Introduction and hypothesis
Diabetes affects bone metabolism. The hypothesis was that type 1 (T1D) and type 2 (T2D) affects BMD and fracture risk differently.

Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes--a meta-analysis.

Equol [7-hydroxy-3-(4'-hydroxyphenyl)-chroman] is a nonsteroidal estrogen of the isoflavone class. It is exclusively a product of intestinal bacterial metabolism of dietary isoflavones and it possesses estrogenic activity, having affinity for both estrogen receptors, ERalpha and ERbeta. Equol is superior to all other isoflavones in its antioxidant activity. It is the end product of the biotransformation of the phytoestrogen daidzein, one of the two main isoflavones found in abundance in soybeans and most soy foods. Once formed, it is relatively stable; however, equol is not produced in all healthy adults in response to dietary challenge with soy or daidzein. Several recent dietary intervention studies examining the health effects of soy isoflavones allude to the potential importance of equol by establishing that maximal clinical responses to soy protein diets are observed in people who are good "equol-producers." It is now apparent that there are two distinct subpopulations of people and that "bacterio-typing" individuals for their ability to make equol may hold the clue to the effectiveness of soy protein diets in the treatment or prevention of hormone-dependent conditions. In reviewing the history of equol, its biological properties, factors influencing its formation and clinical data, we propose a new paradigm. The clinical effectiveness of soy protein in cardiovascular, bone and menopausal health may be a function of the ability to biotransform soy isoflavones to the more potent estrogenic isoflavone, equol. The failure to distinguish those subjects who are "equol-producers" from "nonequol producers" in previous clinical studies could plausibly explain the variance in reported data on the health benefits of soy.

/pdf/the-clinical-importance-of-the-metabolite-equol-a-clue-to-21ogu2q5i9.pdf

The Clinical Importance of the Metabolite Equol—A Clue to the Effectiveness of Soy and Its Isoflavones

Neuroendocrine pharmacology of stress

Despite the fact that many research articles have been written about stress and stress-related diseases, no scientifically accepted definition of stress exists. Selye introduced and popularized stress as a medical and scientific idea. He did not deny the existence of stressor-specific response patterns; however, he emphasized that such responses did not constitute stress, only the shared nonspecific component. In this review we focus mainly on the similarities and differences between the neuroendocrine responses (especially the sympathoadrenal and the sympathoneuronal systems and the hypothalamo-pituitary-adrenocortical axis) among various stressors and a strategy for testing Selye's doctrine of nonspecificity. In our experiments, we used five different stressors: immobilization, hemorrhage, cold exposure, pain, or hypoglycemia. With the exception of immobilization stress, these stressors also differed in their intensities. Our results showed marked heterogeneity of neuroendocrine responses to various stressors and that each stressor has a neurochemical "signature." By examining changes of Fos immunoreactivity in various brain regions upon exposure to different stressors, we also attempted to map central stressor-specific neuroendocrine pathways. We believe the existence of stressor-specific pathways and circuits is a clear step forward in the study of the pathogenesis of stress-related disorders and their proper treatment. Finally, we define stress as a state of threatened homeostasis (physical or perceived treat to homeostasis). During stress, an adaptive compensatory specific response of the organism is activated to sustain homeostasis. The adaptive response reflects the activation of specific central circuits and is genetically and constitutionally programmed and constantly modulated by environmental factors.

/pdf/stressor-specificity-of-central-neuroendocrine-responses-3hrslqz38s.pdf

Stressor specificity of central neuroendocrine responses: implications for stress-related disorders.

This document has been developed as an expert consensus document by the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA), in collaboration with the American Academy of Neurology (AAN), the American College of Physicians (ACP), the American Geriatrics Society (AGS), the American Society of Hypertension (ASH), the American Society of Nephrology (ASN), the American Society for Preventive Cardiology (ASPC), the Association of Black Cardiologists (ABC), and the European Society of Hypertension (ESH). Expert consensus documents are intended to inform practitioners, payers, and other interested parties of the opinion of ACCF and document cosponsors concerning evolving areas of clinical practice and/or technologies that are widely available or new to the practice community. Topics chosen for coverage by expert consensus documents are so designed because the evidence base, the experience with technology, and/or clinical practice are not considered sufficiently well developed to be evaluated by the formal ACCF/AHA practice guidelines process. Often the topic is the subject of considerable ongoing investigation. Thus, the reader should view the expert consensus document as the best attempt of the ACCF and document cosponsors to inform and guide clinical practice in areas where rigorous evidence may not yet be available or evidence to date is not widely applied to clinical practice. When feasible, expert consensus documents include indications or contraindications. Typically, formal recommendations are not provided in expert consensus documents as these documents do not formally grade the quality of evidence, and the provision of “Recommendations” is felt to be more appropriately within the purview of the ACCF/AHA practice guidelines. However, recommendations from ACCF/AHA practice guidelines and ACCF appropriate use criteria are presented where pertinent to the discussion. The writing committee is in agreement with these recommendations. Finally, some topics covered by expert consensus documents will be addressed subsequently by the ACCF/AHA …

ACCF/AHA Expert Consensus Document ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents

We conducted a cross-sectional study of the effects of soybean protein intake on bone mineral density and biochemical markers in 85 postmenopausal Japanese women. Nutrients in the diet of postmenopausal Japanese women visiting the osteoporosis unit, including subjects with normal lumbar spine bone mineral density (L2–4 BMD), were investigated by questionnaire, and the calculated daily energy, protein, soy protein and calcium intake were obtained. L2–4 BMD was measured with dual-energy X-ray absorptiometry, and assays done of serum alkaline phosphatase (ALP) and serum intact osteocalcin (IOC) as bone formation markers and urinary pyridinoline (UPYR) and urinary deoxypyridinoline (UDPYR) as bone resorption markers. Soy protein intake was significantly associated with the Z-score for L2–4 BMD (r= 0.23, p = 0.038) and UDPYR (r =−0.23, p = 0.034). Stepwise multiple regression analyses showed that soy protein intake is significantly associated with the Z-score for L2–4 BMD (β= 0.225, p = 0.04) and UDPYR (β=−0.08, p = 0.03) among four nutritional factors. These results suggest that high soy protein intake is associated with a higher bone mineral density and a lower level of bone resorption, but further studies are needed to confirm the causal dynamic mechanisms.

Effect of Soy Protein on Bone Metabolism in Postmenopausal Japanese Women

Degenerative diseases of lumbar spine commonly noted in elderly people may affect their lumbar spine bone mineral density (BMD). The aim of this study is to determine whether the degree of degenerative spinal diseases is correlated with lumbar spine and femoral neck BMD. This study included 630 women age 60 years or over (mean age 73.3 ± 6.9 years) visiting the Osteoporosis Outpatient Clinic at the Tokyo Metropolitan Geriatric Medical Center. Subjects underwent anteroposterior and lateral X-rays of the lumbar spine. The score of degenerative spinal diseases for each subject was calculated according to the scores for the Kellgren-Lawrence method, osteophyte formation, bone sclerosis, disk space narrowing, and spondylolisthesis involving L1-L2 through L4-L5 interspaces. Moreover, the number of vertebral fractures at L2 through L4 was recorded. The BMD of the second to fourth lumbar spine from anteroposterior projections and femoral neck were measured using an Expert-5000 (GE Lunar, Madison, WI USA). Most subjects had degenerative diseases of the lumbar spine. Scores for the Kellgren-Lawrence method, osteophyte formation, bone sclerosis, disk space narrowing, and spondylolisthesis were positively correlated with lumbar spine BMD, while they were not correlated with femoral neck BMD. Multiple regression analysis indicated that the scores for osteophyte formation, bone sclerosis, and disk space narrowing were independently correlated with lumbar spine BMD. Thus, in this study, the scores for degenerative spinal diseases were correlated with lumbar spine BMD, while they were not correlated with femoral neck BMD. This discrepancy indicates that degenerative spinal diseases are associated with increased lumbar spine BMD measurements. Femoral neck BMD therefore may be more appropriate than lumbar spine BMD in evaluating osteoporosis in elderly women.

Impact of degenerative spinal diseases on bone mineral density of the lumbar spine in elderly women

Insulin-induced hypoglycemia is a potent stress stimulating ACTH release, but the factors responsible for this ACTH secretion are not known. In this study, several ACTH-stimulating factors, such as CRH, arginine vasopressin (AVP), epinephrine (E), norepinephrine (NE), and dopamine, in addition to ACTH, cortisol, and glucose, were simultaneously measured in plasma before and 15, 30, 60, 90, and 120 min after iv administration of 0.1 U/kg BW regular insulin to seven normal subjects. Insulin administration resulted in significant rises in the mean plasma ACTH level from 4.6 +/- 1.1 (+/- SEM) to 21.6 +/- 4.8 pmol/L at 30 min (P less than 0.01) and in plasma cortisol from 330 +/- 60 to 720 +/- 50 nmol/L at 60 min (P less than 0.01). These increases were preceded by a 41.0 +/- 1.9% (P less than 0.001) fall in blood glucose levels. The mean plasma CRH level rose significantly from 1.0 +/- 0.1 to 1.2 +/- 0.1 pmol/L (P less than 0.01) at 30 min and remained elevated until 120 min. In addition, concomitant and significant rises in plasma AVP levels (basal, 1.5 +/- 0.01; peak, 4.5 +/- 1.1 pmol/L at 30 min; P less than 0.01), E (basal, less than 50; peak, 640 +/- 130 pmol/L at 30 min; P less than 0.01), and NE (basal, 0.07 +/- 0.01; peak, 0.17 +/- 0.03 nmol/L at 60 min; P less than 0.05), but not dopamine, also occurred. These results suggest that multiple ACTH-releasing factors, such as CRH, AVP, E, and NE, are involved in ACTH secretion induced by insulin-induced hypoglycemia in man.

Hormonal Responses to Insulin-Induced Hypoglycemia in Man*

Alendronate sodium (alendronate) is a bisphosphonate that potently inhibits bone resorption and is widely used for the treatment of osteoporosis. Alendronate produces a sustained reduction in the levels of biochemical markers of bone remodeling, returning these to the premenopausal range [1,2]. It also increases bone mineral density (BMD) [1–7] and decreases the risk of osteoporotic fracture in postmenopausal women [3–7]. Long-term intervention studies have shown that continuous alendronate therapy is associated with a sustained therapeutic effect on bone density and remodeling, with no indication that the fracture-preventing effect of the drug diminishes over time [8,9]. However, bisphosphonates suppress bone remodeling and thus may prevent the repair of microdamage. In animals, high doses of bisphosphonates (alendronate and risedronate) have been shown to suppress bone remodeling, and to cause the accumulation of microdamage in trabecular bone that reduces its strength [10,11]. Ott [12,13] has speculated that long-term alendronate therapy might begin to have a negative effect due to profound suppression of bone formation. Odvina et al. [14] have described nine patients who developed spontaneous nonspinal fractures after 1–8 years of alendronate therapy, and histomorphometric analysis of the bone biopsy samples has revealed severe suppression of bone turnover. Here we present the case of a patient with insuffi ciency fractures of the pubis and ilium related to severe suppression of bone turnover (SSBT) after nearly 3 years of alendronate therapy.

Pelvic insufficiency fracture associated with severe suppression of bone turnover by alendronate therapy

We simultaneously measured the concentrations of parathyroid hormone related peptide (PTHrP) and cytokines in synovial fluid (SF) to clarify the relationship between PTHrP and cytokine network in the SF of elderly patients with arthritis. SF was collected from knee joints of five RA patients aged 66+/-11 years old and nine osteoarthritis (OA) patients aged 80+/-9 years old. PTHrP in SF was measured by enzyme-linked immunosorbent assay (ELISA), whereas tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6) and interleukin-8 (IL-8) in SF were all measured by ELISA. The PTHrP levels in the SF of RA patients (2.56+/-0.89 pmol/l) were significantly (p<0.05) higher than those of OA patients (1.66+/-0.17 pmol/l). TNF-alpha, IL-1beta, IL-2 and IL-6 concentrations in SF of RA were also significantly higher than those in SF of OA (TNF-alpha 22.5+/-14.8 vs 4.8+/-3.0 pg/ml, p<0.01; IL-1beta 11.8+/-11.4 vs 1.4+/-1.3, p<0.05; IL-2 59.9+/-46.6 vs 12.5+/-8.0 pg/ml, p<0.05; IL-6 18424+/-8901 vs 3547+/-2948 pg/ml, p<0.01). The concentrations of IL-4 and IL-8 in SF of RA were similar to those of OA. Immunohistochemical studies revealed the presence of immunoreactive PTHrP in synovial fibroblasts from RA and OA. Among cytokines, only IL-6 was positively correlated with PTHrP levels in SF (r=0.685, p<0.01). In the culture of synovial cells from RA and OA, PTHrP was produced in RA more than OA after phorbol 12-mysistate 13-acetate (TPA) stimulation. These results indicate that PTHrP and cytokines, especially IL-6, might be involved in the inflammatory processes of elderly RA and OA. This is the first study in which PTHrP and cytokine levels were simultaneously examined in synovial fluid of elderly RA and OA.

Toshiyuki Horiuchi

Papers

Effect of Soy Protein on Bone Metabolism in Postmenopausal Japanese Women

Impact of degenerative spinal diseases on bone mineral density of the lumbar spine in elderly women

Hormonal Responses to Insulin-Induced Hypoglycemia in Man*

Pelvic insufficiency fracture associated with severe suppression of bone turnover by alendronate therapy

The Increase of Parathyroid Hormone-Related Peptide and Cytokine Levels in Synovial Fluid of Elderly Rheumatoid Arthritis and Osteoarthritis