[Prevalence of vertebral spinal deformities in women and men in Germany. EVOS group in Germany]. / Prävalenz der vertebralen Wirbelkörperdeformationen bei Frauen und Männern in Deutschland. EVOS-Gruppe in Deutschland.

BACKGROUND: The prevalence of radiographically defined vertebral deformities, as a marker of vertebral osteoporosis, was calculated in a population based cross-sectional survey in Germany. METHOD: Lateral spine X-rays were taken according to a standardized protocol and evaluated centrally. Three thousand nine hundred and eighty subjects (2064 male and 1916 female) aged 50 to 79 years, have been examined in 8 German centers. RESULTS: Based on McCloskey's method of deformity definition the age-standardized mean prevalence of vertebral deformities in Germany was 10.2% for males and 10.5% for females. Based on the definition by Melton/Eastell a significant higher prevalence was calculated (males 17.8%, females 18.7%). The prevalence increased with age in both sexes with a steeper increase in females. There was no difference in East and West German populations. There were substantial variations between the centers regarding the prevalence of deformities in females and males.

Placebo-controlled multicenter study of oral alendronate in postmenopausal osteoporotic women. FOSIT-Study-Group. Fosamax International Trial.

OBJECTIVES: To evaluate effects on bone mineral density (BMD), safety, and tolerability of a single daily dose of alendronate (10 mg), administered for 1 year to postmenopausal women with osteoporosis. METHODS: This interim analysis includes the first approximately 20% of patients to complete treatment in a large, placebo-controlled study (the Fosamax International Trial (Fosit)), which enrolled 1908 patients from 34 countries. Patients < or = 85-year-old with osteoporosis (lumbar spinal BMD > or = 2 S.D. below mean for mature premenopausal Caucasian women) were randomly assigned to treatment with alendronate or placebo once daily in the morning; all patients received supplemental calcium (500 mg/day). Dual-Energy X-ray Absorptiometry (DXA) was used to measure BMD in spine and proximal femur. RESULTS: A total of 297 patients had BMD data available for analysis. Patients treated with alendronate showed progressive increase of BMD during treatment. At 12 months, mean BMD had increased significantly (P < 0.001) at the lumbar spine (5.6%), trochanter (3.6%), and femoral neck (2.6%) in the alendronate group. Increases in BMD were significantly (P < 0.001) greater than in the placebo group at all sites. Among 442 patients assessed for safety, there were no statistically or clinically significant differences between treatment groups in the incidence of adverse events, including upper gastrointestinal adverse events, or laboratory abnormalities. CONCLUSIONS: Results of this multinational study show that oral alendronate, administered as 10 mg once daily for 1 year, is generally well tolerated and produces significant, progressive increases in BMD at the lumbar spine and proximal femur of postmenopausal women with osteoporosis.

Dose-related changes in the profile of ras mutations in chemically induced CD-1 mouse liver tumors.

We investigated the role of dosing regimen on ras mutations in chemically induced CD-1 mouse liver tumors. The spectra of ras gene mutations in liver tumors that were induced by 15 daily i.p. injections of 7,12-dimethylbenz[a]anthracene (DMBA), 4-aminoazobenzene (AAB), N-hydroxy-2-acetylaminofluorene (N-OH-AAF) or N-nitrosodiethylamine (DEN) were compared to those previously obtained for tumors induced by a single but higher dose of each carcinogen. The principal assay used was a direct tumor analysis involving sequencing of polymerase chain reaction (PCR)-amplified tumor DNA; additional mutations that were present in only a small fraction of tumor cells were detected using a transfection assay or a PCR-engineered restriction fragment length polymorphism method. Spontaneous liver tumors had a relatively low frequency of ras mutations, all found in Ha-ras codon 61, and most of these mutations were present in only a small fraction of tumor cells. With the exception of multiple-dose DEN, each group of single- and multiple-dose carcinogen-induced tumors exhibited a higher frequency of ras mutations compared with spontaneous tumors. For AAB, N-OH-AAF and DEN, the dosing regimen was found to affect significantly the profile of ras mutations. For each of these carcinogens, the multiple-dose tumor group (versus single-dose group) had fewer Ki-ras and N-ras mutations and more tumors in which the Ha-ras codon 61 (C-->A) mutation was present in a large fraction of cells. Our results demonstrate that the dosing procedure can materially affect the pattern of ras gene mutation in mouse liver tumors.

Molecular and genetic analysis of liver oncogenesis in transforming growth factor alpha transgenic mice.

Overexpression of a transforming growth factor alpha (TGF-alpha) transgene induced the development of liver tumors in 69 of 93 (74%) adult male mice. To identify factors associated with oncogenesis, liver tumors from transgenic animals were characterized at the molecular level. TGF-alpha RNA transcripts were elevated in 17 of 25 (68%) liver tumors, relative to adjacent nontumorous tissue. Expression of the endogenous c-myc and insulin-like growth factor II genes was enhanced in 7 of 19 (37%) and 12 of 16 (75%) tumors, respectively. In contrast, epidermal growth factor receptor RNA levels were unchanged or reduced in all liver tumors, and mutations were not detected in either the Ha-ras or Ki-ras genes. The occurrence of liver tumors in castrated TGF-alpha transgenic mice was reduced about 7-fold, while in ovariectomized transgenic animals the incidence was increased about 6-fold. The progeny of a cross between CD1-derived TGF-alpha transgenic (MT42) and C57BL/6 mice exhibited no reduction in tumor burden (83%); however, the incidence of tumor formation in MT42 x FVB/N offspring was substantially lower (19%). We conclude that in these transgenic mice TGF-alpha promotes tumor formation and appears to play a major role in tumor progression. Moreover, other factors that may collaborate in TGF-alpha-induced hepatocarcinogenesis include c-myc, insulin-like growth factor II, sex hormones, and the genetic background upon which the transgene operates.

Activation of the Ki-ras gene in spontaneous and chemically induced lung tumors in CD-1 mice.

As part of an evaluation of the effectiveness of using ras mutation analysis for distinguishing carcinogen-induced from spontaneous tumors, we examined the profile of ras gene point mutations in spontaneous, 7,12-dimethylbenz[a]anthracene (DMBA)-induced, and N-nitrosodiethylamine (DEN)-induced lung tumors from Crl:CD-1(ICR)BR (CD-1) mice. Although all of the lung tumors were assayed for mutations in the Ha-ras, Ki-ras, and N-ras genes (codons 12, 13, and 61), only Ki-ras mutations were found, which is consistent with other studies that have noted a strong preference for Ki-ras gene activation in mouse, rat, and human lung tumors. We found that spontaneous CD-1 mouse lung tumors had a very high frequency of Ki-ras gene activation (17 of 20 tumors; 85%), distributed among codons 12 (5 of 20), 13 (1 of 20), and 61 (11 of 20). DMBA-induced lung tumors had a slightly higher frequency of Ki-ras gene mutations (16 of 16; 100%), again distributed among codons 12 (5 of 16), 13 (2 of 16), and 61 (9 of 16). However, seven of the DMBA tumors had mutations qualitatively different from those found in spontaneous tumors. In contrast to DMBA-induced tumors, DEN-induced tumors had a lower frequency of Ki-ras mutations (36%) when compared with spontaneous lung tumors, suggesting that DEN primarily induces lung carcinogenesis by a mechanism other than ras gene activation. Thus, although spontaneous and induced CD-1 mouse lung tumors have a strong tissue-specific preference for carrying an activated Ki-ras gene, the nature of the initiating carcinogen can influence the frequency or profile of Ki-ras mutations.