Rare bone diseases
P-95
HISTIOCYTOSIS X - LCH ( HAND-SCHUELLER-CHRISTIAN DISEASE): CLINICAL CASE
REPORT
A. S. Smailagic*, H. P. Piranic, F. F. Foco, A. M. AlHalil
University Clinic Center, Sarajevo Clinic for Maxillofacial Surgery,
Bosnia, Herzegovina
Histiocytosis X or Langerhans cell histiocytosis LCH, rare childhood
disease in which there is an overgrowth of a type of tissue cell called a histiocyte.
Annual incidence of 4 per million Etiology is unknown typified by bone involvement.
Case History: The patient was born 1978, male with half-year history of
pain and swelling submandibular left area, seen by a dentist and ortodontist. In July
1994, was seen by Maxillofacial surgeon and hospitalized. X-Ray showed destructive bone
lesions corpus of mandible with aplasion ramus. Skeletal X-ray showed oval radiolucent
lesion surrounded by thick margin of reactive bone affected vertebrae C5 C6, hand bone ,
rib r.5,7, l. 9. CT confirm. Biopsy of mandible lesion showed granulation areas with
specific histiocyte cells for Hand-Schueller-Christian disease.
Treatment:Aimed was to check progression of disease and treatments
included chemotherapy and radiotherapy 1994-1996. After regression 1996, therapy has
included surgical excision lesion of mandible and restore defect with autolog rib graft.
On last control March 2001 progresion of disease torticollis with limitation of motions
and long therm osteolisis and resorption of autolog rib graft. Discusion: Long time of
period disease was not discovered. Clinic symptom was not convincing. Biopsy and skeletal
X-ray imagining are recommended for definitive diagnostics. Chemotherapy and radiotherapy
stopped spreading of disease for 4 years. Is surgery treatment recommended ?. Conclusions:
Clinical LCH have broad spectar of symptoms and difficulty for diagnostics. Biopsy and
characteristic skeleton X-Ray imagining is recommended for certain diagnostic.
Radiotherapy and chemotherapy checked progression of disease for 4 years. Surgery is
recommended in case with extensive bone lesion accompanied with painless disfunction,
pathology fractures pseudoarthtosis and esthetic defects particularly in young person .
Gold standard with autolog bone graft is not recommended because of systems character of
bone disease. Allograft's accompanied with some osteoinductive factors as BMP's are
promising.
[Programme]
P-96
DYNAMOMETRY OF HAND IN MEDICAL PROGNOSIS OF WORKING CAPABILITY IN CHRONIC
REGIONAL PAIN SYNDROME
L. Krapac1*, A. Delija1, F. Skreb1, B.
Rozman1, B. Hranjec2
1University Hospital Dubrava, School of Medicine, University
of Zagreb, Croatia
2Department of Physical Medicine and Rehabilitation,
University Hospital Dubrava, Zagreb, Croatia
As epidemiological indicators are concerned the chronic regional pain
syndromes (CRPS) are mostly connected with injuries, they are more prominent in women. In
Croatia, in a sample of middle-aged patients (35 - 55 years of age) injuries are observed
in 8.3%. Injuries of the hand are registered in 2% and of lower leg in 1% of the examined
patients.
CRPS of hand is diagnosed in Outpatient department for prevention of
bone-joint system diseases in the Dubrava University Hospital on basis of medical
examination, x-ray and /or scintigraphic, densitometric and electrodynamometric treatment.
The MWPC is being observed in relation to disease severity, previous occupation, dominant
hand as well as comorbidity. At the end of medical treatment as part of functional
treatment the grip of the hand is measured by dynamometer. On basis of this finding
medical prognosis of working capability is made. By electrodynamometry (EDM) not only grip
force of the dominant and non-dominant hand, but endurance to bimanual work is obtained.
By multiple check of strength and endurance during treatment a positive retroactive effect
to patients motivation concerning restoration to health is achieved. During 2-year
observation of patients with CRPS no difference between 'white' and 'blue' collar workers
was registered. The age ranged from 30 to 64 years. The diagnosis of CRPS on the hand was
significantly more frequent in women (30:3 men) while on the foot Sudeck-Leriche's
syndrome is equally represented in women (34) and men (30). Significantly less CRPS was
observed on dominant hand (31:2), although epidemiological data point to comparable
injuries caused by traumas in right-hand patients. Only in one female patient CRPS was
manifested on upper and lower extremity. At the end of treatment force of contraction in
unhealthy hand measured by electrodynamometer was by 45% lower than expected.
The case of a commonplace hand injury that results in severe CRPAS (III
grade) was presented, the condition of symptom aggravation after surgical treatment of
carpal tunnel in a female worker as well as dissimulation of discomfort difficulties in
the right hand of a professional guitarist. The necessity of non-aggressive functional
diagnostics of the hand in CRPS, testing of sympathetic nervous system, damaging effect of
long-lasting immobilization as well as benefit of working therapy are being emphasized.
[Programme]
P-97
VALIDITY OF DENSITOMETRY IN DIAGNOSIS AND TREATEMENT OF SUDECK'S DISEASE
A. Delija*, F. Skreb, L. Krapac, B. Rozman, Z. Kuster
University Hospital Dubrava, School of Medicine, Univeristy of Zagreb,
Croatia
Aim of the study :
- prove osteoporotic component by measuring BMC
- administering medicine (Alendronate) and calcium, physical therapy with
special accent on magnetotherapy
- remove painful component and get full function of extremity movement
- follow the recovery of patient in the period of three, six and nine
months after the first therapy session.
Introduction: The lower value of BMC (Bone Mineral Component) as reaction
to the soft tissue and hard particles with injury of ephiphyses and soft particles was
measured in patients with complex regional syndrome (CRPSy - Sudeck syndrome ) by
densitometric method.
Materials and methods: In this study 23 patients aged between 38 and 65
with characteristic symptoms of CRPSy and radiological report showing the state after
fracture with spotted atrophic bone and osteoporotic changes in distal and proximal place
of the fracture were included. Pain and painful reduction of movement for more than 50% of
functional measurement (FOP) are prominent syndrome and after the imobilisation removal.
Densitometric measurements are performed on Hologic QDR - 45 000W (S/N 48111) Whole Body
V8.26a:5 and in all patients it has been proved the deficiency of mineral content in bone
structure from 35 to 85 gr in whole extremity in relation to collaterals. In control group
the biggest difference in assymetry was 4 to 16 grams. After inclusion in therapy process
patients subjectivly had pain reduction in more then 35% to 50%, functional recovery for
more then 50% and measured BMC gained from 5 gr to 22.5 gr in first three months. After 11
months 3 patients were on intermittent treatment, 7 only on Alendronate and active
exercise at home.
Conclusion: Following the dynamics of treatment by densitometry and
inclusion of Alendronate in treatment with already known physical procedures we managed
acceleration of improvement and recovery in patients with CRPSy. At the end reaction of
BMC is positively related to biphosphonate and low frequency magnetic field.
[Programme]
P-98
DISTRACTION OSTEOGENESIS BY ILIZAROV AND UNILATERAL EXTERNAL FIXATORS IN
DOGS
V. Kusec1*, M. Jelic2, F. Borovecki2, S.
Vukicevic2, K. Korzinek2
1Clinical Institute of Laboratory Diagnosis, Clinical Hospital
Centre, Zagreb, Croatia
2Department of Anatomy and Department of Orthopaedic Surgery,
Zagreb School of Medicine, Zagreb, Croatia
Bone tissue's inherent capability for regeneration has been used in limb
lengthening procedures after osteotomy/corticotomy and slow progressive distraction by an
external fixation device. In this study the canine experimental model of distraction
osteogenesis by two types of external fixators was evaluated. Following corticotomy either
Ilizarov (N=6) or AO unilateral (N=9) external fixator was applied. Distraction started 1
week after surgery (2 x 0.5 mm/day) and lasted 3 weeks. Specimens were harvested from week
7-12. The outcome was assessed by x-ray, histology, histomorphometry and microradiographs.
Bone regeneration as observed by X-rays was satisfactory and similar in both groups during
and at the end of the experiment. Both endochondral ossification, emerging from the
cortices, and intramembranous were found simultaneously in both fixator groups. Some
parameters OS/BS, O.Th, MAR, BFR were significantly higher in the regenerate area than in
other bone areas for both groups, and no difference in histomorphometric parameters
existed between the two fixator groups. Percentage of mineralised bone evaluated on
microradiographs varied between 9-49 percent for Ilizarov and 18-44 percent for the
unilateral fixator group in the regenerate area. The outcome of the two external fixators
was similar by x-ray, histology, histomorphometry and microradiographs. In this study
period of 7-12 weeks postoperatively the bone formation was enhanced and prevailed in the
distraction area. This study demonstrated the utility of the canine distraction
osteogenesis experimental model for the investigation of many aspects of this corrective
procedure.
[Programme]
P-99
ALVEOLAR RIDGE RESUMPTION IN COMPLETE DENTURE WEARERS: ONE YEAR STUDY
A. Celebic1*, F. Kovacic2, V. Carek1, I.
Baucic1, J. Stipetic1, D. Knezovic1
1School of Dental Medicine, University of Zagreb, Croatia
2Dental Medicine Polyclinic, Split, Croatia
Residual alveolar ridges show continual resumption after the loss of the
natural dentition resulting in reduction of the morphologic face height and a
counterclockwise rotation of the mandible. The aim of this study was to analyze the
residual ridge resorption (RRR) in different regions of both jaws on teleroentgenograms of
50 complete denture wearers and to correlate such changes with age, sex, number of years
edentulous, nighttime wear of the dentures and the surface of denture bearing area. The
height of residual ridges was measured on 5 different sites of each jaw on
lateral telerontgenographs by using a callibrated grid. The results
revealed that all the patients showed significant RRR in one year period (p less than
0.01), 2.5 times bigger in the mandibular bone compared to the maxilla. RRR was bigger in
men than in women, in patients who had their last extraction within a period of one year
before receiving their dentures than in patients who extracted their teeth earlier, in
younger individuals and in patients with bigger denture bearing area (p less than 0.01).
Nighttime denture wearing made no significant influence on the rate of RRR. The biggest
rate of RRR was recorded at frontal sites of residual ridges compared to the lateral
sites.
[Programme]
P-100
CLINICAL BONE DENSITOMETRIC STUDY ON PATIENTS TREATED WITH ITI IMPLANT
SYSTEM
D. Knezovic Zlataric1*, I. Filipovic Zore1, T.
Svajhler1, A. Celebic2
1School of Dental Medicine, University of Zagreb, Croatia
2Private Dental Office, Zagreb, Croatia
The aim of the study was to measure the bone mineral density (BMD) on
regions of interest (ROIs) on maxillary alveolar ridges close to the implant and to
compare them with BMD ROIs on the opposite sites of the maxilla. In cases if there were
other remaining teeth in the maxilla the aim was also to compare BMD of ROIs close to the
implants with the ROIs close to the remaining teeth. For this reason periapical radiograms
with a 10 steps copper stepwedge attached to each film were made in 10 patients with 23
ITI implants in maxilla. Films were processed together and were digitised. Grey levels of
each step were transformed to optical density values and using the third degree polynomial
the regression formula was calculated for each image. All the measured values (ROIs) were
expressed in actual copper stepwedge thickness equivalents using the calculated regression
formula. Comparison of BMD close to the implant in comparison to BMD close to the
remaining teeth shows the rate of success of osseointegration. This method may help dental
surgeon to assess the success of the osseointegration of the implants and even to assess
the quality of bone prior to the treatment.
[Programme]
P-101
FAILURE OF BULK STRUCTURAL GRAFTS USED FOR ACETABULUM RECONSTRUCTION
D. Delimar*, K. Korzinek, H. Klobucar, N. Cicak
Department of Orthopaedic Surgery, School of Medicine, University of
Zagreb, Croatia
Background: Bulk structural grafts are routinely used for reconstruction
of acetabulum roof during total hip replacement in patients with dysplastic hips.
Materials and methods: Retrograde analysis (from the year 1985) was
performed on two groups of patients. For the reconstruction of the acetabulum during total
hip replacement in one group of patients was used autograft (40 patients) and in another
allograft (20 patients). Inclination of the acetabulum cup coverage was measured from the
sequential roentgenograms in one year intervals. Original questionnaire was designed and
used by four different investigators for the evaluation of graft remodeling and
incorporation.
Results: Despite the excellent primary position and stability of the
grafts used for the reconstruction of the acetabulum roof mid term results show that there
is no adequate incorporation and remodeling under load of grafts causing instability and
migration of the acetabulum cup.
Conclusion: Reconstruction of acetabulum roof with bulk structural grafts
is usually performed in younger patients with dysplastic hips. Such reconstructions show
poor mid term results urging for early reoperations.
[Programme]
P-102
RADIOLOGICAL DIAGNOSIS OF FIBROUS DYSPLASIA
F. Kovacevic*, M. VukelicMarkovic, L. J. Vojnic, M. Jaksic, B. Brkljacic
Clinical Hospital Dubrava, Zagreb, Croatia
Fibrous dysplasia is a congenital malformation caused by postzygotic
somatic mutation of the gene GNAS1 responsible for Gs-alpha regulatory proteins.
The severity of the disorder is dependent on moment when mutation takes
place. Its severe form , known as McCune-Albright syndrome, evolves with an early gene
mutation.
We present three patients, one with McCune-Albright syndrome, and the
other two with monostotic form of fibrous dysplasia. The importance of various
radiological diagnostic methods is discussed.
[Programme]
P-103
THE VALUE OF PARATHYROID SONOGRAPHY IN SECONDARY HYPERPARATHYROIDISM
H. Tomic-Brzac*, D. Pavlovic
University Hospital Zagreb, Sveti Duh General Hospital, Zagreb, Croatia
Parathyroid sonography is used in detection of enlarged parathyroid
glands (PTG) for more than 20 years. Hyperparathyroidisms, i.e. hypertrophy and
hyperplasia of PTG, is a well known complication in uremic patients. During these 20 years
the knowledge of parathyroid gland function has improved, as has sonographic equipment.
Today we use a 2-D high resolution sonography with a 10 MHz probe and colour Doppler. Up
to now, parathyroid sonography was performed in more than 500 patients. In this study we
investigated the sonographic changes of PTG in dialysis patients and a possible
correlation between PTH level and PTG enlargement. In 120 patients (63 males and 57
females), mean age 45 years (14-79), dialysed for 7.8 (0.5- 22) years, PTG sonography (10
MHz colour Doppler probe) was performed. PTH was determined with Allegro intact PTH kit
(normal range 1-6 picomol/l). In 58 (48 percent) patients uniform echoes of PTG was found,
in 34 (28 percent) nodular pattern of PTG and in 28 (23 percent) degenerative changes of
PTG were detected. By colour Doppler sonography paranodular vascularity was found in 38
percent of PTG, hypervascular capsule in 22 percent , internal vascularity in 28 percent
and no vascularity in 12 percent of PTG. The highest PTH level was in patients with
nodular hyperplasia and paranodular vascularity of PTG. Suspected nodular changes were
more often found in male patients, but nodular changes of PTG were more prominent in
female patients with higher level of PTH.
In our experience PTH sonography with high-resolution equipment is very
useful in detection of PTG hyperplasia, i.e. size and shape of parathyroid glands, and is
more important in the management of dialysis patients than localisation of PTG.
[Programme]
P-104
PARATHYROID CARCINOMA IN DIALYSIS PATIENT
D. Pavlovic1*, H. Tomic-Brzac1, B. Sarcevic2,
M. Radetic3
1Sveti Duh, General Hospital, Zagreb, Croatia
2University Hospital Zagreb, Zagreb, Croatia
3Univeristy Hospital for Tumors, Zagreb, Croatia
Hyperplasia of the parathyroid glands (PTG) and increased secretion of
parathyroid hormone (PTH) is an invariable consequence of chronic renal failure. There are
two forms of PTG hyperplasia in patients with chronic renal failure: diffuse hyperplasia
and nodular, more severe form of hyperplasia. Parathyroid carcinoma is seen very rarely in
chronic renal failure patients, i.e. in patients with secondary hyperparathyroidism. We
present a dialysis patient with parathyroid and thyroid carcinoma, and adrenal
hyperplasia. The clinical investigation was done in 54 years old female patient who is
being dialyzed for 12 years. The level of intact PTH was >150 picomol/l and alkaline
phosphatase 389 U/L. Ultrasound of the neck (10 MHz probe and colour Doppler) showed
nodular changes of the thyroid gland and four enlarged PTG, three suspected on diffuse and
one on nodular hyperplasia. Needle aspiration biopsy of the most enlarged PTG was
suspected of medullary carcinoma. Therefore additional investigation was performed.
Calcitonin concentration was 91.6 picomol/l, and serum catecholamines concentration was
increased: 34 microgram/l. CT showed enlarged left adrenal gland. During the first surgery
left nephrectomy and adrenalectomy were performed. A month later, total thyroidectomy and
parathyroidectomy were done. Carcinoma of one PTG ( suspected nodular hyperplasia by
ultrasound) diffuse hyperplasia of three other PTG and follicular carcinoma of the thyroid
gland were pathohistologically documented, as well as hyperplasia of the left adrenal
gland. Two years after the surgery patient was in a good condition, PTH level was 3.2
picomol/l, and catecholamines level was 3.2 microgram/l.
A dialysis patients present a unique group of patients with frequent
impairment of endocrine functions. A careful clinical assessment and follow up is
indispensable in prevention and treatment of complications in dialysis patients.
[Programme]
P-105
CALCIPHYLAXIS: A RARE BUT SEVERE COMPLICATION IN DIALYSIS PATIENTS
D. Pavlovic*, S. Cala, N. Jankovic
Sveti Duh General Hospital, Zagreb, Croatia
Calciphylaxis is a rare but serious complication in dialysis patients the
pathogenesis of which is poorly understood. Dysregulation of calcium and phosphorus
metabolism is thought to be a major pathogenic factor. In six hemodialysis patients
(5F/1M), mean age 53 years on hemodialisys for 7.5 years, calciphylaxis was diagnosed. All
were affected distally: 3 had leg ulcers, 1 had heel ulcers, 1 toe necrosis and in 1
fingers were affected. In 3 patients severe secondary hyperparathyroidism was present, and
in 2 of them ulcers temporarily healed with the decline of PTH during pulse calcitriol
therapy. In other 3 patients normal PTH values were detected. Calcium phosphate product
over 6 micromol/L was only occasionally seen in 3 patients. No patients was remarkably
overweight, but in all 6 patients remarkable loss of body weight (from minus 7 percent to
21 percent) 6-12 months
prior or during manifestation of calciphylaxis occurred. In 4 patients
non insulin depended diabetes mellitus was first noticed during the same period. Three
deaths were caused by acral gangrene and in 1 patient death was cardial.
Prevalence of calciphylaxis in our haemodialysis patients is 1.7 percent
with predominance in the female gender, younger age and longer haemodialysis treatment.
Whether this is the cause or consequence of calciphylaxis remains to be clarified.
[Programme]
P-106
RENAL OSTEODYSTROPHY IN CROATIA BASED ON BONE HISTOMORPHOMETRY: FIFTEEN
YEARS OF EXPERIENCE
D. Krpan1*, Z. Lajtman2
1General Hospital Sveti Duh, University Medical School,
Zagreb, Croatia
2General Hospital Merkur, University Medical School, Zagreb,
Croatia
The metabolic bone disease and mineral metabolism disturbances are
frequent complications in renal failure, and still a great challenge of the modern
medicine. Renal osteodystrophy is the generic term generally used to describe the skeletal
complications of renal failure and it encompasses a wide spectrum of bone disorders. Based
on the predominant histopathologic patterns, it is often classified as: Predominant
Hyperparathyroid Bone Disease, Mixed Uremic Osteodystrophy, Low- Turnover Osteomalacia,
Adynamic Uremic Bone Disease, Mild Uremic Bone Disease. But because of the great
variability of histopathologic patterns no current classification is completely
satisfactory so we could consider the classification of renal osteodystrophy as not final.
Since the current therapeutic approach to the renal osteodystrophy is to normalize the
defect in bone remodeling, histopathologic pattern is the best basis for the accurate
diagnosis and planning the appropriate treatment. Thus, bone biopsy and histomorphometry
are the crucial diagnostic procedures in the evaluation of renal osteodystrophy. This work
provides a review of renal osteodystrophy in Croatia describing the histomorphometric
characteristics of bone in the group of 1000 uremic patients on hemodialysis randomized
among 2600 bone biopsies performed in the last fifteen years.
[Programme]
P-107
PAGET'S DISEASE AS A CAUSE OF SEVERE PARAPLEGIA, WITH COMPLETE RECOVERING
AFTER ALENDRONATE THERAPY: CASE REPORT
D. Krpan1*, J. Buljan-Culej2, D. Dogan1,
K. Orsolic1, Z. Lajtman3
1General Hospital Sveti Duh, University Medical School,
Zagreb, Croatia
2Department of Anatomy, School of Medicine, University of
Zagreb, Zagreb, Croatia
3General Hospital Merkur, University Medical School, Zagreb,
Croatia
Paget's disease is a localized disorder of bone remodeling. Increased
numbers of large osteoclasts initiate the process at affected skeletal sites, and the
increase in bone resorption is followed by an increase in new bone formation, altering
bone architecture.
We report a clinical case of unusual clinical and radiological features
of Paget's disease in a 42-year old, previously healthy Caucasian woman who suffered of
severe paraplegia. Clinical symptoms appeared suddenly as a parastesia and weakening of
the legs and developed to complete paraplegia during next two months. Extended diagnostic
evaluation subsequently done, demonstrated serum alkaline phosphatase levels 50% higher
then normal (145 mmol/l) gamma globulin values slightly higher and other biochemical
parameters in normal range. NMR of the vertebrae showed compression myelopathy of
vertebral bodies in region Th XII caused by the proliferation of vertebral body. X-ray of
frontal bones, vertebrae and the proximal femur showed hyper mineralization and
demineralization zones. Whole-body skeletal scintigraphy was atypical, and thus was no
diagnostic asset. Ascendant lumbar myelography showed stop of the contrast flow in the
region of Th XII and L I. Diagnostic evaluation including repeatable performed bone biopsy
and pathology assessment did not prove neoplastic disease. Since diagnostic evaluation did
not explain the cause of the disease, no therapy was applied and the patient was
completely immobilized during a year and half, before she came in our clinic, where,
transiliacal bone biopsy and histomorphometry has been performed and confirmed the
diagnosis of morbus Paget. The patient was treated daily with 10 mg alendronate and 0.25
mcg calcitriol. Six months later the patient was able to stand up and after eight months
complete recovery has been achieved.
Subsequent analyses indicated: normalization of bone turnover, less
osteoplastic foci on x-ray images of vertebrae and pelvis, regression of hyperosification
in areas of vertebrae Th XI and Th XII on NMR images and improved mobility of the patient.
In conclusion the 8-month therapy with alendronate and calcitriol was effective and
successful.
[Programme]
P-108
ABNORMALITIES OF THE FETAL SKELETON ASSESSED BY THREE-DIMENSIONAL
ULTRASOUND
A. Kurjak*, S. Kupesic, M. Kos
Department of Obstetrics and Gynecology, Sveti Duh Hospital, Medical
School University of Zagreb, Croatia
Objective: To establish the effectiveness and advantages of
three-dimensional ultrasound (3D US) in the evaluation of the abnormal fetal skeleton.
Patients and methods: Since 1995 we examined a total of 1840 high-risk
pregnant patients between 16 and 38 weeks of gestation examined by conventional two-
dimensional (2D) and three-dimensional (3D) ultrasound (Combison 530 D and Voluson 730)
manufactured by Kretztechnique, Austria.
Results: Comparing 2D and 3D ultrasound we found that 3D ultrasound
provided a significant diagnostic gain in 42 out of 58 (72.4 percent) fetuses affected by
different forms of skeletal abnormalities. Viewing data in multiplanar image (coronal,
frontal and axial planes) detection of 38 cases of skeletal abnormalities was enabled.
Volume rendering of the entire volume permitted the continuity or abnormality of the fetal
spine to be viewed in a single image. Three-dimensional ultrasound provided tomographic
evaluation of the fetal skeleton and enabled us to present transparent images, which was
not possible with 2D ultrasound. In each case we compared the prenatal transparent
reconstruction of the fetal skeleton with the postnatal radiogram.
Real-time 3D ultrasound imaging expanded our knowledge on fetal movements
in fetuses affected with skeletal abnormalities. In patients with complex anatomic
deformities and limited mobility (N=8), sonographer extracted detailed diagnostic
information available using various 3D ultrasound modes. In 9 out of 58 cases limited
quality of surface reconstruction aroused from oligohydramnios.
Conclusions: Three-dimensional ultrasound can assist in the diagnosis of
skeletal abnormalities because it offers the potential to better understand spatial
relationships of normal and abnormal fetal anatomy. Improved visualization of fetal
features has improved the skeletal anomaly identification and has been immediately
appealing for clearly sharing development information with the family. Networked imaging
allows problematic cases or cases discovered in remoted areas to be sent for consultation
via networked computer imaging to the specialists with vast experience.
[Programme]
P-109
BONE MARKERS REVEAL DECREASED COLLAGEN TYPE I SYNTHESIS AND CHANGE IN
BONE TURNOVER DURING BISPHOSPHONATE TREATMENT IN OSTEOGENESIS IMPERFECTA
V. Kusec1*, N. Huzjak2, I. Barisic2, A.
Resic2, I. Baric3, D. Anticevic4
1Clinical Institute of Laboratory Diagnosis, Clinical Hospital
Centre, Zagreb, Croatia
2Department of Pediatrics, Children's University Hospital,
Zagreb, Croatia
3Department of Pediatrics, Clinical Hospital Centre, Zagreb,
Croatia
4Orthopaedic Clinic, Clinical Hospital Centre, Zagreb, Croatia
Continuous action of bone cells, i.e. remodeling of the skeleton, is
reflected by measuring the products of their activity in serum or urine. Availability of
methods for determination of bone markers has provided some data on bone turnover in
osteogenesis imperfecta patients and the utility of bone markers in evaluation of
bisphosphonate treatment. It has been demonstrated that procollagen type I propeptide was
reduced in children with osteogenesis imperfecta in comparison to controls, but other bone
markers were not considerably different. In severely affected adults with osteogenesis
imperfecta bone resorption markers were increased, but also both normal and reduced
concentrations were found. Treatment with bisphosphonates caused reduction of bone
markers. Results obtained in a group of 20 osteogenesis imperfecta children and adults
were similar. Levels of procollagen were below or within the reference range for
premenopausal women in the majority of patients which were younger than 15 years, although
increased concentrations would be expected due to intensive skeletal growth. Decreased
procollagen in OI patients probably reflects less collagen type I formation and retarded
skeletal growth. Effect of bisphosphonate therapy was observed as decrease in procollagen
after commencement and as continuous decrease during one year therapy. Bone resorption in
some children younger than 10 years was below the upper limit of reference range for
premenopausal women, but increased in older patients. Similar to procollagen results, much
higher levels of resorption markers characteristic of intensive growth and turnover would
be expected, also suggesting growth impairment. It can be expected that clinical utility
of bone markers in osteogenesis imperfecta patients will be validated after more
experience is gathered generated by bisphosphonate treatment and biochemical assessment.
In comparison to other metabolic bone diseases, a benefit of a choice of specific bone
marker and a degree of change in monitoring can be expected.
[Programme]
P-110
FIBRODYSPLASIA OSSIFICANS PROGRESSIVA: REPORT OF TWO FEMALE PATIENTS
D. Anticevic1*, S. Grazio2, L. Bukovac3
1Department of Orthopaedic Surgery, Medical School, Zagreb,
Croatia
2Department of Rheumatology, Medical School, Zagreb, Croatia
3Department of Paediatrics, Medical School, Zagreb, Croatia
PURPOSE: To present two girls with fibrodysplasia ossificans progressiva
(FOP) who represent maybe all patients with that rare disease in 4,5 million country.
METHODS: A twelve year old girl present herself in orthopaedic
out-patient clinic with typical features of FOP i.e. small great toes, painful soft tissue
heterotopic bone formation around the neck and shoulder and scoliotic deformity of the
spine. The diagnosis of FOP was established in another institution, previously. She was
seeking treatment for her deformed spine. We did not recommend any surgical intervention
due to well known fact that surgery will aggravate already existing deformity. She was
followed-up for next thirteen years and she was given supportive therapy as well as advice
how to avoid more flare-ups and heterotopic bone formations. In a course of the time, her
spine become grossly deformed, still she is able to walk with the cane. A special
hospital-based medical interdisciplinary board was established to help her in a case of an
emergency.
Second patient is one-year girl who presented herself with elbow painful
swelling to the University Department of Paediatrics. Bilateral hallux valgus was noted
but not connected with X-ray revealed calcifications in soft tissues. Paediatrician and
orthopaedic surgeon specialist in oncology because of possible neoplasm considered biopsy.
Due to experience with first FOP patient, second orthopaedic opinion was given, biopsy was
cancelled and correct diagnosis was made. The girl is then followed-up for next five years
and only two episodes of painful soft-tissue swelling were encountered. Currently, she is
happy and playful child waiting to start school years.
SIGNIFICANCE: Two clinical history of this rare and devastating disease
(FOP) showed that long-term follow-up and experience with older patient helped to made
correct and timely diagnosis in a younger patient.
CONCLUSION: Every patient with congenital hallux valgus and ectopic
ossification should be considered for diagnosis of FOP. Multidisciplinary approach is
essential correct diagnosis and management.
[Programme]
P-111
RECONSTRUCTION OF OSSEOUS DEFECTS WITH COMPRESSED ALLOGENIC CANCELLOUS
BONE FRAGMENTS, AUTOLOGOUS RED MARROW AND BMP-7 IN ANIMAL EXPERIMENT
T. Djapic1*, M. Jelic1,3, V. Kusec2, S.
Vukicevic3, M. Pecina1
1Department of Orthopedic Surgery, School of Medicine,
University of Zagreb, Croatia
2Clinical Institute of Laboratory Diagnosis, Clinical Hospital
Centre, Zagreb, Croatia
3Department of Anatomy, School of Medicine, University of
Zagreb, Croatia
Compressed cancellous bone is usual form of bone allogenic
transplantation in orthopaedics surgery especially to fill a large cavity in tumor or cyst
defects or acetabular defect cavity in revision hip surgery. The idea was to improve an
osteointegration of compressed allogenic cancellous bone with addition of autologous red
marrow or BMP-7.
Material and methods: An ulnar segmental-defect model was used to
evaluate bone healing in adult male New Zeland White rabbits. In six rabbits a defect was
filled with compressed allogenic cancellous bone. In another six rabbits a defect was
filled with compressed allogenic cancellous bone with addition of autologous red marrow
and in third group with six rabbits a defect was filled with compressed cancellous bone
with addition of 300 micrograms of recombinant human BMP-7 ( osteogenic protein -1). In
four rabbits that served as a control group defect received no implant. The defects were
examined radiographically periodically for two weeks. All animals were sacrificed 10 weeks
after operation. Amputated limbs were examined radiographically and histologically.
Results: In defects that filled with compressed cancellous bone and
autologous red marrow and BMP-7 osteointegration was significant better.
Conclusions and clinical relevance: Addition of autologous red marrow and
BMP- 7 to compressed allogenic cancellous bone can improved osteointegration.
[Programme]
P-112
OSTEOGENIC PROTEIN-1 (BMP-7) IN THE TREATMENT OF LONG BONE NON-UNIONS IN
THE LOWER EXTREMITY
M. Pecina
Department of Orthopedic Surgery, School of Medicine, University of
Zagreb, Croatia
Osteogenic protein-1 was successfully used in treatment of 5 patients in
long bone non-unions in the lower extremity. Two patients were treated because of femoral
non- union, two because of tibial non-union and one after non-union of radius. In one
patient, M.K., 44 years old, non-union of the femur occurred after war injury. After
osteosynthesis was performed with condylar plate and autologous cancellous bone grafting,
2 doses of OP-1 were applied. Three months postoperatively bone healing was observed. In
another patient, B.S., 32 years old, non-union has occurred after unsuccessful femoral
elongation. After removal of Wagner apparatus, osteosynthesis with a condylar plate and
screws was performed with addition of osteogenic protein-1 device and an autologous
cancellous bone graft. Three months postoperatively bone defect bridging occurred. The
next patient, D.S., 83 years old, had a distal tibial shaft non-union developed after
osteosynthesis with plate and screws. After intramedullary nailing with OP-1 application,
bone healing occurred after 5 months. Another patient, Z.I., 64 years old, had
unsuccessfully been operated 14 times during the time period of 12 years due to distal
tibial shaft non-union. After application of external fixator by Ilizarov together with
OP-1 with resection of fibula, 4.5 months postoperatively bone healing is observed. In
another patient, K.V., 73 years old, after two unsuccessful surgical procedures,
osteogenic protein-1 device has been applied to the radius during the third procedure of
compressive osteosynthesis with plate and screws. Four months postoperatively bone healing
was observed.
Local application of OP-1 did not induce any local or systemic
complications in any of our patients. Application of OP-1 after internal or external
fixation has induced bone healing in all our patients treated for non-unions.
[Programme]
P-113
THE FALL OF PHOSPHORYLATED METABOLITES LEVELS DURING PREGNANCY IS
ASSOCIATED WITH A RISE IN ALKALINE PHOSPHATASE IN SUBJECTS WITH HYPOPHOSPHATASIA
S. J. Iqbal*, T. Davies, R. Cole, A. Daudia, S. Holland
Department of Chemical Pathology, Leicester Royal Infirmary, Leicester,
UK
Hypophosphatasia (HYPOS) is a rare bone disease characterised by low
circulating levels of tissue non-specific alkaline phosphatase (TNSALP) and increased
levels of phosphorylated metabolites (PHOS.MET), including serum pyridoxal phosphate (PP),
and urine phosphoethanolamine (PE), the natural endogenous substrate for TNSALP. In normal
pregnancy, placental alkaline phosphatase (PALP) level rises and is reflected by a raised
level of total serum alkaline phosphatase activity (TALP). We measured TALP and the
PHOS.MET in two female heterzygote carriers for hypophosphatasia; A (26 yrs) and B (31
yrs) around their pregnancy.
TALP was measured by an automated method. AMP buffer, PNPP substrate, 30
deg C (RR 40-130 IU/L) PP by HPLC (RR 12-97 µmol/L) and PE by HPLC (per mmol to urine
creatinine RR<10 µmol/mmol Cr). Results before, during 3rd trimester of pregnancy, and
one week after delivery, were as follows. In A; TALP was 20, 203, 94 and PP 134, 7, 16. In
B; TALP was 13, 46, 19 and PE 19, <5, and 5. The rise in TALP was due to rise in PALP
component.
The reciprocal changes in TALP and PHOS.MET suggests that PALP can
hydrolyse PHOS.MET in HYPOS.
[Programme]
P-114
CADMIUM AND CALCIUM INTERACTIONS: EXPERIMENTAL DATA
M. Piasek*, M. Blanusa, M. M. Saric, K. Kostial
Institute for Medical Research and Occupational Health, Zagreb, Croatia
Due to increasing environmental pollution with toxic metal cadmium (food,
cigarette smoke) in the last decades, potential cadmium effects with regard to the so
called 'Itai-Itai Byo' (ouch-ouch disease) have attracted considerable attention. It is a
syndrome with extensive bone demineralisation and renal tubular damage identified in Japan
after World War II in multiparous women above 45 years of age who were exposed to
cadmium-contaminated water and food. Toxic effects of orally administered cadmium on bone
metabolism in experimental animals fed on calcium- deficient diets have been frequently
reported during seventies. Results of experimental studies in vivo and in vitro
started in eighties by Bhattacharyya and co-workers on mice and dogs, support the view
that cadmium exposure in conjunction with calcium deficiency and pregnancy/lactation are
key etiological factors for the Itai-Itai-like syndrome. Chronic exposure to cadmium has
been directly linked to bone loss, low bone mass, and increased incidence of fracture
independent of cadmium-induced renal toxicity. Our results in rats have shown that
lactating animals present a group with higher susceptibility to cadmium-induced bone mass
loss compared to non- pregnant rats. Our results together with other authors' data have
provided evidence that cadmium causes increased calcium bone loss in midlactating animals.
We also found that adolescent females have increased susceptibility to cadmium-induced
reduction of bone mass, especially under condition of lower (0.3%) calcium intake in the
diet.
We investigated another type of cadmium-calcium interaction in evaluation
of the effect(s) of calcium supplementation during suckling period on toxic metal
retention. In suckling rats supplemented with calcium (1%, 3% and 6% in cow's milk) and
concomitantly exposed to cadmium per os, concentrations of cadmium were
significantly decreased in organs and carcass (skeleton). The effect was dose-related. No
calcium-effect on tissue cadmium was found in pups exposed to cadmium prior to calcium
supplementation. Calcium supplementation per se significantly increased
calcium concentration in the carcass. It was concluded that calcium
supplementation during the suckling period could be an efficient way of reducing oral
cadmium absorption and retention without affecting tissue essential trace elements.
Further research on cadmium-calcium interactions is necessary in both
humans and experimental models.
[Programme]
P-115
LONG BONE BOWING IN HUMAN CAMPOMELIC DYSPLASIA RESULTS FROM AN ECTOPIC
PRIMARY OSSIFICATION CENTER WHERE CARTILAGE GROWS PERPENDICULAR TO THE AXIS OF CARTILAGE
ANLAGEN
A. Corsi1,2*, M. Riminucci1,2, M. Roggini3,
P. Bianco2
1Department of Experimental Medicine, Laboratory of Pathology,
University of L'Aquila, Italy
2Department of Experimental Medicine and Pathology, La
Sapienza University, Rome, Italy
3Department of Pediatrics, Section of Radiology, La Sapienza
University, Rome, Italy
Campomelic dysplasia (CD) is a severe skeletal dysplasia caused by
heterozygous mutations of Sox9 in which most of the endochondrally formed bones are
affected. Although not pathognomonic of CD, symmetric and anterior congenital bowing of
the long bones (CBLB, campomelia) of the lower limbs, especially the tibiae, is the most
striking skeletal feature. Many mechanisms, including abnormalities in lower limb
vascularization, imbalanced muscular development and/or faulty fetal positioning in
uterus, have been proposed to explain CBLB.
We investigated the radiologic and morphological changes observed in the
tibiae of four second trimester fetuses with CBLB. In the younger fetus (15 weeks), the
cartilaginous, unossified cartilage anlagen of the tibiae were hypoplastic and markedly
bowed, and showed an ectopic center of ossification at the apex of the incurvation. Here,
the axis along which chondrocytes matured to hypertrophy was perpendicular to the long
axis of the cartilage anlagen, with the equivalent of the proliferative zone at the
periosteal aspect, and hypertrophy at the opposite end. In three older fetuses (18, 22, 23
weeks), the tibiae were proportionally different in length and extensively ossified at the
diaphysis, but still hypoplastic and similarly bowed; proximal and distal epiphysis and
growth plates were recognizable. The incurvation was included into the fully ossified
region of the shaft. A complex array of secondary bone trabeculae and vascular channels
oriented perpendicularly to the normal longitudinal axis of the bone rudiment was obvious.
Our data show that campomelia in humans may result from a primary bending
of the cartilage anlagen which precedes their ossification and is associated with the
formation of a misaligned and ectopic primary ossification center. Subsequent modeling and
remodeling of this aberrant center restores proximal and distal growth plates, but the
ortogonal growth momentum in the rudiment generates an abnormal direction of secondary
bone formation at the midshaft. It remains to be determined whether these growth plate
dysmorphisms that are upstream of the abnormal bone growth observed in CD are directly
dictated by Sox9 mutations, or rather reflect the interplay of mechanical, muscular and/or
vascular influences on a simple hypoplasia of cartilage anlagen caused by Sox9
haploinsufficiency.
[Programme]
P-116
BISPHOSPHONATE THERAPY IN PATIENTS WITH OSTEOGENESIS IMPERFECTA
N. Huzjak1*, I. Barisic1, A. Resic1, V.
Kusec2, D. Anticevic2, D. Dodig2, D. Primorac3
1Children's Hospital, Zagreb, Croatia
2University Medical Center, Zagreb, Croatia
3University Medical Center, Split, Croatia
Background: Severe osteogenesis imperfecta (OI) is a hereditary disorder
characterised by increased bone fragility and progressive bone deformity. Secondary
osteoporosis is an important feature of OI. So far, no effective medical treatment is
available. Antiresorptive activity of the aminobisphosphonates may improve clinical
outcome in children.
Aim: to assess the clinical impact of the administration of
bisphosphonates in Croatian OI patients.
Methods: We introduced therapy in 1998 encouraged by parents from
Croatian society of OI (HUOI). Here we report results of 1-3 years treatment with
intravenous pamidronate (APD) in seven children with severe OI, 4 female and 3 male with
age distribution ranging from 3 months to 11 years at the entry. Pamidronate was
administered either in the form of monthly infusions at a daily dose of 1- 1.5 mg/kg
during a period of 6 months followed by a pause of three months, or in the form of three
daily infusions every four months, the administered dose being the same. All patients
received 500-1000 mg of calcium and 1000 IU of vitamin D daily.
Results: During treatment, DEXA measurements showed a gradual increase of
bone density. Number of confirmed fractures decreased in all patients. The reduction in
pain as well as improvement in well-being and ability were impressive in two male patients
who had been confined to a wheelchair, but now they are able to walk using crutches.
Well-known acute phase reactions were noted in two children during first infusion cycle
and asymptomatic hypocalcemia was noted in three children. During the treatment body mass
index of three children was significantly increased.
Conclusion: Although the bisphosphonates do not correct basic
abnormalities in OI, they significantly alter the natural course of the disease and
improve patients' quality of life. For the time being they seem not only effective but
also devoid of any adverse effects on bone growth and remodelling.
[Programme]
P-117
CO-EXISTENCE OF OSTEOGENESIS IMPERFECTA AND KLINEFELTER SYNDROME
I. Atanasova*, A. M. Borisova, B. Lozanov, N. Sestrimska, P. Kumanov, R.
Ivanova, L. Diankov
Clinical Centre of Endocrinology and Gerontology, Medical University,
Sofia, Bulgaria
Osteogenesis imperfecta (OI) and Klinefelter syndrome (KS) are separate
genetically determined disorders affecting the skeletal system. OI encompasses
phenotypically and genotypically a heterogeneous group of autosomal, dominantly inherited
diseases due to mutation(s) in the genes encoding procollagen-I with a great variability
of gene expression which suggests the role of yet not identified factors segregating
independently that act to modulate the final phenotype. The X chromosome includes genes
that are known to determine the skeletone structure. Impaired bone mineral density (BMD)
and osteoporosis are common in hypogonadotropic hypogonadism with extra X chromosome (KS).
We report a case in which both OI and KS are present. Our male proband with OI type I
presented with 48 bone fractures since 2 years of age, blue sclerae, hypermobile joints,
dentinogenesis imperfecta, but normal hearing, normal height-175 cm, eunoichoidal
proportions of the skeleton without deformities. His family is affected with OI type I,
mild form and typical autosomal dominant mode of inheritance. The combination of both
diseases in our patient can explain the difference in OI phenotype in comparison with
other affected family members and suggests the probable role of genes in gonosomes in the
phenotype variability of OI. Our case also requires a special treatment approach including
biphosphonate and testosterone substitution which improved the clinical course of both
diseases. The occasional combination of OI with KS in our patient provokes a set of
pathophysiologic, diagnostic and therapeutic questions.
[Programme]
Treatment of osteoporosis
P-118
TREATMENT OF IDIOPATHIC OSTEOPOROSIS IN MALE PATIENTS USING ALENDRONATE
M. Cokolic1, R. Hren2*
1Teaching Hospital Maribor, Maribor, Slovenia
2University of Ljubljana, Ljubljana, Slovenia
In men with osteoporosis, but no obvious cause, the treatment choice
remains to be clearly established. The aim of this study was to assess the effectiveness
of alendronate therapy in treatment of male patients with idiopathic osteoporosis.
Ten men with idiopathic osteoporosis (T-score at lumbar spine or hip <
-2.5 SD, serum concentrations of free testosterone, Ca, P, Mg, and alkaline phosphatase
(ALP) within normal limits) were enrolled in a prospective study between March 1997 and
September 2000. Patients were 48 to 65 years old (mean: 59 years). They were treated with
alendronate sodium (10 mg/d) in combination with 500-mg elemental calcium. The BMD in the
lumbar spine (L2 - L4) and left hip was measured in all patients using dual energy X-ray
densitometry (Hologic QDR2000+) at the start of the treatment and at 12 to 48 months after
initiation of the treatment. The serum levels of Hgb, Hct, WBC, Plt, testosterone, Ca, P,
Mg, Na, K, Cl, ALP, AST, ALT, BUN, and creatinine were measured every 12 months.
Average baseline BMD was 0.762 g/cm2 (n=10, range 0.686 to
0.816 g/cm2) at the lumbar spine and 0.721 g/ cm2 (n=10, range 0.697
to 0.742 g/cm2) at the hip. After treating patients on average for 28 months,
the average BMD was 0.808 g/cm2 (n=10, range 0.729 to 0.888 g/cm2)
at the lumbar spine and 0.775 g/ cm2 (n=10, range 0.751 to 0.795 g/cm2)
at the hip. BMD thus increased on average by 6% at the lumbar spine and 7.5% at the hip.
Serum levels remained within normal limits throughout the treatment, with no adverse
events observed during the study.
Results of our on-going study suggest that alendronate sodium can provide
clinically relevant benefits in male patients with idiopathic osteoporosis.
[Programme]
P-119
TREATMENT INTERVENTIONS IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS IN
SLOVENIA
R. Hren1*, M. Cokolic2
1University of Ljubljana, Ljubljana, Slovenia
2Teaching Hospital Maribor, Maribor, Slovenia
Balancing the treatment goals of the physician with those of the patient
has become an important focus in the clinical management of osteoporosis. It is important
that clinical measures of therapeutic management (such as, bone mineral density increase,
fracture reduction) are correlated with the treatment choice. In this study, we examined
the treatment status of postmenopausal women with osteoporosis in Slovenia.
Women who participated in the study were required to have been previously
diagnosed with osteoporosis. In the survey, we collected the fracture status, age, body
mass index, lumbar spine (L2-L4) bone mineral density, and treatment choice.
The survey was conducted at 10 DEXA centers. We prospectively enrolled
945 women with postmenopausal osteoporosis, with a mean age (±SD) of 64 (±9) years, mean
body mass index of 26 (±4), and mean T-score at lumbar spine of -3.3 (±0.8). The
fracture status of the study group was as follows: 18% of women suffered the wrist
fracture, 3% the hip fracture, 18% had some degree of kyphosis, and 44% experienced the
height loss >3 cm. Women in the study were treated with alendronate sodium (71%),
calcitonin or hormone replacement therapy or etidronate sodium (10%), and calcium and
vitamin D (5%); 14% were not treated.
Results of our survey suggest that in Slovenia, more than 70% of
postmenopausal women diagnosed with osteoporosis are treated with bisphosphonate
alendronate.
[Programme]
P-120
REPEATED INGESTION OF CALCIUM-FORTIFIED WATER DECREASES SERUM
CONCENTRATIONS OF NTX BUT NOT OF ICTP
J. Guillemant1, C. Accarie2, V. de la Guéronnière3,
S. Guillemant1,2*
1Faculté de Médecine Pitié-Salpêtrière, Paris, France
2EPHE, Nutrition Hydrominérale, Paris, France
3Pôle Expertise Eau, Bourg-la-Reine, France
In a previous study (Am J Clin Nutr 2000) we showed that a single oral
intake of calcium-rich water could significantly increase the serum concentration of
ionized calcium (iCa) and suppress serum concentrations of CTX for 4 hours demonstrating
that calcium-rich mineral water could be considered as an efficient source of dietary
calcium to prevent osteoporosis. Until now 3 immunoassays detecting N- or C- terminal
telopeptides fragments of typeI collagen in serum are available. Since it has been
suggested that these fragments could be generated through distinct collagenolytic pathways
we decided to compare the responses of serum NTX and ICTP to the ingestion of
calcium-fortified water. Ten young adult males (21-26 y) ingested at three times (at
08.00, 11.00 and 14.00) 660 ml of either calcium-fortified (as bicarbonate, chloride and
sulfate) spring water (300 mg/L of elemental calcium) or calcium-poor (<10 mg/L)
mineral water. Blood was collected at 08.00, 11.00, 14.00 and 17.00, referred to as P0,
P3h, P6h and P9h, immediately before every intake of water for measurement of iCa, NTX and
ICTP. Oral intake of calcium-fortified water resulted in a progessive increase in serum
iCa (from 1.252 to 1.319 mmol/L) and decrease in serum NTX (by 19.3% at P3h, 24.7% at P6h
and 23.1% at P9h) while serum ICTP concentrations were not affected. Since ingestion of
calcium-poor mineral water induced a modest (-10.6%) but significant (P<0.01) decrease
in NTX we compared the two sets of assays with repeated-measures two-factor analysis of
variance with interaction. Ingestion of calcium-fortified water resulted in a significant
decrease in serum NTX (time, P<0.0001; treatment, P=0.006; time-by-treatment, P=0.09).
The present findings show that NTX and ICTP are not equivalent as indices of the
osteoclastic response to the intake of calcium.
[Programme]
P-121
THE INFLUENCE OF DEHYDROEPIANDOSTERONE THERAPY ON THE SKELETAL METABOLISM
OF MICE WITH SYSTEMIC LUPUS ERYTHEMATOSUS
D. Schapira1*, A. Weiss2, A. Kabala2, Z.
Blumenfeld3
1The B. Shine Department of Rheumatology, Rambam Medical
Center, Haifa, Israel
2Laboratory for Musculoskeletal Research, Faculty of Medicine,
Technion-Israel Institute of Technology, Haifa, Israel
3Department of Obstetrics and Gynecology, Rambam Medical
Center, Haifa, Israel
Introduction: Systemic lupus erythematosus (SLE) is an inflammatory
disease with multisystemic damage. Osteoporosis occurs in patients with SLE. The etiology
is multifactorial and includes prolonged corticosteroid treatment, the effect of
immunological factors on bone resorption, relative immobility, amenorrhea, avoidance of
sunlight, renal failure, etc. Laboratory mice are satisfactory models for human
osteoporosis. In previous studies we have shown that MRL mice (inbred mice which
spontaneously develop SLE) may serve as a model for the skeletal metabolism in SLE.
Dehydroepiandosterone (DHEA) is an adrenal steroid with androgenic activity. Some studies
have shown a beneficial effect of DHEA on disease activity in SLE and on bone density.
Aim of the study: To elucidate the influence of prolonged DHEA treatment
on the skeletal metabolism of SLE mice.
Materials and Methods: MRL mice were divided into two groups: controls
(fed with routine rodent chow) and treated animals (fed with DHEA enriched food) and were
followed from 1.5 to 6 months of life. Measurements at 1.5, 3, 4.5 and 6 months included:
animal and femoral body weights, femoral bone biochemistry (calcium, phosphorus,
magnesium, protein); alkaline and acid phosphatase enzymatic activities, bone histology
and histomorphometry (femoral head and neck).
Results: No intergroup differences in the animal and femoral body weights
and in the bone mineral and protein content; similar alkaline phosphatase enzymatic
activity yet, reduced (-29%) acid phosphatase and higher (+41%) alkaline/acid phosphatase
ratio in treated animals; minimal age-related decreases in the trabecular bone volume in
the treated group as compared to losses of up to 31% in controls, resulting at the end of
the trial in higher values (+37.6% femoral head; +36% femoral neck) in the DHEA fed mice.
Conclusions: DHEA increases skeletal mass in SLE mice but does not seem
to influence the bone mineral content. Further studies using combinations of different
doses of DHEA and calcium and vitamin D are required.
[Programme]
P-122
EFFECT OF DUPLICATE URINE COLLECTION ON RESPONSE RATE TO RISEDRONATE:
DATA FROM THE IMPACT STUDY
R. Eastell1*, R. A. Hannon1, P. Garnero2,
P. D. Delmas2
1Clinical Sciences Center, Northern General Hospital,
Sheffield, UK
2University Claude Bernard, Lyon, France
Risedronate (RIS) treatment produces decreases in the levels of
biochemical markers of bone resorption, with maximal effects observed at about 3 months.
The effect of treatment in individuals can be monitored by using the least significant
change (LSC) in the biochemical markers. We compared the percentage of RIS- treated women
in the IMPACT study who were responders (i.e., whose change in marker level exceeded the
LSC) based on the mean of duplicate measurements of urinary N-telopeptide of type I
collagen (NTX) with the percentage of responders based on single measurements. The IMPACT
study included 2386 women with osteoporosis (T-score at -2.5 or lower at the spine or hip
or a T-score between -2.5 and -1 with a peripheral fragility fracture). This preliminary
report is based on 1030 women who had urinary NTX measurements at baseline, 3 months, and
6 months, using the Ortho Clinical Vitros analyzer. At each time point, 2 samples were
taken 1 day apart (second morning void). The LSC for double measurements was set at
30percent (equivalent to a P-value of 0.1); the LSC for single measurements was 42 per
cent (30 times 1.414). With double measurements, the response rates at 3 and 6 months were
70 per cent and 72 per cent, respectively. With single measurements, the rates at 3 and 6
months were 55 per cent and 61 per cent, respectively. These response rates are
conservative as the subjects were treated with calcium supplements (1000 mg Ca/400 IU
Vitamin D daily) for 2 to 4 weeks prior to obtaining the baseline urine samples. Also, no
adjustments were made with regard to compliance and persistence of the subjects while on
treatment. We conclude that the reduction in variability achieved by taking the mean of
two measurements results in a substantial improvement in the ability to identify
responders to RIS treatment.
[Programme]
P-123
IN VIVO EFFECTS OF PDE-IV INHIBITORS ON MURINE BONE
M. Kometani1, K. Toriyama1, M. Kneissel2,
L. Widler2, M. Glatt2*
1Novartis Pharma Research, Tsukuba, Japan
2Novartis Pharma Research, Basel, Switzerland
Introduction: Inhibitors of phosphodiesterase type 4 (PDE-4) have been
shown in vitro to increase the number of mineralized bone nodules and to reduce the number
of TRAP-positive multinuclated cells in rat bone marrow cultures [1]. We have tested
rolipram and XT-44, two selective PDE-4 inhibitors, for their potential positive effects
on bone of intact mice and ovariectomized rats with established osteopenia.
Methods: 12-week-old female ICR mice were once daily treated with XT-44
(1, 3, or 10 mg/kg, p.o.) or rolipram (5, 10 or 20 mg/kg, i.m.) for 8 weeks (5 d/w). At
the end of the experiments, mice were killed, tibiae and 5th vertebrae were isolated for
DEXA analysis with a Piximus apparatus (Lunar) or compression testing with a mechanical
strength test apparatus (TK-252, Unicom, Tokyo).
6-month-old female Wistar rats were ovariectomized (OVX). 3 months later
treatment was initiated: the animals received XT-44 (1, 3, or 10 mg/kg, p.o. on
alternating days) or rat PTH (1-34) (5 microg/kg, s.c. once daily) for two months. Changes
in bone mass and geometry were monitored by DEXA and pQCT. At necropsy lumbar vertebra 5
was excised and subjected to mechanical loading.
Results: In intact mice, rolipram or XT-44 did not show significant and
dose- dependent, positive effects on bone mineral density or bone mineral content. The
maximum compression load determined on LV5 was not changed either. In OVX rats, DEXA did
not reveal a positive effects of XT-44 treatment, whereas a low dose of rat PTH (1-34)
significantly enhanced BMD. pQCT analysis of the proximal tibia metaphysis showed a
marginal positive effect of XT-44 on cancellous BMD. In
comparison, rat PTH (1-34) significantly increased total and cancellous
BMD and cortical thickness. Compression testing of LV5 showed no effects of XT-44
treatment on maximum load, however rat PTH (1-34) exerted a significant positive effect.
Conclusion: The selective PDE-4 inhibitors rolipram and XT-44 do not
increase bone mass in intact mice. In osteopenic, estrogen-depleted rats, both compounds
are ineffective in restoring tibial bone mass and lost mechanical load resistance in
vertebrae.
[1] Waki et al., Jpn J Pharmacol 79:477 (1999)
[Programme]
P-124
THE EFFECT OF HORMONE REPLACEMENT THERAPY OR ALENDRONATE TREATMENT ON
MARKERS OF BONE TURNOVER AND BONE MINERAL DENSITY IN POSTMENOPAUSAL WOMEN
J. Jelcic1*, V. Kusec2, M. Kifer1, M.
Korsic1
1Department of Endocrinology, Internal Medicine Clinic,
Clinical Hospital Centre, Zagreb, Croatia
2Clinical Institute of Laboratory Diagnosis, Clinical Hospital
Centre, Zagreb, Croatia
Hormone replacement therapy (HRT) and alendronate are well established
antiresorptive agents used for prevention and therapy of osteoporosis. In this study data
for 287 postmenopausal women (132 osteopenic and 155 osteoporotic) were analysed. Bone
mineral density (BMD) was measured for diagnostic and follow-up purposes by DEXA
(dual-energy x-ray absorptiometry). Bone turnover was estimated by measuring serum
osteocalcin, procollagen type-1 propeptide, telopeptide of collagen type I and urine
telopeptide, free deoxypyridinoline and pyridinoline. HRT received 48 percent of
osteopenic and 22 percent of osteoporotic patients, and alendronate received 36 percent of
osteopenic and 65 percent of osteoporotic patients. Patients with established osteoporosis
were older (66±7.9 yr) than those with osteopenia (59.8±8.7 yr). Repeated BMD showed an
average increase of 2.18 percent for both the lumbar spine and the hip. The results did
not differ significantly with respect to age, condition (osteopenia or osteoporosis) or
treatment. BMD change during treatment correlated significantly and positively with the
period of follow-up densitometry (4-24 months) only for the lumbar spine. The average
concentrations of bone turnover markers before the start of therapy were mostly below the
reference range for postmenopausal women. After initiation of either HRT or alendronate
bone markers decreased and continued with this trend or remained decreased. Telopeptide
measured in urine show the highest decrease. The telopeptide values were also
significantly higher in osteoporotic than in osteopenic patients prior to treatment, and
the decrement after therapy was also significantly greater in osteoporotic (75 percent)
than in osteopenic patients (26 percent). These results showed beneficial effect of HRT
and alendronate therapy on bone density, and a more pronounced effect on markers of bone
turnover in osteopenic and osteoporotic patients. Bone marker(s) with the greatest
decrement after therapy should be recommended as a rational course of treatment
monitoring. Monitoring treatment by densitometry should be performed at intervals greater
than 1 year to enable observation of clinically significant changes.
[Programme]
P-125
TOTAL SERUM CALCIUM IN PERIODONTITIS-AFFECTED PATIENTS
D. Plancak1*, A. Bosnjak1, K. Jorgic-Srdjak1,
D. Bozic1, B. Vizner2
1Department of Periodontology, School of Dentistry, University
of Zagreb, Croatia
2Department of Endocrinology, School of Medicine, University
of Zagreb, Croatia
Periodontal disease is characterized by resorption of the alveolar bone
and loss of attachment, which eventually leads to tooth loss. Although it is not actually
evident to which extent calcium is related to periodontal disease, if skeletal bone mass
is related to mineral bone density and periodontal disease, it is plausible that calcium
concentration, as it affects alveolar bone mineral density, will affect periodontal
disease. In order to establish a relationship between periodontal disease and serum
calcium levels we performed laboratory tests on serum and total serum calcium in a
randomly collected sample. The total of 77 subjects was collected randomly from patients
visiting the Department of Periodontology of the School of Dentistry in Zagreb. Patients
were divided in two groups according to the clinical diagnostic procedures (mean
attachment loss, gingival bleeding) and radiographic status which determined the extent
and severity of the periodontal disease. All total serum analyses were performed on venous
blood serum samples collected at the Laboratory for Endocrinology of the Clinical Hospital
'Sestre Milosrdnice' in Zagreb, together with the antropometric variables. The results
show significantly lower serum calcium concentration in subjects with greater attachment
loss and more gingival bleeding (p<0.1 percent). There is also a lower serum calcium
concentration in subjects older than 35 years of age and males. The study demonstrates
that there might be a correlation between total serum calcium levels and more severe
periodontal disease. However, this study did not cover the dietary calcium uptake, and
further work should be directed to correlating the level of serum calcium with the dietary
uptake and possible dysfunctions of its resorption in the gastrointestinal system.
[Programme]
P-126
ACETABULAR FRACTURES IN THE ELDERLY PATIENTS WITH OSTEOPENIA
D. Pericic*, D. Djurdjevic, D. Hudetz
Traumatology Hospital, Zagreb, Croatia
Having the opportunity of treating elderly patients with acetabular
fractures, we tried to evaluate risk, efficiency and complications of open reduction and
internal fixation. In the period between 1994 and 1998 we performed open reduction and
internal fixation in 42 patients. Age of the patients was between 60 and 82 years with
mean age of 69 years. We treated 31 men and 11 women who all suffered from a certain
degree of osteopenia. 20 patients out of 42 had a traffic accident and 22 patients have
fractured their acetabulum after falling. Preoperatively we controlled pain with
continuous epidural analgesia, performed X-ray and CT evaluation, assessed degree of
osteopenia and performed antithrombotic and antibiotic prophylaxis. Postoperatively all
the patients were soon mobilized and continued stationary rehabilitation. As far as
complications are concerned we noted pulmonary embolism, bleeding from the GI tract,
sciatic nerve lesion, infection, loosening of the implanted material, aseptic necrosis of
the femoral head and heterotopic bone ossification.
Primary open reduction is preferable to total hip replacement due to
difficulties in reconstruction of the bone stock and insertion of the prosthesis. The
decision to perform primary open reduction should be based on medical status of the
patient, degree of osteopenia, fracture pattern and experience of the operating team.
[Programme]
P-127
STATINS DECREASE BONE TURNOVER IN POSTMENOPAUSAL WOMEN: A CROSS-SECTIONAL
STUDY
L. Rejnmark1,2*, N. H. Buus2, P. Vestergaard1,
F. Andreasen2, M. L. Larsen3, L. Mosekilde1
1Department of Endocrinology and Metabolism C, Aarhus
Amtssygehus, Aarhus University Hospital, Denmark
2Department of Clinical Pharmacology, Aarhus University,
Denmark
3Department of Medicine and Cardiology, Aarhus Amtssygehus,
Aarhus University Hospital, Denmark
Background: Statins have been suggested as potential agents in the
management of osteoporosis. Reviews of medical records have shown an increased bone mass
and some studies have shown a reduced occurrence of fractures in subjects on long term
treatment with statins. We studied the effects of treatment with statins on calcium
homeostasis, bone turnover, and bone mineral density.
Design: In a cross-sectional design, plasma levels of parathyroid hormone
(PTH) and biochemical bone markers, bone mineral density (BMD), and body composition (fat-
and lean tissue-mass) were measured in 140 postmenopausal women who had been treated with
a statin for more than two years (median 4 years) and compared to 140 age- and
gender-matched population based controls.
Results: Plasma levels of biochemical bone markers were lower in the
statin treated subjects than in the controls: osteocalcin (-9%, p=0.03), bone-specific
alkaline phosphatase (-14%, p<0.01), and C-terminal telopeptide of type I collagen
(-11%, p<0.01). On the other hand, plasma PTH levels were 16% higher in the statin
treated subjects than in the controls (p<0.01). However, body composition and BMD at
the lumbar spine, hip, forearm, and whole body did not differ between the two groups. No
correlation could be demonstrated between changes in biochemical quantities and dose or
duration of statin use.
Conclusion: Our data show that statins affect the function of bone cells.
Most likely, the effect is antiresorptive.
[Programme]
P-128
IBANDRONATE: SERUM KINETICS, TISSUE DISTRIBUTION AND BINDING TO BONE
FOLLOWING INTRAVENOUS BOLUS INJECTION
F. Bauss1,2*, R. Endele1, E. Besenfelder1,
J-P. Hoelck1
1Roche Diagnostics GmbH, Pharma Research, D-82372 Penzberg,
Germany
2Institute of Pharmacology & Toxicology, Heidelberg
University, D-68169 Mannheim, Germany
Bisphosphonates (BPs) when given intravenously are traditionally
administered by slow infusion. Ibandronate is a highly potent, nitrogen-containing BP that
can be administered by i.v. bolus injection in clinical trials, a convenient alternative
to infusion. Here, a series of studies was conducted in rats to characterise the
pharmacokinetics of ibandronate using this approach.
Male and female Sprague-Dawley rats were administered 14C-ibandronate
0.1mg/kg as a single i.v. bolus injection. Radioactivity was analysed in serum, urine,
whole animal sections (autoradiography), soft tissue and bone. As ibandronate is not
metabolised, radioactivity accounts for the intact drug. Ibandronate was rapidly cleared
from plasma and eliminated predominantly by renal excretion. Total body clearance was
13.7ml/min/kg, renal clearance for the entire collection period (0-96 hours) was
3.25ml/min/kg, terminal serum half-life was 7.1 hours and phase of distribution was <2
hours. As demonstrated by serial whole-body autoradiography
after 24-96 hours, ibandronate deposits predominantly in bone, with
negligible amounts in kidney, liver and spleen. When analysed for detailed tissue
distribution, approximately 40-50% of the dose was found in bone, predominantly in
trabecular bone, with <2% in all non-calcified tissues, even after just 2 hours.
Following long- term distribution analysis up to 365 days after dosing, approximately 18%
of the administered 14C-ibandronate was found in total. Detailed analyses of
remnants (% of dose) and elimination half-life (days) after 1 year showed deposition (in
order of decreasing concentration) in carcass (16.1%, 380 days), femoral metaphyses (1.3%,
440 days), femoral diaphyses (0.9%, 500 days), kidney (0.005%, 24 days), liver (bql, 22
days) and spleen (0.01%, 77 days).
Thus, as with other bisphosphonates, ibandronate is rapidly cleared from
serum, with renal elimination being the predominant route, and binds selectively to bone,
where it has a long elimination half-life. The potency and high concentration of
ibandronate in bone are consistent with recent data supporting its long-term activity in
preventing bone loss and maintaining bone quality in aged ovariectomised rats with
treatment intervals of up to 6 weeks. The clinical role of ibandronate i.v. bolus
injections with extended drug-free intervals is currently being defined in postmenopausal
osteoporosis.
[Programme]
P-129
STRONGER EFFECT OF ALENDRONATE THAN ETIDRONATE ON LUMBAR SPINE BMD GAIN
AFTER ONE YEAR OF TREATMENT
D. Kastelan*, Z. Giljevic, V. Plavsic, I. Aganovic, M. Korsic
Division of Endocrinology, Department of Internal Medicine, Clinical
Hospital Centre Zagreb, Croatia
Background: Bisphosphonates are powerful inhibitors of osteoclasts
induced bone tissue resorption. Their chemical structure is characterised by two P-C
bonds. The purpose of this study was to asses and compare efficacy of alendronate and
etidronate in the treatment of osteoporosis.
Methods: 146 women with osteopenia/osteoporosis were divided into two
groups. Group 1 (n=91, mean age = 63.9±1.1, lumbar spine BMD = 0.726±0.01, Tsc. = -
2.9±0.1, total hip BMD = 0.726±0.01, Tsc. = -2.9±0.1) received alendronate 10 mg daily
and group 2 (n=55, mean age = 64.3±1.0, lumbar spine BMD = 0.758±0.02, Tsc. = -2.5±0.2,
total hip BMD = 0.786±0.02, Tsc. = -1.4±0.2) received etidronate 400 mg for 14 days in
three months intervals. All patients received calcium and vitamin D at a dose depending on
a level of urinary calcium. Bone mineral density was assessed using a dual X-ray
absorptiometry at baseline and after 12 and 24 months. Student's T-test was used for data
analysis.
Results: After one year of treatment the mean percent of BMD increase in
alendronate group was 7.4±1.4 percent in lumbar spine (p<0.00001) and 4.8±1.2 percent
in total hip (p<0.00001). In etidronate group BMD increased 3±0.9 percent in lumbar
spine (p<0.01) and 3±1.1 percent in total hip (p<0.005). Average lumbar spine BMD
gain induced by alendronate was significantly higher comparing to etidronate (p<0.01).
After 2 years of therapy, alendronate induced 9.6±2.1 percent increase of lumbar spine
BMD and 11±4.5 percent increase of total hip BMD while in etidronate group 5.4±1.5
percent increase in lumbar spine BMD and 4.6±3.1 percent increase in total hip BMD was
observed. Differences between groups were not statistically significant.
Conclusion: Study confirmed both agents to be effective in treatment of
osteoporosis with significantly stronger effect of alendronate in lumbar spine after one
year of treatment. After 2 years of treatment although BMD gain in alendronate group was
higher in all measured area the differences between groups were not statistically
significant, probably because of low number of women being treated for two years.
[Programme]
P-130
INHIBITION OF THE OSTEOBLASTIC MATRIX METALLOPROTEASE ACTIVITY INDUCES
INCREASED BONE MASS IN VIVO
V. Geoffroy1*, N. Legoupil1, P. Clément-Lacroix2,
C. Morieux1, S. Roux1, I. Terraz3, J. Rossert3,
M-C. de Vernejoul1
1INSERM U349, Hôpital Lariboisière, Paris, France
2Aventis Pharma, Romainville, France
3INSERM U489, Hôpital Tenon, Paris, France
Matrix metalloproteases (MMPs) play an essential role in the
physiological process of matrix remodelling especially in bone. Recently, osteoblastic
MMPs have been suggested to be involved in the osteoclastic process of bone resorption as
coupling agents and therefore to be regulators of bone mass. Mice overexpressing the
Tissue Inhibitor of Metalloprotease 1 (TIMP-1) under control of the osteoblast specific
elements of the collagen type 1 promoter were generated and analysed. Transgenic mice
overexpressed TIMP-1 at physiological level, specifically in the osteoblasts. Bone mineral
density (BMD) at the total body, femur and caudal vertebrae was measured by Dual-energy
X-ray absorptiometry (DEXA) using a Piximus (Lunar) in 1-, 2.5- and 4-month-old mice. BMD
was identical in males at any site and at any time. By contrast, in females, BMD was
higher in 1-month-old transgenic mice compared to wild type's, at the caudal vertebrae, a
site rich in trabecular bone. We therefore analysed more in detail 1-month-old transgenic
and wild type mice. Peripheral quantitative computed tomography (pQCT) showed that in the
tibia of females transgenic mice, total and trabecular BMD were increased whereas cortical
bone was unaffected. In addition, micro computed tomography (microCT) and histomorphometry
showed that trabecular bone volume was increased in tibia and trabecular separation, a
hallmark of osteoclastic bone resorption, was markedly decreased. These results favour the
hypothesis that osteoblastic metalloproteases are required for resorption of trabecular
bone in vivo. The reason why the phenotype was present only in females is not yet
understood.
[Programme]
P-131
CP-533,536, A NOVEL NON-PROSTANOID EP2 RECEPTOR SELECTIVE PROSTAGLANDIN
E2 (PGE2) AGONIST, STIMULATES LOCAL NEW BONE FORMATION IN RATS
H. Z. Ke*, H. Qi, D. T. Crawford, M. Li, V. M. Paralkar, T. A. Owen, L.
C. Pan, K. O. Cameron, B. A. Lefker, B. Lu, W. A. Grasser, L. J. Yu, P. DaSilva-Jardine,
D. D. Thompson
Pfizer Global Research and Development, Groton Labs., Groton,
Connecticut, USA
PGE2 significantly increases bone mass and bone strength when
administered systemically or locally to the skeleton. PGE2 binds to all four receptor
subtypes, EP1- EP4. We have found that the EP2 receptor subtype plays an important role in
the local bone anabolic activity of PGE2. CP-533,536 is a newly discovered, non-prostanoid
EP2 receptor selective agonist. CP-533,536 binds selectively to the EP2 receptor with an
IC50 of 11 nM (binding IC50 is greater than 2800 nM for EP1, EP3, and EP4). Similarly,
CP-533,536 was selective as an EP2 receptor agonist when measured against other prostanoid
receptors including the prostaglandin D2 (DP), prostaglandin F2a (FP), prostacyclin (IP),
and thromboxane receptors (TP) in the prostanoid receptor family. CP-533,536 stimulated
the EP2 receptor to initiate signaling by the cAMP pathway with an EC50 value of 5 nM. To
determine the local anabolic effects of CP-533,536, we locally injected this compound into
the bone marrow of the proximal tibial metaphysis in 6-week-old male rats. Single
injection was given on day 1 at doses of 0, 0.3, 1 or 3 mg/kg (n=10 per group), and the
rats were necropsied on day 7. The injected tibia was analyzed using PQCT, bone
histomorphometry and biomechanical testing. The PQCT and histomorphometric analysis showed
that CP- 533,536 dose-dependently increased new bone formation in the injected site. Total
mineral content and density significantly increased at 1 mg/kg or 3 mg/kg of the CP-
533,536-treated groups as compared with vehicle controls. Area of new bone induction
increased significantly by 606% and 1280% at 1 or 3 mg/kg of the CP- 533,536-treated
groups as compared with vehicle controls, respectively. The initial maximal load increased
significantly by 172% and 181%, respectively, at 1 or 3 mg/kg of the CP-533,536-treated
groups as compared with vehicle controls. These results showed that CP-533,536, a novel,
non-prostanoid EP2 receptor agonist stimulated local bone formation, increased bone mass
and bone strength when delivered locally to bone marrow cavity in rats. These results
indicated that EP2 receptor plays an important role in PGE2's local bone anabolism, thus
agonizing the EP2 receptor provide therapeutic potentials for local bone augmentation and
bone healing.
[Programme]
P-132
COMPARISON OF THE EFFECT OF ALENDRONATE AND ALENDRONATE WITH HRT ON BONE
MINERAL DENSITY
Z. Giljevic*, D. Kastelan, M. Kralik, I. Hruskar, M. Korsic
Division of Endocrinology, Internal Medicine, Clinical Hospital Centre,
Zagreb, Croatia
Estrogens and bisphosphonates are well-established antiresorptive agents
in treatment of osteoporosis. This study evaluated effect of hormone replacement therapy
(HRT) and alendronate combination therapy in comparison to alendronate alone.
In the study we administered a combination of alendronate 10 mg daily and
HRT to 24 osteoporotic/osteopenic women, mean age 56.3±1.72 years (x±SE), average lumbar
spine BMD 0.747±0.03 g/cm 2 (Tsc.-2.6±0.23), average femoral neck BMD
0.622±0.02 g/cm 2 (Tsc.-2.7±0.24) and average total hip BMD 0.743±0.02 g/cm 2
(Tsc.-1.9±0.19). Control group (n=57) with mean age 59.8±1.38 years, average lumbar
spine BMD 0.732±0.02 g/cm 2 (Tsc.-2.8±0.15), average femoral neck BMD
0.615±0.01 g/cm 2 (Tsc.-2.7±0.12) and average total hip BMD 0.718±0.02 g/cm 2
(Tsc.-2.2±0.17) received only alendronate 10 mg daily. All patients received calcium in
daily dose between 800 and 1500 mg, depending on calcium serum and urinary level. Bone
mineral density of lumbar spine, femoral neck and total hip was measured by DEXA, at
baseline and after 12 and 24 months of therapy.
After 12 months of treatment BMD increased at almost all measured sites
in both groups. In alendronate plus HRT group, rate of BMD increase was 4.1 percent in
lumbar spine, 0.6 percent in femoral neck and 3.6 percent in total hip. In the control
group 6.2 percent increase of BMD was observed in lumbar spine and 3.6 percent in femoral
neck. The cumulative change from baseline BMD, after 24 months of follow up, was 7.78
percent in lumbar spine, 1 percent in femoral neck and 6.1 percent in total hip in
alendronate plus HRT group and 10.77 percent in lumbar spine, 1.4 percent in femoral neck
and 2 percent in total hip in the control group.
Combination of alendronate and HRT is an effective therapy for
osteoporosis, especially in non-responders to HRT. Effect on total hip bone density was
significantly greater in women who received alendronate plus HRT than in women who
received alendronate alone.
[Programme]
P-133
EFFECT OF EGG-SHELL CALCIUM AND COMBINATION THERAPY WITH COLLAGEN ON THE
OVARIECTOMIZED RATS
K. Svik*, R. Istok, M. Stancikova, P. Masaryk
Institute of Rheumatic Diseases, Piestany, Slovak Republic
Objective. The effect of egg-shell calcium and combination therapy with
collagen type I in preventing OVX-induced bone loss was studied in an animal model of
postmenopausal osteoporosis. The aim of the study was to determine the influence of
egg-shell as a source of calcium and the additive effect of collagen on ovariectomy
induced osteoporosis in the rats.
Methods. Adult female Sprague-Dawley rats 250±10 g body weight were
subjected to bilateral ovariectomy (OVX) and sham operation (SHAM). Forty animals were
divided into four groups: (1) sham-operated controls, (2) OVX controls, (3) OVX rats
treated with egg-shell calcium 30 mg/kg, (4) OVX rats treated with combination of collagen
type I (0.36 mg/kg, isolated from bovine Achilles tendon) and egg-shell calcium (30
mg/kg). For a period of 9 weeks the control animals were on a calculated diet containing
7.5 g Ca/kg, 6.5 g P/kg and 1000 IU vitamin D3/kg diet of the rats usual dietary
requirements. Bone mineral density (BMD) and bone mineral content (BMC) of the whole body
and femur was determined using DEXA. Pyridinoline (Pyr), deoxypyridinoline (Dpyr) and
creatinine were assessed by HPLC method in the urine.
Results. BMD, BMC of the whole body and the femur were markedly decreased
in OVX rats in comparison with SHAM controls. These densitometric parameters were
significantly increased by egg-shell calcium and even more manifestly in combination
therapy - egg-shell calcium plus collagen. The beneficial effect of egg-shell calcium and
the combination therapy egg-shell calcium plus collagen was demonstrated also with urinary
markers of osteoresorption Pyr and Dpyr.
Conclusion. Our data suggests that preventive treatment of ovariectomized
rats with egg-shell calcium and combination therapy of egg-shell calcium plus collagen
type I markedly inhibit loss of bone mineral density and content as well as increase of
biochemical markers of bone resorption Pyr and Dpyr in urine.
[Programme]
P-134
CANCELLOUS BONE MASS AND COMPRESSIVE STRENGTH ARE INCREASED IN ADULT RATS
AFTER STATIN TREATMENT
H. Oxlund*, T. T. Andreassen
Dept of Connective Tissue Biology, Inst of Anatomy, University of Aarhus,
Aarhus, Denmark
Statins are widely used as cholesterol-lowering agents. Some of the
statins possess bone anabolic properties: statins increased expression of the bone
morphogenetic protein-2 gene in osteoblasts resulting in increased bone formation of mice
calvariae, increased the cancellous bone volume in 3-month-old rats and induced a minor
decrease in osteoclast number (Mundy et al., Science 286, 1946-1949, 1999). Simvastatin
increased the femoral periosteal bone apposition rate, but did not change the body weight
or femoral length of 12-month old rats (Oxlund, J Bone Miner Res 14(S1), S313, 1999), and
increased the vertebral bone mass and strength (Oxlund et al., J Bone Miner Res
15(S1):S549). In the present study the effects of statin on cancellous bone were examined
further. Twenty-one female Wistar rats, 12 months old, was given Simvastatin MSD (10
mg/kg/day) or placebo by a gastric tube for 3 months. Two mm high specimens was cut
transversely from the distal femoral metaphysis and from the 5th lumbar vertebral body.
The specimens were composed of cancellous bone surrounded by a shell of cortical bone
which were analysed by histomorphometry and by a micro-CT-scanner. The cancellous bone
within the cortical and endocortical shell of each specimen was then submitted to a
biomechanical compression test in a materials testing machine between a set of upper and
lower platens with diameters corresponding to the diameter of the cancellous bone of each
specimen. The cancellous bone volume and compressive stress of the cancellous bone in the
distal femoral metaphysis of the statin group (19.1±2.5 % and 21.3±7.5 millinewton/mm2,
mean values±SEM) were increased (2p<0.001 and 2p=0.02) compared with the placebo group
(10.5±1.6 % and 9.9±3.1 millinewton/mm2). The cancellous bone volume and
compressive stress of the vertebral bodies from the statin group (52.7±1.6 % and
31.8±2.7 newton/mm2) was increased (2p<0.001 and 2p<0.04) compared with
the placebo group (42.8±1.7 % and 24.1±1.9 newton/mm2). In conclusion, statin
given per orally to adult rats increased the cancellous bone mass and compressive strength
in both distal femoral metaphyses and vertebral bodies.
[Programme]
P-135
BONE MORPHOGENETIC PROTEIN-6 INCREASES BONE MINERAL DENSITY OF
OVARIECTOMIZED RATS
J. Buljan-Culej*, P. Simic, G. Grahovac, A. Grskovic, M. Habek, S.
Vukicevic
Department of Anatomy, School of Medicine, University of Zagreb, Zagreb,
Croatia
We have discovered that human recombinant bone morphogenetic protein-6
(BMP- 6), given systematically, can completely restore lost bone in aged ovariectomized
rats. To determine whether discontinuation of BMP-6 therapy results in rapid bone loss we
performed the following set of experiments.
SD female rats were ovariectomized at 6 months of age and therapy started
5 months later. The animals were divided into three groups: (1) sham (n=20), (2)
ovariectomized (OVX) plus acetate buffer as a vehicle (n=20) and (3) OVX plus BMP-6 (n=40)
(3x/week, 10 microg/kg iv). At twelve weeks hind limbs of BMP-6 treated rats reached the
values of sham animals confirming that BMP-6 can effectively restore lost bone. We next
divided the BMP-6 treated rats into three subgroups as follows: (1) OVX plus BMP-6 (n=15)
(3x/week, 10 microg/kg iv), (2) OVX plus 17alpha-estradiol (n=15) (3x/week, 50 plus 50
plus 75 microg/kg sc) and (3) OVX with no therapy (n=10). Bone mineral density (BMD) of
total body, lumbar spine and hind limbs was measured 6 weeks later and no significant
differences of BMD was found in animals previously treated with BMP-6. However, animals
which continued to receive BMP-6 had significantly higher hind limb BMD as compared to
sham animals. In conclusion these results suggest that the bone restored in ovariectomized
BMP-6 treated rats was not lost after discontinuation of the BMP-6 therapy.
[Programme]
P-136
BONE MORPHOGENETIC PROTEIN-6 RESTORES LOST BONE IN OVARIECTOMIZED RATS
J. Buljan-Culej1*, V. Kusec2, P. Simic1,
G. Grahovac1, A. Grskovic1, M. Habek1, K. Sampath3,
S. Vukicevic1
1Department of Anatomy, School of Medicine, University of
Zagreb, Zagreb, Croatia
2Central Laboratory, University Hospital Zagreb, Zagreb,
Croatia
3Creative BioMolecules, Hopkinton, USA
Since current therapy for osteoporosis is based only on antiresorptive
drugs, there is a great need for agents that could restore lost bone and prevent
fractures. Good candidates are bone morphogenetic proteins (BMPs), which can, when applied
locally, induce formation of new tissues like bone, cartilage and ligament.
There is no evidence that a human recombinant BMP, given systematically,
can restore bone in an osteoporotic animal model.
SD female rats were ovariectomized at 4 months of age and therapy started
12 months later. Bone mineral density (BMD) of total body, lumbar spine and hind limbs was
measured at 6 and 12 weeks period. Animals were divided into six groups: (1) sham (n=30),
(2) ovariectomized (OVX, n=20), (3) OVX plus 17beta-estradiol (n=20) (3x/week, 50+50+75
microg/kg sc), (4) OVX plus BMP-6 (n=20) (3x/week, 10 microg/kg iv), (5) OVX plus BMP-6
(n=20) (3x/week, 50 microg/kg iv) (6) OVX plus 17beta-estradiol+BMP-6 - 10 microg/kg
(n=20). BMD values of hind limbs in BMP-6 rats treated for three months reached the values
of sham rats. The effect of the lumbar spine showed less efficacy. 17beta-estradiol alone
was significantly less effective at both sites. Ex vivo BMD values of excised femur, tibia
and lumbar spine, were similar to the in vivo measurements. Results of pQCT analyses
showed an increase in the cortical thickness of BMP-6 treated animals. Since the size of
bones was not change the increased cortical thickness in BMP-6 treated rats was the result
of endocortical bone formation. Histomorphometry in aged animals showed significant
enhancement in bone volume at the sites where at least some bone was present at the
beginning of therapy, since 1.7 years old animals did not have any permanent trabecular
bone in the mid methaphysis at the beginning of therapy.
These results show, for the first time that systemically administered
BMP-6 has a significant anabolic effect in osteoporotic rats.
[Programme]
P-137
INTERMITTENT HPTH ADMINISTRATION PREVENTS THE REDUCTION OF TRABECULAR
BONE VOLUME DUE TO SKELETAL UNLOADING
S. Tanaka*, A. Sakai, H. Tsurukami, S. Ikeda, S. Uchida, T. Nakamura
Dept. of Orthopaedic Surgery, University of Occupational and
Environmental Health, School of Medicine, Kitakyushu, Japan
To clarify the effects of intermittent hPTH(1-34) administration on
trabecular bone turnover and bone marrow cell development in skeletal unloaded limbs, we
performed experiments with tail-suspended mice. Eighty C57BL/6J male mice, 8 weeks of age,
were assigned to 4 weight-matched groups (Groups 1, 2, 3 and 4; n=20 each). Mice of Groups
3 and 4 were tail suspended. Mice were given subcutaneous injections of hPTH five times a
week at the respective dose of 0 (vehicle) for Groups 1 and 3, 40 micro gram /kg body
weigh for Groups 2 and 4. Bilateral tibia were harvested at 8 days and 15 days after the
start of the experiment. We performed histomorphometric analyses on the proximal
metaphyses and bone marrow cell cultures. Bone histiomorphometry: At 8days, the value of
trabecular bone volume (BV/TV) and bone formation rate (BFR/BS) of Group 3 was
significantly reduced compared to that of
Group 1. But, the values of Group 4 was larger than that of Group 3,
maintaining at the similar level as that of Group 1. At 15 days, the value of BV/TV of
Group 3 was significantly reduced. BV/TV value of Group 4 reduced to the level of Group 3.
While BFR/BS values of Group 4 maintained larger compared to Group 3, the value of Oc.N/BS
significantly increased compared to the values of Groups 2 and 3. Bone marrow cell: At 8
days. The number of ALP positive CFU-f colonies of Group 3 reduced, and that of Group 2
increased compared to Group 1. In Group 4, the value also increased to Group 1. The number
of TRAP positive cell developed from bone marrow cell culture of Group 3 did not differ,
and that of Group 2 increased compared to that of Group 1. In Group 4, however, the value
further increased compared to that of Group 2. These data clearly indicated that the bone
mass increasing effect of intermittent hPTH administration reduced during the unloading of
the skeleton. Intermittent hPTH injections increased osteogenic and osteoclastogenic
activities in bone marrow cells, consequently leading to bone mass increase in the ground
condition. But, during unloading, the increase in osteoclastogenic activity seemed to
further increase with passage of time, leading to alleviate the bone mass increasing
action of the agent.
[Programme]
P-138
PREVENTION, EARLY DIAGNOSTIC AND MANAGEMENT OF OSTEOPOROSIS IN
PERIMENOPAUSAL WOMAN IN FOUR MUNICIPALITIES OF SARAJEVO CANTON
I. Gavrankapetanovic1*, F. Gavrankapetanovic1, E.
Kucukalic-Selimovic1, J. Dizdarevic2, D. Ivanisevic1, B.
Hadjihasanovic1, I. Hrizar2
1University Clinic Center Sarajevo, Sarajevo, Bosnia and
Herzegovina
2Ministry of Health Sarajevo Canton F. BiH, Sarajevo, Bosnia
and Herzegovina
Goals: Evaluation of menopausal-dependent metabolic disorders in woman,
determination of bone density in selected groups, therapeutic measures where is necessary,
follow up of treated and borderline cases, development of prevention measures and early
diagnostic procedures in prevention of complications and decreasing risk of fractures in
topic group.
Patients and methods: We are targeting women of four Sarajevo Canton
municipalities. Each of them will be announced to visit her gynecologist 3-6 months after
spontaneous break of menstruation cycles (age 44-45). With each of them we plan to make a
detail introductory conversation, clinical examination, and evaluation of factor of risk;
in selected cases - bone densitometry and measuring of bone markers (osteocalcin and
telopeptid), scintigrafy if necessary. Densitometry and bone markers will be realized in
every case of two or more factors of risk, earlier fractures, and in cases where women
can't or don't want to use hormonal therapy even if it is necessary (contraindications,
lose of faith etc.).
Results (what we expect): Osteoporosis was not problem of great interest
in our Canton in last years. Ordinary, it was mainly surgical problem, without cooperation
of other specialists. We didn't develop measures of early diagnostics and prevention. We
expect bad results in all groups in the beginning of research, and good results with
continually improvement in field of understanding and continually struggle in field of
prevention of osteoporosis.
[Programme]
Late submissions
[Programme]
P-139
EFFECT OF CHOLINE STABILIZED ORTHOSILICIC ACID ON BONE DENSITY IN CHICKS.
M. R. Calomme1*, P. Wijnen3, J. B. Sindambiwe1,
P. Cos1, J. Mertens2, P. Geusens2,4, D. A. Vanden Berghe1
1Faculty of Pharmaceutical, Biomedical and Veterinary
Sciences, University of Antwerp, Antwerp, Belgium
2BIOMED, Limburg University Center, Diepenbeek, Belgium
3Poultry Practice De Achterhoek, Ruurlo, The Netherlands
4Department of Rheumatology, University Hospital, Maastricht,
The Netherlands
Broiler chicks on a normal diet (1.4mg Si/g) were supplemented with
choline stabilized orthosilicic acid (Ch-OSA) to investigate the effect of silicon on the
serum calcium concentration and bone mineral content (BMC) density (BMD) in the femur.
A group of 42,500 chicks was administered Ch-OSA (13.5mg Si/100kg
bodyweight/2days) in their drinking water for 6 weeks which increased the total dietary Si
intake with less than 0.5%. A control group of 42,600 chicks of the same age was started
in parallel with identical feeding but without Ch-OSA supplementation. Samples of 30
randomly chosen chicks were taken in each group at the age of six weeks to analyse the
serum calcium concentration and femura. Femoral BMC and BMD were analyzed by Dual Energy
X-ray Absorptiometry. Scans were recorded for both total femur and 5 regions of interest
in the femur. Differences between means were evaluated with a one-tailed Student t-test.
The serum Ca concentration was significantly higher (p<0.05) in
supplemented chicks (74.85±13.82mg/ml, n=60) compared to controls (69.47±15.99 mg/ml,
n=60).
The BMC was significantly higher for supplemented chicks compared to the
controls in all the scanned areas of the femur. Total BMC was also significantly higher
(+8.4%, p=0.016) for supplemented chicks compared to controls.
The BMD was significantly higher at the midshaft (+4.25%, p=0.0209), the
distal metaphysis (+4.88%, p=0.0102), and the hip region(+5.6%, p=0.014) for supplemented
chicks compared to controls.
In conclusion, increasing the total dietary intake of broiler chicks with
less than 0.5% in the form of Ch-OSA resulted in a significant higher serum calcium
concentration and higher bone mass and density in cortical and trabecular bone of the
femur. These results confirm earlier studies suggesting an essential role of silicon in
bone (1) and collagen (2) metabolism.
(1) Seaborn et al. (1994). J. Trace Elem Exp Med, 7, 11.
(2) Calomme et al. (1997), Biol Trace Elem Res, 56, 153.
[Programme]
P-140
RISEDRONATE BUT NOT ALENDRONATE SLOWS DISEASE PROGRESSION IN THE GUINEA
PIG MODEL OF PRIMARY OSTEOARTHRITIS
J. M. Meyer*, R. W. Farmer, M. C. Prenger
Procter & Gamble Pharmaceuticals, Mason, Ohio, USA
Most animal models of osteoarthritis involve chemical or surgical
initiation of the disease, although the majority of human OA is considered primary. The
Duncan- Hartley guinea pig is a model of primary OA and mimics human disease in many
aspects. Cartilage lesions begin at about 3 months of age or 750g weight. They are
bilateral and begin primarily on the medial tibial plateau (MTP). Chondrocyte cloning,
osteophytes and tidemark duplication can also be seen. Disease severity progresses as the
animals age and gain weight. This may be a useful model for testing potential structure
modifying OA drugs.
Animals were randomized into the treatment groups shown in Table 1. The
bisphosphonates risedronate (Actonel(r)) and alendronate (Fosamax(r))
or sterile isotonic saline (vehicle control) were administered via subcutaneous injection
5 consecutive days/week for 12 months. At sacrifice, the left tibia of the stifle joint
was disarticulated and stained with Evan's blue dye. Joints were then placed in 10%
neutral buffered formalin and digitally photographed. These images were analyzed using a
BDS Image Analysis System (Oncor Image, Gaithersburg, MD). Lesion, MTP and osteophyte
areas were manually outlined by a single blinded grader, and area calculated by the
software program. A non-parametric Friedman's rank sum test was used to compare treatment
groups to control. Median scores are reported.
Risedronate but not alendronate had a statistically significant effect on
cartilage lesion and osteophyte size in the guinea pig model of primary OA. This is
consistent with previous data (ASBMR:SA472, 2001) suggesting not all bisphosphonates are
effective at slowing disease progression in this model. These data suggest risedronate may
be efficacious as a structure modifying drug in OA.
Treatment & Dose |
Lesion area |
Osteophyte area |
(mg/kg) |
mm2 |
% |
mm2 |
% |
Vehicle --- |
8.3 |
35.2 |
12.1 |
42.8 |
Risedronate 0.004 |
8.6 |
36.1 |
9.5 |
41.1 |
Risedronate 0.012 |
8.4 |
28.4* |
8.6 |
34.1* |
Risedronate 0.03 |
6.2* |
26.9* |
7.2* |
24.4* |
Alendronate 0.005 |
11 |
43.2 |
12.4 |
47.1 |
Alendronate 0.012 |
9.6 |
36.8 |
11.7 |
40.1 |
Alendronate 0.03 |
12.2 |
41.1 |
11.7 |
41.5 |
*=p<0.05 vs vehicle, two sided
test |
|