Effects of Yearly Zoledronic Acid 5 mg on Bone Turnover Markers and Relation of PINP With Fracture Reduction in Postmenopausal Women With Osteoporosis

In patients with osteoporosis treated with antiresorptive agents, reduction in bone turnover explains much of the observed fracture risk reduction. Lower levels of bone turnover markers (BTMs) appear to be associated with a lower risk of fracture in bisphosphonate‐treated patients. BTMs were measured in a subset of subjects in the HORIZON Pivotal Fracture Trial. Annual infusions of zoledronic acid 5 mg significantly reduced BTMs: median decrease of 50% for β‐C‐terminal telopeptides of type 1 collagen (β‐CTX), 30% for bone alkaline phosphatase (ALP), and 56% for procollagen type 1 amino‐terminal propeptide (PINP). The mean level of BTMs decreased in treated patients but remained within the premenopausal range before the next injection. The percentage of zoledronic acid–treated patients with values below the premenopausal reference range at all time points was 1.7%, 17.8%, and 19% for bone ALP, CTX, and PINP, respectively. The third injection of zoledronic acid resulted in 60% reduction of β‐CTX within 9–11 days, followed by a gradual increase, indicating the persistence of osteoclastic bone resorption. The association between changes in BTMs and fracture incidence was assessed in 1132 patients who had PINP measurements at baseline and 1 yr. There was no association between low PINP levels at 1 yr and increased fracture incidence. In summary, (1) annual injections of zoledronic acid reduced BTMs in the premenopausal range, with a significant response persisting after the third infusion; and (2) low levels of PINP were not associated with increased fracture risk.     

Effects of salmon calcitonin on trabecular microarchitecture as determined by magnetic resonance imaging: results from the QUEST study.

The unique noninvasive MRI technique was used to assess trabecular microarchitecture at multiple skeletal sites in 91 postmenopausal osteoporotic women receiving nasal spray salmon calcitonin (CT-NS) or placebo over 2 years. In the distal radius and lower trochanter of the hip, individuals treated with CT-NS exhibited significant preservation of trabecular bone microarchitecture compared with placebo, where significant deterioration was shown. MRI analyses of os calcis or microCT/histomorphometric analyses of bone biopsies did not reveal consistent differences in architecture between CT-NS and placebo. INTRODUCTION: It is postulated that the reduction in osteoporotic fracture risk in response to certain antiresorptive osteoporosis therapies is caused less by effects on bone quantity than on bone quality (specifically trabecular microarchitecture). To test this hypothesis, the QUEST study was conducted to assess the effects of nasal spray salmon calcitonin (CT-NS) or placebo on parameters of trabecular microarchitecture at multiple skeletal sites using noninvasive MRI technology and iliac crest bone biopsies by microCT/histomorphometry. MATERIALS AND METHODS: Ninety-one postmenopausal osteoporotic women were followed for 2 years (n = 46 for CT-NS, n = 45 for placebo); all women received 500 mg calcium daily. MRI measurements at distal radius, hip (T2 relaxation time [T2*]), and os calcis (obtained yearly), iliac crest bone biopsies with 2D histomorphometry and 3D microCT (obtained at study onset and conclusion), DXA-BMD at spine/hip/wrist/os calcis (obtained yearly), and markers of bone turnover (obtained at 2-week to 12-month intervals) were analyzed, with an analysis of covariance model used to assess treatment effect for parameters of interest. RESULTS AND CONCLUSIONS: MRI assessment of trabecular microarchitecture at individual regions of the distal radius revealed significant improvement, or preservation (no significant loss), in the CT-NS-treated group compared with significant deterioration in the placebo control group, as reflected in apparent BV/TV (p < 0.03), apparent trabecular number (p < 0.01), and apparent trabecular spacing (p < 0.01). Also, at the hip, the CT-NS group exhibited preservation of trabecular microarchitecture at the lower trochanter (p < 0.05) as determined by T2* MRI technology. Significant deterioration of trabecular bone architecture was noted in the placebo group at the femoral neck, Ward's triangle, and lower trochanteric sites. Apart from a significant increase in apparent trabecular number in the CT-NS group, significant changes within or between groups were not noted at the os calcis. Combined microCT/histomorphometric analysis of iliac crest bone biopsies did not reveal significant differences between treated and placebo groups. In the CT-NS group, regardless of the change in BMD (gain or loss) at the spine, hip, or distal radius, preservation of parameters of trabecular microarchitecture was noted, whereas in the placebo group, regardless of the change in BMD (gain or loss) at the spine, hip, or distal radius, loss or preservation was noted; however, changes in DXA/BMD (of the spine, hip, wrist, os calcis) between CT-NS and placebo groups were not significant. Serum C-telopeptide (S-CTx), a specific bone resorption marker, was reduced by 22.5% at 24 months (p = 0.056). The results of the QUEST study suggest therapeutic benefit of CT-NS compared with placebo in maintaining trabecular microarchitecture at multiple skeletal sites and support the use of MRI technology for assessment of trabecular microarchitecture in clinical research trials. However, the results also highlight site specific differences in response to antiresorptive therapies and the importance of sufficiently large sampling volumes (areas) to obtain reliable assessment of bone architecture.     

Evidence for an altered balance between matrix metalloproteinase-9 and its inhibitors in calcific aortic stenosis

BACKGROUND: Recently, aortic valve stenosis has been demonstrated to exhibit increased expression of certain matrix metalloproteinases (MMPs), and this has relevantly raised the question about possible interdependency between these and their tissue inhibitors. We sought to assess the expression of elastolytic MMPs and their inhibitors (TIMPs) in nonrheumatic aortic stenosis. METHODS: The study comprised 30 stenotic and six noncalcified human aortic valves. To measure the expression levels and the amount and molecular forms of gelatinases (MMP-2, MMP-9) and TIMPs (1, 2), in situ hybridization, gelatin zymography, and reverse zymography were carried out. Antielastin staining by a monoclonal BA-4 antibody was performed to investigate the changes of one of the main substrates of these MMPs, and to substantiate the nature of the putative MMP- synthesizing cell. The cases were also immunostained with an antibody to alpha-smooth muscle actin. Inflammatory cell characterization was managed by monoclonal mouse antibodies (UCHL-1, L26, and PGM-1). RESULTS: Compared with the controls, the calcific valves showed increased mRNA expression and activation of MMP-9, and this was associated with typical characteristics of valve disease. MMP-2 mRNA production was rare, but proMMP-2 protein was detected in all valves. In agreement with the interdependency between MMP-9 and its inhibitors, a suggestive imbalance came out in diseased valves. CONCLUSIONS: The disproportion between MMP-9 and its tissue inhibitors may favor a persistent MMP activation state within the calcific valve and likely contribute to the valvular remodeling process in the setting of developing aortic stenosis.     

Severity of vertebral fracture reflects deterioration of bone microarchitecture

Introduction Bone microarchitecture, a component of bone strength, is generally measured on transiliac bone biopsy samples. The objective of this study was to determine whether assessment of four grades of vertebral fracture severity could serve as a noninvasive surrogate marker for trabecular bone volume and microarchitecture. Methods Baseline vertebral fracture severity was determined by semiquantitative assessment of spine radiographs from 190 postmenopausal women with osteoporosis. Bone-structure indices were obtained by 2D histomorphometry and 3D microcomputed tomography (CT) analyses. Significance of differences was determined after adjusting for age, height, and lumbar spine bone mineral density. Results There were significant (P < 0.05) trends in decreasing bone volume, trabecular number, and connectivity, and increasing trabecular separation with greater vertebral fracture severity. Histomorphometric bone volume was 25 and 36% lower (P < 0.05) in women with moderate and severe fractures than in women with no fractures, respectively. Compared with women without fractures, women with mild, moderate, and severe fractures had lower (P < 0.05) microCT bone volume (23, 30, and 51%, respectively). Conclusions Microarchitectural deterioration was progressively worse in women with increasing severity of vertebral fractures. We conclude that assessment of vertebral fracture severity is an important clinical tool to evaluate the severity of postmenopausal osteoporosis.     

Potential mediators of the mortality reduction with zoledronic acid after hip fracture

Zoledronic acid reduces the risk of death by 28% after hip fracture, but the mechanisms are not known. This exploratory analysis sought to identify potential pathways for the reduction in mortality with zoledronic acid after hip fracture. This was a retrospective analysis of a randomized, controlled trial. Patients with recent hip fracture (n = 2111) were treated with zoledronic acid or placebo infusion yearly, as well as calcium and vitamin D supplementation. Causes of death were adjudicated by a blinded central review committee. Baseline comorbidities, events occurring during the study period, including subsequent fracture, change in bone density, infections, cardiovascular events, arrhythmias, and falls, were included in multivariable analyses. In a model adjusted for baseline risk factors, zoledronic acid reduced the risk of death by 25% [95% confidence interval (CI) 0.58–0.97). The effect was consistent across most subgroups. Subsequent fractures were significantly associated with death (hazard ratio 1.72, 95% CI 1.17–2.51) but explained only 8% of the zoledronic acid effect. Adjusting for acute events occurring during follow‐up eliminated the death benefit, and zoledronic acid–treated subjects were less likely to die from pneumonia (interaction p = .04) and arrhythmias (interaction p = .02) than placebo‐treated subjects. Only 8% of zoledronic acid's death benefit is due to a reduction in secondary fractures. Zoledronic acid may have an effect on cardiovascular events and pneumonia. Further studies of zoledronic acid in other acute illnesses may be warranted. Copyright © 2010 American Society for Bone and Mineral Research     

The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age

The increase in demand for renal replacement therapy makes it important to investigate the prognosis of the earlier stages of chronic kidney disease (CKD). We examined the change in glomerular filtration rate (GFR), and patient and renal survival in CKD stage 3 in the municipality of Troms?, a well-defined European community with a population of 58,000. All patients with estimated GFR between 30 and 59 ml/min/1.73 m(2) for more than 3 months during a 10-year study period were identified from a complete database of all 248 560 measurements of serum creatinine made in the community in the study period. Change in GFR was estimated for each patient using a multilevel model. A complete follow-up with respect to patient and renal survival was obtained from hospital databases. A total of 3047 patients was included. The median number of measurements of creatinine for each patient was 9, and the median observation time was 44 months. Mean estimated change in GFR was--1.03 ml/min/1.73 m(2)/year. Seventy-three percent of the patients experienced a decline in GFR. The 10-year cumulative incidence of renal failure was 0.04 (95% CI 0.03-0.06) and mortality 0.51 (95% CI 0.48-0.55). Female gender was associated with slower decline in GFR and better patient and renal survival. In this population-based study, the decline in GFR in CKD was slower than in previously studied selected patient groups. A high mortality pre-empted the development of renal failure in many patients. The prognosis of CKD depended strongly on gender.     

Psychometric methods for diagnosing and monitoring minimal hepatic encephalopathy —current validation level and practical use

Metabolic Brain Disease - Hepatic encephalopathy (HE) is cerebral dysfunction caused by liver failure and inflicts 30-40% of patients with liver cirrhosis during their disease course. Clinically...     

Physical Functioning,Mental Health,and Quality of Life in Different Congenital Heart Defects: Comparative Analysis in 3538 Patients From 15 Countries

BackgroundWe compared physical functioning, mental health, and quality of life (QoL) of patients with different subtypes of congenital heart disease (CHD) in a large international sample and investigated the role of functional class in explaining the variance in outcomes across heart defects.MethodsIn the cross-sectional Assessment of Patterns of Patient-Reported Outcome in Adults with Congenital Heart Disease-International Study (APPROACH-IS), we enrolled 4028 adult patients with CHD from 15 countries. Diagnostic groups with at least 50 patients were included in these analyses, yielding a sample of 3538 patients (median age: 32 years; 52% women). Physical functioning, mental health, and QoL were measured with the SF-12 health status survey, Hospital Anxiety and Depression Scale (HADS), linear analog scale (LAS) and Satisfaction with Life Scale, respectively. Functional class was assessed using the patient-reported New York Heart Association (NYHA) class. Multivariable general linear mixed models were applied to assess the relationship between the type of CHD and patient-reported outcomes, adjusted for patient characteristics, and with country as random effect.ResultsPatients with coarctation of the aorta and those with isolated aortic valve disease reported the best physical functioning, mental health, and QoL. Patients with cyanotic heart disease or Eisenmenger syndrome had worst outcomes. The differences were statistically significant, above and beyond other patient characteristics. However, the explained variances were small (0.6% to 4.1%) and decreased further when functional status was added to the models (0.4% to 0.9%).ConclusionsSome types of CHD predict worse patient-reported outcomes. However, it appears that it is the functional status associated with the heart defect rather than the heart defect itself that shapes the outcomes.     

Cure or Protection? The meaning of smallpox inoculation,ca 1750–1775

The idea that smallpox could be eradicated was not necessarily the ultimate aim when inoculation was introduced in Europe in the 1720s. This potentiality was not clearly articulated as an aim until the end of the eighteenth century. This article argues that during most of the eighteenth century, the main aim of inoculation was to lead people as safely as possible through what was regarded as an unavoidable disease. Inoculation became safer, simpler and less expensive from the 1760s, but the changing ideas about its potentiality had more complex roots. A new understanding was produced through an interaction between inoculation practice, more general medical theory and developments within probabilistic thinking and political arithmetic. The first part of the article explores how smallpox inoculation was incorporated into existing medical thinking based on traditional humoral pathology. Inoculation was a new technology, but as it was perceived in the early eighteenth century, the innovation did not first and foremost concern the medical principles of the treatment. The second part of the article investigates arguments about why and when to inoculate: what kind of remedy was inoculation for eighteenth-century agents? The article concludes with a discussion on changes emerging towards the end of the century, and relates them to developments during the preceding decades rather than seeing them as inspired precursors of events and ideas to come. Keywords : Smallpox inoculation, Eighteenth century, Humoral pathology, Reluctance to changeWhat was the meaning of eighteenth-century smallpox inoculation? Traditional medical history used to present a continuity from inoculation to Jenner’s vaccine in 1798 and subsequently to the national vaccination programmes of the nineteenth and twentieth centuries, ending in total triumph with the global eradication of smallpox in the 1980s. ¹ The new medical history from the 1970s onwards has done much to change the general perspectives claiming a linear progressive development in medicine. ² As early as in 1985, Roy Porter argued the importance of studying beliefs about illness and health, situated in their historical contexts. ³ While Porter drew attention chiefly towards beliefs among the laity, recent studies in the history of technology and science have also pointed to the influence of cultural factors among scientists themselves. Not least can this be claimed to be relevant in the case of medicine, situated as it is between science and social practice. Ludmila Jordanova contrasts this modern interest in investigating meanings, beliefs and interest with traditional history of science and medicine, saying that ‘in a progressivist narrative, the search for truth was told in terms of blind alleys and right answers; the model was a journey, and the main emphasis was on content’. ⁴ She goes on to point out that few questions were asked about mediating processes, or about ‘how problems requiring explanations were defined’. ⁵ The new medical history, on the other hand, was, as Jordanova argues, shaped by a number of theoretical influences which may all be grouped as ‘social constructionist’. This implied a shifting of focus from the content of the ‘right’ answers to the processes by which knowledge – including scientific knowledge – is produced and negotiated. Jordanova describes this by saying that ‘between the material world and our representations of it there now appeared to be a space, which it was the job of historians (and sociologists and philosophers) to examine’. ⁶ This article will enter such a space, and ask how smallpox and smallpox inoculation were understood in the second part of the eighteenth century.The idea that smallpox could be conquered, even eradicated, was not a necessary companion to the new method when it was introduced in Europe. This potentiality only gradually emerged and was not clearly articulated until the end of the eighteenth century. The main focus of the present article will be the years approximately between 1750 and 1775. Often called the second phase of smallpox inoculation in Europe (after its introduction in the 1720s), this period saw important changes in the way inoculation was carried out. The method became both safer, simpler and less expensive than before. The changes made new ideas possible, but it is important that they were not initiated by the ideas and projects which they later inspired. It also would be overly simplistic to view changing understandings as mere reflections of improved method. The new ideas had more complex roots than technical improvements alone. This article will argue that the slowly changing understanding of the potentialities of inoculation was produced by an interaction between inoculation practice, more general medical theory and developments within probabilistic thinking and political arithmetic.Because the idea of the article is not to discuss the actual practice of inoculation, some issues that have figured prominently in historical research on inoculation will not be touched upon. This concerns the questions of mortality rates and population growth, as well as popular resistance against inoculation. Moreover, the article will discuss a period before the more extensive state initiatives to combat smallpox epidemics had been launched, and thus not go into the idea of public health as it emerged through such programmes. What rather is at stake in the following is the meaning of smallpox inoculation to its eighteenth-century advocates and practitioners. What was inoculation to them? As will appear from the following investigation, this question concerns the medical workings of the new remedy, but also its religious and ethical implications. The meaning of inoculation moreover relates to understandings of chance, luck, hazard and risk, and to the changing conceptualisation of the relation between the individual subject and the population at large.The method chosen to explore this is a close reading of influential texts on inoculation, produced in three different European countries. They represent voices in a public debate on why, when and, to some degree, how to inoculate.As a method of analysis, close reading insists on taking seriously what goes on in the text. The aim is not primarily to detect the intentions of the authors or the influence of their historical contexts, but to study texts as historical realities carrying meaning in themselves. The texts to be investigated here reflect how inoculation was spoken of, what kind of metaphors it was surrounded by, how disease and epidemics were conceptualised. Moreover, they provide the possibility of understanding something about the self-evident premises of the arguments. What is not said, what is not made an issue in these text – because it was unthinkable, or because it was self-evident? To understand the motives and ideas of eighteenth-century medical agents, studies of technology and medical practices alone are not sufficient. The ways the disease and its remedies were spoken of and turned into arguments of a public debate are equally important.The first part of the article explores how smallpox inoculation in Europe was incorporated into existing medical thinking based on traditional humoral pathology. Inoculation was a new technology, and radically so, but as it was perceived in the eighteenth century the radicality did not first and foremost concern the medical principles of the treatment. The middle part of the article investigates arguments as to why and when to employ the new technology. What kind of remedy was inoculation to mid-eighteenth century agents? What kind of situations made its use relevant, and what was the expected outcome? The article concludes with a discussion on changes that emerged towards the end of the century, relating them to developments during the preceding decades rather than seeing them as inspired precursors of events and ideas to come.The material for this study is taken from England, France and Denmark–Norway. England was the first country in Europe where inoculation was introduced from the Middle East, and also the country where it was most generally used. Comparing England to France, where inoculation never became common practice and powerful institutions like the Sorbonne even pronounced themselves against it, it appears obvious that even the arguments in favour of the method differed. One reason for this difference, as Andrea A. Rusnock has pointed out, was that in England the physicians themselves advocated the method, which made it possible to unite practical experience with theoretical argument. In France, local corporations controlled medical practice to a far greater extent, and most of them opposed inoculation for a longer period of time. Here the method was advocated by philosophes who were not physicians, or by physicians who were not French. ⁷ Both countries hold central positions in the history of European smallpox inoculation.Denmark, and not least its northern province Norway, represents a European periphery. The first inoculations in this twin monarchy appear to have taken place in Trondheim (Norway) in 1754. In the capital Copenhagen, a royal inoculation house was established in 1755, but met with little success and closed down after just five years. Apart from this, inoculation in Denmark–Norway seems to have occurred only sporadically and due to private and in some cases lay initiatives. ⁸   Pro-inoculation debate was strongly influenced by texts in English and French, some of which were read in the original, others translated. The earliest text on inoculation to have been published in Denmark–Norway was by J.-A. Butini, originally published in 1752 and translated from French in 1753. La Condamine’s internationally influential pamphlet appeared in Danish in 1755, one year after the French original. ⁹ The texts examined in this article are two medical treatises, written by the English physician J. Kirkpatrick and the Danish professor of medicine Chr. Friis Rottböll, respectively. ¹⁰ Together with a short article by the Swedish physician L. Montin, these texts discuss medical theory concerning smallpox and the effect of inoculation. ¹¹ The texts by the Swiss physicians J.-A. Butini and S.A.D. Tissot, the Italian Angelo Gatti and the English Thomas Dimsdale are manuals, giving instructions on how to carry out inoculation. ¹² They cite arguments in defence of the new technology, but do not enter into discussions on how it works. The texts by Cramer and Bredal, la Condamine, Tronchin and Smith, finally, all promote inoculation by explaining its advantages and also by answering the objections that were most commonly raised against it. ¹³ The aim of the investigation is not to elaborate on national differences, but rather to show how the inoculation debate was fairly international. Influential texts circulated widely and crossed national borders. Pro-inoculation arguments were quoted extensively, and long passages of texts by one author could be incorporated into that of another. Works advocating inoculation constituted an intertextual network, explicitly and implicitly referring to each other. In this network, the three countries of this investigation held different roles. All produced texts and arguments that circulated. The English and French texts had international influence, the Danish and Norwegian probably merely national. Including material from this part of Europe nonetheless adds to our general knowledge about the history of inoculation. It demonstrates the range and significance of ideas and literature from the larger countries, but it also shows that the time lag was small. Despite their role mainly as receivers of ideas, the physicians and intellectuals in the northern periphery were well oriented, quick to import novelties and to relate themselves to international debates.All the texts have been influential. They set the debates and shaped opinion, though in different contexts. Some of their authors, like Dimsdale, la Condamine and Tissot, were men of international renown. As a general trait, it may also be worth noting that medical men were not the only ones to contribute to the inoculations debate. Other men of letters and enlightened philosophy took part, which is an indication that inoculation was not only considered to be a matter of medicine but also concerned the welfare of society at large. On the other hand, it is equally interesting to note that no statesmen or men of political influence are to be found among the authors. In all three countries there were only few and mostly weak attempts at organising larger public programs of inoculation in this period, and they do not seem to have resulted in texts that can be taken to indicate pro-inoculation engagements or ideas on the official level of the state.     

Modern Health Worries, Subjective Health Complaints, Health Care Utilization, and Sick Leave in the Norwegian Working Population

Background

Modern health worries (concerns about aspects of modern life affecting health) heve been associated with subjective health complaints and health care utilization.

Purpose

The aim of this study was to investigate the association between modern health worries (MHW) and subjective health complaints (SHC), health care utilization, and sick leave related to such complaints in the Norwegian working population.

Methods

A sample of the Norwegian working population (N?=?569) answered a questionnaire which included the Subjective Health Complaints Inventory and a Norwegian version of the Modern Health Worries Scale.

Results

Ninety-one percent of the participants reported at least one complaint in the past 30 days, and 96 % of the participants reported concerns for at least one of the items in the MHW scale. Women reported significantly more and more severe complaints compared to men and significantly more concern about aspects of modern life affecting health. Participants who reported a high level of MHW showed nearly twice the risk of reporting a high level of SHC (odds ratio (OR)?=?1.83; 95 % confidence interval (CI)?=?1.30–2.71; p?=?0.001), and they showed twice the risk for self-certified sick leave related to SHC (OR?=?2.04; 95 % CI?=?1.01–3.92; p?=?0.048). High levels of MHW showed no significant association with health care utilization or doctor-certified sick leave.

Conclusions

Subjective health complaints and concerns about aspects of modern life affecting health are very common, even among healthy workers. Women have more complaints and more concerns compared to men. Within the health care system, it may be advantageous to pay close attention to the association between high levels of MHW and high levels of SHC.