"Non-Classical" Indication for Provocative Testing of Growth Hormone: A Retrospective Cohort Study in Adult Patients Under Replacement Therapy.
Mancini Antonio,Bruno Carmine,Vergani Edoardo,Brunetti Alessandro,Palmisano Gerardo,Pontecorvi Alfredo
Endocrine, metabolic & immune disorders drug targets
BACKGROUND:Adult growth hormone deficiency (GHD) is considered a rare condition. Current guidelines state that GH provocative test is indicated in patients affected by organic hypothalamic/ pituitary disease or with a history of head injury, irradiation, hemorrhage or hypothalamic disease with multiple pituitary deficiencies. Nevertheless, the clinical picture related to GHD may be subtle. OBJECTIVE:We have retrospectively evaluated the indication to GHRH+arginine test in our monocentric cohort of patients treated with hrGH in order to assess whether other conditions had been considered as a rationale for provocative testing. METHODS:Ninety-six patients (51 females and 45 males), aged 19-67 years were included. The GHRH+arginine test had been performed in 29 patients with organic hypothalamic/pituitary disease and in 4 patients for Childhood onset-GHD (CoGHD). In other patients, the diagnosis was suspected for "non classical" reasons in the clinical picture suspected for GHD. RESULTS:Classical indications included previously known primary empty sella (n=15), pituitary surgery (n=14), pituitary cyst (n=1), non-secreting pituitary tumors (n=3) but more than half of the patients (57.3%) had been studied for "non classical" indications: metabolic syndrome (n=25), asthenia (n=13), heart failure (n=4), osteoporosis (n=6), unexplained hypoglycaemia (n=1) and infertility (n=6). The latter represented a significant percentage in the male subgroup under 45 ys. IGF-1 levels were lower than 50th percentile in 63% of patients. Finally, among non-classical reasons, organic pituitary disease was discovered in 22 patients. CONCLUSION:Idiopathic GHD may be unrecognized due to its subtle manifestations and that an extended use of dynamic GH tests may reveal such conditions. A potential field of investigation could be to identify subsets of patients with clinical conditions caused or worsened by underlying unrecognized GHD.
A GABAergic neural circuit in the ventromedial hypothalamus mediates chronic stress-induced bone loss.
Yang Fan,Liu Yunhui,Chen Shanping,Dai Zhongquan,Yang Dazhi,Gao Dashuang,Shao Jie,Wang Yuyao,Wang Ting,Zhang Zhijian,Zhang Lu,Lu William W,Li Yinghui,Wang Liping
The Journal of clinical investigation
Homeostasis of bone metabolism is regulated by the central nervous system, and mood disorders such as anxiety are associated with bone metabolism abnormalities, yet our understanding of the central neural circuits regulating bone metabolism is limited. Here, we demonstrate that chronic stress in crewmembers resulted in decreased bone density and elevated anxiety in an isolated habitat mimicking a space station. We then used a mouse model to demonstrate that GABAergic neural circuitry in the ventromedial hypothalamus (VMH) mediates chronic stress-induced bone loss. We show that GABAergic inputs in the dorsomedial VMH arise from a specific group of somatostatin neurons in the posterior region of the bed nucleus of the stria terminalis, which is indispensable for stress-induced bone loss and is able to trigger bone loss in the absence of stressors. In addition, the sympathetic system and glutamatergic neurons in the nucleus tractus solitarius were employed to regulate stress-induced bone loss. Our study has therefore identified the central neural mechanism by which chronic stress-induced mood disorders, such as anxiety, influence bone metabolism.
Stroke and osteoporosis: a Taiwan cohort study.
Zhang Li,Zhang Zi-Hao,Wang Qing-Rui,Su Ying-Ju,Lu Ying-Yi,Zhang Cong-Liang,Tsai Hung-Pei,Wu Chieh-Hsin
Postgraduate medical journal
BACKGROUND:Osteoporosis and stroke are major health problems that have potentially overlapping pathophysiological mechanisms. The aim of this study was to estimate osteoporosis risk in Taiwan patientswho had a stroke. METHOD:This study retrieved data contained in the Taiwan National Health Insurance Research Database for a population-based sample of consecutive patients either hospitalised for stroke or treated for stroke on an outpatient basis. A total of 7550 newly diagnosed patientswho had a stroke were enrolled during 1996-2010. Osteoporosis risk in these patients was then compared with a matched group of patients who had not had a stroke randomly selected from the database at a ratio of 1:4 (n=30 200). The relationship between stroke history and osteoporosis risk was estimated with Cox proportional hazard regression models. RESULTS:During the follow-up period, osteoporosis developed in 1537 patients who had a stroke and in 5830 patients who had not had a stroke. The incidence of osteoporosis for cohorts with and without stroke was 32.97 and 14.28 per 1000 person-years, respectively. After controlling for covariates, the overall risk of osteoporosis was 1.82-fold higher in the stroke group than in the non-stroke group. The relative osteoporosis risk contributed by stroke had apparently greater impact among male gender and younger age groups. CONCLUSION:History of stroke is a risk factor for osteoporosis in Taiwan. Much attention to stroke-targeted treatment modalities might minimise adverse outcomes of osteoporosis.
Acetylcholinesterase Inhibitors Are Associated with Reduced Fracture Risk among Older Veterans with Dementia.
Ogunwale Abayomi N,Colon-Emeric Cathleen S,Sloane Richard,Adler Robert A,Lyles Kenneth W,Lee Richard H
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Acetylcholinesterase inhibitors (AChEIs) have been noted to increase bone density and quality in mice. Human studies are limited but suggest an association with improved bone healing after hip fracture. We examined the relationship between AChEI use and fracture risk in a national cohort of 360,015 male veterans aged 65 to 99 years with dementia but without prior fracture using Veterans Affairs (VA) hospital, Medicare, and pharmacy records from 2000 to 2010. Diagnosis of dementia, any clinical fracture (excluding facial and digital), comorbidities, and medications were identified using ICD-9 and drug class codes. Cox proportional hazard models considering AChEI use as a time-varying covariate and adjusting for fall and fracture risk factors compared the time-to-fracture in AChEI users versus non-AChEI users. Potential confounders included demographics (age, race, body mass index), comorbidities associated with fracture or falls (diabetes, lung disease, stroke, Parkinson's, seizures, etc.) and medications associated with fracture or falls (bisphosphonates, glucocorticoids, androgen deprivation therapy [ADT], proton pump inhibitors [PPIs], selective serotonin receptor inhibitors [SSRIs], etc.). Competing mortality risk was considered using the methods of Fine and Gray. To account for persistent effects on bone density or quality that might confer protection after stopping the medication, we completed a secondary analysis using the medication possession ratio (MPR) as a continuous variable in logistic regression models and also compared MPR increments of 10% to minimal/no use (MPR 0 to <0.10). Among older veterans with diagnosis of dementia, 20.1% suffered a fracture over an average of 4.6 years of follow-up. Overall, 42.3% of the cohort were prescribed AChEIs during the study period. The hazard of any fracture among AChEI users compared with those on other/no dementia medications was significantly lower in fully adjusted models (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.75-0.88). After considering competing mortality risk, fracture risk remained 18% lower in veterans using AChEIs (HR = 0.82; 95% CI 0.76-0.89). © 2019 American Society for Bone and Mineral Research. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.
Bone mineral loss and cognitive impairment: The PRESENT project.
Kang Hyun Goo,Park Hyun Young,Ryu Han Uk,Suk Seung-Han
Low bone mineral density (BMD) is correlated with Alzheimer's disease and its severity, but the association remains unclear in adults (≥50 years) without a history of stroke or dementia.We assessed BMD and cognitive function using the Mini-Mental Status Examination (MMSE) in 650 stroke- and dementia-free subjects (≥50 years) who were recruited for an early health check-up program between January 2009 and December 2010.The mean age was 62.9 ± 8.0 years and mean MMSE score was 27.6 ± 3.6. A total of 361 subjects had reduced BMD: 197 (30.3%) had osteopenia and 154 (23.6%) had osteoporosis, based on criteria of world health organization. A total of 5.4% of the male subjects had osteoporosis, versus 19.8% of the female subjects. After adjusting for age, sex, education, and other possible confounding factors such as hypertension, diabetes mellitus, and smoking, the estimated odds ratio for cognitive impairment was 1.72 for the osteopenia group (95% confidence interval [CI] 1.09-2.14, P = .019) and 2.81 for the osteoporosis group (95% CI 1.78-4.45, P < .001).Low BMD is correlated with cognitive impairment in community-dwelling adults aged 50 years and above without any medical history of stroke or dementia, especially in women. A community-based, early life, preventive osteoporosis education campaign might decrease the incidence of dementia.
Medical Comorbidity in Alzheimer's Disease: A Nested Case-Control Study.
Wang Jen-Hung,Wu Ya-Ju,Tee Boon Lead,Lo Raymond Y
Journal of Alzheimer's disease : JAD
BACKGROUND:Little is known about the distribution of medical comorbidities in Alzheimer's disease (AD). OBJECTIVE:We aimed to describe the comorbidity pattern of AD in a nested case-control study. METHODS:Incident AD cases were identified by International Classification of Diseases codes in a random sample of 2 million individuals in Taiwan National Health Insurance program during 2001-2011. We further restricted cases to those treated with AD drugs of approved reimbursement. We sampled a set of age- and sex-matched control subjects (2:1 ratio) and employed conditional logistic regression to estimate the associations between pre-specified 14 comorbidities and AD. The clusters of multiple chronic diseases were then identified by exploratory factor analysis. RESULTS:A total of 2,618 AD cases were identified during 2001-2011 with a mean age of 76.1 years and female preponderance (59%). The most common 5 comorbidities in AD were hypertension (55.1%), osteoarthritis (38.2%), depression (32.3%), diabetes mellitus (DM) (25.7%), and cerebrovascular disease (CVD) (22.7%). After adjusting for age and sex, DM, osteoporosis, depression, and CVD were significantly associated with AD. The number of comorbidity was 3-fold greater in the AD group. The cluster of hypertension, DM, and hyperlipidemia was the most common combination in old age, whereas the cluster osteoarthritis and osteoporosis was the only multimorbidity pattern significantly associated with AD. CONCLUSION:Multimorbidity is common in AD. Depression, CVD, osteoporosis, and DM are associated with incident AD, supporting that their co-existence is a typical feature of AD at old age. Comorbidity care should be integrated into current management for patients with AD.
P2Y12 Receptor Antagonist, Clopidogrel, Does Not Contribute to Risk of Osteoporotic Fractures in Stroke Patients.
Jørgensen Niklas R,Schwarz Peter,Iversen Helle K,Vestergaard Peter
Frontiers in pharmacology
Stroke is a leading cause of mortality and morbidity. It is associated with excessive bone loss and risk of fracture in stroke patients is high. The P2Y12R antagonist and platelet inhibitor, clopidogrel, is widely used for secondary prevention after a stroke. However, recent studies have shown that clopidogrel has negative effects on bone and that long-term clopidogrel use is associated with increased fracture risk. The purpose of the current study was therefore to investigate the association of clopidogrel treatment with risk of fractures in stroke and TIA patients. The study was a cohort study including all subjects who were prescribed clopidogrel between 1996 and 2008 in Denmark ( = 77,503). Age- and gender matched controls ( = 232,510) were randomly selected from the background population. The study end-points were occurrence of stroke or TIA and occurrence of fracture. Clopidogrel use was primary exposure. Ischemic stroke increased risk of fracture by 50% while haemorrhagic stroke and TIA increased the risk by 30%. However, after adjusting for multiple confounders only patients with ischemic stroke and haemorrhagic stroke had increased fracture risk. Clopidogrel use was not associated with increased fracture risk in subjects with ischaemic stroke or TIA. In contrast, after adjusting for multiple confounders clopidogrel treatment was associated with a 10-35% reduced risk of fracture. Patients with stroke have increased risk of osteoporotic fractures, but clopidogrel treatment does not increase fracture risk. In contrast, patients less adherent to the treatment have lower risk of fractures than non-users and patients with high adherence. However, based on the increased risk in stroke patients, clinicians should consider evaluation of bone status of these patients.
The Effect of Depression, Generalized Anxiety, and Selective Serotonin Reuptake Inhibitors on Change in Bone Metabolism in Adolescents and Emerging Adults.
Calarge Chadi A,Mills James A,Janz Kathleen F,Burns Trudy L,Schlechte Janet A,Coryell William H,Zemel Babette S
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
The purpose of this study was to prospectively examine the independent contribution of major depressive disorder (MDD), generalized anxiety disorder (GAD), and selective serotonin reuptake inhibitors (SSRIs) use to changes in bone metabolism in older adolescents and emerging adults. Medically healthy 15- to 20-year-olds who were unmedicated or within 1 month of starting an SSRI were prospectively followed. Psychiatric functioning and medication treatment were assessed monthly. Every 4 months, trabecular and cortical volumetric bone mineral density (vBMD) at the radius and markers of bone metabolism were evaluated. Every 8 months, total body less head areal bone mineral content and lumbar spine (LS) areal BMD (aBMD) were determined. Linear mixed-effects regression analysis examined associations between bone measures on the one hand and MDD, GAD, and SSRI indices on the other. A total of 264 participants were followed for 1.51 ± 0.76 years. After adjusting for age, sex, vitamin D concentration, physical activity, lean mass or grip strength, and time in the study, MDD severity was associated with increasing LS aBMD. Similarly, SSRI use was associated with increasing LS aBMD and bone formation in female participants. In contrast, SSRI use was associated with decreasing LS aBMD in males. After accounting for depression, GAD was independently, albeit weakly, associated with increased bone mineralization. In older adolescents and emerging adults, MDD and GAD are associated with increasing bone mass, particularly in the lumbar spine and in females, whereas SSRIs are associated with increasing bone mass in females but decreasing bone mass in males. © 2017 American Society for Bone and Mineral Research.
Depression and Disturbed Bone Metabolism: A Narrative Review of the Epidemiological Findings and Postulated Mechanisms.
Rosenblat J D,Gregory J M,Carvalho A F,McIntyre R S
Current molecular medicine
Major depressive disorder (MDD) is a pervasive chronic condition that contributes substantially to the global burden of disease and disability. Adding to the complexity of this disorder are numerous associated medical comorbidities with a bidirectional impact on morbidity and mortality. In recent years, osteoporosis has been increasingly identified as a significant comorbidity of MDD. This narrative review examines the literature to summarize key epidemiological studies and discuss postulated mechanisms of interaction. Epidemiological studies have repeatedly shown an increased co-prevalence of fractures and decreased bone mineral density (BMD) in MDD. The pathophysiological mechanism underlying this interaction is undoubtedly complex and multifactorial, and proposed pathways have varying levels of evidence from preclinical and clinical models. Conceptually, the mechanisms by which depression might influence bone metabolism can be categorized into biological, behavioral, iatrogenic, and comorbidity-related factors. Biological factors include the inflammatory-mood pathway, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, metabolic dysfunction, and serotonin's direct and indirect effects on bone cells. Behavioral factors incorporate lifestyle choices typical in depressed patients, such as increased tobacco use or limited exercise. The prominent iatrogenic factor is the independent effects of anti-depressants on bone metabolism. Psychiatric and medical comorbidities common to both osteoporosis and MDD are also important to consider. Physical activity promotion, vitamin D supplementation, and routine BMD screening of MDD patients are simple interventions that might lead to improved outcomes for both conditions. An improved understanding of the underlying mechanisms may yield insights into novel prevention and treatment strategies to target osteoporosis and fractures in the MDD population.
Chronic Psychological Stress as a Risk Factor of Osteoporosis.
Azuma Kagaku,Adachi Yasuhiro,Hayashi Haruki,Kubo Kin-Ya
Journal of UOEH
Osteoporosis, the most common metabolic skeletal disease, is characterized by decreased bone mass and deteriorated bone quality, leading to increased fracture risk. With the aging of the population, osteoporotic fracture is an important public health issue. Organisms are constantly exposed to various stressful stimuli that affect physiological processes. Recent studies showed that chronic psychological stress is a risk factor for osteoporosis by various signaling pathways. The purpose of this article is to review the recent progress of the association between chronic psychological stress and osteoporosis. Increasing evidence confirms the physiological importance of the central nervous system, especially the hypothalamus, in the regulation of bone metabolism. Both animal and human studies indicate that chronic psychological stress induces a decrease of bone mass and deterioration of bone quality by influencing the hypothalamic-pituitary-adrenocortical (HPA) axis, sympathetic nervous system, and other endocrine, immune factors. Active mastication, proven to be an effective stress-coping behavior, can attenuate stress-induced neuroendocrine responses and ameliorate stress-induced bone loss. Therefore, active mastication may represent a useful approach in preventing and/or treating chronic stress-associated osteoporosis. We also discuss several potential mechanisms involved in the interaction between chronic stress, mastication and osteoporosis. Chronic stress activates the HPA axis and sympathetic nervous system, suppresses the secretion of gonadal hormone and growth hormone, and increases inflammatory cytokines, eventually leading to bone loss by inhibiting bone formation and stimulating bone resorption.
Parkinson's disease: A risk factor for osteoporosis.
Malochet-Guinamand Sandrine,Durif Franck,Thomas Thierry
Joint bone spine
Parkinson's disease is the most common neurodegenerative disease after Alzheimer's disease. On the long term, it may be complicated by various musculoskeletal problems, such as osteoporotic fractures, that have significant socioeconomic consequences. Indeed, patients suffering from Parkinson's disease have a higher fracture risk, particularly hip fracture risk, than other subjects of the same age because of both a higher risk of falls and lower bone mineral density. Bone loss in Parkinson's disease may be associated with the severity and duration of the disease. We review here the different suspected mechanisms of accelerated bone loss in Parkinson's disease, amongst which weight loss and reduced mobility appear to play key roles. Antiparkinsonian drugs, particularly levodopa, may also be associated with decreased bone mineral density as a result of hyperhomocysteinaemia. We discuss the role of other nutritional deficiencies, such as vitamin B12, folate or vitamin K. In conclusion, it seems necessary to screen for and treat osteoporosis in this at-risk population, while actions to prevent falls are still disappointing. A better understanding of the factors explaining bone loss in this population would help implementing preventive actions.
[Osteoporosis and major depression: open debate on a bidirectional relationship].
Carlone Cristiano,Rusconi Anna Carlotta,Valeriani Giuseppe,Todini Liliana,Coccanari de' Fornari Maria Antonietta,Biondi Massimo
Rivista di psichiatria
Osteoporosis and depression are two chronic diseases that affect large population groups with great impact on morbidity, mortality and quality of life. Existing studies of the relationship between depression and osteoporosis have been heterogeneous in their design and use of diagnostic instruments for depression, which might have contributed to the different results on the comorbidity of these two conditions. Moreover, the direction of the causative link is still controversial and the etiology remains unclear. Definitely, limited data suggest that osteoporosis may enhance depressive symptoms, while far more studies have shown that depression adversely affects bone density and increases fracture risk. Thus the correlation of these diseases is still under research. This review comments on a plausible causative relationship and underlying mechanisms that might elucidate the link between two very common diseases. We describe the possible impact of osteoporosis on moods and the effect of depression on bone health. In particular, we focus on the role of the hypothalamic-pituitary-adrenocortical and sympathoadrenal axes, of the parathyroid hormone and cytokines. We also describe the effect of the antidepressant drugs as well as lifestyles that may explain this effect.
Risk of osteoporotic fractures following stroke in older persons.
Benzinger P,Rapp K,König H H,Bleibler F,Globas C,Beyersmann J,Jaensch A,Becker C,Büchele G
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
UNLABELLED:The aim of this study was to explore the increased risk of stroke survivors to different sustained osteoporotic fractures. We used hospital data and data on functional impairment. We found a higher risk in stroke survivors without functional impairment with the risk higher for lower than for upper extremity fractures. INTRODUCTION:Stroke survivors are at high risk of osteoporotic fractures due to frequent falls and an increased risk to develop osteoporosis. Data on their relative risk to sustain other than hip fractures is limited. Furthermore, the role of severe functional impairment on their fracture risk has not been considered yet. The aim of this study was to determine the relative risk of stroke survivors to sustain different osteoporotic fractures with regard to the presence of severe functional impairment. METHODS:Data from 2004 to 2009 of more than 1.2 million individuals aged 65 years or older and insured at a large German health insurance company were used for the analyses. Incident stroke and fractures were obtained from hospital diagnoses. Analyses were stratified by gender and information on severe functional impairment. Persons without preceding incident stroke were used as the reference group. Multistate models were used to estimate hazard ratios. RESULTS:Stroke survivors had a higher risk for fractures. However, a strong effect modification by functional impairment was apparent. Stroke survivors with functional impairment had no significantly increased risk for any fractures site compared to the corresponding reference group with functional impairment. In contrast, stroke survivors without functional impairment had a clearly and significantly increased fracture risk for most fracture sites. In these persons, the relative fracture risk for fractures of the lower extremities was higher than for fractures of the upper extremities. CONCLUSION:To evaluate the relative risk of stroke survivors for osteoporotic fractures, functional status appears to be a relevant parameter.
A population-based five-year study on the risk of stroke in patients with osteoporosis in Taiwan.
Lin Chia-Hsien,Chang Wei-Chiao,Kuo Chun-Nan,Yu Hann-Chin,Yang Chien-Chang,Lin Yea-Wen,Hung Kuo-Sheng,Chang Wei-Pin
OBJECTIVES:Osteoporosis and stroke are common diseases in elder patients. The relationship between these two diseases is unclear. This study was intended to estimate the risk of stroke among elder persons aged ≥ 50 years within five years of being diagnosed with osteoporosis. METHODS:We retrieved data from the Longitudinal Health Insurance Database 2005 (LHID2005) in Taiwan to perform a nationwide population-based study. There were 2580 patients with osteoporosis aged 50 years of age and older in the study cohort. All of them had at least 2 ambulatory care claims or at least 1 inpatient service claim. Each osteoporotic patient was matched to 5 non-osteoporotic patients based on gender, age, and the index year. Subjects in both groups were followed up for five years. Risk of developing stroke and 5-year stroke-free survival rates were evaluated. RESULTS:The risk of developing stroke was 1.24 times higher in osteoporotic patients within a 5-year follow-up period compared to an age- and gender-matched cohort without osteoporosis (95% confidence interval = 1.11-1.39; p < 0.001). Patients with osteoporosis also had a significantly lower 5-year stroke-free survival rate. CONCLUSIONS:Our results indicated that patients with osteoporosis history had higher risk for development of stroke.
Functional hypothalamic amenorrhea and its influence on women's health.
Meczekalski B,Katulski K,Czyzyk A,Podfigurna-Stopa A,Maciejewska-Jeske M
Journal of endocrinological investigation
INTRODUCTION:Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea. There are three types of FHA: weight loss-related, stress-related, and exercise-related amenorrhea. FHA results from the aberrations in pulsatile gonadotropin-releasing hormone (GnRH) secretion, which in turn causes impairment of the gonadotropins (follicle-stimulating hormone and luteinizing hormone). The final consequences are complex hormonal changes manifested by profound hypoestrogenism. Additionally, these patients present mild hypercortisolemia, low serum insulin levels, low insulin-like growth factor 1 (IGF-1) and low total triiodothyronine. AIM:The aim of this work is to review the available data concerning the effects of FHA on different aspects of women's health. RESULTS:Functional hypothalamic amenorrhea is related to profound impairment of reproductive functions including anovulation and infertility. Women's health in this disorder is disturbed in several aspects including the skeletal system, cardiovascular system, and mental problems. Patients manifest a decrease in bone mass density, which is related to an increase in fracture risk. Therefore, osteopenia and osteoporosis are the main long-term complications of FHA. Cardiovascular complications include endothelial dysfunction and abnormal changes in the lipid profile. FHA patients present significantly higher depression and anxiety and also sexual problems compared to healthy subjects. CONCLUSIONS:FHA patients should be carefully diagnosed and properly managed to prevent both short- and long-term medical consequences.
Osteoporosis in neurodegeneration.
Roos Per M
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)
Osteoporosis affects bone microarchitecture and reduces bone mass. There are more than 200 million people with osteoporosis worldwide, and the prevalence is slowly increasing. The highest prevalences are found in Scandinavia and USA, also slowly increasing. A parallel increase in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and multiple sclerosis has been noted since the middle of this century. Osteoporosis is more common in patients with each of these neurodegenerative conditions than in the general population. Several metals with neurotoxic properties accumulate in bone and can substitute for calcium in hydroxyapatite, the main mineral component of bone. Especially cadmium, but also lead, aluminum and arsenic affect bone mineral density negatively. Metals with neurotoxic properties have also been found in brain and cerebrospinal fluid from patients with Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and multiple sclerosis, and markers for neurodegeneration such as amyloid beta peptide and amyloid precursor protein have been detected in bone tissue from patients with osteoporosis. A common mechanism contributing to the pathogenesis of both neurodegeneration and osteoporosis can be suspected. The hypothesis that neurodegenerative disorders are associated with osteoporosis is presented and discussed.
Osteoporotic fractures and persistent non-fusion of the hand epiphyses caused by empty sella syndrome in an adult: a case report.
Xu Peng,He Hailong,Chen Yongfen,Wang Ce,Zhu Yunrong,Ye Xiaojian
The Journal of international medical research
We report a case of primary empty sella syndrome (ESS) resulting in osteoporotic fractures and persistent non-fusion of the hand epiphyses, and discuss the potential pathogenesis of this disease. A 41-year-old man presented with pain in the right hand and back after a fall. X-radiographs revealed persistent epiphyses and severe osteoporosis. Serum phosphorus and prolactin levels were above normal levels, and free triiodothyronine, free thyroxine and testosterone levels were below normal limits. Magnetic resonance imaging of the head revealed empty sella. A lumbar bone mineral density examination indicated severe osteoporosis. ESS caused a systemic hormone disorder in this patient, resulting in osteoporotic fractures and persistent non-fusion of the hand epiphyses. Possible causes of this anomaly are chronic or congenital abnormities of the pituitary gland.
Majumdar Abha,Mangal Nisha Sharma
Journal of human reproductive sciences
Prolactin (PRL) is an anterior pituitary hormone which has its principle physiological action in initiation and maintenance of lactation. In human reproduction, pathological hyperprolactinemia most commonly presents as an ovulatory disorder and is often associated with secondary amenorrhea or oligomenorrhea. Galactorrhea, a typical symptom of hyperprolactinemia, occurs in less than half the cases. Out of the causes of hyperprolactinemia, pituitary tumors may be responsible for almost 50% of cases and need to be investigated especially in the absence of history of drug induced hyperprolactinemia. In women with hyperprolactinemic amenorrhea one important consequence of estrogen deficiency is osteoporosis, which deserves specific therapeutic consideration. Problem in diagnosing and treating hyperprolactinemia is the occurrence of the 'big big molecule of prolactin' that is biologically inactive (called macroprolactinemia), but detected by the same radioimmunoassay as the biologically active prolactin. This may explain many cases of very high prolactin levels sometimes found in normally ovulating women and do not require any treatment. Dopamine agonist is the mainstay of treatment. However, presence of a pituitary macroadenoma may require surgical or radiological management.
Hospitalized osteoporotic vertebral fracture increases the risk of stroke: a population-based cohort study.
Chen Yu-Chun,Wu Jau-Ching,Liu Laura,Huang Wen-Cheng,Cheng Henrich,Chen Tzeng-Ji,Thien Peck-Foong,Lo Su-Shun
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
The association between osteoporosis and cardiovascular diseases has been demonstrated. Higher cardiovascular risk has also been correlated with vertebral fractures. However, the association between osteoporotic vertebral fracture and the possibly higher risk of stroke remains uncertain. This study aimed to evaluate the incidence, risk, and type of stroke in patients with osteoporotic vertebral fracture. Patients with osteoporotic vertebral fracture were identified (n = 380) and 10 age- and sex-matched controls per case (comparison group, n = 3795) were chosen from a nationwide representative cohort of 999,997 people from 1998 to 2005. Both groups were followed-up for stroke events for 3 years, matched by propensity scores with adjustments for covariates such as comorbidities (ie, hypertension, diabetes, arrhythmia, or coronary heart diseases) and exposure to medications (ie, aspirin, lipid lowering drug, or nitrates), and assessed by Kaplan-Meier and Cox regression analyses. The incidence rate of stroke in the osteoporotic vertebral fracture group (37.5 per 1000 person-years; 95% confidence interval [CI], 27.5-51.2) was significantly higher than in the comparison group (14.0 per 1000 person-years; 95% CI, 12.0-16.4, p < 0.001). Stroke was more likely to occur in the osteoporotic vertebral fracture patients than in the normal controls (crude hazard ratio [HR] 2.68, 95% CI 1.89-3.79, p < 0.001; adjusted HR 2.71, 95% CI 1.90-3.86, p < 0.001). In conclusion, patients with osteoporotic vertebral fracture have a higher risk of stroke (ie, both ischemic and hemorrhagic) and require stroke prevention strategies.
Bone mineral density and bone metabolism in patients with major depressive disorder without somatic comorbidities.
Malik P,Gasser R W,Moncayo R C,Kandler C,Koudouovoh-Tripp P,Giesinger J,Sperner-Unterweger B
Progress in neuro-psychopharmacology & biological psychiatry
BACKGROUND:Major depressive disorder (MDD) has been linked with accelerated bone loss leading to the development of low bone mineral density (BMD). Several mechanisms have been discussed as causative factors, e.g. lifestyle, selective serotonin reuptake inhibitor (SSRI) intake, or the influence of proinflammatory cytokines. METHODS:In a cross-sectional study of in-patients with a current episode of MDD, without somatic comorbidities, we determined various parameters of bone metabolism, inflammatory parameters and parameters of depression. BMD was measured by dual x-ray absorptiometry. RESULTS:Of 50 patients, only one had low BMD in any of the measure sites. Body mass index (BMI) correlated positively with Z-scores. 83.3% of the examined patients had elevated osteoprotegerin (OPG) levels. SSRI intake did not have an effect on BMD. BMD in the femoral neck was significantly lower in smokers. We also found a positive correlation between the level of physical activity and osteocalcin levels. CONCLUSIONS:In our sample, young to middle-aged, somatically healthy, and acutely depressed patients with a history of MDD showed no reduction of BMD. This could be due to compensatory mechanisms, as suggested by elevated OPG levels. Physical activity and high BMI could also have served as protective factors. Still, as patients with MDD often suffer from comorbidities or take medication with a negative effect on bone, this population should be appreciated as a high-risk group for the development of osteopenia and osteoporosis.
Kilicli Fatih,Dokmetas Hatice Sebila,Acibucu Fettah
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
Sheehan's syndrome (SS) is characterized by various degrees of hypopituitarism, and develops as a result of ischemic pituitary necrosis due to severe postpartum hemorrhage. Increased pituitary volume, small sella size, disseminated intravascular coagulation and autoimmunity are the proposed factors in the pathogenesis of SS. Hormonal insufficiencies, ranging from single pituitary hormone insufficiency to total hypopituitarism, are observed in patients. The ﬁrst most important issue in the diagnosis is being aware of the syndrome. Lack of lactation and failure of menstrual resumption after delivery that complicated with severe hemorrhage are the most important clues in diagnosing SS. The most frequent endocrine disorders are the deficiencies of growth hormone and prolactin. In patients with typical obstetric history, prolactin response to TRH seems to be the most sensitive screening test in diagnosing SS. Other than typical pituitary deficiency, symptoms such as anemia, pancytopenia, osteoporosis, impairment in cognitive functions and impairment in the quality of life are also present in these patients. Treatment of SS is based on the appropriate replacement of deficient hormones. Growth hormone replacement has been found to have positive effects; however, risk to benefit ratio, side effects and cost of the treatment should be taken into account.
Bone mineral density and vitamin D status in Parkinson's disease patients.
van den Bos F,Speelman A D,van Nimwegen M,van der Schouw Y T,Backx F J G,Bloem B R,Munneke M,Verhaar H J J
Journal of neurology
Bone loss is more common in Parkinson's disease (PD) than in the general population. Several factors may be involved in the development of bone loss, including malnutrition, immobilization, low body mass index, decreased muscle strength, vitamin D deficiency and medication use. This study investigates the prevalence of osteoporosis and possible risk factors associated with bone loss in early stage PD. In 186 PD patients (Hoehn and Yahr stage 1-2.5, mean age 64.1 years, 71 % men) bone mineral density (BMD) measurements were performed with DEXA. T- and Z-scores were calculated. Univariate linear regression analysis was performed to identify variables that contributed to BMD. 25-OH-vitamin D status of PD patients was compared with 802 controls (mean age 63.3 years, 50 % men) using linear regression analysis. Osteoporosis (11.8 %) and osteopenia (41.4 %) were common in PD patients. Mean Z-score for the hip was 0.24 (SD 0.93), and for the lumbar spine 0.72 (SD 1.91). Female gender, low weight, and low 25-OH-vitamin D were significantly correlated with BMD of the hip and lumbar spine. PD patients had lower 25(OH)D serum levels than controls (B = -10, p = 0.000). More than half of the patients with early stage PD had an abnormal BMD. Female gender, low weight, and low vitamin D concentration were associated with bone loss. Furthermore, vitamin D concentrations were reduced in PD patients. These results underscore the importance of proactive screening for bone loss and vitamin D deficiency, even in early stages of PD.
The roles of the sympathetic nervous system in osteoporotic diseases: A review of experimental and clinical studies.
He Ji-Ye,Jiang Lei-Sheng,Dai Li-Yang
Ageing research reviews
With the rapid aging of the world population, the issue of skeletal health is becoming more prominent and urgent. The bone remodeling mechanism has sparked great interest among bone research societies. At the same time, increasing clinical and experimental evidence has driven attention towards the pivotal role of the sympathetic nervous system (SNS) in bone remodeling. Bone remodeling is thought to be partially controlled by the hypothalamus, a process which is mediated by the adrenergic nerves and neurotransmitters. Currently, new knowledge about the role of the SNS in the development and pathophysiology of osteoporosis is being generated. The aim of this review is to summarize the evidence that proves the involvement of the SNS in bone metabolism and to outline some common osteoporotic diseases that occur under different circumstances. The adrenergic signaling pathway and its neurotransmitters are involved to various degrees of importance in the development of osteoporosis in postmenopause, as well as in spinal cord injury, depression, unloading and the complex regional pain syndrome. In addition, clinical and pharmacological studies have helped to increase the comprehension of the adrenergic signaling pathway. We try to individually examine the contributions of the SNS in osteoporotic diseases from a different perspective. It is our hope that a further understanding of the adrenergic signaling by the SNS will pave the way for conceptualizing optimal treatment regimens for osteoporosis in the near future.
Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research.
Stetler Cinnamon,Miller Gregory E
OBJECTIVES:To summarize quantitatively the literature comparing hypothalamic-pituitary-adrenal (HPA) axis function between depressed and nondepressed individuals and to describe the important sources of variability in this literature. These sources include methodological differences between studies, as well as demographic or clinical differences between depressed samples. METHODS:The current study used meta-analytic techniques to compare 671 effect sizes (cortisol, adrenocorticotropic hormone, or corticotropin-releasing hormone) across 361 studies, including 18,454 individuals. RESULTS:Although depressed individuals tended to display increased cortisol (d = 0.60; 95% confidence interval [CI], 0.54-0.66) and adrenocorticotropic hormone levels (d = 0.28; 95% CI, 0.16-0.41), they did not display elevations in corticotropin-releasing hormone (d = 0.02; 95% CI, -0.47-0.51). The magnitude of the cortisol effect was reduced by almost half (d = 0.33; 95% CI, 0.21-0.45) when analyses were limited to studies that met minimal methodological standards. Gender did not significantly modify any HPA outcome. Studies that included older hospitalized individuals reported significantly greater cortisol differences between depressed and nondepressed groups compared with studies with younger outpatient samples. Important cortisol differences also emerged for atypical, endogenous, melancholic, and psychotic forms of depression. CONCLUSIONS:The current study suggests that the degree of HPA hyperactivity can vary considerably across patient groups. Results are consistent with HPA hyperactivity as a link between depression and increased risk for conditions, such as diabetes, dementia, coronary heart disease, and osteoporosis. Such a link is strongest among older inpatients who display melancholic or psychotic features of depression.
Of sound mind and body: depression, disease, and accelerated aging.
Wolkowitz Owen M,Reus Victor I,Mellon Synthia H
Dialogues in clinical neuroscience
Major depressive disorder (MDD) is associated with a high rate of developing serious medical comorbidities such as cardiovascular disease, stroke, dementia, osteoporosis, diabetes, and the metabolic syndrome. These are conditions that typically occur late in life, and it has been suggested that MDD may be associated with "accelerated aging." We review several moderators and mediators that may accompany MDD and that may give rise to these comorbid medical conditions. We first review the moderating effects of psychological styles of coping, genetic predisposition, and epigenetic modifications (eg, secondary to childhood adversity). We then focus on several interlinked mediators occurring in MDD (or at least in subtypes of MDD) that may contribute to the medical comorbidity burden and to accelerated aging: limbic-hypothalamic-pituitary-adrenal axis alterations, diminution in glucocorticoid receptor function, altered glucose tolerance and insulin sensitivity, excitotoxicity, increases in intracellular calcium, oxidative stress, a proinflammatory milieu, lowered levels of "counter-regulatory" neurosteroids (such as allopregnanolone and dehydroepiandrosterone), diminished neurotrophic activity, and accelerated cell aging, manifest as alterations in telomerase activity and as shortening of telomeres, which can lead to apoptosis and cell death. In this model, MDD is characterized by a surfeit of potentially destructive mediators and an insufficiency of protective or restorative ones. These factors interact in increasing the likelihood of physical disease and of accelerated aging at the cellular level. We conclude with suggestions for novel mechanism-based therapeutics based on these mediators.
Osteoporosis in Parkinson's disease.
Invernizzi Marco,Carda Stefano,Viscontini Giovanni Sguazzini,Cisari Carlo
Parkinsonism & related disorders
Patients affected by Parkinson's disease are at a high risk for fractures, mainly of the hip. These fractures are caused by falls due to postural imbalance, neurological impairment and reduced bone mass. The purpose of this study was (1) to investigate the correlations and the pathophysiological mechanisms underlying bone loss in Parkinson's disease and appraise bone loss or fracture risk reduction interventions; (2) to develop a research agenda that informs the design and development of risk reduction strategies. Osteoporosis and osteopenia are very common findings in patients with Parkinson's disease, affecting up to 91% of women and 61% of men. Reduced bone mass in Parkinsonian patients seems to be caused mainly by reduced mobility through a mechanism similar to that observed in other neurological diseases. Endocrine (such as vitamin D deficiency), nutritional and iatrogenic factors also play an important role in bone mass depletion. Female gender, disease duration and severity (Hoehn and Yahr stages III and IV), old age and low body mass index are related to more severe osteoporosis. Vitamin D supplementation and bisphosphonates seem to be effective in reducing the risk of nonvertebral fractures in patients affected by Parkinson's disease. Prevention and evaluation of osteoporosis through bone mass density assessment should be considered in all patients with Parkinson's disease.
Depression and bone metabolism. A review.
Williams Lana J,Pasco Julie A,Jacka Felice N,Henry Margaret J,Dodd Seetal,Berk Michael
Psychotherapy and psychosomatics
BACKGROUND:There are data to suggest low bone mineral density is disproportionately prevalent among those with psychiatric disorders. This paper aims to review the current evidence on the relationship between depression and bone mineral density, and identify potential mechanisms. METHODS:Relevant sources were identified from the Pubmed and Web of Science (ISI) databases from the first relevant publication in 1994 to the present, 2007, using a combination of key words and terms including depression, major depressive disorder, osteoporosis, bone mineral density, hypothalamic-pituitary-adrenal axis, cortisol, cytokines, leptin, antidepressants, selective serotonin reuptake inhibitors, smoking, alcohol, physical activity and diet. Reference lists of chosen articles were further reviewed for associated publications. RESULTS:The possible association between psychiatric illness, in particular depression, and osteoporosis has been the subject of a growing body of research yielding various findings, although most identify some effect on bone. In addition to medication-related processes and/or modifiable lifestyle factors associated with mood disturbances, endocrine and immune alteration secondary to depression may play a pathogenetic role in bone metabolism. CONCLUSIONS:Additional longitudinal studies, with the advantage of temporal sequencing, remain to be conducted, as well as research into potential mechanisms surrounding the association. Nevertheless, the current findings are of clinical relevance, given the health burden of both depression and osteoporosis.
Vitamin D and Parkinson's disease--a hypothesis.
Newmark Harold L,Newmark Jonathan
Movement disorders : official journal of the Movement Disorder Society
Parkinson's disease (PD), a common disease of the elderly, is a movement disorder characterized by tremor, akinesia, and loss of postural reflexes, leading to immobility and frequent falls. It results from selective loss (death) of dopaminergic neurons in the substantia nigra region of the brain, largely developed prior to clinical diagnosis, and continuous after diagnosis, despite use of current therapeutic modalities. In PD in the United States the cause and mechanism of continued neuron cell death in the substantia nigra is currently unknown. We hypothesize, based upon several lines of evidence, that documented chronically inadequate vitamin D intake in the United States, particularly in the northern states and particularly in the elderly, is a significant factor in the pathogenesis of PD. This hypothesis implies that dietary aid for prevention and therapy for PD is possible.
Depression and osteoporosis in men: association or casual link?
Ilias Ioannis,Alesci Salvatore,Gold Philip W,Chrousos George P
Hormones (Athens, Greece)
The longer life expectancy of women than that of men and, therefore, the longer exposure to fracture risk has, at least partially, led to neglect of osteoporosis in men. Recently, unipolar depression, which is 2 times more frequent in women than in men, has been linked to osteoporosis. However, it is quite possible that this diagnosis may escape detection in men because of a different behavioral phenotype between the genders. A potential mechanism of bone loss in depression has been proposed, involving concurrent activation of the hypothalamo-pituitary-adrenal and sympatho-adrenal axes, suppression of the gonadal and somatotrophic axes, and high interleukin-6 and low leptin levels. We suggest that similar neurohormonal changes may cause osteoporosis in men.
Menopause and bone density issues for women with epilepsy.
Harden Cynthia L
Menopausal women with epilepsy present several unique management challenges. They have an elevated risk for osteoporotic fracture because of the adverse effects of antiepileptic drugs (AEDs) on bone metabolism, combined with the chance of trauma during seizures and the subtle effects of AEDs on coordination that promote falling. A uniform effect of AEDs on vitamin D metabolism or bone turnover has not yet been revealed by clinical or basic studies, although the enzyme-inducing AEDs appear to decrease serum vitamin D levels. However, bone density is frequently decreased in patients with epilepsy. Clinicians must be familiar with the recommendations for calcium and vitamin D supplementation and recognize when to refer patients for bone density evaluations. Perimenopause is a transition during which women with epilepsy are at risk for increased seizure frequency, probably because of alterations in the estrogen:progesterone ratio over this period. Women with epilepsy who have had a catamenial seizure pattern during their reproductive years are at particular risk for an increase in seizure frequency during perimenopause but may experience a seizure reduction after becoming menopausal (cessation of menses for 1 year). These women appear to represent a subgroup of patients with epilepsy who have heightened sensitivity to endogenous reproductive hormone levels. The use of hormone replacement therapy may also increase seizure occurrence. Finally, the age at menopause may be reduced in women with poorly controlled seizures. This is probably related to an effect of seizures on hypothalamic function, although primary ovarian dysfunction may also be operative in this setting.
Anorexia nervosa in female adolescents: endocrine and bone mineral density disturbances.
Muñoz M T,Argente J
European journal of endocrinology
Anorexia nervosa (AN) is a chronic childhood psychiatric illness that involves a reduction in caloric intake, loss of weight and amenorrhea, either primary or secondary. The diagnostic criteria for AN have been established by the American Psychiatric Association. The prevalence of this disease amongst adolescents and young adults is between 0.5 and 1% and the incidence of new cases per year is approximately 5-10/100,000 between 15 and 19 years of age.A number of endocrine and metabolic disturbances have been described in patients with AN including amenorrhea-oligomenorrhea, delayed puberty, hypothyroidism, hypercortisolism, IGF-I deficiency, electrolyte abnormalities, hypoglycemia and hypophosphatemia, among others. In addition to prolonged amenorrhea, osteopenia and osteoporosis are the most frequent complications leading to clinically relevant fractures and increased fracture risk throughout life. Patients exhibit an alteration in the hypothalamic-pituitary-gonadal axis, which is responsible for the menstrual disorders. The increase in gonadotropin secretion that can be observed after ponderal recuperation suggests that malnutrition could be the most important mechanism involved in the decrease in gonadotropin secretion. The loss of fat tissue as a consequence of nutrient restriction has been associated with hypoleptinemia and abnormal secretion of peptides implicated in food control (neuropeptide Y, melanocortins and corticotropin-releasing factor, among others).A review of the endocrine abnormalities, disturbances in neurotransmitters, as well as a detailed analysis of bone markers and bone mineral density in patients with AN is described.
Occurrence of osteopenia among adolescent girls with oligo/amenorrhea.
Csermely T,Halvax L,Schmidt E,Zámbó K,Vadon G,Szabó I,Szilágyi A
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
The occurrence of reduced bone mineral density (BMD) among adolescent girls with oligomenorrhea or secondary amenorrhea, due to 'pure' dysfunction of the hypothalamo-pituitary-ovarian (HPO) axis (without anorexia nervosa, excessive sport or ballet, slimming diet, etc.) was examined. The study group consisted of 19 adolescent girls (age 16-18 years) with oligo/amenorrhea. Clinical (height, weight, age at menarche, duration of amenorrhea, body mass index (BMI)), hormonal (follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, testosterone, prolactin), and ion (calcium, sodium, potassium, phosphate, chloride) parameters and the BMD of the lumbar spine were investigated. Correlations between BMD and other parameters were also examined. Twenty healthy volunteers (same age and regular cycles) served as controls. Three girls had osteoporosis, with a BMD below -2 standard deviations (SD). Ten showed osteopenia, with a BMD value between -1 and -2 SD. Only six of the study group had a normal BMD within +/- 1 SD. A positive correlation was observed between the BMD and the BMI (r = 0.73; p < 0.05). All the controls had normal hormonal, ion and BMD parameters. 'Pure' dysfunction of the HPO axis in adolescents, causing oligomenorrhea or secondary amenorrhea, might result in reduced BMD and, consequently, lower peak bone mass. Treatment of menstrual cycle disorders is necessary for the prevention of osteoporosis.
Fractures in the prodromal period of Parkinson disease.
Camacho-Soto Alejandra,Gross Anat,Searles Nielsen Susan,Miller Anna N,Warden Mark N,Salter Amber,Racette Brad A
OBJECTIVE:To examine the association between fractures and Parkinson disease (PD) during the 5-year prodromal phase as compared to controls. METHODS:We performed a population-based case-control study of Medicare beneficiaries in the United States from 2004 to 2009. We identified 89,632 incident PD cases and 117,760 comparable controls 66-90 years of age in 2009. PD case status was the outcome, and noncranial fracture the independent variable. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for association between fracture and PD in yearly time intervals prior to PD diagnosis/control reference date, after adjusting for covariates. RESULTS:There were 39,606 total fractures (25.4% cases, 14.3% controls) over the 5 years prior to the PD diagnosis/control reference date. PD was positively associated with fractures even after adjusting for age, sex, race/ethnicity, Charlson comorbidity index, alcohol use, tobacco use, and osteoporosis. The association between PD and fracture was evident at yearly time windows prior to PD diagnosis/control reference date. The association between PD and each type of fracture strengthened as the PD diagnosis/control reference date approached (all time interaction values ≤0.02). Among beneficiaries with a mechanism of injury, the majority were attributed to falls (74.6% cases, 72.8% controls). CONCLUSION:Fractures occur more commonly during the prodromal period of PD compared to controls, especially as diagnosis date approached, suggesting that patients with PD may experience unrecognized motor and nonmotor symptoms.
Association Between Acetylcholinesterase Inhibitors and Osteoporotic Fractures in Older Persons With Alzheimer's Disease.
Won Dae Yeon,Byun Seong Jun,Jeong Jin Sook,Shin Ju-Young
Journal of the American Medical Directors Association
OBJECTIVE:To identify the association between the use of acetylcholinesterase inhibitors (AChEIs) and risk of osteoporotic fractures in older persons with Alzheimer's disease (AD). DESIGN, SETTING, AND PARTICIPANTS:A nested case-control study was conducted using the Korean National Health Insurance Service-National Elderly Cohort database. Patients with AD who were newly diagnosed with osteoporotic fractures were identified as cases. Up to 3 controls were matched with cases according to age, sex, and duration of follow-up. METHODS:Participants were considered as exposed to AChEIs if they had been prescribed at least 1 AChEI during a period of 2 years before the index date. A conditional logistic regression was performed to estimate the adjusted odds ratios with 95% confidence intervals for the association between the use of AChEIs and osteoporotic fractures in patients with AD. We also examined the impact of dose, duration of treatment, and timing of exposure on the estimates of the association between the use of AChEIs and risk of osteoporotic fractures. RESULTS:The study cohort comprised 45,006 patients diagnosed with AD, of which 9470 patients, including 2385 cases and 7085 controls, were available for the study. The mean ages (standard deviations) were 78.6 (6.9) years in the cases and 80.0 (6.9) years in the controls. Adjusted odds ratios for the association between the use of AChEIs and osteoporotic fractures in patients with AD was 1.18 (95% confidence interval 1.07-1.31). CONCLUSIONS AND IMPLICATIONS:Our data indicated that the use of AChEIs was not associated with a reduced risk of osteoporotic fractures in patients with AD; in contrast, their use was associated with a mild increased risk of osteoporotic fractures. Thus, clinicians should consider the possibility of AChEIs-associated fractures among older persons with AD. Findings of this study will support shared decision making among prescribers, patients, and caregivers.
No impact of anti-Rank ligand and PTH analogs on cardiovascular risk in postmenopausal osteoporosis: a systematic literature review and meta-analysis.
Ferrieres Laurence,Degboe Yannick,Laroche Michel,Constantin Arnaud,Ruyssen-Witrand Adeline
Archives of osteoporosis
The mutual effects of drugs used in osteoporosis and cardiovascular diseases are a point of interest. A literature review and meta-analysis were conducted to address the impact of PTH analogs and anti-Rank ligand on cardiovascular events and overall mortality in individuals with idiopathic osteoporosis; these treatments do not appear to have any effect. INTRODUCTION:Two meta-analyses have been conducted to explore the cardiovascular effects of bisphosphonates. There is no review for other osteoporosis treatments. A literature review and meta-analysis were conducted to address the impact of PTH analogs and anti-Rank ligand on cardiovascular events and overall mortality in individuals with idiopathic osteoporosis. METHODS:A systematic review was conducted in December 2017 in the PubMed, Embase, and Cochrane databases and updated on PubMed in July 2019, selecting trials with a treatment and a control group. We also conducted a search for abstracts of the French Rheumatology Society, American College of Rheumatology, and European League Against Rheumatism's annual meetings over the past 4 years. The main endpoint was the occurrence of cardiovascular events; the secondary was mortality (all causes). RESULTS:Of the 2782 reports initially found, 16 articles were used for the meta-analysis (6 for the anti-Rank ligand and 10 for the PTH analog group). After meta-analysis, there was no significant difference between the placebo group and the anti-Rank ligand group for overall mortality (p = 0.13), the combined endpoint (overall mortality, coronary artery disease, and stroke; p 0.77), and the individual risk of coronary artery disease (p 0.53), arrhythmia (p 0.95), and stroke (p 0.62). After meta-analysis, there was no significant difference between the placebo group and the PTH analogs group for overall mortality (p 0.77), the combined endpoint (p = 0.95), and the individual risk of coronary artery disease (p = 0.74), arrhythmia (p = 0.28), and stroke (p = 0.61). CONCLUSIONS:The anti-Rank ligand and PTH analogs have no impact on cardiovascular risk and overall mortality in idiopathic osteoporosis. To better answer the question whether these treatments can reduce the long-term cardiovascular risk, further comparative studies with longer duration are required.
The risk of hip and non-vertebral fractures in patients with Parkinson's disease and parkinsonism: A systematic review and meta-analysis.
Schini Marian,Vilaca Tatiane,Poku Edith,Harnan Susan,Sutton Anthea,Allen Isabel Elaine,Cummings Steven Ron,Eastell Richard
Parkinson's disease (PD) is a neurodegenerative disorder that is common in older individuals. PD patients have an increased risk of fractures compared to the general population, perhaps due to multiple falls. However, the fracture risk has not been fully assessed. To assess the impact of PD on the risk of hip and non-vertebral fractures, we conducted a systematic review and meta-analysis. Comprehensive searches of three key bibliographic databases were conducted to identify reviews and primary studies relating to the risk of fractures in patients with PD. Search terms included all relevant terms for Parkinson's disease and for fractures. We selected observational studies with data on the risk of fractures in adults with PD compared to controls without the diagnosis. Study quality was assessed using the Newcastle Ottawa Scale. The random-effects model was used to pool the results. Eighteen studies were included in the review. Seventeen independent studies (14 cohort and 3 case-control studies) were included in the hip fracture analysis. Nine studies (all cohorts, no case-control studies) were included in the non-vertebral fracture analysis. Study quality was judged to be moderate to good. Overall, PD patients had an increased risk for both hip fractures (2.40, 95% CI 2.04 to 2.82) and non-vertebral fractures (1.80, 95% CI 1.60 to 2.01) compared to controls. The relative risk for hip fractures was higher in men (2.93, 95% CI 2.05 to 4.18) than in women (1.81, 95% CI 1.61 to 2.04). There were no effects of the study design, geographical region, or criteria for diagnosing Parkinson's disease on these estimates of fracture risk. There is an increase in the risk of hip and non-vertebral fractures in patients with Parkinson's disease and we recommend a re-evaluation of the clinical guidelines on bone health in patients with PD to address this.
Bile acid abnormality induced by intestinal dysbiosis might explain lipid metabolism in Parkinson's disease.
Hasuike Yuhei,Endo Takuyuki,Koroyasu Michiyo,Matsui Misa,Mori Chiaki,Yamadera Misaki,Fujimura Harutoshi,Sakoda Saburo
Intestinal dysbiosis refers to an imbalance in the intestinal flora. The concept of small intestinal bacterial overgrowth (SIBO), a condition of abnormal proliferation of the small intestine microbiota, has been proposed as a form of small intestine dysbiosis. In Parkinson's disease patients, weight loss and metabolic disorders such as lipid abnormalities are frequently encountered. This was a prospective investigation of the presence of SIBO using the lactulose breath test, Parkinson's disease symptoms, medications, abdominal symptoms, and blood data involving 39 Parkinson's disease patients. Of the 39 patients, 19 were positive for SIBO, 16 were negative, and 4 were equivocal. SIBO-positive patients had a significantly smaller dopaminergic drug load (dopamine replacement of Parkinson's disease drug potency) (P = 0.009) and significantly lower serum triglyceride (TG) (P = 0.024) and total bilirubin (P = 0.019) levels. No relationship was seen between the presence or absence of SIBO and motor or abdominal symptoms. The following hypothesis was developed with regard to the possibility that intestinal bacterial overgrowth has various effects that are exhibited via bile acid metabolism in Parkinson's disease patients. Serum bilirubin levels become higher as bilirubin metabolism declines with decreases in the intestinal bacteria. At the same time, bile acid is broken down due to increased intestinal bacteria, and lipid absorption decreases. This induces low serum TG levels and leads to weight loss. By a similar mechanism, there is less absorption of vitamin D as bile acid levels decrease, leading to osteoporosis and fractures. The possibility that some of the non-motor manifestations accompanying Parkinson's disease are caused by intestinal dysbiosis needs to be considered.
Chlorpyrifos Exposure Induces Parkinsonian Symptoms and Associated Bone Loss in Adult Swiss Albino Mice.
Ali Shaheen Jafri,Ellur Govindraj,Patel Kalpana,Sharan Kunal
Prenatal and early life exposure of chlorpyrifos (CPF), a widely used pesticide, is known to cause neuronal deficits and Parkinson's disease (PD). However, data about the effect of its exposure at adult stages on PD-like symptoms and associated bone loss is scanty. In the present study, we investigated the impact of CPF on the behavioral alterations seen in PD using adult Swiss albino mice. PD is often associated with bone loss. Hence, skeletal changes were also evaluated using micro-computed tomography and histology. MPTP was used as a positive control. Cell culture studies using MC3T3E-1, SHSY5Y, and primary osteoclast cultures were done to understand the cellular mechanism for the behavioral and skeletal changes. Our results showed that CPF treatment leads to PD-like symptoms due to the loss of dopaminergic neurons. Moreover, CPF has a deleterious effect on the trabecular bone through both indirect changes in circulating factors and direct stimulation of multinucleate osteoclast cell formation. The impact on the bone mass was even stronger than MPTP. In conclusion, this is the first report demonstrating that CPF induces parkinsonian features in adult Swiss albino mice and it is accompanied by loss of trabecular bone.
Prolactin - a pleiotropic factor in health and disease.
Bernard Valérie,Young Jacques,Binart Nadine
Nature reviews. Endocrinology
The principal role of prolactin in mammals is the regulation of lactation. Prolactin is a hormone that is mainly synthesized and secreted by lactotroph cells in the anterior pituitary gland. Prolactin signalling occurs via a unique transmembrane prolactin receptor (PRL-R). The structure of the PRL-R has now been elucidated and is similar to that of many biologically fundamental receptors of the class 1 haematopoietic cytokine receptor family such as the growth hormone receptor. The PRL-R is expressed in a wide array of tissues, and a growing number of biological processes continue to be attributed to prolactin. In this Review, we focus on the newly discovered roles of prolactin in human health and disease, particularly its involvement in metabolic homeostasis including body weight control, adipose tissue, skin and hair follicles, pancreas, bone, the adrenal response to stress, the control of lactotroph cell homeostasis and maternal behaviour. New data concerning the pathological states of hypoprolactinaemia and hyperprolactinaemia will also be presented and discussed.
Long-term thiazide use and risk of low-energy fractures among persons with Alzheimer's disease-nested case-control study.
Taipale H,Rysä J,Hukkanen J,Koponen M,Tanskanen A,Tiihonen J,Kröger H,Hartikainen S,Tolppanen A-M
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
We investigated the association between thiazide use and the risk of low-energy fractures among community dwellers with Alzheimer's disease. Longer use was associated with a decreased risk of low-energy fractures. This study extends the previous knowledge of reduced fracture risk of thiazides to persons with Alzheimer's disease. INTRODUCTION:To investigate the association between thiazide use and the risk of low-energy fractures (LEF), and hip fracture among community dwellers with Alzheimer's disease (AD). No prior study has evaluated the effect of thiazides on LEF risk of AD patients. METHODS:LEF cases were identified from the MEDALZ study, including all community-dwelling persons diagnosed with AD in Finland 2005-2011. During the follow-up from AD diagnoses until the end of 2015, cases with LEF (N = 10,416) and hip fracture (N = 5578) were identified. LEF cases were matched with up to three controls without LEF, according to time since AD diagnosis, age and gender. Thiazide use identified from the Prescription register data was modeled with PRE2DUP method. Current use was defined in 0-30 days' time window before the fracture/matching date, and duration of current use was assessed. The association between thiazide exposure and LEFs was assessed with conditional logistic regression. RESULTS:Current thiazide use was observed in 10.5% of LEF cases and 12.5% of controls. Current thiazide use was associated with a decreased risk of LEF (adjusted OR [aOR] 0.83, 95% CI 0.77-0.88). In terms of the duration of use, no association was observed with short-term use (< 1 year or 1-3 years), while longer use (> 3 years) was associated with a reduced risk of LEF (aOR 0.77, 95% CI 0.71-0.83) and hip fracture (aOR 0.68, 95% CI 0.60-0.78). CONCLUSIONS:Our study extends the previous knowledge of reduced fracture risk of thiazides to persons with AD, a population with significantly increased background risk of fractures.
Compston Juliet E,McClung Michael R,Leslie William D
Lancet (London, England)
Fractures resulting from osteoporosis become increasingly common in women after age 55 years and men after age 65 years, resulting in substantial bone-associated morbidities, and increased mortality and health-care costs. Research advances have led to a more accurate assessment of fracture risk and have increased the range of therapeutic options available to prevent fractures. Fracture risk algorithms that combine clinical risk factors and bone mineral density are now widely used in clinical practice to target high-risk individuals for treatment. The discovery of key pathways regulating bone resorption and formation has identified new approaches to treatment with distinctive mechanisms of action. Osteoporosis is a chronic condition and long-term, sometimes lifelong, management is required. In individuals at high risk of fracture, the benefit versus risk profile is likely to be favourable for up to 10 years of treatment with bisphosphonates or denosumab. In people at a very high or imminent risk of fracture, therapy with teriparatide or abaloparatide should be considered; however, since treatment duration with these drugs is restricted to 18-24 months, treatment should be continued with an antiresorptive drug. Individuals at high risk of fractures do not receive adequate treatment and strategies to address this treatment gap-eg, widespread implementation of Fracture Liaison Services and improvement of adherence to therapy-are important challenges for the future.
Clinical aspects of thyroid function during ageing.
Chaker Layal,Cappola Anne R,Mooijaart Simon P,Peeters Robin P
The lancet. Diabetes & endocrinology
Globally, populations are ageing at a rapid rate. The increase in the number of older citizens is accompanied by an increased prevalence of thyroid dysfunction, one of the most common disorders in older people. However, the diagnosis of thyroid dysfunction in older people is hindered by several factors, including the scarcity of thyroid dysfunction symptoms in older people. We describe the physiological changes in thyroid function that occur with increasing age, focusing on literature regarding changes in thyroid function test results in older populations. We also discuss treatment considerations for clinical and subclinical thyroid dysfunction according to international guidelines for older people. Finally, we discuss the relationship between variations in thyroid function and common diseases of old age including cardiovascular disease, osteoporosis, cognitive impairment, and frailty and suggest directions for future research.
Role of Marrow Adipocytes in Regulation of Energy Metabolism and Bone Homeostasis.
Cornish Jillian,Wang Tao,Lin Jian-Ming
Current osteoporosis reports
PURPOSE OF REVIEW:The goal of this review is to gain a better understanding of marrow adipocyte development, its regulation of energy, and its characterization responsible for bone homeostasis. RECENT FINDINGS:Despite major advances in uncovering the complex association of bone-fat in the marrow, the underlying basic biological process of adipose tissue development, as well as its interaction with bone homeostasis in pathophysiological conditions, is still not well understood. This review identifies many pro- and anti-osteogenic factors secreted by adipocytes to play a role in the manipulating the fate of mesenchymal stem cells as well as the osteoblastic activity during bone remodeling. It also addresses the function of adipose tissue capable of negative regulation of the hematopoietic microenvironment to influence the bone quantity and the nature of bone homeostasis.
The National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease: Perspectives from the Research Roundtable.
Knopman David S,Haeberlein Samantha Budd,Carrillo Maria C,Hendrix James A,Kerchner Geoff,Margolin Richard,Maruff Paul,Miller David S,Tong Gary,Tome Maria B,Murray Melissa E,Nelson Peter T,Sano Mary,Mattsson Niklas,Sultzer David L,Montine Thomas J,Jack Clifford R,Kolb Hartmuth,Petersen Ronald C,Vemuri Prashanthi,Canniere Megan Zoschg,Schneider Julie A,Resnick Susan M,Romano Gary,van Harten Argonde Corien,Wolk David A,Bain Lisa J,Siemers Eric
Alzheimer's & dementia : the journal of the Alzheimer's Association
The Alzheimer's Association's Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimer's Association Research Framework. This review will summarize the "A, T, N System" (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed.
Osteoporosis: A Hidden Nonmotor Face of Parkinson's Disease.
Metta Vinod,Sanchez Tamara C,Padmakumar Chandrasekhara
International review of neurobiology
Osteoporosis is a "hidden nonmotor face" of Parkinson's disease and a cause of considerable morbidity in the older general population and in Parkinson's disease patients. Some regard this as a "hidden epidemic." Women are overrepresented and have considerable problems related to osteoporosis. In general osteoporosis leads to reduced mobility aggravating the motor syndrome of PD. The nonmotor aspects and impact of osteoporosis in PD have remained unexplored. Possible nonmotor consequences include a range of pain syndromes related to local pain, fractures, falls, and injuries as well as pathological fractures and radiculopathy. In addition depression, sleep dysfunction, dementia, as well as fear of falling also complicate the clinical picture. Quality of life deteriorates both for the patient and career. Pathways of care do not always include assessments for osteoporosis and needs to become obligatory particularly in older female PD patients. Active management strategies then need to be undertaken for osteoporosis in PD. Related motor and nonmotor consequences also highlight the importance of multidisciplinary treatment in PD particularly when dealing with osteoporosis.
MACF1, versatility in tissue-specific function and in human disease.
Hu Lifang,Xiao Yunyun,Xiong Zhipeng,Zhao Fan,Yin Chong,Zhang Yan,Su Peihong,Li Dijie,Chen Zhihao,Ma Xiaoli,Zhang Ge,Qian Airong
Seminars in cell & developmental biology
Spectraplakins are a family of evolutionarily conserved gigantic proteins and play critical roles in many cytoskeleton-related processes. Microtubule actin crosslinking factor 1 (MACF1) is one of the most versatile spectraplakin with multiple isoforms. As a broadly expressed mammalian spectraplakin, MACF1 is important in maintaining normal functions of many tissues. The loss-of-function studies using knockout mouse models reveal the pivotal roles of MACF1 in embryo development, skin integrity maintenance, neural development, bone formation, and colonic paracellular permeability. Mutation in the human MACF1 gene causes a novel myopathy genetic disease. In addition, abnormal expression of MACF1 is associated with schizophrenia, Parkinson's disease, cancer and osteoporosis. This demonstrates the crucial roles of MACF1 in physiology and pathology. Here, we review the research advances of MACF1's roles in specific tissue and in human diseases, providing the perspectives of MACF1 for future studies.
Role of hypothalamic cannabinoid receptors in post-stroke depression in rats.
Wang Shanshan,Sun Hong,Liu Sainan,Wang Ting,Guan Jinqun,Jia Jianjun
Brain research bulletin
One of the most common psychological consequences of stroke is post-stroke depression (PSD). While more than 30 percent of stroke patients eventually develop PSD, the neurobiological mechanisms underlying such a phenomenon have not been well investigated. Given the critical involvement of hypothalamic-pituitary-adrenal axis and endocannabinoid system in response to stressful stimuli, we evaluated the hypothesis that cannabinoid receptors in the hypothalamus are critical for modulation of post-stroke depression-like behaviors in rats. To this end, rats were treated with middle cerebral artery occlusion (MCAO) followed by chronic unpredictable mild stress (CUMS) treatment procedure. We then assessed the expression of CB1 and CB2 receptors in the hypothalamus, and evaluated the effects of pharmacological stimulations of CB1 or CB2 receptors on the expression and development of depression-like behaviors in PSD rats. We found that PSD rats exhibited decreased the expression of CB1 receptor, but not CB2 receptor, in the ventral medial hypothalamus (VMH). Such an effect was not observed in the dorsally adjacent brain regions. Furthermore, intra-VMH injections of CB2 receptor agonist, but not CB1 receptor agonist, attenuated the expression of depression-like behaviors in PSD rats. Finally, repeated intraperitoneal injections of CB1 or CB2 receptor agonists during CUMS treatment inhibited the development of depression-like behaviors in PSD rats. Taken together, these results suggest that decreased CB1 receptor expression is likely associated with the development of post-stroke depression, and CB2 receptor may be a potential therapeutic target for the treatment post-stroke depressive disorders.
[Mental time dysfunction in Parkinson's and Alzheimer's diseases].
Honma Motoyasu,Kuroda Takeshi,Futamura Akinori,Sugimoto Azusa,Kawamura Mitsuru
Brain and nerve = Shinkei kenkyu no shinpo
Mental time is altered by a number of factors and the underlying neural processing involved is highly complicated. Recent research suggests that mental time in patients with particular neurological diseases is perceptually shorter than in normal individuals. This review introduces mental time dysfunction and a model for processing of mental time in Parkinson's and Alzheimer's disease. Although the two diseases show the same dysfunction of mental time in behavior, we expect the underlying neural mechanism to vary in each disease. It is possible that the dysfunction of mental time in Parkinson's disease is caused by the abnormal striatum acting as a pacemaker, while that in Alzheimer's disease is caused by abnormal hippocampal memory.
Differential effects of sympathetic nervous system and hypothalamic-pituitary-adrenal axis on systemic immune cells after severe experimental stroke.
Mracsko Eva,Liesz Arthur,Karcher Simone,Zorn Markus,Bari Ferenc,Veltkamp Roland
Brain, behavior, and immunity
Infectious complications are the leading cause of death in the post-acute phase of stroke. Post-stroke immunodeficiency is believed to result from neurohormonal dysregulation of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. However, the differential effects of these neuroendocrine systems on the peripheral immune cells are only partially understood. Here, we determined the impact of the hormones of the SNS and HPA on distinct immune cell populations and characterized their interactions after stroke. At various time points after cortical or extensive hemispheric cerebral ischemia, plasma cortisone, corticosterone, metanephrine and adrenocorticotropic hormone (ACTH) levels were measured in mice. Leukocyte subpopulations were flow cytometrically analyzed in spleen and blood. To investigate their differential sensitivity to stress hormones, splenocytes were incubated in vitro with prednisolone, epinephrine and their respective receptor blockers. Glucocorticoid receptor (GCR) and beta2-adrenergic receptor (β2-AR) on leukocyte subpopulations were quantified by flow cytometry. In vivo effects of GCR and selective β2-AR blockade, respectively, were defined on serum hormone concentrations, lymphopenia and interferon-γ production after severe ischemia. We found elevated cortisone, corticosterone and metanephrine levels and associated lymphocytopenia only after extensive brain infarction. Prednisolone resulted in a 5 times higher cell death rate of splenocytes than epinephrine in vitro. Prednisolone and epinephrine-induced leukocyte cell death was prevented by GCR and β2-AR blockade, respectively. In vivo, only GCR blockade prevented post ischemic lymphopenia whereas β2-AR preserved interferon-γ secretion by lymphocytes. GCR blockade increased metanephrine levels in vivo and prednisolone, in turn, decreased β2-AR expression on lymphocytes. In conclusion, mediators of the SNS and the HPA axis differentially affect the systemic immune system after stroke. Moreover, our findings suggest a negative-feedback of corticosteroids on the sympathetic axis which may control the post-stroke stress-reaction. This complex interplay between the HPA and the SNS after stroke has to be considered when targeting the neurohormonal systems in the post acute phase of severe stroke.
Pituitary stalk lesion in a 13-year-old female.
Zilbermint Mihail,Ramnitz Mary S,Lodish Maya B,Kanaka-Gantenbein Christina,Kattamis Antonis,Lyssikatos Charalampos,Patronas Nicholas J,Quezado Martha M,Stratakis Constantine A
Journal of pediatric endocrinology & metabolism : JPEM
Germinomas presenting with a pituitary stalk lesion and panhypopituitarism are rare in children, and their definite diagnosis is challenging. An invasive diagnostic approach, such as a transsphenoidal biopsy, is often required prior to establishing a treatment regimen. A 13-year-old female presented with 1 year of secondary amenorrhea, fatigue, and progressive thirst with polyuria. Laboratory work-up revealed panhypopituitarism (central hypothyroidism, hypogonadotropic hypogonadism, adrenal insufficiency and central diabetes insipidus). α-Fetoprotein and β-human chorionic gonadotropin were not elevated in serum nor in cerebrospinal fluid. The magnetic resonance imaging (MRI) of the pituitary region showed an enhancing infundibular lesion, extending into the hypothalamus, and infiltrating the pituitary gland. A transsphenoidal biopsy of the infundibular lesion confirmed the diagnosis of germinoma (germ-cell tumor). After appropriate hormone replacement therapy, chemotherapy and low-dose radiation therapy, the patient achieved complete resolution of the pituitary stalk lesion on the MRI.
Into the groove: can rhythm influence Parkinson's disease?
Nombela Cristina,Hughes Laura E,Owen Adrian M,Grahn Jessica A
Neuroscience and biobehavioral reviews
Previous research has noted that music can improve gait in several pathological conditions, including Parkinson's disease, Huntington's disease and stroke. Current research into auditory-motor interactions and the neural bases of musical rhythm perception has provided important insights for developing potential movement therapies. Specifically, neuroimaging studies show that rhythm perception activates structures within key motor networks, such as premotor and supplementary motor areas, basal ganglia and the cerebellum - many of which are compromised to varying degrees in Parkinson's disease. It thus seems likely that automatic engagement of motor areas during rhythm perception may be the connecting link between music and motor improvements in Parkinson's disease. This review seeks to describe the link, address core questions about its underlying mechanisms, and examine whether it can be utilized as a compensatory mechanism.
Infiltrative neurosarcoidosis presenting as secondary amenorrhea: case report and review of the literature.
Aghajanova Lusine,Jaffe Robert B,Herndon Christopher N
Obstetrical & gynecological survey
In this report, we describe abrupt onset of secondary amenorrhea in a woman with history of chronic systemic sarcoidosis. Endocrinologic evaluation of her hypothalamic-pituitary axis revealed abnormally low levels of follicle-stimulating hormone, luteinizing hormone, and insulinlike growth factor 1 and elevated prolactin. Urine osmolality was low, and serum osmolality was high. Magnetic resonance imaging revealed diffuse extensive leptomeningeal enhancement, with involvement of the hypothalamus, pituitary stalk, and the optic chiasm. Clinical diagnosis was consistent with neurosarcoidosis with hypothalamic-pituitary infiltration resulting in clinical hypogonadotropic hypogonadism, hyper-prolactinemia, and diabetes insipidus. In our report, we provide an overview of basic reproductive neuroendocrinology and discuss salient concepts of the pathogenesis, clinical manifestations, evaluation, and management of hypogonadotropic hypogonadism. The current literature on neurosarcoidosis with involvement of the hypothalamic-pituitary axis is summarized. The possibility of infiltrative process should be considered in patients with new diagnosis of hypogonadotropic hypogonadal amenorrhea.
Sheep model for osteoporosis: sustainability and biomechanical relevance of low turnover osteoporosis induced by hypothalamic-pituitary disconnection.
Oheim Ralf,Beil Frank Timo,Köhne Till,Wehner Tim,Barvencik Florian,Ignatius Anita,Amling Michael,Clarke Iain J,Pogoda Pia
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
Hypothalamo-pituitary disconnection (HPD) leads to low bone turnover and osteoporosis in sheep. To determine the sustainability of bone loss and its biomechanical relevance, we studied HPD-sheep 24 months after surgery (HPD + OVX-24) in comparison to untreated control (Control), ovariectomized sheep (OVX), and sheep 12 months after HPD (HPD + OVX-12). We performed histomorphometric, HR-pQCT, and qBEI analyses, as well as biomechanical testing of all ewes studied. Twenty-four months after HPD, histomorphometric analyses of the iliac crest showed a significant reduction of BV/TV by 60% in comparison to Control. Cortical thickness of the femora measured by HR-pQCT did not change between 12 and 24 months after HPD but remained decreased by 30%. These structural changes were caused by a persisting depression of osteoblast and osteoclast cellular activity. Biomechanical testing of the femora showed a significant reduction of bending strength, whereas calcium content and distribution was found to be unchanged. In conclusion, HPD surgery leads to a persisting low turnover status with negative turnover balance in sheep followed by dramatic cortical and trabecular bone loss with consequent biomechanical impairment.
PROP-1 gene mutations in a 63-year-old woman presenting with osteoporosis and hyperlipidaemia.
Andrikoula Maria,Sertedaki Amalia,Andrikoula Sofia,Dacou-Voutetakis Catherine,Tsatsoulis Agathocles
Hormones (Athens, Greece)
PROP-1 gene mutations have been reported as a cause of combined pituitary hormone deficiency. Physical and hormonal phenotypes of affected individuals are variable. We report a 63-year-old female who presented with osteoporosis. She was short, did not enter puberty spontaneously and had primary amenorrhea. Biochemical evaluation revealed secondary hypothyroidism and mixed hyperlipidaemia, while dynamic testing of pituitary function was diagnostic of hypopituitarism. Bone density in the lumbar spine disclosed osteoporosis. DNA analysis showed that the patient was homozygote for the R73H mutation of the PROP-1 gene. The unfavourable long-term course of an untreated patient with PROP-1 gene mutation emphasizes the need for early aetiologic classification and proper management and follow-up of patients with short stature and/or disturbances of pubertal development.
Parkinson's disease and osteoporosis.
van den Bos Frederiek,Speelman Arlene D,Samson Monique,Munneke Marten,Bloem Bastiaan R,Verhaar Harald J J
Age and ageing
BACKGROUND:patients with Parkinson's disease (PD) have a high risk of sustaining osteoporotic fractures as a result of falls and reduced bone mass. OBJECTIVE:to summarise the underlying pathophysiological mechanisms of bone loss in PD by reviewing the available literature. METHODS:a Medline search was performed for articles published between January 1975 and January 2011, using the keywords 'bone mineral density', 'bone loss', 'bone metabolism', 'osteoporosis', 'osteopenia', 'Parkinson's disease' and 'Parkinsonism'. RESULTS:PD patients have a lower bone mineral density (BMD) than age-matched controls. Bone loss in PD is multifactorial, resulting from immobility, decreased muscle strength, and low body weight. Vitamin D deficiency is also important, not only because it reduces BMD, but also because cell function in the substantia nigra depends on vitamin D. Lastly, hyperhomocysteinaemia, an independent risk factor for osteoporosis, is common in PD, due to levodopa use, as well as vitamin B12 and folic acid deficiency. A few studies have demonstrated that treatment with bisphosphonates, vitamin D and calcium can increase BMD and reduce fractures in PD patients. CONCLUSION:bone loss in PD is multifactorial. It is clinically important because of the concomitant risk of fractures. Screening for osteoporosis should be considered more often, and therapeutic interventions should be initiated.
Acetylcholinesterase inhibitors and the risk of hip fracture in Alzheimer's disease patients: a case-control study.
Tamimi Iskandar,Ojea Tomas,Sanchez-Siles Juan Manuel,Rojas Facundo,Martin Ignacio,Gormaz Irene,Perez Almudena,Dawid-Milner Marc Stefan,Mendez Luis,Tamimi Faleh
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Recent studies have reported the presence of acetylcholine (ACh) receptor subtypes in bone tissue, and have demonstrated that inhibition of the ACh receptors has negative effects on bone mass and fracture healing capacity. However, little is known about the potential clinical effects that increased ACh signaling might have on bone. Accordingly, this study was designed to determine whether the use of acetylcholinesterase inhibitors (AChEIs), a group of drugs that stimulate ACh receptors and are used to treat Alzheimer's disease (AD), is associated with a decreased risk of hip fracture in AD patients. To accomplish this objective, a case-control analysis was performed using the AD population, aged above 75 years, based in the local health area of the Carlos Haya Hospital, in Malaga, Spain. The cases were 80 AD patients that suffered a hip fracture between January 2004 and December 2008. The controls were 2178 AD patients without hip fracture followed at our health care area during the same period of time. Compared with patients who did not use AChEIs, the hip fracture adjusted odds ratio (OR) for users of AChEIs was 0.42 (95% confidence interval [CI], 0.24-0.72), for users of rivastigmine was 0.22 (95% CI, 0.10-0.45), and for users of donepezil was 0.39 (95% CI, 0.19-0.76). Data were adjusted for the following parameters: body mass index, fall risk, smoking habits, cognition, dependence, degree of AD, comorbidity score, treatment with selective serotonin reuptake inhibitors, age, and gender. Our data suggests that use of AChEIs donepezil and rivastigmine is associated with a reduced risk of fractures in AD patients. Many elderly patients with AD disease who are at risk of developing osteoporosis may potentially benefit from therapy with the AChEIs donepezil and rivastigmine.
How might physical activity benefit patients with Parkinson disease?
Speelman Arlène D,van de Warrenburg Bart P,van Nimwegen Marlies,Petzinger Giselle M,Munneke Marten,Bloem Bastiaan R
Nature reviews. Neurology
Parkinson disease (PD) is a neurodegenerative disorder characterized by progressive motor and nonmotor impairments. These impairments incline many patients towards a sedentary lifestyle, which has many deleterious consequences. Accumulating evidence suggests that patients with PD might benefit from physical activity and exercise in a number of ways, from general improvements in health to disease-specific effects and, potentially, disease-modifying effects (suggested by animal data). Many issues remain to be addressed, including the need to perform clinical trials to demonstrate these presumed benefits of physical activity and exercise in patients with PD. These trials must also address safety issues, such as an increased risk of falls and cardiovascular complications in more-active patients. Identifying ways to induce a sustained behavioral change, using specifically tailored programs that address potential barriers such as depression, apathy and postural instability, may lead to an improved quality of life in individuals with PD.
Therapeutic potential of the original incretin hormone glucose-dependent insulinotropic polypeptide: diabetes, obesity, osteoporosis and Alzheimer's disease?
Irwin Nigel,Gault Victor,Flatt Peter R
Expert opinion on investigational drugs
IMPORTANCE TO THE FIELD:Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that potentiates nutrient-induced insulin release. To date, the physiological importance of GIP has received much less attention than its younger sister incretin hormone glucagon-like peptide-1. Thus, it is worthwhile to refocus on this important and somewhat neglected incretin hormone. AREAS COVERED IN THIS REVIEW:The potential role of GIP as a treatment option for type 2 diabetes is highlighted. Furthermore, the use of GIP as a new therapeutic option for obesity, osteoporosis and cognitive impairment is also considered. WHAT THE READER WILL GAIN:Long-acting GIP receptor agonists offer a potential new class of antidiabetic drugs. Furthermore, recent observations suggest an as yet untapped potential for GIP agonists in the treatment of osteoporosis and cognitive impairment. In addition, GIP is known to play a role in lipid metabolism and fat deposition. Accordingly, both genetic and chemical ablation of GIP signalling in mice with obesity-diabetes can protect against, or reverse, many of the obesity-associated metabolic disturbances. This review focuses on preclinical data generated to date. TAKE HOME MESSAGE:GIP-based therapeutics have potential for the treatment of type 2 diabetes and obesity, with the possibility of further beneficial actions in osteoporosis and cognitive decline.
Hyperhomocysteinemia due to levodopa treatment as a risk factor for osteoporosis in patients with Parkinson's disease.
Lee Seung Hun,Kim Mi Jung,Kim Beom-Jun,Kim Sung Reul,Chun Sail,Kim Hong-Kyu,Ryu Jin Sook,Kim Ghi Su,Lee Myoung Chong,Chung Sun Ju,Koh Jung-Min
Calcified tissue international
Parkinson's disease (PD) patients have been reported to have lower bone mineral density (BMD) and higher fracture risk than individuals without PD. We assessed the association between hyperhomocysteinemia due to levodopa intake and BMD in PD patients. We measured serum homocysteine (Hcy) concentrations and BMD in the proximal femur and lumbar spine of PD patients aged 55 years or older (n = 95) and three age-/gender-matched control subjects (n = 285). The prevalence of osteoporosis was higher in both men (2.5-fold) and women (1.7-fold) with PD than in controls, and adjusted odds ratios for osteoporosis were 3.57 (95% confidence interval [CI], 1.25-10.20) for men and 2.54 for women (95% CI, 1.31-4.93) with PD. Serum Hcy concentrations were significantly higher in PD patients (median = 13.0 micromol/l) than controls (median = 11.5 micromol/l) (P = 0.005). Serum Hcy concentrations were independently associated with BMD values at all proximal femur sites in all subjects (P = 0.005 to 0.012). In PD patients, higher serum Hcy concentrations were independently associated with higher fracture risk (P = 0.029). PD patients taking higher doses of levodopa had significantly higher serum Hcy concentrations (P = 0.013), and greater levodopa intake was associated with lower BMD values in some areas (P = 0.008 to 0.029). In conclusion, these findings indicate that hyperhomocysteinemia due to levodopa intake may be one additional risk factor for osteoporosis and fracture in PD patients. Reducing Hcy may be a therapeutic modality for treating osteoporosis in PD patients taking levodopa.
Muscle strength is significantly associated with hip bone mineral density in women with Parkinson's disease: a cross-sectional study.
Pang Marco Y C,Mak Margaret K Y
Journal of rehabilitation medicine
OBJECTIVE:To study the influence of physical impairments on hip bone mineral density in women with Parkinson's disease. DESIGN:Cross-sectional study. SUBJECTS/PATIENTS:Thirty-four women with Parkinson's disease and 30 age-matched healthy controls. METHODS:Patients with Parkinson's disease underwent a hip scan using dual-energy X-ray absorptiometry and total hip bone mineral density values were obtained. Motor Examination III of the Unified Parkinson Disease Rating Scale was used to assess leg tremor, leg agility, leg rigidity and postural stability. In addition, all subjects were evaluated for walking speed, walking endurance, and leg muscle strength. RESULTS:Based on the hip bone mineral density values, 12 patients with Parkinson's disease (35%) had osteopaenia and another 3 patients (9%) had osteoporosis. Patients with Parkinson's disease had significantly lower walking velocity (p = 0.002), walking endurance (p < 0.001) and leg muscle strength (p = 0.047) than controls. Multiple regression revealed that leg muscle strength alone accounted for 8.8-10.6% of the variance in hip bone mineral density among patients with Parkinson's disease, after controlling for body mass index, post-menopausal years, Hoehn and Yahr stage, and postural stability (p < 0.05). CONCLUSION:Hip bone mineral density is independently associated with leg muscle strength in women with Parkinson's disease.
Low bone mass is associated with carotid atherosclerosis in postmenopausal women: the Japanese Population-based Osteoporosis (JPOS) Cohort Study.
Tamaki J,Iki M,Hirano Y,Sato Y,Kajita E,Kagamimori S,Kagawa Y,Yoneshima H
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
UNLABELLED:We analyzed 609 women belonging to the JPOS study in a 10-year follow-up survey, to examine the association of osteoporosis with atherosclerosis. Osteoporosis or prevalent vertebral fracture at baseline was associated with increased intima-media thickness of the carotid bifurcation in postmenopausal women, adjusted for age, BMI, and other variables at baseline. INTRODUCTION:Whether low bone mass predicts increased carotid atherosclerosis has not been fully investigated. METHODS:In 2006, we conducted a 10-year follow-up survey of 1,040 women (follow-up rate: 68.6%). We analyzed 609 women > or =50 years old in 2006 without a history of cardiovascular or connective tissue diseases at baseline. BMD and evaluation of vertebral fracture at baseline were used. The intima-media thickness of carotid bifurcation (BIF-IMT) was measured by B-mode ultrasonography in 2006. RESULTS:Adjusted BIF-IMT values of subjects with spine T-score > or =-1, between-2.5 and -1, and <-2.5 or prevalent vertebral fracture were 1.19 mm, 1.34 mm, 1.57 mm, respectively, in women with less than 10 years since menopause (YSM) (n = 159), 1.30 mm, 1.32 mm, 1.53 mm, in women with YSM > or =10 without a history of hypertension at baseline (n = 144) (both with p < 0.05 for linear trend). Those values among no versus prevalent vertebral fracture in women with YSM > or =10 were 1.40 mm, 1.66 mm with p < 0.05 (n = 202). Those associations were independent of age, BMI, total cholesterol, smoking and drinking habits, history of diabetes mellitus, and hypertension (for women with YSM < 10) at baseline. CONCLUSION:Osteoporosis including prevalent vertebral fracture may be associated with carotid atherosclerosis in the first 10 years of postmenopausal women.
Risedronate and ergocalciferol prevent hip fracture in elderly men with Parkinson disease.
Sato Yoshihiro,Honda Yoshiaki,Iwamoto Jun
BACKGROUND:There is a high incidence of hip fractures in patients with Parkinson disease (PD). Bone mineral density (BMD) is decreased in patients with PD, correlating with the immobilization-induced bone resorption and hypovitaminosis D with compensatory hyperparathyroidism. OBJECTIVE:To evaluate the effectiveness of risedronate, an inhibitor of bone resorption, on osteoporosis and the risk of hip fractures in elderly men with PD. METHODS:This was a 2-year, randomized, double-blind, placebo-controlled trial. In a prospective study of patients with PD, 121 patients received a daily dose of 2.5 mg risedronate and vitamin D2 1,000 IU for 2 years, and the remaining 121 received placebo and vitamin D2 1,000 IU. Incidence of hip fractures was compared between the two groups. RESULTS:Nine patients sustained hip fractures in the placebo group, and three hip fractures occurred in the risedronate group. The relative risk of a hip fracture in the risedronate group vs the placebo group was 0.33 (95% CI, 0.09 to 1.20). BMD increased by 2.2% in the risedronate group and decreased by 2.9% in the placebo group (p < 0.0001). Urinary deoxypyridinoline, a bone resorption marker, decreased by 46.7% in the risedronate group and by 33.0% in the placebo group. CONCLUSION:Treatment with risedronate and vitamin D2 increases bone mineral density in elderly men with Parkinson disease and reduces the risk of hip fractures.
Estrogen, neuroinflammation and neuroprotection in Parkinson's disease: glia dictates resistance versus vulnerability to neurodegeneration.
Morale M C,Serra P A,L'episcopo F,Tirolo C,Caniglia S,Testa N,Gennuso F,Giaquinta G,Rocchitta G,Desole M S,Miele E,Marchetti B
Post-menopausal estrogen deficiency is recognized to play a pivotal role in the pathogenesis of a number of age-related diseases in women, such as osteoporosis, coronary heart disease and Alzheimer's disease. There are also sexual differences in the progression of diseases associated with the nigrostriatal dopaminergic system, such as Parkinson's disease, a chronic progressive degenerative disorder characterized by the selective degeneration of mesencephalic dopaminergic neurons in the substancia nigra pars compacta. The mechanism(s) responsible for dopaminergic neuron degeneration in Parkinson's disease are still unknown, but oxidative stress and neuroinflammation are believed to play a key role in nigrostriatal dopaminergic neuron demise. Estrogen neuroprotective effects have been widely reported in a number of neuronal cell systems including the nigrostriatal dopaminergic neurons, via both genomic and non-genomic effects, however, little is known on estrogen modulation of astrocyte and microglia function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. We here highlight estrogen modulation of glial neuroinflammatory reaction in the protection of mesencephalic dopaminergic neurons and emphasize the cardinal role of glia-neuron crosstalk in directing neuroprotection vs neurodegeneration. In particular, the specific role of astroglia and its pro-/anti-inflammatory mechanisms in estrogen neuroprotection are presented. This study shows that astrocyte and microglia response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injury vary according to the estrogenic status with direct consequences for dopaminergic neuron survival, recovery and repair. These findings provide a new insight into the protective action of estrogen that may possibly contribute to the development of novel therapeutic treatment strategies for Parkinson's disease.
Immune responses and bone loss: the estrogen connection.
In addition to its effects on sexual differentiation and reproduction, estrogen has important impact on the immune system and on bone. It has also been evident that the effects of estrogen on bone to a large extent are mediated via its action on immune cells. Estrogen has a dichotomous impact on the immune system by downregulation of inflammatory immune responses but simultaneous upregulation of immunoglobulin production. Consequently, immune-mediated diseases in humans and in animal models are modulated by estrogen. Estrogen deficiency after ovariectomy in mice and after menopause in women is associated with significant bone loss. In rheumatic diseases such as rheumatoid arthritis (RA), osteoporosis is frequent, and in patients with postmenopausal RA, the degree of bone loss is dramatically increased. Hormone replacement therapy (HRT) in murine and human arthritis has beneficial effects on bone loss, as expected, but it also ameliorates inflammation and inflammation-triggered joint destruction. Long-term use of HRT has been associated with increased risk of breast cancer, thrombosis, and possibly also stroke. Accordingly, there is great need for new activators of estrogen receptors (ERs) selectively reproducing only the beneficial effects of estrogen. To achieve this aim, better knowledge of the mechanisms of how activation of ER-alpha and ER-beta modulates the immune system and bone at the cellular and molecular levels is necessary.
Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa.
Chan Jean L,Mantzoros Christos S
Lancet (London, England)
Leptin is an adipocyte-secreted hormone that plays a key part in energy homoeostasis. Advances in leptin physiology have established that the main role of this hormone is to signal energy availability in energy-deficient states. Studies in animals and human beings have shown that low concentrations of leptin are fully or partly responsible for starvation-induced changes in neuroendocrine axes, including low reproductive, thyroid, and insulin-like growth factor (IGF) hormones. Disease states such as exercise-induced hypothalamic amenorrhoea and anorexia nervosa are also associated with low concentrations of leptin and a similar spectrum of neuroendocrine abnormalities. We have recently shown in an interventional, proof-of-concept study that leptin can restore ovulatory menstrual cycles and improve reproductive, thyroid, and IGF hormones and bone markers in hypothalamic amenorrhoea. Further studies are warranted to establish the safety and effectiveness of leptin for the infertility and osteoporosis associated with hypothalamic amenorrhoea, and to clarify its role in anorexia nervosa.
Major depressive disorder is a risk factor for low bone mass, central obesity, and other medical conditions.
Dialogues in clinical neuroscience
Major depressive disorder (MDD) is one of the most common psychiatric illnesses in the adult population. It is often associated with an increased risk of cardiovascular disease. Osteoporosis is also a major public health threat. Multiple studies have reported an association between depression and low bone mineral density, but a causal link between these two conditions is disputed. Here the most important findings of the POWER (Premenopausal, Osteoporosis Women, Alendronate, Depression) Study, a large prospective study of bone turnover in premenopausal women with major depression, are summarized. The endocrine and immune alterations secondary to depression that might affect bone mass, and the possible role of poor lifestyle in the etiology of osteoporosis in subjects with depression, are also reviewed, as is the potential effect of antidepressants on bone loss. It is proposed that depression induces bone loss and osteoporotic fractures, primarily via specific immune and endocrine mechanisms, with poor lifestyle habits as potential contributory factors.
Bone health in Parkinson's disease: a systematic review and meta-analysis.
Torsney Kelli M,Noyce Alastair J,Doherty Karen M,Bestwick Jonathan P,Dobson Ruth,Lees Andrew J
Journal of neurology, neurosurgery, and psychiatry
OBJECTIVE:Parkinson's disease (PD) and osteoporosis are chronic diseases associated with increasing age. Single studies have reported associations between them and the major consequence, namely, increased risk of fractures. The aim of this systematic review and meta-analysis was to evaluate the relationship of PD with osteoporosis, bone mineral density (BMD) and fracture risk. METHODS:A literature search was undertaken on 4 September 2012 using multiple indexing databases and relevant search terms. Articles were screened for suitability and data extracted where studies met inclusion criteria and were of sufficient quality. Data were combined using standard meta-analysis methods. RESULTS:23 studies were used in the final analysis. PD patients were at higher risk of osteoporosis (OR 2.61; 95% CI 1.69 to 4.03) compared with healthy controls. Male patients had a lower risk for osteoporosis and osteopenia than female patients (OR 0.45; 95% CI 0.29 to 0.68). PD patients had lower hip, lumbar spine and femoral neck BMD levels compared with healthy controls; mean difference, -0.08, 95% CI -0.13 to -0.02 for femoral neck; -0.09, 95% CI -0.15 to -0.03 for lumbar spine; and -0.05, 95% CI -0.07 to -0.03 for total hip. PD patients were also at increased risk of fractures (OR 2.28; 95% CI 1.83 to 2.83). CONCLUSIONS:This systematic review and meta-analysis demonstrate that PD patients are at higher risk for both osteoporosis and osteopenia compared with healthy controls, and that female patients are at greater risk than male patients. Patients with PD also have lower BMD and are at increased risk of fractures.
Parkinson's disease and risk of fracture: a meta-analysis of prospective cohort studies.
Tan Li,Wang Ying,Zhou Lingling,Shi Yun,Zhang Fan,Liu Li,Nie Shaofa
BACKGROUNDS/OBJECTIVE:Parkinson's disease (PD) is the second most common neurodegenerative disease among the elderly population. However, epidemiological evidence on the relationship of PD with risk of fracture has not been systematically assessed. Therefore, we performed this meta-analysis of prospective studies to explore the association between PD and risk of fracture. METHODS:PubMed, Embase, Web of Science and Cochrane Library up to February 26, 2014 were searched to identify eligible studies. Random-effects model was used to pool the results. RESULTS:Six studies that totally involved 69,387 participants were included for analysis. Overall, PD patients had an increased risk of fracture compared with control subjects (pooled hazard ratio = 2.66, 95% confidence interval: 2.10-3.36). No publication bias was observed across studies and the subgroup as well as sensitivity analysis suggested that the general results were robust. CONCLUSION:The present study suggested that PD is associated with an increased risk of fracture. However, given the limited number and moderate quality of included studies, well-designed prospective cohort studies are required to confirm the findings from this meta-analysis.
TSH, the bone suppressing hormone.
Novack Deborah Veis
The skeleton is a dynamic organ whose structural integrity depends on constant remodeling, controlled by many local and systemic factors. In this issue of Cell, identify thyroid-stimulating hormone (TSH) as an important regulator of this process.
Loss of chemoreceptive properties of the rabbit carotid body after destruction of the glomus cells.
Verna A,Roumy M,Leitner L M
Glomus cells of the rabbit carotid body were destroyed by local freezing. Electrophysiological recording of baroreceptor afferent activities showed that carotid sinus nerve regeneration was completed after 3 months. Nevertheless, ventilatory reaction as well as chemoreceptor afferent activity were no longer observed in response to the usual stimuli of arterial chemoreceptors (O2 test, NaCN). Results support the view that glomus cells are necessary for chemoreception and question the specificity of their afferent innervation.
Role of the pituitary-bone axis in skeletal pathophysiology.
Imam Aliza,Iqbal Jameel,Blair Harry C,Davies Terry F,Huang Christopher L-H,Zallone Alberta,Zaidi Mone,Sun Li
Current opinion in endocrinology, diabetes, and obesity
PURPOSE OF REVIEW:Embedded within textbooks for decades is the hard fact that releasing hormones from the anterior pituitary, namely, follicle-stimulating hormone, thyroid-stimulating hormone and adrenocorticotropic hormone, stimulate master hormone secretion from target endocrine organs. We propose a paradigm shift in endocrine physiology, which is that these hormones act by design on bone directly, also now considered an endocrine organ. RECENT FINDINGS:Complementary investigations using mouse genetic and cell biological approaches reveal that follicle-stimulating hormone and thyroid-stimulating hormone act on bone cells directly to regulate bone remodeling and bone mass. Thyroid-stimulating hormone inhibits bone remodeling, whereas follicle-stimulating hormone stimulates it. We also find that the posterior pituitary hormone oxytocin is anabolic to the skeleton. SUMMARY:An ambitious extrapolation is that a plurality of pituitary hormones acts in concert as part of a 'pituitary-bone' axis to regulate skeletal integrity in health and disease. When dysregulated master hormone levels during hypogonadism and hyperthyroidism cause altered pituitary hormone secretion through hypothalamic feedback, the latter hormones contribute to the skeletal loss.
Role of Thyroid Hormones in Skeletal Development and Bone Maintenance.
Bassett J H Duncan,Williams Graham R
The skeleton is an exquisitely sensitive and archetypal T3-target tissue that demonstrates the critical role for thyroid hormones during development, linear growth, and adult bone turnover and maintenance. Thyrotoxicosis is an established cause of secondary osteoporosis, and abnormal thyroid hormone signaling has recently been identified as a novel risk factor for osteoarthritis. Skeletal phenotypes in genetically modified mice have faithfully reproduced genetic disorders in humans, revealing the complex physiological relationship between centrally regulated thyroid status and the peripheral actions of thyroid hormones. Studies in mutant mice also established the paradigm that T3 exerts anabolic actions during growth and catabolic effects on adult bone. Thus, the skeleton represents an ideal physiological system in which to characterize thyroid hormone transport, metabolism, and action during development and adulthood and in response to injury. Future analysis of T3 action in individual skeletal cell lineages will provide new insights into cell-specific molecular mechanisms and may ultimately identify novel therapeutic targets for chronic degenerative diseases such as osteoporosis and osteoarthritis. This review provides a comprehensive analysis of the current state of the art.
Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits.
Baribeau Danielle A,Anagnostou Evdokia
Frontiers in neuroscience
Oxytocin and vasopressin are pituitary neuropeptides that have been shown to affect social processes in mammals. There is growing interest in these molecules and their receptors as potential precipitants of, and/or treatments for, social deficits in neurodevelopmental disorders, including autism spectrum disorder. Numerous behavioral-genetic studies suggest that there is an association between these peptides and individual social abilities; however, an explanatory model that links hormonal activity at the receptor level to complex human behavior remains elusive. The following review summarizes the known associations between the oxytocin and vasopressin neuropeptide systems and social neurocircuits in the brain. Following a micro- to macro- level trajectory, current literature on the synthesis and secretion of these peptides, and the structure, function and distribution of their respective receptors is first surveyed. Next, current models regarding the mechanism of action of these peptides on microcircuitry and other neurotransmitter systems are discussed. Functional neuroimaging evidence on the acute effects of exogenous administration of these peptides on brain activity is then reviewed. Overall, a model in which the local neuromodulatory effects of pituitary neuropeptides on brainstem and basal forebrain regions strengthen signaling within social neurocircuits proves appealing. However, these findings are derived from animal models; more research is needed to clarify the relevance of these mechanisms to human behavior and treatment of social deficits in neuropsychiatric disorders.
Two Birds with One Stone: Possible Dual-Role of Oxytocin in the Treatment of Diabetes and Osteoporosis.
Elabd Seham,Sabry Ismail
Frontiers in endocrinology
Oxytocin (OT), a hormone most commonly associated with labor and lactation, may have a wide variety of physiological and pathological functions, which makes OT and its receptor potential targets for drug therapy. In this review, we highlight the newly discovered metabolic role of OT in diabetes and its complication, such as diabetic osteopathy. OT may have positive metabolic effects; this is based on the change in glucose metabolism, lipid profile, and insulin sensitivity. It may modify glucose uptake and insulin sensitivity both through direct and indirect effects. It may also cause regenerative changes in diabetic pancreatic islet cells. Moreover, it has an anabolic effect on the bone biology. So, the activation of the OT receptor pathway by infusion of OT, OT analogs, or OT agonists may represent a promising approach for the treatment of diabetes and some of its complications, including diabetic osteopathy.
Oxytocin and vasopressin neural networks: Implications for social behavioral diversity and translational neuroscience.
Johnson Zachary V,Young Larry J
Neuroscience and biobehavioral reviews
Oxytocin- and vasopressin-related systems are present in invertebrate and vertebrate bilaterian animals, including humans, and exhibit conserved neuroanatomical and functional properties. In vertebrates, these systems innervate conserved neural networks that regulate social learning and behavior, including conspecific recognition, social attachment, and parental behavior. Individual and species-level variation in central organization of oxytocin and vasopressin systems has been linked to individual and species variation in social learning and behavior. In humans, genetic polymorphisms in the genes encoding oxytocin and vasopressin peptides and/or their respective target receptors have been associated with individual variation in social recognition, social attachment phenotypes, parental behavior, and psychiatric phenotypes such as autism. Here we describe both conserved and variable features of central oxytocin and vasopressin systems in the context of social behavioral diversity, with a particular focus on neural networks that modulate social learning, behavior, and salience of sociosensory stimuli during species-typical social contexts.
Functions of vasopressin and oxytocin in bone mass regulation.
Sun Li,Tamma Roberto,Yuen Tony,Colaianni Graziana,Ji Yaoting,Cuscito Concetta,Bailey Jack,Dhawan Samarth,Lu Ping,Calvano Cosima D,Zhu Ling-Ling,Zambonin Carlo G,Di Benedetto Adriana,Stachnik Agnes,Liu Peng,Grano Maria,Colucci Silvia,Davies Terry F,New Maria I,Zallone Alberta,Zaidi Mone
Proceedings of the National Academy of Sciences of the United States of America
Prior studies show that oxytocin (Oxt) and vasopressin (Avp) have opposing actions on the skeleton exerted through high-affinity G protein-coupled receptors. We explored whether Avp and Oxtr can share their receptors in the regulation of bone formation by osteoblasts. We show that the Avp receptor 1α (Avpr1α) and the Oxt receptor (Oxtr) have opposing effects on bone mass: Oxtr(-/-) mice have osteopenia, and Avpr1α(-/-) mice display a high bone mass phenotype. More notably, this high bone mass phenotype is reversed by the deletion of Oxtr in Oxtr(-/-):Avpr1α(-/-) double-mutant mice. However, although Oxtr is not indispensable for Avp action in inhibiting osteoblastogenesis and gene expression, Avp-stimulated gene expression is inhibited when the Oxtr is deleted in Avpr1α(-/-) cells. In contrast, Oxt does not interact with Avprs in vivo in a model of lactation-induced bone loss in which Oxt levels are high. Immunofluorescence microscopy of isolated nucleoplasts and Western blotting and MALDI-TOF of nuclear extracts show that Avp triggers Avpr1α localization to the nucleus. Finally, a specific Avpr2 inhibitor, tolvaptan, does not affect bone formation or bone mass, suggesting that Avpr2, which primarily functions in the kidney, does not have a significant role in bone remodeling.
Erythromyeloid-Derived TREM2: A Major Determinant of Alzheimer's Disease Pathology in Down Syndrome.
Raha-Chowdhury Ruma,Henderson James W,Raha Animesh Alexander,Stott Simon R W,Vuono Romina,Foscarin Simona,Wilson Liam,Annus Tiina,Fincham Robert,Allinson Kieren,Devalia Vinod,Friedland Robert P,Holland Anthony,Zaman Shahid H
Journal of Alzheimer's disease : JAD
BACKGROUND:Down syndrome (DS; trisomy 21) individuals have a spectrum of hematopoietic and neuronal dysfunctions and by the time they reach the age of 40 years, almost all develop Alzheimer's disease (AD) neuropathology which includes senile plaques and neurofibrillary tangles. Inflammation and innate immunity are key players in AD and DS. Triggering receptor expressed in myeloid cells-2 (TREM2) variants have been identified as risk factors for AD and other neurodegenerative diseases. OBJECTIVE:To investigate the effects of TREM2 and the AD-associated R47H mutation on brain pathology and hematopoietic state in AD and DS. METHODS:We analyzed peripheral blood, bone marrow, and brain tissue from DS, AD, and age-matched control subjects by immunohistochemistry and western blotting. TREM2-related phagocytosis was investigated using a human myeloid cell line. RESULTS:TREM2 protein levels in brain and sera declined with age and disease progression in DS. We observed soluble TREM2 in brain parenchyma that may be carried by a subset of microglia, macrophages, or exosomes. Two DS cases had the AD-associated TREM2-R47H mutation, which manifested a morphologically extreme phenotype of megakaryocytes and erythrocytes in addition to impaired trafficking of TREM2 to the erythroid membrane. TREM2 was shown to be involved in phagocytosis of red blood cells. TREM2 was seen in early and late endosomes. Silencing TREM2 using siRNA in THP1 cells resulted in significant cell death. CONCLUSION:We provide evidence that peripheral TREM2 originating from erythromyeloid cells significantly determines AD neuropathology in DS subjects. Understanding the molecular signaling pathways mediated by TREM2 may reveal novel therapeutic targets.