Bone Microarchitecture Phenotypes Identified in Older Adults Are Associated With Different Levels of Osteoporotic Fracture Risk

Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a “one-size-fits-all” approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p < 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Thiazide diuretics and the risk of hip fracture. Results from the Framingham Study

Thiazide diuretics may preserve bone mass and prevent elderly women's osteopenic fractures, but studies have not distinguished between thiazide preparations or examined former users. We performed a case-control study looking at thiazide use and subsequent hip fracture in postmenopausal female members of the Framingham Study cohort. Cases who had experienced a first hip fracture (n = 176) were compared with age-matched controls (n = 672). Results showed a modest protective effect of any recent thiazide use (not significant). However, recent pure thiazide users experienced significant protection against fracture (adjusted odds ratio, 0.31; 95% confidence interval, 0.11 to 0.88), whereas recent users of combination drugs containing thiazides experienced no protection (adjusted odds ratio, 1.16; 95% confidence interval, 0.44 to 3.05). Combination drugs generally contained only 25 mg of hydrochlorothiazide, suggesting that the small amount of thiazide was insufficient to preserve bone mass. Former thiazide users were not protected against fracture. In sum, recent pure thiazide use in women protects against hip fracture.     

Rede zur Er?ffnungsfeier der 110.Tagung der Deutschen Gesellschaft für Innere Medizin am 18.April 2004 in Wiesbaden

Ohne Zusammenfassung     

Double-outlet right ventricle and severe systemic outflow tract hypoplasia

Double-outlet right ventricle and severe systemic outflow tract hypoplasia comprises a subset of patients in whom total correction or palliation requires complex surgical procedures in the neonatal period. Our experience with 3 patients illustrates the difficulties associated with treatment and suggests possible surgical options for this otherwise lethal variant of the Taussig-Bing syndrome.     

Estrogen receptor beta polymorphisms are associated with bone mass in women and men: the Framingham Study.

ESR2 is expressed in bone cells, yet few studies have tested its variation for association with BMD, an important determinant of osteoporotic fractures. This was investigated in 723 men and 795 women from the Framingham study. Results show association of variation in this gene with BMD in both women and men. INTRODUCTION: Osteoporotic fracture risk is highly dependent on bone density, a quantitative multifactorial trait with a substantial genetic component. In contrast to the growing body of evidence that estrogen receptor alpha (ESR1) plays a role in bone metabolism, few studies have examined the estrogen receptor beta (ESR2) gene for association with BMD. An ESR2 CA repeat polymorphism, D14S1026, was associated with BMD in two small studies, each with <200 women. MATERIALS AND METHODS: The objective of this investigation was to assess whether D14S1026 or four other intronic polymorphisms were associated with BMD in 723 men and 795 women (mean age, 60 years) from the offspring cohort of the population-based Framingham Study. BMD was measured at the femur (neck, trochanter, and Ward's area) and the lumbar spine (L(2)-L(4)). RESULTS: In both women and men, there was significant association of D14S1026 genotype with measures of femoral but not spinal BMD. In addition, genotypes of two common single nucleotide polymorphisms, rs1256031 and rs1256059, in strong linkage disequilibrium with one another but not with D14S1026, were associated with measures of femoral BMD in men. The rs1256031 genotypes had up to a 4.0% difference in mean femoral BMD. An inferred rs1256031-D14S1026-rs1256059 haplotype C-23CA-T was significantly associated with reduced femoral BMD in women (p = 0.03, 0.003, and 0.01 for neck, trochanter, and Ward's area, respectively). Haplotype-based BMD differences ranged from 3.0% to 4.3%. CONCLUSIONS: We have observed significant association of common ESR2 variants with measures of femoral BMD in both men and women.     

The role of the endoscopic extraperitoneal approach in large inguinal scrotal hernias

The role of endoscopic extraperitoneal herniorrhaphy (EEPH) in the management of giant scrotal hernias has not been well defined, and the technical details relating to operations on such hernias have not been described. We present our experience with 17 patients undergoing repair of giant scrotal hernias. Foley catheter bladder decompression was routinely employed. The Retzius space was developed early in the procedure and hernia sac contents were reduced in all cases. The inferior epigastric vessels were likewise divided in all patients. The average operative time was 76 min and all patients were discharged home the same day. There have been no recurrences on follow-up. There was no mortality, and morbidity was limited to seroma formation in two patients. We conclude that with certain technical modifications, EEPH can be safely employed for the treatment of giant scrotal hernias. Received: 7 May 1996/Accepted: 12 July 1996     

Clinical results of the transurethreal resection and evaluation of superficial bladder carcinomas by means of fluorescence diagnosis after intravesical instillation of 5-aminolevulinic acid

BACKGROUND AND OBJECTIVE: The high recurrence rate of superficial bladder carcinomas requires new approaches in diagnosis and therapy. Particularly, an improvement in detection, resulting in better resection of flat lesions, which are poorly or not detectable under white light, is necessary. The effectiveness of fluorescence diagnosis for detection and transurethral resection of bladder carcinomas was investigated in a prospective study. MATERIALS AND METHODS: From 120 patients, 347 biopsies were taken or tumors resected with the aid of fluorescence from 5-aminolevulinic acid. Urothelial carcinomas and dysplasias were detected in 124 cases. RESULTS: Of the lesions, 119 were fluorescence positive (N = 74 pTaG1/2; N = 9 pT1G1/2; N = 11 pT1G3; N = 7 carcinoma in situ; N = 6 p > T1; N = 12 dysplasia II), and 5 were falsely negative (N = 3 pTaG1/2; N = 1 pT1G1/2; N = 1 dysplasia II). The sensitivity of the fluorescence diagnosis (96.0%) was significantly higher than the 67.5% sensitivity of white-light cystoscopy (P < 0.0001). Taking the data for primary or recurrent tumor resection and secondary resection separately, the sensitivity was 100% and 80%, respectively, and was significantly higher than that of white-light cystoscopy, which was 80.8% and 20 %, respectively (P < 0.0001 and P < 0.0008). The lower sensitivity of fluorescence diagnosis in secondary transurethral resection is attributed to the higher rate of false-negative findings in areas of former resection. CONCLUSIONS: The high rate of false-positive findings limits the correct interpretation of fluorescence findings. In spite of this, fluorescence diagnosis is superior to white-light cystoscopy in every case. By means of better detection of urothelial neoplasias and dysplasias, as well as more thorough and extensive resection under fluorescence control, it should be possible to reduce the recurrence rate of superficial bladder carcinomas.     

The effect of smoking at different life stages on bone mineral density in elderly men and women

To assess the effect of smoking on bone mineral density (BMD) at different life stages, to examine whether the effect of smoking differs between men and women, and to discover whether its effect in women differs according to history of estrogen use, a cohort study was carried out with single cross-section measurement of BMD by single and dual photon absorptiometry. The setting was the Framingham Study, a population-based cohort study with over 40 years prospectively collected data on smoking. Subjects (n=1164) consisted of cohort members participating in the 20th biennial Framingham examination (1988–1989). The measurements included in the study were BMD measured at the hip, spine and radius, smoking history ascertained at all Framingham Study examinations since 1948, and other factors affecting BMD (age, weight, estrogen use, caffeine use, alcohol use and physical activity). Neither current smoking, recent (last 10 years) smoking, nor early adulthood smoking resulted in significantly lower BMD at any skeletal site among women who had not taken estrogen. Among women who had taken estrogen, BMD at most sites was lower among current or recent smokers, although the small numbers of smokers made it difficult to find significant differences at all skeletal sites. Among men, a consistently lower BMD at all skeletal sites was observed for smokers regardless of when in their life they smoked (4–15.3% lower), although the effect of smoking during early adulthood was of a lesser magnitude (4–8% lower). Former male smokers who had quit <10 years ago had lower BMD than men who had quit 10 years ago. In conclusion, in women who had used estrogen, BMD was lower in current or recent smokers than it was in non-smokers. In men, smoking at any stage of life had adverse effects on the skeleton that was independent of weight, alcohol or caffeine use, implying other mechanisms for smoking's effect on bone.     

A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.

PURPOSE: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. EXPERIMENTAL DESIGN: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. RESULTS: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. CONCLUSIONS: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.     

Elderly cohort study subjects unable to return for follow-up have lower bone mass than those who can return

Longitudinal studies of osteoporosis in older persons may underestimate bone loss because of a lack of follow-up measurements on subjects too frail to return. The authors addressed this possible bias as part of the population-based Framingham Study; in 1996-1997, they used quantitative ultrasound to assess the bone status of elderly subjects regardless of their ability to return to the clinic. Broadband ultrasound attenuation (BUA) and speed of sound of the calcaneus (heel) were measured in 433 subjects at the Framingham, Massachusetts, clinic and in 167 subjects at their homes or nursing homes. All ultrasound parameters were measured with intramachine coefficients of variation of <6.0%. The mean BUA for those subjects evaluated at the clinic was higher than for those measured at home (9.2% higher for men, p = 0.081; 8.6% higher for women, p = 0.034). After adjustment for age and weight, the differences in BUA were no longer significant. Among the elderly subjects participating in this longitudinal cohort study, those who were unable to return for follow-up were older, weighed less, and had a lower BUA than those who did return, suggesting that longitudinal studies of changes in bone mass with aging may underestimate the true population values.