In 34 female patients suffering from osteoporotic vertebral compression fractures, the spine deformity index (SDI(M)) was determined, according to the method of Minne et al (1988), to reflect the radiological severity of established osteoporosis. Peripheral (single-photon absorptiometry (SPA) of the non-dominant distal forearm) and axial (quantitative computed tomography (QCT) of the lumbar spine) bone mineral measurements, as well as the broadband ultrasound attenuation of the os calcis, were performed in the osteoporotic patients and in a control group of 20 age-matched women. No correlation could be found between bone mineral measurements and radiological severity of osteoporosis, expressed as SDI(M). All three densitometry methods showed clearly reduced values in patients with vertebral crush fractures. Correlations established in the control group between peripheral and axial bone mass (SPA versus QCT) could no longer be found in the osteoporotic group, thus indicating changes in bone mineral density of the spine after the occurrence of osteoporotic fractures. Our data show that SDI(M) is an additional parameter of osteoporotic change in the spine, independent from bone mass measurements. In the management of osteoporotic patients, quantitative radiological methods (i.e. SDI(M)) in addition to densitometry might be of value for grading and monitoring the progress of disease.

Abstract Abstract #2128 Background: Liposomal encapsulation of Doxorubicin (DOX) was designed to minimize healthy tissue distribution by altering pharmacokinetics (PK) thus reducing cardiotoxicity while preserving antitumour efficacy. Study objective was to compare the PK behaviour of the two main liposomal formulations of DOX, i.e. pegylated (Caelyx, C) versus non pegylated (Myocet, M), in a single center study including 17 MBC patients, all Anthracyclin pretreated with additional risk faktors. Methods: Cohort 1 consisted of 10pts (mean age 62, 49-77) treated by C as 1HR infusion of 50mg/m²/4 wks. Plasma samples were collected at timepoints min 0, 30, 60, 120, 180 and d1, 7, 14, 28. In cohort 2, 7 pts (mean age 58, 51 – 70) received M 75mg/m² 1H Infusion / 3wks, plasma levels determined at min 0, 30, 60, 90, 120, 180 and d1, 2, 3. Total amount of DOX was determined following the 1st infusion respectively, analytic procedure included solid phase extraction quantification by HPLC and PK analysis by Win Nonlin Pro. Doxorubicinol was detected after M only. Results: in Cohort1 after C, mean Cmax of 6.8 µg/ml surprisingly occured at a mean tmax of 2.3 d, log conc time curve showed linear decrease of DOX conc suggesting continuous release into the tissue (mean conc d 7 3.3, d 14 1.0, d 21 0.3, d 28 0.09 µg/ml) . No metabolites were found, AUC (does not represent reliable drug exposure and bioavailability of DOX) expressed as µg/ml.d was 54.6. In contrast AUClast of M was calculated as 35µg ml.H and mean Cmax by 7.5 µg/ml at infusion end. DOXol was measured in all M treated patients at a slower metabolisation rate and late appearance compared to conventional DOX. t/2 el of C was 6 times longer than that of M (HR 90 vs 15). Differences in plasma disposition and PK of M vs C are depicted in table 1 and compared to pooled data of conventional DOX derived from former studies (50 mg/m² 30min inf, n=40). Cltot of conv. DOX was 10 fold higher than M and 500 fold higher than C, Vss about 12 times that of M and 70 times that of C. These PK differences underlines a different toxicity profile between PEGL (C, PPE syndrome) and NPEGL (M, myelotox, nausea), both reducing cardiac tox by avoiding peak plasma levels due to prolonged circulation time. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2128.

3540 Background: The monoclonal antibody (mab) bevacizumab (BEV) inhibits VEGF, downregulates angiogenesis and lowers interstitial pressure, by which blood tissue transfer and metabolism of a drug could be modulated. CPT 11 produced survival benefit combined with BEV and undergoes complex biotransformation by different enzymatic routes: carboxylesterase hCE2 (SN 38), UGT1A1 (detoxificition to SN 38 glucuronide) and CYP 3A4 (APC), the latter enzyme has been described to be reversibly inhibited by mabs. Therefore it seems worthwhile to investigate a potential influence of BEV on plasma disposition and pharmacokinetics (PK) of CPT11 and metabolites. Methods: 10 pts with advanced colorectal cancer (5 first line, 5 second line after FOLFOX) were treated by FOLFIRI schedule (with CPT 11 180 mg/m2 1HR infusion) preceeded by BEV 5 mg/kg (90–60–30 min infusion) every 2 weeks. At cycle 1, CPT 11 was applied before BEV to allow baseline PK analysis of CPT 11 and its metabolites, at cycle 4 (i.e. after 8 weeks) determination of CPT 11 plasma conc was repeated after a 30 min infusion of BEV. Plasma samples were collected every 30 min over 4 HR and analysed by HPLC. Results: PK of CPT 11 remained unaffected by BEV, only a small decrease in cmax and AUC was found. Contrary, SN 38 formation seemed to be delayed and formation rate decreased when combined with BEV, resulting in lower cmax (-24%) and AUC (-20%). SN 38 glucuronide levels were generally found to be higher than those of SN 38, cmax and AUC reduced by 35% when BEV was preadministered. A similar effect was also observed in PK parameters of APC (about 30% reduction of cmax and AUC). Conclusion: A changed plasma disposition of all 3 metabolites - generated by 3 different enzymatic pathways - is unlikely to be caused by BEV influencing CPT 11 metabolism. The observed effect could be explained by increased blood tissue transfer, alteration of microvasculature by BEV may favour tissue uptake of the drug. [Table: see text] No significant financial relationships to disclose.

Age-related changes in bone metabolism are of interest in the pathogenesis of postmenopausal and senile osteoporosis; however, data in the literature give conflicting results. Thus, the aim of our study was to measure serum levels of osteocalcin, a specific biochemical parameter of bone formation, as well as serum levels of midregional parathyroid hormone (PTH) and alkaline phosphatase in healthy males and females of various age groups. We studied 155 healthy subjects (91 females, 64 males, mean age: 43 years, age range: 20-81 years). Serum levels of osteocalcin, alkaline phosphatase and PTH increased with age and were significantly higher in the postmenopausal than in the premenopausal females (osteocalcin: 8.7 +/- 0.4 vs. 6.5 +/- 0.3 ng/ml, p < 0.0001; alkaline phosphatase: 126 +/- 7 vs. 89 +/- 5 U/l, p < 0.0003; PTH: 111 +/- 10 vs. 61 +/- 9 pmol/l, p < 0.0001). In contrast, serum levels of osteocalcin, alkaline phosphatase and PTH were similar in the male subjects above or below the age of 50 years (osteocalcin: 6.5 +/- 0.5 vs. 7.2 +/- 0.4 ng/ml, non significant; alkaline phosphatase: 104 +/- 8 vs. 105 +/- 5 U/l, non significant; PTH: 59.6 +/- 6 vs. 61 +/- 5 pmol/l, non significant. Serum calcitonin levels were significantly lower in postmenopausal women and men above 50 years of age. Our data suggest different age-related alterations in bone metabolism in males and females. The increased levels of osteocalcin, alkaline phosphatase and PTH in postmenopausal females give evidence of increased bone turnover in these subjects. In healthy men bone-specific markers remained unchanged, indicating no relationship between bone turnover and age.

Während Immobilisation von vermehrtem Knochensubstanzverlust begleitet ist, gilt körperliche Aktivität als eine der Determinanten der Knochenformation. Vermutlich stimuliert mechanische Belastung die Knochenneubildung, während Inaktivität zu vermehrtem Knochensubstanzverlust führt [3]. Obwohl forcierte Aktivität über einen relativ kurzen Zeitraum die Knochenmasse erhöhen kann [1, 4], sind bei weniger intensiver Beanspruchung keine Veränderungen im Knochenstoffwechsel zu beobachten. Sportliche Aktivität über längere Zeit scheint unter der Annahme, daß bereits in der Jugend einsetzende Aktivität im mittleren Lebensalter eine erhöhte „peak bone mass“ bildet, sehr wichtig [2]. Dadurch kann die klinische Manifestation einer Osteoporose im späteren Lebensalter verzögert werden.

Die Osteoporose tritt in Populationen mit hoher Lebenserwartung in hoher Inzidenz auf und trägt zur Steigerung der Morbidität und Mortalität beim älteren Menschen ganz entschieden bei.

Since it has been suggested that gastric resections are followed by changes in bone metabolism, the aim of our study was to determine the biochemical parameters of bone metabolism and radial and lumbar bone density in 15 male ulcus patients treated by partial gastrectomy (Billroth II). Comparing the data with those of a corresponding control group, the lumbar bone density measured by quantitative computed tomography was statistically significantly lower (P < 0.04) in the patient group, whereas the peripheral bone mass of the distal part of the nondominant forearm measured by single-photon absorptiometry showed no statistically significant difference. In addition, a marked increase in alkaline phosphatase (P < 0.002) and urinary excretion of hydroxyproline (P < 0.003) was found in the gastrectomy group, whereas the 25-hydroxy-vitamin D levels were found to be significantly decreased (P < 0.04). Osteocalcin, a biochemical marker for osteoblast activity, and the carboxy-terminal propeptide of type I procollagen (PICP), a marker of collagen formation, were slightly but not significantly higher in gastrectomy-treated patients. The serum parathyroid hormone levels were similar in both groups. As none of the patients had any radiologic evidence of osteopenia, the changes in biochemical parameters of bone metabolism and bone mass in patients who had undergone partial gastrectomy could be a marker of latent bone loss.

Abstract. With advancing age both sexes have an increased incidence of osteoporotic fractures, although fractures are more common in women than in men. Whereas in women several potential risk factors have been identified, less is known about osteoporosis in men. A total of 27 Austrian men (mean age: 65 ± 2 years) with atraumatic spine fractures were studied. In all patients, medical history gave no evidence of disease or medications causing osteoporosis. Peripheral bone mass was determined by single‐photonabsorptiometry on the distal non‐dominant forearm; lumbal bone density was measured by quantitative computed tomography. Serum levels of calcium, phosphate, alkaline phosphatase, osteocalcin, testosterone, estrogen, parathyroid hormone and 25‐hy‐droxy‐vitamin D as well as 2‐h‐urinary‐OH proline and calcium excretion were measured. All data were compared with those of an age and sex matched control group consisting of 19 healthy males. A significant difference in mean peripheral and axial bone mass (SPA: P<0.004; QCT: (P<0.001) was observed between osteoporotic men and controls. When compared to controls, serum levels of alkaline phosphatase (P<0.012), urinary OH proline (P<0.05) and urinary calcium excretion (P<0.003) were significantly higher in the osteoporotic males. Additionally, there was a significant positive correlation between serum alkaline phosphatase and urinary OH proline excretion (r=0.32; P<0.04) in the osteo‐porotics. All other biochemical parameters showed no significant differences. Our results may lead to the assumption that osteopenia in men is related to increased bone turnover.

Osteocalcin is a 49 amino acid non collagenous bone matrix protein which is synthesized by the osteoblasts. The serum levels of osteocalcin have been found to be a specific biochemical parameter of bone formation. We determined the serum levels of osteocalcin, parathyroid hormone, calcitonin and alkaline phosphatase as well as the 2 hour fasting hydroxyproline excretion in 26 patients with postmenopausal osteoporosis and in 24 postmenopausal control subjects. Serum levels of osteocalcin were significantly lower in the patients with postmenopausal osteoporosis than in the control subjects (p less than 0.002). In contrast, serum levels of parathyroid hormone, calcitonin, alkaline phosphatase and the 2 hour hydroxyproline excretion in the patients with postmenopausal osteoporosis and the control subjects were not statistically different. Our data give evidence of a decreased bone formation in patients with postmenopausal osteoporosis.

Unter dem Eindruck der großen sozio-ökonomischen Bedeutung der Osteoporose stellt sich zunehmend die Frage nach Möglichkeiten der Früherkennung und der Reproduzierbarkeit der Wirkung von verschiedenen Behandlungskonzepten, um eine gezielte Prävention beziehungsweise Stabilisierung des Knochenstoffwechsels zu erreichen. Erstrebenswert ist eine einfach zu handhabende Screening-Methode, die, in der perimenopausellen Zeit angewandt, die Frau mit dem erhöhten Risiko einer Osteoporoseentstehung erkennen läßt

In experimental and clinical studies, conflicting results regarding the effect of oral anticoagulant therapy on bone metabolism have been reported. To measure a possible influence of long-term anticoagulant therapy with phenprocoumon on peripheral bone mass, measurements of peripheral bone mineral content (BMC) and serum osteocalcin levels were performed with single photon absorptiometry in a total of 78 patients on anticoagulant treatment. We studied 43 women (mean age 66 years +/- 2 SEM) and 35 men (mean age 65 years +/- 2 SEM) with a median duration of phenprocoumon therapy of 1 year (1-9 years). In all patients, the medical history gave no symptoms of metabolic bone disease, or diseases or medications causing osteoporosis. Both in the male and female groups, mean peripheral BMC was significantly decreased (male: P less than 0.01, female: P less than 0.003) when compared with corresponding controls. Serum OC-levels measured in 16 patients were also significantly lower than those of the controls (P less than 0.02). Our data of decreased BMC and low serum OC-levels indicate reduced bone mass in patients on long-term anticoagulant therapy with phenprocoumon. This may imply an influence of anticoagulants on bone metabolism resulting in decreased bone formation.

Measurements of bone mass were performed in 133 healthy Austrian women using the quantitative computed tomography technique of the lumbar spine and single photon absorptiometry of the distal forearm. The data were compared with those of 110 Austrian females with osteoporotic spine fractures. A significant difference in mean bone density of the lumbar spine was observed between normal and osteoporotic patients in every decade, whereas forearm measurements showed statistical differences in the seventh and eighth decade but not in the sixth decade. Compared to age matched controls, bone mass of osteoporotic women showed the following diminution: sixth decade: distal forearm: -12.7%, spine: -46.8%; seventh decade: distal forearm: -19.0%, spine: -36.7%, eighth decade: distal forearm: -15.4%, spine: -33.7%. It appears that postmenopausal osteoporosis involves greater loss of bone in the spine in the first decade after menopause and slows down after this period, whereas loss of forearm bone mineral density (BMD) increases with advancing age.

Die Hormonsubstitutionstherapie entweder mit Östrogenen oder kombiniert mit Gestagenen ist ein etabliertes Therapieprinzip, um den beschleunigten Knochensubstanzverlust in der Menopause zu verhindern [8, 2, 7]. Zahlreiche klinische Studien belegen den präventiven Effekt einer Langzeit-Hormontherapie auf den postmenopausellen Knochensubstanzverlust [8, 2]. Die Hormonsubstitutionstherapie erscheint jedoch nicht nur präventiv wirksam zu sein, sondern auch bei Patienten mit bereits etablierter Osteoporose und Wirbelkörperfrakturen [9, 3]. Diesbezüglich zeigen auch epidemiologische Studien eine deutliche Reduktion der Frakturrate unter postmenopausaler Östroge-Gabe [10, 5]. Nachdem bislang angenommen wurde, daß der osteoprotektive Effekt von Östrogen über eine Reihe anderer Hormone gleichsam als Mediatoren vermittelt wird, wie z.B. durch Änderung der Serumkalzitonin-Konzentrationen [12], Aktivierung der renalen 1-Alpha-Hydroxylase [11] oder durch sekundären Hyperparathyreoidismus und vermehrter Kalzitrolsynthese [1] konnten Eriksen et al 1988 in vitro Östrogenrezeptoren an Osteoblasten nachweisen, so daß neuerdings eine direkte Wirkung von Östrogen an den Osteoblasten anzunehmen ist [4]. Die Hormontherapie gleichsam als Präventivtherapie perimenopausal oder unmittelbar postmenopausal angewandt, ist in der Literatur gut belegt Die Östrogenmonotherapie oder kombinierte Östrogen-Gestagen-Therapie bei schon älteren Patienten wird jedoch nur von wenigen Autoren beschrieben [8, 5, 6].