained from non-compartmental analyses. The IBN
effects on the biomarker urinary CTX, a collagen breakdown product indicative of changes
in osteoclast activity, were described by an indirect response model added to the PK
model. Considerable reduction in the complexity of the model could be achieved by
abstracting the PK and considering drug effects elicited through a dose rate rather than
drug concentrations (K-PD model approach [2]). Changes in BMD were coupled to changes in
urinary CTX alone using an effect compartment approach.
This modelling scenario was applied to three studies
comprising more than 700 patients who had received iv or oral treatment regimens. Using
the K-PD model, effects of placebo (i.e. disease progression), vitamin D/calcium
supplementation and IBN could be estimated with an intersubject variability of about
30%CV. The equilibration half-life between urinary CTX and BMD was estimated to be 0.6
years. Validation of this model on other studies supported its credibility.
Simulation based on this model will be used in the future
to identify dosing regimens (iv and oral) that have the greatest probability of sustained
long-term clinical efficacy.
References:
[1] Delmas PD, et al. Oral ibandronate significantly
reduces fracture risk in postmenopausal osteoporosis when administered daily or with a
unique drug-free interval: results from a pivotal phase III study. Osteoporos Int 2002;13
(Suppl. 1):S15 (Abstract O37).
[2] Jacqmin P, et al. Modeling drug induced changes in
biomarkers without using drug concentrations: Introducing the K-PD Model. PAGE 2001 10th
Meeting, 7-8 June 2001, Basel, Switzerland.
[Programme]
P-285
EFFECT ON BONE REMODELLING PARAMETERS OF VARIOUS DOSES OF PAMIDRONATE
WITH CONSTANT YEARLY DOSE IN WOMEN WITH OSTEOPOROSIS : A PILOT STUDY
O. Lamy*, C. Mischler, L. Sandini, M. A. Krieg, P. Burckhardt
Service de médecine A, Department of Internal Medicine, Centre
Hospitalier Universitaire Vaudois, Lausanne - CHUV, Switzerland
Aims : Bisphosphonates are potent drugs for osteoporosis,
but tolerance and compliance to oral treatment is often poor. Pamidronate (APD)
administered iv every three months is well tolerated. However the best regimen is not
known yet. We tested the effect on bone markers of various doses of pamidronate with
constant yearly dose in post-menopausal women with osteoporosis.
Methods : 13 osteoporotic post-menopausal women (age
66±11, BMI 23.8±3.6) were randomised to receive 120 mg/year iv APD in 4x30 mg (n=4),
3x40 mg (n=4) or 2x60 mg (n=5) for two years. All got calcium and vitamin D. Corrected
calcemia, osteocalcine (OC), urinary C-telopeptides (UCTX) were measured at months
0,1,2,3,4,5,6,8 and 12; PTH and vitamin D at months 0 and 12.
Results : UCTX decreased by 78, 69, 71, 90, 74, 74 and 74
% (group 30 mg), by 92, 85, 71, 61, 87, 74 and 71 % (group 40 mg), and by 79, 49, 48, 40,
38, 27 and 2 % (group 60 mg) at months 0, 1, 2, 3, 4, 5, 6 and 12. OC decreased by 10, 30,
43, 41, 39, 40 and 56 % (group 30), by 16, 27, 38, 36, 42, 42 and 50 % (group 40), and by
13, 29, 32, 34, 30, 18 and 37 % (group 60) at months 0, 1, 2, 3, 4, 5, 6 and 12. Corrected
calcemia, PTH and vitamin D did not change during the study.
Conclusions : UCTX decreased by near 70 % and osteocalcin
by near 40 to 50 % before the next injection, only when APD was given every 3 to 4 months.
When APD was given every 6 months, the decrease of bone remodelling parameters after 5 to
6 months was particularly low. These results suggest that three to four months, but not
six, is an appropriate interval between two intravenous doses of pamidronate.
[Programme]
P-286
DEFINING A BIOLOGICAL RESPONSE TO RALOXIFENE THERAPY USING ADHERENCE TO
GREATER THEN 95% OF THERAPY
J. A. Clowes*, N. F. A. Peel, R. Eastell
Bone Metabolism Group, University of Sheffield, UK
Monitoring response to therapy using a surrogate marker
may enable prediction of fracture risk reduction. The threshold percentage change, which
defines an adequate response to therapy with bone turnover markers, is currently unclear.
We have defined the biological response to therapy by identifying responders based on
adherence to greater then 95% of prescribed therapy.
Fifty postmenopausal women (mean age 62 ±1 year) with
osteopenia were randomised to treatment with raloxifene and calcium or no treatment for 24
months. Duplicate serum samples and 4 urine samples were obtained fasting at 24 weeks.
Bone formation was measured using procollagen type I N terminal propeptide (PINP; Roche
Elecsys) and osteocalcin (OC; Roche Elecsys). Bone resorption was measured using serum
beta C terminal telopeptide of type I collagen (sBCTX; Roche Elecsys) and urine N terminal
telopeptide of type I collagen (uNTX; Vitros ECi). Adherence was assessed using electronic
monitoring devices.
The mean percentage change and least significant change
(LSC) for multiple measurements are shown (Table). The signal (percentage change) to noise
(CV) ratio was greatest for PINP. The biological response to therapy was determined from
subjects (n = 10) adhering to greater then 95% of the prescribed therapy and calculated
using percentage change in bone turnover markers and 80% confidence intervals (CI). If the
80% CI did not overlap with the LSC then bone turnover markers will discriminate between a
responder and poor-adherence or poor-responder with 95% sensitivity and 95% specificity,
any overlap will result in reduced sensitivity. PINP had the highest sensitivity and
specificity at 24 months (Table).
In conclusion bone formation markers had a similar or
greater signal to noise ratio compared to bone resorption markers. The percentage change
in bone markers in response to therapy had a high specificity (95%) and sensitivity (65 to
95%) to discriminate between responders and poor-adherence or poor-responders.
|
|
Greater 95% Adherence to Raloxifene
Therapy |
Bone Marker |
LSC |
Mean % Change |
Upper Limit 80 % CI |
Lower Limit 80 % CI |
Sensitivit y |
Specificit y |
Osteocalcin |
26.7 |
- 34.0 |
- 9.8 |
- 58.2 |
65 % |
95 % |
PINP |
24.5 |
- 45.5 |
- 22.2 |
- 68.7 |
95 % |
95 % |
sBCTX |
46.7 |
- 65.5 |
- 6.1 |
- 124.9 |
66 % |
95 % |
uNTX |
29.6 |
- 43.4 |
- 3.2 |
- 83.7 |
67 % |
95 % |
[Programme]
P-287
RISEDRONATE IS WELL TOLERATED IN OSTEOPOROTIC PATIENTS IN A CLINICAL
PRACTICE SETTING: RESULTS FROM AN INTERIM ANALYSIS OF A PROSPECTIVE COHORT STUDY (ORFEO
STUDY)
F. Morales1, P. Orozco2, F. I. Romero3,
I. Aristegui3*, P. O'Shea4
1University of Valencia, Spain
2CAP Gotic, Barcelona, Spain
3Aventis Pharma, Spain
4Biometrica, Spain
Objective: The tolerability of risedronate has been
assessed in placebo-controlled studies for up to 3 years, in which patients were not
excluded because of either an underlying history of gastrointestinal (GI) disease or
concomitant medication intake. The aim of this study was to confirm the safety profile of
risedronate 5 mg/d in actual clinical practice. This is the first pharmacovigilance
prospective study with an oral bisphosphonate conducted in Spain.
Patients and Methods: Patients: 2301 patients with
postmenopausal or glucocorticoid-induced osteoporosis (median age: 64 years) were enrolled
and followed up for up to six months in 202 primary care centres in Spain. For this
interim analysis 2102 patients were evaluated, who had either completed the study or
having withdrawn, with a filled in Study Discontinuation Form.
Methods: multicentre, observational, prospective cohort
study. All the patients were requested to give their informed consent before entering the
study.
Results: 1240 patients (59%) had an underlying history of
upper GI disease prior to entering the study, and over 30% of the whole sample had been
taking NSAIDs or aspirin for longer than 1 month.
Over 90% of the patients fully complied with
risedronate's administration instructions.
127 (6%) of all the patients in the study reported at
least one Adverse Event (AE), and in total 237 AEs were reported, among which 159 were
Upper GI (UGI) AEs. The most common UGI AEs were Abdominal Pain (2.52% of all the study
patients) and Dyspepsia (1.38%). The average time from the beginning of risedronate intake
to the onset of any AEs was 35.8 days. Most of the AEs were mild to moderate. Patients'
withdrawal due to tolerability complaints was 4.1%.
Conclusion: The results of this cohort study shows that
oral daily riesdronate 5 mg is well tolerated in osteoporotic patients under actual
clinical practice conditions, and its GI safety profile is comparable to that shown in
placebo-controlled clinical trials.
[Programme]
P-288
CLINICAL FACTORS RELATED WITH DIET-RELATED CALCIUM INTAKE
M. Ciria*, L. Perez-Edo, J. Blanch, M. J. Robles, M. Coll, P. Lisbona, X.
Garcia, P. Benito, J. Carbonell
Rheumatology Service, IMAS
Objective: to assess the effect of different clinical
parameters on diet-related calcium intake.
Patients and methods: calcium intake is measured by a
semiquantitative questionnaire to people who made a densitometric exploration in our
center between July and December of 2002. We measured the bone mineral density (BMD) in
lumbar spine and femoral neck (four interest areas), body mass index, age, solar exposure
level, tobacco and alcohol usage, existence of previous autoreferred fractures in
vertebral spine, forearm or femur and its relationship with the previous performance of a
first exploration or a control visit. BMD was measured with an Hologic QDR 1000 equipment.
The statistical analysis included assessment of the normality of the variables, parametric
and non-parametric tests, lineal regression and correlation tests.
Results: Five hundred and twenty explorations were
reported. 163 were first explorations, and 357 were control visits. Both groups were
comparated by age, sex, tobacco or alcohol usage and body mass index. Calcium intake was
statistically different between people that did a first exploration and those that did a
control visit. (x=0.623 ±0.257 versus x=0.701±0.305 mg/day, respectively; p=0.014), as
well bone mass in every studied interest area except in trochanter, being higher in first
explorations than in successive visits. Existence of previous fractures did not show
correlation with lactic intake, neither BMD in any of the interest areas studied, body
mass index, age, physical activity or tobacco usage. Alcohol intake was negatively
correlated with the calcium intake (r:-0. 136; p=0.002), whereas solar exposure showed a
very weak positive correlation (r: 0.098; p=0.026).
Conclusions: in our sample, calcium intake was only
associated with the previous performance of a densitometry. The increase of diet-related
calcium intake can be owed to the previous diagnosis of osteoporosis, but we can not
assure this with a cross-sectional study. We emphasize the absence of correlation between
the existence of previous fractures and the diet-related calcium intake and with the
values of BMD.
[Programme]
P-289
EVALUATION OF 3-D MICROARCHITECTURE OF HUMAN OSTEOPOROTIC SPINE IN VIVO
BY USING HIGH-RESOLUTION COMPUTED TOMOGRAPHY
T. Mawatari1*, H. Miura1, S. Hamai1, T.
Shuto1, Y. Nakashima1, T. Kawano1, N. Tsukamoto1,
H. Higaki2, Y. Iwamoto1
1Department of Orthopaedics, Graduate School of Medical
Sciences, Kyushu University, Fukuoka, Japan
2Department of Mechanical Engineering, Faculty of Engineering,
Kyushu Sangyo University, Fukuoka, Japan
While bone mineral density (BMD) is the established
measure in clinical evaluation of osteoporosis, bone microarchitecture is also one of the
major determinants of the bone strength, and has been evaluated by using microcomputed
tomography only in laboratory study. The purpose of this study was to evaluate the 3D
microarchitecuture of the human osteoporotic lumber spine by using high- resolution
computed tomography (HRCT) in vivo. 19 normal postmenopausal women and 31 rheumatoid
arthritis (RA) patients including 9 and 16 osteoporosis patients respectively according to
the diagnostic criteria, were examined by dual X-ray absorptiometry (DXA) and the whole
body of the third lumber vertebra was scanned by HRCT at a spatial resolution of 351 x 351
x 500 micron. All the gray-value slice images were then noise-eliminated, segmented, and
transformed to binary images, which included local thresholding procedure. Preliminary
experiments on the cadaveric human third
lumber spine were designed specifically to select the
correct threshold value. Finally, from the reconstructed 3D volume data, arbitrary-shaped
trabecular bone volume which cover the whole trabecular space were extracted.
Bone volume fraction (%), connectivity density (/mm3)
(the first Betti number/total volume) as the measure of connectivity, and fractal
dimension as the measure of complexity were calculated by custom-made software. Both in
normal postmenopausal women group and RA patient group, the bone volume fraction, fractal
dimension, and connectivity density decreased significantly in osteoporosis patients
compared with the non-osteoporosis subjects. HRCT provided satisfactory in vivo assessment
of consecutive slice images corresponding reasonably well to the histological sections,
even though a resolution of 351 micron seems to be the lowest resolution level available
for human trebecular bone. Despite this limitation, the relative differences in each group
were revealed quantitatively, and our method must be useful for evaluation of efficacy of
therapeutic intervention in vivo.
[Programme]
P-290
PAIN AND HEALTH RELATED QUALITY OF LIFE IN WOMEN WITH VERTEBRAL FRACTURES
J. A. Falch*, H. Bentzen, A. A. Dahl
Aker University Hospital, Oslo, Norway
As Norwegian women have a very high risk of sustaining
osteoporotic fractures, we wanted to study the impact of vertebral fractures (VFx) on the
patients experience of pain and HQOL. Consecutively,100 women with VFx age 50-87 years
attaining our outpatient clinic (Group A) were asked to complete a visual analog scale
(VAS 0-10) for maximum, minimum and average backpain last week, the Hospital Anxiety and
Depression Scale (HADS) questionnaire for scoring of anxiety and depression, and SF-12
(short form of SF-36) for HQOL. From Group A, 20 women with primary osteoporosis
participated in an extension of the study, completing the osteoporosis specific QUALEFFO
questionnaire (Group B). As controls for Group B, 21 women age 71 years without VFx
completed the QUALEFFO. The age of Group A was 73 (8) and for Group B 72 (4) years. The
maximum pain reported by Group A (VAS) was 5.3 (2.8), average 4.0 (2.4), and minimum 2.4
(2.2). In a large Norwegian population based study of rheumatoid arthritis, the VAS for
pain was 4.6 (2.4). The HADS anxiety score was 6.2 (4.1) and the depression score 4.9
(3.0). These scores are below 8, which is suggested as the cut-off score for clinical
disease. Compared to a large Norwegian population study using HADS, the scores are not
clinically significantly higher than that norm. For SF-12, the normalized mental score was
46.2 (10.0) and the physical score 31.7 (7.7). The normal US population will for both
scores have a value 50 (10), and although the mental score in the patients was
significantly influenced, the deviation from the mean value was only 0.4 SD compared to
nearly 2 SD for physical score. In Group B, the total score for QUALEFFO was significantly
higher in patients than controls, indicating a reduced HQOL. This was significant for all
five domains except the domain of mental function. In conclusion, our patients with
osteoporotic
VFx experience a high degree of pain, reduced physical
functional capacity and HQOL. However, in spite of this, they seem to have preserved a
normal mental function without increased levels of anxiety and depression.
[Programme]
P-291
SEX HORMONES INFLUENCE THE PEAK BONE MASS - A CASE OF 17
ALPHA-HYDROXYLASE DEFICIENCY
D. Kastelan*, Z. Giljevic, Z. Perkovic, M. Korsic
Division of Endocrinology, Department of Internal Medicine, University
Hospital Zagreb, Zagreb, Croatia
17 alpha-hydroxylase is an enzyme required for production
of cortisol in adrenal cortex and C-19 androgen precursors of the sex hormones in both,
adrenals and gonads. Deficit of the enzyme is associated with hypertension, sex
infantilism and female phenotype in both genetic sexes. Peak bone mass is influenced by
genetic factors, nutrition, physical activity and sex hormones. Here we present a patient
with 17 alpha-hydroxylase deficiency, a rare form of congenital adrenal hyperplasia,
characterised by late puberty and consequent low bone mass.
A 23-yr old female patient was first diagnosed with
primary amenorrhoea, absent secondary sexual development and hypertension. The patient had
female external genitalia, with small uterus and ovaries as revealed by pelvic ultrasound.
High level of progesterone and low levels of 17-hydroxyprogesterone and sex steroids were
found. Bone mineral density was also decreased. Dual x-ray absorptiometry showed low bone
mineral density of the lumbar spine (T score = -4,37) and the total hip (T score = -2,67).
One year following treatment with sex hormone therapy, a significant gain of bone mass was
observed at all measured sites.
Low bone mineral density observed in this patient and the
subsequent increase in BMD, indirectly proves the role of sex hormone on bone mass.
[Programme]
P-292
EVALUATION OF INHOMOGENEITY OF HUMAN VERTEBRAL CANCELLOUS BONE BY USING
HIGH-RESOLUTION COMPUTED TOMOGRAPHY IN VIVO
S. Hamai1*, T. Mawatari1, H. Miura1, T.
Shuto1, Y. Nakashima1, T. Kawano1, N. Tsukamoto1,
H. Higaki2, Y. Iwamoto1
1Department of Orthopaedics,Graduate school of Medical
Science, Kyusyu University, Fukuoka, Japan
2Department of Mechanical Engineering, Faculty of Engineering,
Kyusyu Sangyo University, Fukuoka, Japan
Clinical evaluation of bone mineral density (BMD) is
commonly performed in the lumber vertebrae by Dual X-ray absorptiometry (DXA), however,
the localization of the bone inside the vertebral body which will contribute to the
mechanical strength, cannot be taken into consideration. The purpose of this study was to
evaluate the inhomogeneity of human vertebral cancellous bone by using high-resolution
computed tomography (HRCT) in vivo. 19 normal postmenopausal women and 31 rheumatoid
arthritis patients including 9 and 16 osteoporosis patients respectively, were examined by
DXA, and the whole body of the third lumber vertebra was scanned by HRCT at a spatial
resolution of 351x 351 x 500 micron. All the gray-value slice images were then
noise-eliminated, segmented. Preliminary experiments on the cadaveric human third lumber
spine were designed specifically to select the correct threshold value. Finally, from the
reconstructed 3D volume data, arbitrary-shaped trabecular bone volume which is then
divided into six parts (upper-anterior, upper- posterior, middle-anterior,
middle-posterior, lower-anterior, lower-posterior) were extracted. Bone volume fraction
(%) was calculated, and 3-D image reconstruction was done. The decreasing pattern of the
cancellous bone were classified as the localized pattern which shows the zone specific
loss remarkable at the upper and anterior half of the vertebral body, and the homogeneous
pattern. Banse et al. examined 6 longitudinal cancellous bone cores from 9 autopsy lumber
vertebrae samples, and have shown inhomogeneity of human vertebral cancellous bone. In
accordance with their findings, we confirmed the localized pattern in most of the cases by
in vivo whole body analyses of the lumber vertebrae using HRCT, whereas some vertebral
body showed the homogeneous pattern. The pathogenesis of these differences of decreasing
pattern is still unknown. Correct quantification of the decreasing pattern and
identification of the weakest parts of the vertebra may lead to better prediction of
fracture risk.
[Programme]
P-293
EFFICACY OF TERIPARATIDE FOR FRACTURE RISK REDUCTION IN WOMEN WITH
VARYING BASELINE RISK FOR OSTEOPOROTIC FRACTURE
J. H. Krege*, G. Crans, S. Vargas, W. H. Scheele
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
We hypothesized that teriparatide [rhPTH(1-34)] therapy
is effective across the entire spectrum of baseline risk for fracture in postmenopausal
women having osteoporosis, as estimated from baseline BMD and number of prior vertebral
fractures. In the Fracture Prevention Trial (Neer, NEJM, 2001), women having osteoporosis
and prevalent vertebral fractures were treated with teriparatide 20 or 40 µg once daily
for a median of 19 months. Treatment reduced the relative risk for new vertebral fracture
by 65% and 69%, respectively, compared with placebo. Of the original study population, 77%
(1262/1637) volunteered for additional observation to determine the safety and long-term
durability of teriparatide effects on fracture incidence. During the initial 18 months
after stopping study drug, vertebral fracture efficacy was sustained [Lindsay, JBMR
2001;16 (Suppl 1):S163]. For patients receiving teriparatide 20 µg (the marketed dose),
the relative risk (RR) for new fracture over the total 39 months of observation was 0.54,
the absolute risk reduction (ARR) was 12.7% (P<0.0001), and the number needed to treat
(NNT) to prevent a new fracture was 7.9. In women with more than 1 baseline vertebral
fracture, the RR was 0.45, the ARR 18.5% (P<0.0001), and the NNT 5.4. Women with BMD
T-scores at either the femoral neck or lumbar spine of -2.5 or less had RR of 0.54, ARR
14.6% (P<0.0001), and NNT 6.8. Women with both characteristics (low BMD T-score and
baseline vertebral fractures) had RR of 0.44, ARR 21.7% (P<0.0001), and NNT 4.6. Thus,
once-daily administration of teriparatide 20 µg/d robustly decreased fracture risk over
an extended period (39 months), across a broad span of baseline fracture risk. Even
patients most severely affected by osteoporosis and at high risk of fracture are likely to
benefit from the bone forming activity of teriparatide.
[Programme]
P-294
DIVERGING EFFECTS OF TERIPARATIDE AND ALENDRONATE ON BONE FORMATION IN
POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS. A HISTOMORPHOMETRIC STUDY AFTER 6 MONTHS OF
THERAPY
P. J. Meunier1*, M. E. Arlot1, J. San Martin2,
G. Boivin1, D. W. Donley2, R. Correa- Rotter3, S. Jasqui3,
J. Tamayo4, E. F. Eriksen2
1Laboratoire d'Histodynamique Osseuse and INSERM Unit 403,
Faculty of Medicine R. Laennec, Lyon, France
2Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, IN, USA
3Department of Nephrology and Mineral Metabolism, Instituto
Nacional de Ciencias Médicas Y Nutrición Salvador Zubiran, 14000 Mexico DF, Mexico
4COMOP Osteoporosis Research Center, Mexico DF Mexico
Teriparatide (rDNA origin) injection [rhPTH(1-34)], a
bone formation agent for osteoporosis, and alendronate, a bisphosphonate, both increase
bone mineral density and decrease the risk of fracture. To compare the effects of
teriparatide (20 µg/d) and alendronate (10 mg/d) on bone remodeling, we conducted a
cross-sectional bone biopsy study in a subset of patients enrolled in a randomized,
double-blind, prospective clinical trial. After 6 months of treatment, biochemical markers
of bone turnover were significantly increased by teriparatide and decreased by alendronate
in postmenopausal women with osteoporosis. Tetracycline double-labeled iliac crest bone
biopsies were obtained from patients treated with teriparatide (n=8) or alendronate (n=9)
for 6 months. The histomorphometric analysis was performed separately for cortical,
endocortical and cancellous bone. Despite the short treatment period, significant
differences were demonstrated between groups. Activation frequency was markedly increased:
0.99 ±0.56 (mean ±SD)/yr in the teriparatide group vs. 0.02 ±0.03/yr in the alendronate
group (P<0.0001). The marked suppression of bone formation with alendronate treatment
was also reflected in the mineralizing surface (8.1 ±4.4% vs. 0.2 ±0.3%, P<0.0001),
osteoid surfaces (17.3 ±7.9% vs. 6.8 ±5.2%, P<0.004), adjusted appositional rate
(0.37 ±0.17 vs. 0.03 ±0.01 µm/d, P<0.002) and bone formation rate (0.062 ±0.035 vs.
0.002 ±0.001 µm/d, P<0.02) (teriparatide vs. alendronate). Eroded surfaces were
similar between teriparatide and alendronate treated groups. In the endocortical envelope,
similar pronounced reductions in bone formation were observed for alendronate as reflected
by mineralizing surfaces (18.7 ±10.4% vs. 0.4 ±0.9%, P<0.0001) and bone formation
rate (0.097 ±0.053 vs. 0.006 ±0.008 µg/d (P<0.04). In the latter envelope, the
teriparatide group displayed an increase in erosion surface (5.6 ±3.8% vs. 2.8 ±1.3%,
P<0.04). Cortical bone thickness, cortical porosity, and endosteal mineral apposition
rates were not different between treatment groups.
In conclusion, these results demonstrate the marked
difference in mechanism of action between teriparatide, which directly stimulates bone
formation, and alendronate, which markedly reduces bone remodeling.
[Programme]
P-295
WITHDRAWN
[Programme]
P-296
ELECTRONIC MONITORING OF ADHERENCE TO THERAPY IN POSTMENOPAUSAL
OSTEOPOROSIS: THE IMPACT STUDY
B. Vrijens1*, J. D. Ringe2, N. B. Watts3,
H. A. P. Pols4, C. Roux5, R. Eastell6, L. van de
Langerijt7, D. Cahall7, P.D. Delmas8
1AARDEX Ltd, Vise, Belgium
2Klinikum Leverkusen, University of Cologne, Leverkusen,
Germany
3University of Cincinnati, Cincinnati, OH, USA
4Erasmus University, Rotterdam, The Netherlands
5Hōpital Cochin, University René-Descartes, Paris, France
6University of Sheffield, Sheffield, UK
7Aventis Pharmaceuticals, Bridgewater, New Jersey, USA
8INSERM Research Unit 403 and Claude Bernard University of
Lyon, Lyon, France
Adherence to prescribed postmenopausal osteoporosis
treatment is important for clinical effectiveness. While pill counts are widely used to
assess adherence in clinical trials, they only give an average adherence level over the
whole study period and they significantly overestimate actual compliance relative to that
determined by electronic monitoring devices. The present paper focuses on the 1-year
Improving Measurements of Persistence on Actonel Treatment (IMPACT) study to assess
adherence to prescribed therapy in the control group where no reinforcement was given to
the patients. This analysis includes a total of 1113 postmenopausal women aged 65 to 80
years with osteoporosis in 21 countries. Two measures of adherence were used: a)
conventional pill counts in which the remaining number of tablets were counted at each
visit; and b) electronic monitoring with the Medication Event Monitoring System (MEMS,
AARDEX, Ltd.). The child-proof closure of the MEMS cap contains a microprocessor that
records the date and time of each opening of individual drug containers over time. We
observed vastly different temporal patterns of adherence both within and between patients
and we found it useful to distinguish two dimensions of the adherence patterns: the
patient's (a) persistence and (b) compliance to therapy. Persistence was defined as the
time since first dose until discontinuation of treatment, with 'discontinuation' defined
as the last day on which the patient has taken at least 7 doses over the 14 last days and
at least 50% of the doses since first dose. 'Compliance' reflects the quality of execution
of the drug regimen while the patient persists. Overall, 96.3% of women returned their
MEMS caps. At 1 year, 77% of women were persistent by MEMS caps, while the average
compliance with therapy over the study period was 95%, again by MEMS caps. These results
indicate that compliance to risedronate 5 mg/d therapy in postmenopausal women with
osteoporosis is very good while persistence can be improved. The results also showed that
pill counts overestimate adherence to therapy as compared with MEMS cap monitoring (P=0.022).
MEMS is therefore a useful method to monitor patient adherence of osteoporosis therapy.
[Programme]
P-297
INFLUENCE OF PATIENT COMPLIANCE WITH RISEDRONATE THERAPY ON BONE TURNOVER
MARKER AND BONE MINERAL DENSITY RESPONSE: THE IMPACT STUDY
R. Eastell1*, P. Garnero2, B. Vrijens3,
L. van de Langerijt4, H. A. P. Pols5 J. D. Ringe6,
C. Roux7, N. B. Watts8, D. Cahall4, P.D. Delmas9
1University of Sheffield, Sheffield, UK
2Hopital Edouard Herroit, Lyon, France and Synarc, Lyon,
France
3AARDEX Ltd, Vise, Belgium
4Aventis Pharmaceuticals, Bridgewater, New Jersey, USA
5Erasmus University, Rotterdam, The Netherlands
6Klinikum Lverkusen, University of Cologne, Lverkusen, Germany
7Hōpital Cochin, University René-Descartes, Paris, France
8University of Cincinnati, Cincinnati, Ohio, USA
9INSERM Research Unit 403 and Claude Bernard University of
Lyon, Lyon, France
Short-term (3-6 month) changes in bone turnover markers
(BTMs) produced by risedronate are significantly correlated with reduced vertebral
fracture risk. It is important to determine whether changes in BTMs are related to
compliance. This analysis evaluated the effect of compliance with risedronate 5 mg/d on
BTMs and bone mineral density (BMD) in 2302 postmenopausal women with osteoporosis aged 65
to 80 years enrolled in the IMPACT study. Urinary N-terminal cross-linking telopeptide of
type I collagen (uNTX) and serum type I collagen C-telopeptide (sCTX) levels were measured
at baseline after 2 weeks (mean = 19 days) of calcium treatment alone, and at weeks 10 and
22 of risedronate treatment. Spine BMD was measured at baseline and 1 year. Compliance was
assessed using electronic monitoring caps (MEMS, AARDEX Ltd.). Change in uNTX, sCTX, and
BMD from baseline were categorized and related to compliance using a proportional odds
model. At 10 and 22 weeks, mean changes in uNTX were -35% and -39%, respectively (both P<0.0001)
and mean changes in sCTX were -49% and -55%, respectively (both P<0.0001). Mean
change in spinal BMD at 1 year was +4% (P<0.0001). Urinary NTX, sCTX, and BMD
responses to treatment improved as compliance increased. For example (see figure), at week
22, a decrease in sCTX from baseline of >50% can be expected in about 20% of
noncompliant patients (left-hand side of figure) and in more than 60% of compliant
patients (right-hand side of figure). These results show that compliance of postmenopausal
women with risedronate 5 mg/d is an important correlate of their achievement of better
outcomes in terms of BTMs and BMD. Poor compliance should be considered in patients who
have not responded to risedronate therapy. In conclusion, BTM change can reflect the
degree of compliance to risedronate treatment in postmenopausal osteoporotic women.
[Programme]
P-298
COST-EFFECTIVENESS OF PARATHYROID HORMONE IN THE TREATMENT OF
OSTEOPOROSIS IN POSTMENOPAUSAL WOMEN IN SWEDEN
J. Lundkvist1*, O. Johnell2, D. Sykes3,
L. Jönsson1
1Stockholm Health Economics, Stockholm, Sweden
2UMAS, Dept. of Orthopaedics, Malmö, Sweden
3UK Lilly Research Centre, Erl Wood Manor, Windlesham, UK
Background
Parathyroid hormone (PTH) is a new treatment for
osteoporosis that has in clinical trials been shown to reduce the risks of vertebral and
nonvertebral fractures in postmenopausal women. The objective of this study was to
estimate the cost- effectiveness of PTH compared with no treatment, using a computer-based
simulation model.
Method
The analysis was conducted for a cohort of 69-year old
women in Sweden with at least one previous vertebral fracture and low BMD. The model
simulated the course of events in individual patients until death or 100 years of age. The
simulation was conducted in 6-month cycles. During each cycle the patients were at risk of
having clinical hip, vertebral or wrist fractures, or to die. Total accumulated life time
costs and quality adjusted life years (QALYs) were estimated. Swedish data on costs of
fractures, utility reductions after fracture, fracture risks and mortality rates were
used. The model took into account new epidemiological evidence which indicate that
fracture risks and mortality rates are higher in subsequent years after a fracture.
Results
The incremental cost-effectiveness ratio was about
260,000 SEK (28,000 EUR) per QALYs gained for PTH treatment compared to no treatment. The
result was based on a PTH price of 126 SEK (14 EUR) per day. The sensitivity analyses
included variations in fracture costs, treatment efficacy, utility reductions, fracture
risks and mortality rates, and showed that the results were fairly stable.
[Programme]
P-299
QUANTITATIVE ULTRASOUND VARIANCE IN ELDERLY INSTITUTIONALIZED WOMEN
J. Zochling1*, L. M. March1, R. G. Cummming2,
I. D. Cameron3, S. R. Lord4, J. Schwarz1, P. N. Sambrook1
1Institute of Bone and Joint Research, Department of Medicine,
University of Sydney, Sydney, Australia
2Department of Public Health, University of Sydney, Sydney,
Australia
3Rehabilitation Studies Unit, University of Sydney, Sydney,
Australia
4Prince of Wales Medical Research Institute, University of New
South Wales, Sydney, Australia
Aim: To compare the reliability and reproducibility of
two calcaneal ultrasound machines in a population of elderly institutionalized women, and
how variance changed with age.
Methods: Subjects were 1210 female residents of nursing
homes and hostels in the Northern Sydney area, participating in a multi-dimensional study
of the risks of falls and fractures in the institutionalized elderly, the FREE study
(Fracture Risk Epidemiology in the Elderly). Broadband ultrasound attenuation (BUA) was
measured in all participants using the same CUBA Mark II ultrasound instrument (McCue
Ultrasonics, London, UK). BUA was also measured using a Metra QUS2 ultrasound machine in
509 of the participants.
Results: The precision of BUA in normal individuals aged
18 to 80 in our laboratory for the CUBA machine is 2.4%. The mean difference between
repeated BUA measures on the CUBA machine was 0.362 dB/MHz, standard deviation 2.292
(t=5.5, p<0.0001), which was statistically significant. The mean difference between
repeated BUA measures on the QUS2 machine was 0.138 dB/MHz, standard deviation 2.775
(t=-1.1, p=0.3). Most of the variance in measurement is between- subjects not within
subjects, suggesting good reproducibility. For CUBA, variance (age)=71.16 and variance
(error)=260.07, and for QUS2 variance (age)=111.31 and variance (error)=107.22. Within
subject variance increases with age with both machines. There is no significant difference
in variability of repeated measures between the machines (F=1.8, p=0.2).
Conclusion: Quantitative ultrasound (QUS) is a reliable,
reproducible instrument for measuring bone quality in the institutionalized elderly
population, and has the advantage of portability and ease of use over the gold standard
for bone density assessment, dual energy x-ray absorptiometry. Variance estimated with
both methods was stable with increasing age suggesting this is a useful method for
estimation fracture risk even in the frail elderly.
[Programme]
P-300
BETWEEN CITY DIFFERENCES IN BONE TURNOVER, PTH AND 25(OH)D IN THE HEALTHY
FEMALE POPULATION: ARE COMMON REFERENCE VALUES JUSTIFIED?
A. Blumsohn1*, C. C. Glüer2, D. M. Reid3,
D. Felsenberg4, C. Roux5, R. Eastell1
1University of Sheffield, UK
2University Hospital Kiel, Germany
3University of Aberdeen, UK
4Free University Berlin, Germany
5Rene Descartes University, Paris
Geographical differences in skeletal metabolism in the
healthy general population are poorly characterised. Studies may be biased by different
selection criteria or exclusion, pre-analytical factors, non-concurrent sample collection
or assay.
We established reference intervals for bone turnover,
parathyroid hormone (PTH) and 25(OH) Vitamin D in 5 European centers (Aberdeen, Berlin,
Kiel, Paris, Sheffield) participating in the Osteoporosis and Ultrasound study (OPUS).
Serum (12:00 to 15:00 non fasting) and second void urine were obtained from 2780 female
reference individuals selected from population registers (approx. 600 per center).
Participants were classified by center, menopausal status, disease and confounding drug
therapy. Collection was completed over 24 months ending April 2001. Assays included serum
b Crosslaps (sbCTX), procollagen I N-terminal propeptide (PINP), osteocalcin (OC), PTH
(Elecsys, Roche Diagnostics), urine N-terminal telopeptide of type I collagen (NTX/Cr;
Ortho) and 25(OH)D. Storage was at -75C, and assays were performed in a single center in a
randomised order.
There was no significant heterogeneity of variance for
any analyte between center (Bartlett test, P>0.05). There were very small but
significant (ANOVA P<0.001) differences between center for all analytes in the total
postmenopausal population, but these were largely accounted for by differential use of
HRT. 25(OH)D was slightly lower in Paris (41.1 ±1.9SEM nmol/L) in comparison with the
other 4 centers (ANOVA P<0.01; Aberdeen 50.4 ±2.0, Berlin 54.0 ±2.3, Kiel, 52.3
±1.9, Sheffield 49.9 ±1.8). After exclusion for disease and drug therapy there were no
other substantial between-center differences for any analyte. In premenopausal women there
were no substantial differences between center for any analyte apart from lower bone
resorption in Paris and Kiel as judged by urine NTX/Cr and sbCTX (for uNTX/Cr: Paris 33.6
±2.0nmol/mmol; Kiel 44.8 ±1.9; Sheffield 50.7 ±2.9, Aberdeen 48.8 ±3.0, Berlin 51.9
±3.0; ANOVA P<0.01). In conclusion: Postmenopausal reference limits are similar
between these European cities. Lower premenopausal bone resorption in Paris and Kiel would
imply that T-scores may not be transferable between these centers. Sunshine behaviour,
skin pigmentation and protection are probably more important determinants of 25(OH)D than
latitude.
[Programme]
P-301
ASSOCIATION BETWEEN TARGET ORGAN RESPONSES DURING HORMONE REPLACEMENT
THERAPY: BONE VERSUS LIPIDS
S. Silvestri1*, A. B. Thomsen2, C. Christiansen2,
M. L. Brandi3, N. H. Bjarnason2
1Department of Clinical Phatophysiology, University of
Florence, Florence, Italy
2Center for Clinical and Basic Research, Ballerup, Denmark
3Department of Internal Medicine, University of Florence,
Florence, Italy
The aim of the study was to investigate whether in
postmenopausal women taking Hormone Replacement Therapy (HRT), those with a large response
in bone mineral density (BMD) were also those with the most favourable response in
lipid-profile.
Study design
A double blind placebo controlled trial including 278
postmenopausal women randomly assigned to five groups each receiving different
combinations of 17beta- estradiol and gestodene. The study period was 3 years and a total
number of 133 postmenopausal women were evaluated as valid completers.
The response in bone mass was expressed as the percentage
change in BMD from the baseline calculated by linear regression from semi-annual
measurements and analysed for between-group differences by one way analysis of variance.
The response in lipid-profile was evaluated as the
percentage change from baseline during the study period.
Results
A significant correlation between the increase in BMD of
the lumbar spine and hip with the decrease in serum total cholesterol and LDL was found
(P<0.001).
Conclusions
Our study shows that it is the same woman who has a
favourable response in BMD as in the lipid profile during HRT. The associations is most
likely driven by a common response in FSH to exogenous estradiol therapy despite the same
17beta-estradiol plasma levels.
In conclusion these results might improve the selection
of women who can benefit the most from HRT concerning both osteoporosis and cardiovascular
disease.
[Programme]
P-302
IS THERE ANY ASSOCIATION BETWEEN THE RESPONSE TO LEVORMELOXIFENE AND
RALOXIFENE IN DIFFERENT TARGET ORGANS?
S. Silvestri1*, A. B. Thomsen2, N. H. Bjarnason2,
M. L. Brandi3, C. Christiansen2
1Department of Clinical Phatophysiology, University of
Florence, Florence, Italy
2Center for Clinical and Basic Research, Ballerup, Denmark
3Department of Internal Medicine, University of Florence,
Florence, Italy
Estrogen Replacement Therapy (ERT) is used to alleviate
climateric complaints, to prevent bone loss and others chronic disease. To gain the full
benefits ERT must be administered for several years but the compliance to its long-term
use is poor due to side effects. Thus there is big interest in developing new drugs with
the beneficial effects of ERT and without its side effects. Among Selective Estrogen
Receptor Modulators (SERMs) Raloxifene has been proved to preserve Bone Mineral Density
(BMD) and to lower serum atherogenic lipids without producing significant effect on the
endometrium.
The Levormeloxifene (L-enantiomer of the racemic compound
Ormeloxifene) has been shown to prevent bone loss in the ovariectomized rat model. It
seemed to have the same estrogenic effects on bone and lipid profile without inducing
endometrial hyperplasia, but unfortunally, due to its important side effect on female
genitalia (uterovaginal prolapse) the development of this compound has been stopped.
Materials and Methods
Study I: phase II, double blind, placebo controlled,
multicenter trial. 133 healthy postmenopausal women aged between 45-65 years, at least one
year postmenopausal and with intact uterus, were randomly assigned to one of six groups
(Levormeloxifene 1.25, 5, 10, or 20 mg/day; continuous combined HRT 1mg estradiol and 0.5
mg noretisterone acetate and placebo).
Study II: double blind, placebo controlled, multicenter
trial. 248 healthy postmenopausal women aged between 45-60, within 2-8 years of menopause
were randomly assigned to one of 4 groups (Raloxifene 30, 60, 150 mg/day or placebo)
All women in both studies received 400-600 mg Calcium per
day. The participants were similar as far as baseline characteristics are concerned.
Results
No correlation was found between baseline lipid levels
(total cholesterol, LDL, HDL, tryglicerides) and lumbar spine and hip BMD.
We found a highly significant correlation (P<0.01)
between the response to Levormeloxifene and Raloxifene therapy as BMD of the lumbar spine
and hip with the decrease in serum lipids (total cholesterol and LDL).
In addiction we confirmed that Levormeloxifene had a
stronger estrogenic effect on serum lipids than 60 mg of Raloxifene, while the effect on
BMD was of the same magnitude as that of 60 mg Raloxifene.
[Programme]
P-303
BONE MINERAL DENSITY MEASUREMENT IN ANKYLOSING SPONDYLITIS (AS)
M. Korkosz1*, P. Gluszko1, P. Marcinek2
1Jagiellonian University School of Medicine, Dept of Medicine,
Div. of Rheumatology, Krakow, Poland
2Jagiellonian University School of Medicine, Dept of Medicine,
Radiology Unit, Krakow, Poland
Objective: To determine whether there is a relationship
between bone mineral density (BMD) measured at lumbar spine by quantitative computed
tomography (QCT) and BMD of lumbar spine and proximal femur measured by dual-energy x-ray
absorptiometry (DXA) in patients with AS. In addition, to assess possible correlations
between BMD values, x-ray scores and various clinical data.
Material and methods: 38 male patients fulfilling the New
York criteria of AS aged 23-67 years with disease duration of 3-30 years, underwent QCT
(lumbar spine) and DXA (lumbar spine and proximal femur) measurements and x-ray (thoracic
and lumbar spine). 12 male patients with lumbar spine osteoarthritis served as controls
for QCT evaluation.
Results: Lumbar spine trabecular BMD (region of interest)
measured by QCT correlated significantly only with BMDs of Ward's triangle measured by DXA
(r=0,63; p<0,05) Both measurements (lumbar spine QCT and Ward's triangle DXA)
correlated with disease duration (r=-0,51; p<0,05, and r=-0,37; p<0,05
respectively), however only QCT values of the lumbar vertebra negatively correlated with
the radiological grading of disease progression at spine.
Conclusions: Our data indicate that in AS only trabecular
bone BMD assessment regardless of the technique, i.e. DXA or QCT, carries valuable
information which correlates with the duration of disease and radiological grading of the
spine. The DXA
assessment of lumbar spine or femoral neck possess a
significant accuracy error due to perivertebral calcification of the soft tissues and has
no value for monitoring BMD changes in AS.
[Programme]
P-304
PERFORMANCE AND LIMITS OF IN VIVO MICRO-CT IMAGING OF TRABECULAR BONE IN
RATS AND MICE, WITH CONSIDERATION OF ANIMAL WELFARE AND TISSUE-WEIGHTED DOSIMETRY
P. L. Salmon*, E. G. G. Buelens, A. Sasov
Skyscan, Aartselaar, Belgium
Important advantages to experimental design of
preclinical bone studies are available, if trabecular bone of rats and mice can be imaged
in vivo under anaesthesia. However, in vivo scanning of rodents imposes constraints on
micro-CT scanner design, measurement geometry and imaging parameters, with the result that
the 3D x- ray image resolution is reduced compared to that attainable in ex vivo scanners.
The specific constraints include (a) rotating source-detector assembly around immobile
subject, (b) fixed source-detector separation, (c) loss of image contrast due to x-ray
absorption in live soft tissue surrounding bone, (d) limits to radiation dose to the
animal, and (e) breathing and heart-related movement of the animal during scanning. A
further constraint is stress to animals and consequent weight loss caused by anaesthesia,
an important consideration when contemplating multiple sequential scans. We demonstrate
that adequate resolution of trabecular bone structures can be achieved in rodents in vivo,
while not compromising animal welfare by excessive periods of anaesthesia or excessive
radiation dose. The scanner employed was the Skyscan 1076. 3D images with pixel size of
8.9 microns (Gaussian resolution of 12.5 microns) can be obtained at the rodent hindlimb
knee with local absorbed dose of about 0.6 Gray and whole body effective dose equivalent
of 10 milliSieverts (using ICRP tissue weighting factors). This resolution allows
structural histomorphometric analysis of rat and mouse trabecular bone. X-ray source
shuttering can reduce dose by a further 50%. The sensitivity of micro-CT-measured bone
parameters to changes in resolution and contrast are systematically evaluated. Parameters
vary in sensitivity, with connectivity parameters such as Euler connectivity being
especially sensitive to resolution. It emerges that the fixed scanning parameters of the
in vivo scanner are partly advantageous in that they impose standardisation on scanned
images and calculated structural parameters of trabecular bone.
[Programme]
P-305
MICROMECHANICS OF OSTEOPOROTIC BONE MEASURED BY SCANNING ACOUSTIC
MICROSCOPY
J. Brandt*, A. Franke, K. Raum
Laboratory of Experimental Orthopaedics, Martin-Luther University, Halle,
Germany
The Scanning Acoustic Microscopy (SAM) reveals the
possibility to deliver information on elastomechanical properties. The sound velocity
depends on elastic moduli and the elastic stiffness directly correlates with the sound
velocity in the direction of propagation. We used the acoustic impedance as a suitable
parameter for characterization of bone. Latest SAM-devices with frequencies up 2 GHz gain
a spatial resolution of about 0.5 micrometer, comparable with the light micropcopy, which
allows distinction of cellular and subcellular structures. We developed the image
processing software Multi Layer Analysis (MLA) to exclude the influence of surface
topography and to focus the images for quantitative investigation at frequencies up to 900
MHz. Consecutively a well focussed output image was calculated by MLA finding the maximum
V(z)-position for every pixel. The mechanical properties of osteoporotic bone were
measured in iliac crest biopsies. The bone was embedded in PMMA and specimens with
planparallel surfaces had been prepared by grinding and polishing. The acoustic procedure
is nondestructively, the correlation with nanoindentation measurement of elastic moduli at
the same location allows the calculation of material parameters. The results of impedance
measurement in osteoporotic and normal bone will be presented at the session. Besides
measurement the images deliver morphological information. Especially the transition of
regions containing hydroxyapatite minerals to neighbouring structures of organic
components and the process of maturation become clearly visible, contrasted without any
staining or alteration of the tissue. By means of image processing we gain well focussed
images and an extended procedure of calibrating ensures the reproducibility of
measurements. Contemporary trials to model bone in biomechanical theories and to judge its
loading capacity reveal a lack of measuring procedures, capable to deliver information on
bulk properties of bone and on the distribution of these properties in two or three
dimensions. But even loading capacity of bone becomes more and more interesting to
evaluate the quality of bone in case of osteopathies. Scanning acoustic microscopy seems
to be a valuable tool to detect elastomechanical properties via measurement of acoustic
parameters.
[Osteoporosis: Pathophysiology,
Genetics, Epidemiology] |