I A Ivan
email: ivan@valahia.ro

V Stihi
email: cstihi@yahoo.com

M Ivan

C Stihi

M Rakotondrabe

A Jelea

BATTERY POWERED COST EFFECTIVE TDS LOGGER INTENDED FOR WATER TESTING

Keywords: water quality, conductivity-meter, TDS, microcontroller

The paper presents a cost-effective device designed for measuring and monitoring the TDS (total dissolved solids) level of drinkable, surface (lakes, rivers) and/or industrial waters. Providing a first reading of potential water pollutions, the device is dedicated to the sectors of environment and consumer protection. The device was implemented and a series of continuous measurements is depicted, discovering some abnormalities in the quality of Targoviste city water utility.

INTRODUCTION

In recent years, the need for water quality sensors spread from industry to environment and domestic applications. One of the most direct methods is the TDS (Total Dissolved Solids) measurement.

TDS devices are, in reality, conductivity meters. Pure water shows intrinsically a very reduced electrical conductivity (0,00548 mS/m). When impurities are mixed and dissolved into water, ions separate and conductivity increase. Upon application of a voltage between two or more electrodes made of non-reactive materials, positively charged ions (e.g. Na + , Ca ++ , Mg ++ , H + etc.) and negatively charged ions (e.g. Cl -, SO [START_REF]PIC 18Fxxxx Microcontroller Data Sheet[END_REF] --, HCO 3 -etc.) will constitute an electrical current. The conductivity of water may afterwards be converted into a measure of the total quantity of ions or dissolved solids. The method is not selective, meaning that the nature of ions cannot be determined but only the total quantity, from where the term TDS (Total Disolved Solids). TDS meters also give a relatively accurate reading of some colloidal compounds such as silver [START_REF] Craun | Problems associated with metals in drinking water[END_REF].

Our device is a modified version of a TDS meter initially designed for the control of a brackish water desalinating system utilizing the novel capacitive deionization technology (CDT). This second version of the meter module is hermetically sealed and is capable to sample, convert and record in-situ conductivity, temperature and TDS values over extended periods of time (up to 21 days of logging and with 60 minutes sample interval).

Instead of using DC current, we propose to use an electrical field that oscillates very rapidly, where there is no overall movement of ions toward the electrodes. In fact, the ions move one way for a tiny fraction of a second, and then back the other direction for the second half of the cycle. Overall, the solution and electrodes stay unchanged and the conductivity is accurately measured. Based on 8-bit Microchip PIC18F architecture [START_REF]PIC 18Fxxxx Microcontroller Data Sheet[END_REF], the devices use a cycle of alternated charging-discharging small capacitors. Threshold voltage detection and derived period of time is made using onboard CMOS trigger and 16-bit counter. The electronic schematic is thus simplified, with no need of A/D converters or voltage references.

Given the fact that the conductivity of ions in water depends nonlinearly upon temperature, the conversion of sampled conductance (mS/cm) in TDS units (ppm) is compensated by aid of internal EEPROM stored look-up tables. The designed TDS device has been calibrated with standard "442" solution, and readings were compared with a commercial Hach CO150 TDS meter. First measurements were carried-out in the city of Targoviste water utility system.

EXPERIMENTAL METHODS

WATER CONDUCTIVITY MEASUREMENT PRINCIPLE

At a first view, simplistically speaking, water and ions appear as an electric resistance and we might tempt to measure its conductivity in direct current, which is a wrong method. By applying a constant electric field between the two electrodes, ions will migrate and deposit on the electrodes, finally electrically isolating the positive electrode. If the applied voltage is larger than 1.3 volts then the electrolysis phenomena appear between the two electrodes and the conductivity measurement will be completely erroneous.

The measurement of conductivity of liquids may be done in several ways [START_REF] Singh | Specific conductance method for in situ estimation of total dissolved solids[END_REF], provided that no continuous level of voltage is applied, nor impulse voltage. The frequency of the alternating signal should be larger than 3 kHz, as above this frequency water does not decompose nor plate the electrodes, and as the applied voltage amplitude is no longer limited to 1.3V.

The proposed method is simple and ready to be implemented in logic circuits -no analog circuits being required. A microcontroller PIC18F1220 [START_REF]PIC 18Fxxxx Microcontroller Data Sheet[END_REF] was chosen for its fast setting of pins state (input/output) and for its symmetry of output portsthey sink and source the same current which is internally limited. The performance of reduced 8-bit architecture is convenient for this type small and low-cost application.

The measurement schematic is shown in the figure 1. Rx is the unknown water resistance and C1 is a fixed small capacitor (3,3nF). On the left, C+, C-and EC are some pins of the microcontroller [START_REF]PIC 18Fxxxx Microcontroller Data Sheet[END_REF] (noted uC).

The measurement algorithm of the Rx value is based of the following steps: 1. Pin EC is set as input (high impedance state) then C+ is put on high logic (3V) and pin C-is driven in low state, charging the capacitor very close to the Vcc supply voltage (5V or 3V battery). 2. Pin C+ is set as input and EC pin is set as output on low state. Pin C-continues to stay on low level. Practically C-and EC are "linked to ground" and in this configuration the charged capacitor and water resistance are in parallel and referenced to the ground. The capacitor will discharge following the known exponential decay law. Time constant is proportional to the factor Rx⋅C1. 3. Microcontroller inputs are Schmitt triggers, switching low when the voltage reaches less or equal a 1/3 of supply voltage value. Time of capacitor discharge between Vcc and one third of Vcc is measured and recorded as T1. In the case that T1 exceeds a maximum preset value, T1 will be considered equal to the preset value. This value is determined from the minimum frequency condition of 3 kHz that prevents ions to plate the electrodes. It will only be in the case of ultra-pure water or electrodes outside water, and corresponding TDS value will afterwards be reported as zero. 4. To prepare the next measurement step, pin EC is set to input and pins C-and C+ are set both on high output states. Thus, the capacitor will be completely discharged. 5. Pin C+ is brought to the low state, charging the capacitor to an opposite voltage than that of step (1). 6. Pin C+ direction is set to input (high impedance) and pin EC is set as output (high logic level). In this way, Rx and C1 are put in parallel and referenced to Vcc. The discharge time T2 in which the C+ voltage rises to 2/3 of Vcc is measured. 7. Pin EC is set as high impedance, pins C-and C+ are set to low level output.

Temperature value is read from the sensor. Next cycle can start from step [START_REF] Craun | Problems associated with metals in drinking water[END_REF].

A number of 16 cycles will be performed and finally the all-corresponding T1 and T2 time values will be averaged and converted by means of look-up tables stored in EEPROM, as in this case it is conversely proportional to Rx value. Two voltage waveforms across Rx (electrodes) are presented in figure 2 for different water resistivities. The curve in magenta is for a higher water conductivity value than that of the grayed curve. The geometry of electrodes is important and has to be respected; otherwise the cell constant k will change and the device will need to be recalibrated. In our case the electrodes were small stainless steel rods of 1 mm in diameter, of 5 mm in length and placed in parallel at a distance of 3,5 mm between their symmetry axes (figure 3). Close-up of the sensing probe. 544

Recalibration is also recommended if tests are performed on different water sources with quite different dissolved compounds. In figure 4 a calibration characteristic is presented. It is known that different conductivities might be reported for different solutions of the same TDS.

THE BATTERY-POWERED DEVICE: DESIGN AND CALIBRATION

The device is powered from a 3V lithium coin cell battery. Most of the time the device is on the stand-by mode, requiring a very small power supply. The data interface is a simple serial asynchronous (TTL levels) for reading the logged data or writing the calibration table into an external EEPROM or in the internal flash memory. The microcontroller is configured with two oscillators: the first is a 32kHz low power oscillator serving for regularly waking-up the microcontroller from stand-by (60 seconds intervals) and keeping the date and hour, while the second oscillator uses a high speed 10 MHz resonator for the clock source and to count the small time intervals required during acquisition.

Two versions were designed (figures 5-8), the first one is temperatureuncompensated while the second one uses a TC77 temperature sensor featuring internal A/D conversion and SPI interface. In figures 9 and 10 are presented the characteristics conductivity versus temperature for the different concentration of the KCl and NaCl standard solutions used in this work. The conversion algorithm implemented on the second device was modified to compensate the readings. As seen, there is a large difference between figures 11 (without reading compensation) and 12 (with reading compensation) taken at different temperature values.

EXPERIMENTAL RESULTS AND DISCUSSIONS

Water plays an intrinsic role in living environment. Water of suitable quality and quantity is essential to all life forms. Water is never in a pure status, it always contains minerals and microorganisms [START_REF] Oprean | Results of Physical and Chemical Parameters Monitoring of the "Râul Mare" River[END_REF][START_REF] Anton | Study Regarding the Water Pollution in Romania and Spain[END_REF]. Human activities can contaminate water with various substances. But water should be clean in order to ensure a good health. Actually, some minerals present in water can have benefit consequences. Surface water is an important component of fresh water systems and surface water monitoring [START_REF] Stihi | Inductively Coupled Plasma (ICP) and Total Dissolved Solids (TDS) Measurements of Surface Waters from Ialomiţa River[END_REF][START_REF] Dima | Mn and Zn concentration determination from Ialomita river by atomic absorption spectroscopy[END_REF][START_REF] Coskun | Determination of Environmental Quality of a Drinking Water Reservoir by Remote Sensing, GIS and Regression Analysis[END_REF] is essential in attaining a comprehensive understanding of the physical, chemical, and biological characteristics of aquatic systems.

Total Dissolved Solids (TDS) are solids in water that can pass through a filter. Therefore, TDS can be used to measure the amount of material dissolved in water. This material can include carbonate (HCO 3 -), chloride (Cl -), sulphate (SO 4 2-), calcium (Ca ++ ), magnesium (Mg ++ ), sodium (Na + ), potassium (K + ), iron (Fe ++ , Fe +++ ), nitrate (NO 3 -) and other ions. A certain level of these ions in water is necessary for aquatic life. However, if TDS concentrations are out of admissible limits, the growth of many aquatic lives can be limited, and death may occur [START_REF] Craun | Problems associated with metals in drinking water[END_REF]. A high concentration of TDS may also reduce water clarity, contributes to the decrease of photosynthesis, may combine toxic compounds and heavy metals and leads to an increase in water temperature.

Table below presents the normal variation of conductivity for several types of water, according to [START_REF]CO150 Conductivity Meter Model 50150 Instruction Manual[END_REF]. Table 1 Conductivity range of common aqueous solutions [START_REF]CO150 Conductivity Meter Model 50150 Instruction Manual[END_REF] Experimental measurements were conducted on the water utility system of Targoviste city. Usually, logged data showed minor daily fluctuations within the normal range (figure 13). During the afternoon when the domestic water flow increases, a slight decrease of the TDS level is recorded. We noticed that on the 5 th of July (day 8 on recordings) at 22 hrs the pumping switched off for a current repair, which lasted until the next day in the morning at 5 AM. As consequence, the recorded level of TDS (figure 14) showed a significant increase, and it took about 30 hours to retrieve the initial level.

CONCLUSIONS

The aim of this paper was the design and test of a cost-effective TDS logger intended for water quality monitoring. Such battery-powered devices are intended for large scale monitoring, e.g. along rivers or in urban water systems. It is based on a 8-bit microcontroller architecture and a small EEPROM memory. An additional temperature sensor allows the reading compensation. Data exchange is performed over a simple SPI serial synchronous interface. Up to 512 readings are possible with the provided memory capacity. The autonomy at a 1 hour sampling rate is of 21 days and it can be easily improved by replacing the memory chip.

First off-line TDS measurements and logs were performed on one end-point of the Targoviste city water utility. The results were within the limits except for a single day when the utility was shut-down for a night for maintenance. In the morning there were noticed abnormally high TDS values. It should be noticed that according to the Romanian standard [START_REF]National Standard STAS 4706 For Surface Waters, Quality Categories and Conditions[END_REF] the maximum allowed level of 2000 mg/l was not attained; however we can notice that the recommended value of 1 mS/cm shown in Table 1 or 670 mg/l was exceeded for a period of 7 hours after the utility resumed the pumping. We appreciate that a utility shutdown of a longer period, let's say of one day, would raise even further the TDS level, making the water undrinkable.

Finally, the developed low cost device for continuous monitoring can provide a quick test of the water quality, preventing unwanted health problems. As further improvements, these devices could be connected in wired or wireless distributed networks for reporting instant alarms.

Fig. 1 -

 1 Fig. 1 -Basic measurement schematic.

Fig. 2 -

 2 Fig. 2 -Electrodes signal waveforms for two different water conductivities.

Fig. 3 -

 3 Fig. 3 -Photographs of the reference CO150 conductivity meter and of the designed device.Close-up of the sensing probe.

Fig. 4 -

 4 Fig. 4 -TDS measured by device versus conductivity measured by the referencing device (in a mixture of KCl+NaCl solutions at 20 0 C).

Fig. 5 -Fig. 7 -

 57 Fig. 5 -Schematic of the first uncompensated model. Fig. 6 -Printed circuit board.

Fig. 9 -

 9 Fig. 9 -Conductivity to temperature characteristics for different concentrations. Fig. 10 -Same graph re-scaled.

Fig. 11 -

 11 Fig. 11 -Non-compensated model TDS to temperature characteristic. Fig. 12 -Compensated model TDS to temperature characteristic (various concentrations).

Fig. 13 -

 13 Fig. 13 -Daily normal TDS fluctuations.

Rom. Journ. Phys., Vol. 56, Nos. 3-4, P. 540-549, Bucharest, 2011


Vincent Arsigny
email: vincent.arsigny@polytechnique.org

Olivier Commowick

Xavier Pennec

Nicholas Ayache

Statistics on Diffeomorphisms in a Log-Euclidean Framework

In this article, we focus on the computation of statistics of invertible geometrical deformations (i.e., diffeomorphisms), based on the generalization to this type of data of the notion of principal logarithm. Remarkably, this logarithm is a simple 3D vector field, and can be used for diffeomorphisms close enough to the identity. This allows to perform vectorial statistics on diffeomorphisms, while preserving the invertibility constraint, contrary to Euclidean statistics on displacement fields.

Statistics on Diffeomorphisms in a Log-Euclidean Framework Overview

In this article, which is an extended abstract of [START_REF] Arsigny | A Log-Euclidean framework for statistics on diffeomorphisms[END_REF], we focus on the computation of statistics of general diffeomorphisms, i.e. of geometrical deformations (non-linear in general) which are both one-to-one and regular (as well as their inverse). To quantitatively compare non-linear registration algorithms, or in order to constrain them, computing statistics on global deformations would be very useful as was done in [START_REF] Commowick | Incorporating statistical measures of anatomical variability in atlasto-subject registration for conformal brain radiotherapy[END_REF] with local statistics.

The computation of statistics is closely linked to the issue of the parameterization of diffeomorphisms. Many algorithms, as in [START_REF] Chefd'hotel | Flows of diffeomorphisms for multimodal image registration[END_REF], provide transformations are always diffeomorphic, and parameterize them via their displacement field. However, Euclidean means of displacement fields do not necessary yield invertible deformations, which makes Euclidean statistics on these parameters problematic for diffeomorphisms. In [START_REF] Marsland | Constructing diffeomorphic representations for the groupwise analysis of nonrigid registrations of medical images[END_REF], it was proposed to parameterize arbitrary diffeomorphisms with Geodesic Interpolating Splines control points [START_REF] Camion | Geodesic interpolating splines[END_REF], and then to perform Euclidean operations on these low-dimensional parameters. However, although this guarantees the invertibility of the results, this may not be adequate for the whole variety of invertible transformations used in medical imaging.

To fully take into account the group structure of diffeomorphisms, it has been proposed to parameterize dense deformations with Hilbert spaces of time-varying speed vector fields, which yield geometrical deformations via the integration of an Ordinary Differential Equation (ODE) during one unit of time [START_REF] Trouvé | Diffeomorphisms groups and pattern matching in image analysis[END_REF][START_REF] Beg | Computing large deformation metric mappings via geodesic flows of diffeomorphisms[END_REF]. In [START_REF] Vaillant | Statistics on diffeomorphisms via tangent space representations[END_REF], it is suggested that the linear space of intial momenta of the geodesics of these spaces could provide an appropriate setting for statistics on diffeomorphisms. However, this is illustrated in [START_REF] Vaillant | Statistics on diffeomorphisms via tangent space representations[END_REF] only in the case of landmark matching. To our knowledge, this statistical framework has not been used yet in the general case, certainly because of the iterative nature of the computation of the mean in this setting, which requires very stable numerical algorithms to converge.

In this work, we introduce a novel parameterization of diffeomorphisms, based on the generalization of the principal logarithm to non-linear geometrical deformations. Interestingly, this corresponds to parameterizing diffeomorphisms with stationnary speed vectors fields. As for matrices, this logarithm can be used only for transformations close enough to the identity. However, our preliminary numerical experiments on 3D non-rigid registration suggest that this limitation affects only very large deformations, and may not be problematic for image registration results. This novel setting is the infinite-dimensional analogous of the Log-Euclidean framework proposed in [START_REF] Arsigny | Fast and simple calculus on tensors in the Log-Euclidean framework[END_REF] for tensors. In this framework, usual Euclidean statistics can be performed on diffeomorphisms via their logarithms, whith excellent mathematical properties like inversion-invariance.

In [START_REF] Arsigny | A Log-Euclidean framework for statistics on diffeomorphisms[END_REF], our contributions are presented as follows. We first present the Log-Euclidean framework for diffeomorphisms, which is closely linked to the notion of one-parameter subgroups. Then, we present two efficient algorithms to compute the exponential of a vector field and the logarithm of a diffeomorphism, which are exemplified on synthetic data. Finally, we apply our framework to non-linear registration results to compute a Log-Euclidean mean deformation between a 3D atlas and a dataset of 9 T 1 MR images of human brains.

Mathematical Foundations of Computational Anatomy (MFCA'06)


Dr Sundaram G Veerappan
email: sveerappan@rcsi.ie

Colm A O'morain

Jacqueline S Daly

Barbara M Ryan

Effects of anti-tumour necrosis factor-α on bone metabolism in inflammatory bowel disease

Keywords: Inflammatory bowel disease < Disease-based, Bone disorders < Topics, Osteoporosis < Topics, X Anti-TNF alpha, bone metabolism, inflammatory bowel disease

Background

Patients with inflammatory bowel disease (IBD) are at increased risk of osteoporosis. A number of studies have emerged in recent years indicating that tumour necrosis factor (TNF) blockade appears to have a beneficial effect on bone mineral density (BMD) in IBD patients.

Aims

To provide a review of the available data regarding the effect of the currently licensed anti-TNF-α therapies on bone metabolism and BMD in IBD patients.

Methods

A Medline search was performed using the search terms 'infliximab', 'bone metabolism', 'IBD', 'BMD', 'bone markers', 'adalimumab', 'bone disease', 'Crohn's disease', and 'ulcerative colitis'.

Results

Infliximab has a beneficial effect on bone turnover markers in Crohn's disease (CD) patients in the short term. The longest study to date comprising 24 CD patients showed an overall improvement in two bone formation markers -b-alkaline phosphatase (p=0.022) and osteocalcin (p=0.008) at 4 months post treatment. Moreover, the largest study to date comprising 71 CD patients showed significant improvement in sCTx, a bone resorption marker (p=0.04) at week 8 post treatment. There is little data looking at the effect of anti-

TNF-α therapy on bone metabolism in ulcerative colitis. Moreover, the long term effects of anti-TNF-α therapy on bone structure and fracture risk in IBD patients are currently not known. The effect of cessation of anti-TNF-α therapy on bone metabolism is also unknown.

Conclusions

Properly controlled long term trials are needed to fully evaluate the impact of TNF blockade on BMD.

INTRODUCTION

Bone demineralisation and osteoporosis in patients with inflammatory bowel disease (IBD) was first reported 35 years ago. [START_REF] Genant | Skeletal demineralization and growth retardation in inflammatory bowel disease[END_REF] The largest risk was observed at the spine, with a 6.5 fold increase in fracture risk. [START_REF] Vestergaard | Fracture risk in patients with coeliac disease, Crohn's disease, and ulcerative colitis: A nationwide follow-up study of 16416 patients in Denmark[END_REF] In a recent population based cohort study, the relative risk of hip fracture was 1.41 (0.94-2.11) for ulcerative colitis (UC) and 1.68 (1.01-2.78) for Crohn's disease (CD). [START_REF] Card | Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: A population based cohort study[END_REF] This study also concluded that the risk of hip fracture is increased approximately 60% in IBD patients and that the majority of hip fracture risk in IBD patients cannot be attributed to steroid use. [START_REF] Card | Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: A population based cohort study[END_REF] The pathogenesis of reduced bone mineral density (BMD) in IBD is multi-factorial. General risk factors as seen in the general population, such as age, gender, estrogen deficiency, alterations in calcium homeostasis, nutritional and dietary factors, smoking, alcohol and immobility are likely to play a role. Additional risk factors that have been shown to influence bone metabolism in some IBD patients includes Vitamin D deficiency, [START_REF] Silvennoinen | Relationship between vitamin D, parathyroid hormone and bone mineral density in inflammatory bowel disease[END_REF][START_REF] Bischoff | Altered bone metabolism in inflammatory bowel disease[END_REF] glucocorticoid treatment, [START_REF] Silvennoinen | A controlled study of bone mineral density in patients with inflammatory bowel disease[END_REF][START_REF] Bernstein | Decreased bone mineral density in inflammatory bowel disease is related to corticosteroid use and not disease diagnosis[END_REF][START_REF] Adinoff | Steroid-induced fractures and bone loss in patients with asthma[END_REF][9] hypogonadism, [START_REF] Robinson | Sex hormone status and bone metabolism in men with Crohn's disease[END_REF] and Vitamin K deficiency. [START_REF] Szulc | Is vitamin-K deficiency a risk factor for osteoporosis in Crohn's disease?[END_REF][START_REF] Hyams | Alterations in bone metabolism in children with inflammatory bowel disease: An in vitro study[END_REF] However, emerging evidence suggests that these factors play a relatively weak role in the pathogenesis of BMD loss in IBD and are overshadowed by the effect of the IBD itself. [START_REF] Silvennoinen | A controlled study of bone mineral density in patients with inflammatory bowel disease[END_REF][START_REF] Abitol | Metabolic bone assessment in patients with inflammatory bowel disease[END_REF][START_REF] Jahnsen | Bone mineral density is reduced in patients with Crohn's disease but not in patients with ulcerative colitis[END_REF][START_REF] Robinson | Effect of low-impact exercise program on bone mineral density in Crohn's disease. A randomized controlled study[END_REF] Furthermore, newly diagnosed untreated IBD patients been reported to have reduced BMD. [START_REF] Lamb | Metabolic bone disease is present at diagnosis in patients with inflammatory bowel disease[END_REF] In IBD, use of corticosteroids as a therapy is a common. Approximately 70% of patients with CD are treated with corticosteroids and 35% become dependent on this therapy. [START_REF] Wa | The natural history of glucocorticoid therapy for inflammatory bowel disease: a population-based study[END_REF][START_REF] Munkholm | Frequency of glucocorticoid resistance and dependency in Crohn's disease[END_REF] The negative effects of corticosteroids on bone metabolism are well known; they include both reduction of bone formation and concomitant increased bone resorption effects. Corticosteroids are also known to increase receptor activator of NF kappa ligand (RANKL) synthesis and inhibit osteoprotegerin (OPG) production which in turn results in net increase in the osteoclastogenesis. In vitro, addition of corticosteroids to osteoprogenitor cells increases their bone forming capacity while also increasing apoptosis of mature osteoblasts resulting in an overall reduction of bone formation capacity. [START_REF] Gregorio | Glucocorticoid induced osteoporosis[END_REF] Corticosteroids also cause vitamin D catabolism and inhibit calcium absorption in the gastrointestinal tract resulting in deficiency of these two crucial bone nutrients for bone maintenance. [START_REF] Gregorio | Glucocorticoid induced osteoporosis[END_REF] Elevated pro-inflammatory cytokines and active inflammation have been implicated in the pathogenesis of bone loss in a variety of inflammatory models. [START_REF] Ammann | Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency[END_REF][START_REF] Bickel | Cytokine gene expression in chronic periodontitis[END_REF][START_REF] Udagawa | The molecular mechanism of osteoclastogenesis in rheumatoid arthritis[END_REF][START_REF] Origuchi | IL-1-mediated expression of membrane type matrix-metalloproteinase in rheumatoid osteoblasts[END_REF][START_REF] Oelzner | Relationship between soluble markers of immune activation and bone turnover in post-menopausal women with rheumatoid arthritis[END_REF][START_REF] Matsuno | The role of TNF-alpha in the pathogenesis of inflammation and joint destruction in rheumatoid arthritis[END_REF] Pro-inflammatory cytokine levels are elevated in IBD patients with active inflammation [START_REF] Murch | Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease[END_REF][START_REF] Komatsu | Tumor necrosis factor-alpha in serum of patients with inflammatory bowel disease as measured by a highly sensitive immuno-PCR[END_REF][START_REF] Lanfranchi | Serum and faecal tumour necrosis factor-alpha as marker of intestinal inflammation[END_REF] suggesting that disease activity could also play a role in IBD related bone disease. A rat model of colitis was associated with a dramatic 33% loss in trabecular bone and an even greater suppression in bone formation rate. [START_REF] Lin | Colitis causes bone loss in rats through suppression of bone formation[END_REF] Healing of colitis was associated with an increased bone formation rate and a return of bone measurements to normal levels. Serum from children with CD affects bone mineralization in an organ culture model without altering bone resorption. [START_REF] Hyams | Alterations in bone metabolism in children with inflammatory bowel disease: An in vitro study[END_REF] These observations suggest that mediators produced during intestinal inflammation may alter osteoblast function and bone formation, suggesting in turn that demineralisation in patients with IBD occurs primarily as a consequence of the intestinal inflammation. TNF-α, IL -1β and IL-6, are potent activators of bone resorption. [START_REF] Origuchi | IL-1-mediated expression of membrane type matrix-metalloproteinase in rheumatoid osteoblasts[END_REF][START_REF] Kumar | IL-1-and TNF-induced bone resorption is mediated by p38 mitogen activated protein kinase[END_REF][START_REF] Sylvester | Effect of Crohn's disease on bone metabolism in vitro: a role for interleukin-6[END_REF] These proinflammatory cytokines cause net bone loss through a number of by mechanisms. These cytokines have been shown to stimulate osteoclast differentiation [START_REF] Zhang | Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways[END_REF][START_REF] Lam | TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand[END_REF][START_REF] Zou | Tumor necrosis factor-alpha mediates RANK ligand stimulation of osteoclast differentiation by an autocrine mechanism[END_REF] , increase osteoclast activation [START_REF] Fuller | TNF alpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL[END_REF] , inhibit osteoclast apoptosis [START_REF] Lee | Tumor necrosis factor-alpha supports the survival of osteoclasts through the activation of Akt and ERK[END_REF] and inhibit osteoblast differentiation [START_REF] Gilbert | Inhibition of osteoblast differentiation by tumor necrosis factor-alpha[END_REF] . They also reduce bone formation in cultured osteoblasts in in vitro. [START_REF] Sylvester | Effect of Crohn's disease on bone metabolism in vitro: a role for interleukin-6[END_REF][START_REF] Taichman | Effects of interleukin-1 beta and tumor necrosis factor-alpha on osteoblastic expression of osteocalcin and mineralized extracellular matrix in vitro[END_REF] Like, IL-1, TNFstimulated induction of osteoclast-like-cell formation in bone marrow culture [START_REF] Pfeilschifter | Interleukin 1 and tumour necrosis factor stimulate the formation of human osteoclast like cells in vitro[END_REF] is mediated by increases in RANKL expression. [START_REF] Hofbauer | Interleukin 1 beta and tumour necrosis factor α, but not interleukin 6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells[END_REF] However, in addition to increasing RANKL expression, TNF also inhibits OPG in an osteoblastic model. 41 Thus, proinflammatory cytokines potentially cause bone loss by both increasing bone resorption and inhibiting bone formation. In IBD patients, elevated TNF-α are noted not only in patients with active disease but even in patients with inactive disease who have morphologically normal intestinal biopsies [START_REF] Reimund | Increased production of tumour necrosis factor-alpha interleukin-1 beta, and interleukin-6 by morphologically normal intestinal biopsies from patients with Crohn's disease[END_REF] and recently is implicated as being an important mediator of bone loss in this group of patients. [START_REF] Lichtenstein | Evaluation of bone mineral density in IBD: Current safety focus[END_REF][START_REF] Nanes | TNF-alpha: Molecular and cellular mechanisms in skeletal pathology[END_REF] Osteoblasts are also now known to express a surface ligand RANKL that can bind to osteoclast precursors (the RANK) or an osteoblast-derived soluble decoy receptor known as OPG. [START_REF] Aubin | Osteoprotegerin and its ligand: a new paradigm for regulation of osteoclastogenesis and bone resorption[END_REF] The binding of RANK to RANKL results in differentiation and maturation of osteoclasts. OPG blocks this interaction, thereby inhibiting osteoclast formation. There is emerging evidence that the RANKL-OPG system may be the final common pathway and mediator of osteoclastic bone resorption. The discovery of the RANK ligand pathway and its inhibition by OPG has had important implications for bone physiology. These interactions suggest that TNF-α blockade may have beneficial effect on bone generally.

INFLIXIMAB

Infliximab is a chimeric IgG1 monoclonal antibody comprised of 75% human and 25% murine sequences, which has a high specificity for and affinity to TNF-α. Infliximab neutralizes the biologic activity of TNF-α by inhibiting binding to its receptors. However, infliximab's mechanism of action most likely involves the destruction of activated effector cells bearing receptor bound TNF-α through apoptosis and/or other mechanisms. [START_REF] Scallon | Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions[END_REF][START_REF] Su | Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis[END_REF][START_REF] Lugering | Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspasedependent pathway[END_REF][49][START_REF] Van Den Brande | Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease[END_REF] Infliximab has a half life of approximately 10 days. Infliximab is the first biologic agent to be licensed for use in IBD. Besides its use in IBD, infliximab is also licensed for use in rheumatoid arthritis (RA), plaque psoriasis, psoriatic arthritis and ankylosing spondylitis.

Infliximab is approved for the treatment of moderate to severe CD who have not responded well to other conventional therapies. [START_REF] Targan | A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group[END_REF][START_REF] Hanauer | Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial[END_REF] In clinical studies, infliximab has been shown to decrease histologic and endoscopic disease activity and to induce and maintain remission in patients with active CD. Infliximab is also approved for use in fistulizing CD based upon the results of two randomized controlled trials. [START_REF] Present | Infliximab for the treatment of fistulas in patients with Crohn's disease[END_REF][START_REF] Sands | Infliximab maintenance therapy for fistulizing Crohn's disease[END_REF] Accumulating evidence has suggested that scheduled, maintenance therapy with infliximab has substantial clinical benefits compared with episodic treatment in CD patients who achieved remission with initial infliximab induction therapy. [START_REF] Rutgeerts | Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease[END_REF] For this reason most centers have now moved to scheduled as opposed to episodic maintenance therapy.

Infliximab is the first and only biologic currently approved for the treatment of moderate to severe UC failing to respond to conventional therapies. [START_REF] Rutgeerts | Infliximab for induction and maintenance therapy for ulcerative colitis[END_REF] In clinical studies, infliximab treatment was associated with achievement of clinical response and clinical

INFLIXIMAB AND BONE MARKERS

The first studies to suggest that a beneficial effect was seen with TNF blockade on bone metabolism in IBD patients were published in 2004. Franchimont et al. [START_REF] Franchimont | Rapid improvement of bone metabolism after infliximab treatment in Crohn's disease[END_REF] after infliximab treatment at eight weeks. The authors reported that a relative improvement in bone formation (defined as an increase of at least 30% in the bone formation marker) was found after infliximab treatment in 29.7%, 60.8% and 46.5% of the patients when considering b-ALP, OC or P1NP as marker, respectively. Serum concentration of sCTx was significantly increased in CD at baseline but no longer different from controls after infliximab treatment at eight weeks. Relative improvement in bone resorption (decrease of at least 30% in sCTx serum levels) was found after infliximab treatment in 38.2% of patients. The authors concluded that in their study infliximab showed a significant and rapid normalisation in the biochemical markers of bone turnover in CD patients and that this could probably be considered as clinically relevant in approximately 60% of the patients. This improvement didn't seem to be selectively associated with demographic or clinical characteristics of the patients, including clinical or biological response to infliximab or even steroid weaning. There was no significant difference when comparing median change in bone markers in luminal (treated with single infliximab infusion) and fistulizing CD (treated with three infliximab infusions).

Ryan et al. [START_REF] Ryan | Effect of antitumour necrosis factor-α therapy on bone turnover in patients with active Crohn's disease: a prospective study[END_REF] in a prospective trial studied 24 patients with active CD who were treated with infliximab (5mg/kg) for the first time. The majority of the patients had refractory luminal CD and only 2 patients had refractory luminal and fistulizing CD. There was no control group included in this study. Only one confounding factor which is the clinical response based on CDAI score was considered in this study. 42% of the patients were on steroids and 50% of the patients were on calcium/Vitamin D supplements at the start of the study. Five time points were assayed, namely; baseline, 1-2, 4-6, 8-10 and 12-18 Furthermore in this study, maximal reduction in CDAI was seen between 8 and 10 weeks, whereas bone formation markers continued to increase up to 16 weeks post treatment, suggesting that there might be a lag in the biological effect of the infliximab on bone metabolism.

Following on this, Abreu et al. [START_REF] Abreu | Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn's disease[END_REF] in small, short prospective study involving 38 refractory CD patients reported a significant increase in b-ALP (p=0.010) whereas serum NTx, was not increased (p=0.801) at week 4 compared to baseline post a single infliximab infusion. Again, this study did not compare its findings with an age matched control group and only two confounding factors, i.e. the effects of glucocorticoid use and the clinical response based on CDAI score on the changes seen were analysed in detail. In this study sera were also analyzed for immunoreactive parathyroid hormone (iPTH), calcium and pro-inflammatory cytokines (IL-1α, IL-6, and TNF-α) at baseline and 4

weeks following infliximab infusion. Overall, treatment with infliximab was associated with a statistically significant decrease in PTH levels (p=0.008) and statistically previously, in this study the authors sub analyzed the data based on whether the patients were receiving glucocorticoids at the time of their initial infliximab infusion and whether patients were responders or non-responders. 22/38 (57.9%) patients were receiving glucocorticoids at their time of initial infliximab infusion. The increase in bone formation occurred in both glucocorticoid treated individuals and those not on glucocorticoid, concluding that glucocorticoid use is not the principal reason for osteoporosis in patients with CD. Importantly, in this study the effect was also seen in both infliximab responders and non-responders, again suggesting an independent effect of infliximab on bone metabolism.

Miheller et al. [START_REF] Miheller | Infliximab therapy improves the bone metabolism in fistulizing Crohn's disease[END_REF] in a small study studied the effect of infliximab on bone formation and resorption marker in 27 fistulizing CD patients and compared the results with 54 patients with inactive CD who acted as controls and again the only confounding factor taken into account was based on clinical response to therapy defined by the decrease in the number of draining fistulas by half (responders) or no improvement in the number of draining fistulas post treatment (non-responders). Again, this was a short term study of just 42 days, and in treated patients, there were significant difference in β-CrossLaps (bCL), a marker for bone resorption on days 0 and 14 (p<0.01) and days 0 and 42 (p<0.05). OC levels increased significantly between day 0 and 42 (p<0.05) corroborating the results from previous studies that infliximab has beneficial effects on bone turnover markers in CD. In this study, the beneficial effect of infliximab on bone markers was only noted to be significant in the responder group. Mean duration between DXA scans was 2.2 +/-0.99 years. A number of confounding factors which could affect the study outcome were analysed including sex, number of post menopausal women, number of women on hormone replacement therapy, follow up time, number of patients with recorded corticosteroid use during the study and number of infliximab infusions. After controlling for corticosteroid use, patients with concurrent infliximab and bisphosphonate treatment exhibited a greater increase in BMD compared to those on bisphosphonate alone (+6.7%/year vs. +4.46%/year,p=0.045); corticosteroids inhibited this effect (p=0.025). However, infliximab alone had no effect on BMD. In this study, only lumbar spine BMD measurements were included for analysis and there was no control group.

In another retrospective study by Mauro et al. [START_REF] Mauro | Improvement of lumbar bone mass after infliximab therapy in Crohn's disease patients[END_REF] of four to eight weeks for a mean period of 18 months. The first and second DXA evaluations were 22.6 +/-11 months apart in the infliximab group and 20.4 +/-8 months apart in the control group. The infliximab group had a significant increase in lumbar bone area, bone mineral content (BMC) and BMD between both evaluations compared to control (CD patients who had never received infliximab). The increase in BMC, i.e. the bone mass measurements in patients who had received infliximab treatment was significant when compared with control patients who had received glucocorticoids (n=8) or who had evidence of disease activity.

Bernstein et al. [START_REF] Bernstein | Maintenance infliximab treatment is associated with improved bone mineral density in Crohn's disease[END_REF] also found that maintenance treatment with infliximab (5mg/kg) at 6-8 weeks intervals for 1 year in 46 CD patients improved BMD after one year in the lumbar spine (2.4% increase, p=0.002), at the femoral trochanter (2.8% increase, p=0.03), and at the femoral neck (2.6% increase, p=0.001) and that this effect was independent of concurrent administration of glucocorticoids, calcium supplementation, or changes in Creactive protein. Also BMD gain at the lumbar spine and the left femur between the groups without and with osteopenia were not different. However, whilst in confounding factors were anlaysed, there was no control group.

INFLIXIMAB AND OSTEOCLASTOGENESIS MARKERS

Only one study has evaluated changes in osteoclastogenesis markers (OPG and RANKL) with infliximab therapy. Miheller et al. [START_REF] Miheller | Changes of OPG and RANKL concentrations in Crohn's disease after infliximab therapy[END_REF] studied 29 refractory CD patients who were treated with infliximab at week 0, 2 and 6. In 19 cases CD was associated with fistulas. There were no postmenopausal females in this cohort, and all of these patients were steroid free for at least 1 month before the first infliximab infusion. No patients in this study had been treated with bisphosphonates or vitamin D. Six patients were on calcium supplements. Serum OC as a bone formation marker, serum beta-crosslaps (bCL) as a marker of bone resorption, serum OPG, and serum RANKL were measured before each course of infliximab therapy. BMD measurements were also performed at baseline in all patients using a DXA scan. In this study, four of 29 patients had osteoporosis and 14 of 29 had osteopenia. Serum levels of OC, the bone formation marker along with RANKL increased after infliximab therapy at week 6. Concentrations of bCL, the bone resorption marker along with OPG decreased at the same time. Femoral BMD correlated with baseline serum bCL and sRANKL concentrations (0.548; p<0.05 and 0.532; p<0.05). There were no significant correlations between bone remodeling markers (OC and bCL) and osteoclastogenesis markers (OPG and sRANKL) and lumbar BMD.

Whilst at first viewing the results they seem a little paradoxical the authors concluded that elevated OPG in CD could be a counter-regulatory response to inflammatory cytokines or may reflect T-cell activation. No control groups were analysed but patient results were sub-analysed based on whether patients were considered to be responders or non-responders. Responders were defined as having a decrease in the number of fistulas by half, or a declining CDAI by 70 points. Significant changes were only seen in the responder group.

ADALIMUMAB

Adalimumab is a human IgG1 monoclonal antibody specific for human TNF. Unlike, infliximab which requires an intravenous infusion, adalimumab is administered by subcutaneous injection. [START_REF] Plosker | Adalimumab; in Crohn's disease[END_REF] Adalimumab has been recently approved for the treatment of severe CD has been demonstrated in four pivotal studies. [START_REF] Hanauer | Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial[END_REF][START_REF] Colombel | Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial[END_REF][START_REF] Sandborn | Adalimumab induction therapy for Crohn disease previously treated with infliximab[END_REF][START_REF] Sandborn | Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial[END_REF] All these studies have shown adalimumab to be superior to placebo for inducing and maintaining remission.

Maintenance adalimumab therapy is administered as a subcutaneously every two weeks.

The approved induction dosing of adalimumab in CD is 160 mg given subcutaneously initially at week zero, 80 mg at week two, followed by a maintenance dose of 40 mg every other week beginning at week four. The drug is available in a single-use prefilled pen (HUMIRA Pen) or in a single-use, prefilled glass syringe. At present time, adalimumab is only licensed for use in CD patients.

ADALIMUMAB AND BONE METABOLISM IN IBD

To the best of our knowledge, there are currently no published data investigating the effect of adalimumab on bone metabolism in IBD patients. However, one such report exists studying BMD in a population of RA patients treated for 1 year with adalimumab. [START_REF] Wijbrandts | Bone mineral density in rheumatoid arthritis patients 1 year after adalimumab therapy: arrest of bone loss?[END_REF] In this study, fifty patients with active RA (defined as having a 28-joint disease activity score (DAS28) of ≥ 3.2) who started adalimumab treatment (40 mg subcutaneously every other week) were included in an open label prospective study. The BMD of both the lumbar spine (L1-L4) and left femoral neck was measured before treatment and after one year by DXA. Both disease activity at baseline (DAS28) and disease duration were inversely correlated with femoral neck BMD and lumbar spine BMD (p<0.05). Mean BMD of both lumbar spine and femur neck remained unchanged after one year of adalimumab therapy (+0.3% and +0.3%, respectively). The authors concluded that their result shows that with adalimumab therapy, progression of bone loss is halted. However, measurements of bone turnover were not performed in this study and there was no control group.

SUMMARY

To date, the data, available examining the effect of infliximab on bone metabolism in CD are limited. Moreover, there are considerable limitations with the studies which are in print. Firstly, the existing studies are not randomised. Secondly, the sample numbers included are small; with the largest being 71 patients. [START_REF] Franchimont | Rapid improvement of bone metabolism after infliximab treatment in Crohn's disease[END_REF] Therefore, meaningful analyses of various subgroups are restricted. Thirdly, the duration of follow up is by-and-large short, with longest being only for 14 weeks. [START_REF] Ryan | Effect of antitumour necrosis factor-α therapy on bone turnover in patients with active Crohn's disease: a prospective study[END_REF] Hence the long term effect of infliximab maintenance therapy on bone markers -which most likely to correspond to a meaningful effect on bone density or even fracture rates -is not currently known, however tantalising it might be to extrapolate from existing short term studies. Fourthly, only few studies to date, [START_REF] Franchimont | Rapid improvement of bone metabolism after infliximab treatment in Crohn's disease[END_REF][START_REF] Ryan | Effect of antitumour necrosis factor-α therapy on bone turnover in patients with active Crohn's disease: a prospective study[END_REF][START_REF] Abreu | Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn's disease[END_REF][START_REF] Miheller | Infliximab therapy improves the bone metabolism in fistulizing Crohn's disease[END_REF][START_REF] Miheller | Changes of OPG and RANKL concentrations in Crohn's disease after infliximab therapy[END_REF] have looked to some extent at differences in bone marker changes between responders and non-responders. The benefits on bone metabolism seen with anti-TNF therapy in those who respond (either clinically or biologically) compared to nonresponder show no clear cut differences. Two studies failed to show any difference between the two groups. [START_REF] Franchimont | Rapid improvement of bone metabolism after infliximab treatment in Crohn's disease[END_REF][START_REF] Abreu | Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn's disease[END_REF] Another study, [START_REF] Ryan | Effect of antitumour necrosis factor-α therapy on bone turnover in patients with active Crohn's disease: a prospective study[END_REF] showed a trend towards a greater increase in both bone formation markers and a greater decrease in bone resorption markers in responders compared with non-responders, but this did not reach statistical significance.

In two of the remaining studies [START_REF] Miheller | Infliximab therapy improves the bone metabolism in fistulizing Crohn's disease[END_REF][START_REF] Miheller | Changes of OPG and RANKL concentrations in Crohn's disease after infliximab therapy[END_REF] statistical significance was recorded only in the responder groups suggesting biological response may play a role. Hence the question arises -is it simply the neutralization of TNF-α that is critical if in fact these drugs have a role? Or is it that those whose disease activity improves secondary to suppression of TNF-α mediated inflammation are the ones whose bone markers improves? At the moment, the answer is not clear although the evidence leans towards the latter possibility. This is a crucial question as, if this latter is true, then it is likely that improvements in bone markers might be not specific to anti-TNF agents but rather are simply sequelae of reducing the inflammatory response and hence other medications such as thiopurines or methotrexate might well have similar effects. Finally, confounding factors that could affect the outcome of changes seen in bone markers such as the age, gender, current smoking, disease duration, disease location, current steroid treatment, number of infliximab infusions, and steroid weaning were only examined in a number of studies. 57,61,62 Given the limitations outlined above, at most with the currently available data, one can conclude that infliximab appears to positively impact on bone metabolism in CD patients, but it is as yet unclear whether this is specific to the anti-TNF-α therapy alone or if it is secondary to reducing active inflammation and the associated pro-inflammatory cytokines. The beneficial effect does seem to be heterogeneous in aetiology and to vary from patient to patient. Primarily, the main beneficial effect appears to be related to an increase in bone formation although a decrease in bone resorption also appears to play a role in some patients. The effects seem to be independent on response or non-response to treatment based on clinical score, although in two studies [START_REF] Miheller | Infliximab therapy improves the bone metabolism in fistulizing Crohn's disease[END_REF][START_REF] Miheller | Changes of OPG and RANKL concentrations in Crohn's disease after infliximab therapy[END_REF] the beneficial changes were only statistically significant in the responder groups. Furthermore, the beneficial effects on bone metabolism appear to be independent of steroid therapy. Case-control studies (which are few) indicated that CD patients in general had lower bone formation markers It's likely that several different mechanisms play a role in this positive effect of infliximab on bone metabolism. Firstly, reduction of TNF-α, which has been shown to have a beneficial effect on bone metabolism in vitro, might also play a role in vivo. [START_REF] Zou | Tumour necrosis factor-alpha mediates RANK ligand stimulation of osteoclast differentiation by an autocrine mechanism[END_REF][START_REF] Abu-Amer | Tumour necrosis factor receptors types 1 and 2 differentially regulate osteoclastogenesis[END_REF] Secondly, reduction of other pro-inflammatory cytokines known to cause bone loss, such as IL-6 and IL-1β 50 by infliximab [START_REF] Oelzner | Relationship between soluble markers of immune activation and bone turnover in post-menopausal women with rheumatoid arthritis[END_REF][START_REF] Sylvester | Effect of Crohn's disease on bone metabolism in vitro: a role for interleukin-6[END_REF] is likely to play a pivotal role. A third possible mechanism is that improvement in general well being and physical activity might also improve net bone formation. Fourthly, by reducing gut inflammation, infliximab might also improve bone metabolism indirectly by increasing absorption of crucial bone nutrients such as Vitamin D and calcium.

F o r P e e r R e v i e w

F o r P e e r R e v i e w

Abreu et al [START_REF] Abreu | Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn's disease[END_REF] [START_REF] Abreu | Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn's disease[END_REF] and reduced disease activity. [START_REF] Miheller | Infliximab therapy improves the bone metabolism in fistulizing Crohn's disease[END_REF][START_REF] Miheller | Changes of OPG and RANKL concentrations in Crohn's disease after infliximab therapy[END_REF] However, the beneficial effects seen with infliximab seem to be independent of steroid weaning. [START_REF] Franchimont | Rapid improvement of bone metabolism after infliximab treatment in Crohn's disease[END_REF][START_REF] Abreu | Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn's disease[END_REF][START_REF] Bernstein | Maintenance infliximab treatment is associated with improved bone mineral density in Crohn's disease[END_REF] To date, studies looking at the effects of anti-TNF-α therapy on bone metabolism in IBD are limited, and have only evaluated the role of infliximab on bone metabolism in CD patients. A number of major limitations exist, with published studies as outlined above, hence the apparent beneficial effects seen with infliximab on bone metabolism in these studies require further validation. No studies have yet evaluated the effects of adalimumab therapy on bone metabolism in IBD or the effect of anti-TNF α therapy in UC patients. Furthermore, currently available studies have only been carried out for a relatively short term, with the longest being for 14 weeks. [START_REF] Ryan | Effect of antitumour necrosis factor-α therapy on bone turnover in patients with active Crohn's disease: a prospective study[END_REF] Hence the long term effect of maintenance therapy with anti-TNF-α on bone metabolism in IBD patients is not yet known. Moreover, the effects of these therapies on bone cells have not yet been studied. This is crucial to understanding the direct effect of anti-TNF-α on bone cells. Long term studies are also needed to compare changes in cytokines, osteoclastogenesis markers

F o r P e e r R e v i e w

(

Figure 1 :

 1 Figure 1: Effects of various cytokines on bone metabolism.

  healing and elimination of corticosteroid use. Despite its now widespread use in inflammatory disorders, only limited data exist on the role of infliximab on the bone metabolism in IBD. Furthermore most of the published data pertain to small cohorts of patients.

  studied 71 infliximab naïve CD patients treated with infliximab (5mg/kg) for refractory CD and compared their results to 68 matched healthy controls. The study included 21 fistulizing refractory CD patients and 50 luminal refractory CD patients. Patients were treated with a single infusion of 5mg/kg infliximab at baseline for refractory luminal disease and with three infusions of 5mg/kg infliximab at baseline, week 2 and week 6 for refractory fistulizing disease. Serum bone formation markers -bone alkaline phosphatase (b-ALP), osteocalcin (OC) and pro-collagen type 1 N propeptide (P1NP), and the serum carboxyterminal telopeptide (sCTx); a bone resorption marker were measured at baseline and 8 weeks after completion of infliximab treatment (week 8 for refractory luminal CD and week 14 for refractory fistulizing CD). Clinical activity of the disease based of Crohn's Disease Activity Index (CDAI) score and C-reactive protein (CRP) levels were also measured in this study at baseline and 4 weeks after completion of therapy as a marker of biological response. In this study, the authors observed that the serum concentration of the bone formation markers; (b-ALP, OC and P1NP) were lower in CD before infliximab treatment than in healthy controls while they return to normal levels

  post single infliximab infusion. In this study, infliximab infusion led to a significant increase in both markers of bone formation, b-ALP (p=0.022) and OC (p=0.008). Levels of both bone formation markers remained significantly increased even at 4 months post treatment. No significant change in serum N-telopeptide (sNTx) was observed although at 4 months post treatment, levels were lower than at baseline. Of particular interest, the benefit seen on bone metabolism with infliximab treatment appeared to occur independently of the clinical response in terms of effect on CD activity; however the trend of increase in both bone formation markers and decrease in bone resorption marker was greater in responders compared with non-responders.

  increase in serum calcium (p=0.034) at week 4. No significant changes in serum cytokine measurements from baseline to week 4 were noted. As mentioned

  To date, few published studies have examined the effect of infliximab on actual bone loss in CD patients by measurement of BMD. A retrospective cohort analysis was performed by Pazianas et al.[START_REF] Pazianas | The effect of anti-TNF-alpha therapy on spinal bone mineral density in patients with Crohn's disease[END_REF] on 61 patients with CD and low BMD as measured by DXA scans. 23 patients were on infliximab and 36 patients were on bisphosphonates.

  data from 15 patients with CD who had received treatment with infliximab for the first time and who underwent DXA before and during infliximab treatment were compared with 30 CD patients who had never received treatment with infliximab and who had two DXA evaluations at least 12 months apart. Certain confounding factors such as age, sex, age at diagnosis, years of disease, final weight, weight change, bisphosphonate use, corticosteroids use and disease activity were analysed in this study. Patients in this study received infliximab (5m/kg) at intervals

  The clinical efficacy and safety of adalimumab in patients with moderate to

  resorption markers as compared to healthy subjects and that infliximab therapy reverses this balance. Patients who received infliximab have also been shown to increase BMD during therapy.

Table 1 :

 1 Summary of published articles looking at the effect of infliximab on bone metabolism in IBD patients.

	Bernstein et al	46	CD	No	Yes	Maintenance	No	No	Yes	No	No	At baseline	Improved BMD
	63					therapy						and 1 year	after 1 year in the
						every 6-8						post	lumbar spine
						weeks for 1						infliximab	(p=0.002), femoral
						year						treatment	trochanter (p=0.03)
													and at femoral neck
													(p=0.001) and this
													was independent of
													concurrent
													administration of
													glucocorticoids,
													calcium
													supplementation or
													changes in CRP.
	Miheller et al	29	CD (19	No	Responders	3	Yes (OC)	Yes	Yes (only	No	Yes	At baseline,	Serum levels of OC
	64		fistulizing)		vs.			(b-CL)	at			week 2 and	and RANKL
					Non				baseline)			week 6 post	increased, while
					responders							infliximab	bCL and OPG
													decreased at week
													6. Femoral BMD
													correlated with
													basic serum bCL
													and sRANKL.

  OPG and RANKL), bone nutrients (PTH and vitamin D) and most importantly BMD, to fully understand the mechanisms involved. Finally, what happens to the beneficial effects seen on bone metabolism in IBD patients following cessation of anti-TNF-α therapy is not known. Properly controlled long term trials are necessary to fully evaluate the effects of TNF blockers in this regard. Hence to conclude; larger, longer, randomized controlled trials are needed to address the most important question of all; i.e. "Does anti-TNF-α have a role in the treatment of osteoporosis?" ACKNOWLEDGMENT Declaration of personal interest: Prof. Colm O'Morain is on the international advisory board of Abbott, Schering Plough and Shire pharmaceutical companies. Compston JE. Detection of osteoporosis in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 1997; 9: 931-3. 41. Hofbauer LC, Dunstan CR, Spelsberg TC, et al. Osteoprotegerin production by human osteoblast lineage cells is stimulated by vitamin D, bone morphogenetic

	F o F o F o study using a human RA/SCID mouse chimera. Rheumatology (Oxford) 2002; 41: 9. F o F o F o F o F o F o F o F o
	r r r r r r r r r r r
	P Declaration of funding interests: None. P P P P P P P P P P
	e e r e e r e e r e e r e e r e e r e e r e e r e e r e e r e e r
	R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w

209x297mm (150 x 150 DPI)


Dr Ellen Kuhlmann
email: e.c.kuhlmann@bath.ac.uk

Dr Viola Burau

Dr Christa Larsen
email: c.larsen@em.uni-frankfurt.de

Dr Roman Andrzej Lewandowski

Dr Christos Lionis
email: lionis@galinos.soc.med.uoc.gr

Dr José Repullo
email: jrepullo@isciii.es

Medicine and management in European healthcare systems: how do they matter in the control of clinical practice?

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Ellen Kuhlmann, Viola Burau, Christa Larsen, Roman Lewandowski, Christos Lionis, and José Repullo During recent years, management has brought tighter controls into all areas of clinical practice, responding mainly to financial shortages coupled with increasing public demand for quality and safety of care. Management is not simply expanding and creating new roles for non-clinical managers, but doctors, too, are charged with managerial responsibilities. Consequently, the boundaries between medicine and management are no longer sustainable and this, in turn, may have complex implications for control and leadership in clinical practice.

The notion of control, as defined here, includes a wide range of bureaucratic measures and managerial tools, such as target setting; performance indicators; and interventions for which doctors have oversight, such as evidence-based clinical guidelines or continuing professional development. The pros and cons of managerialist regimes in clinical practice, as well as the challenges of managing doctors, are widely debated. A growing body of literature reveals the problematic outcomes of new managerial tools, which include standardisation, evidencebased medicine, and target setting, as well as financial incentives and new managerial roles [START_REF] Galloway | The effects of targets on working in UK emergency departments -a personal perspective[END_REF][START_REF] Knorring | Managers' perceptions of the manager role in relation to physicians: a qualitative interview study of the top managers in Swedish healthcare[END_REF][START_REF] Mcdonald | Incentives and control in primary health care: findings from English pay-for-performance case studies[END_REF][START_REF] Minhas | Hitting the target and missing the point?[END_REF]Timmermans and Amelung, 2009).

But what is next in exploring how the transformations in medicine and management matter in the control of clinical practice? If medicine and management are no longer sitting on 'different planets', it is time to move beyond the 'either-or' questions of professional or managerialist controls and, instead, explore the connections. There is an urgent need to develop and implement models that are able to effectively connect professional self-governing and management-based controls in clinical practice. The way forward is informed by rich casestudy material from Denmark, England, Germany, Greece, Poland, and Spain. Research was carried out by the authors and includes analyses of policy documents and primary and secondary sources.

Where are we now?

Across European healthcare systems the attempts towards tighter control of clinical practice seek to improve both cost-efficiency and quality of care. Thus, two key areas in need of control can be identified:

• Control of budgets: In many countries, this has taken the form of DRGs, and the focus is consequently on the organisation. In addition, pay-for-performance schemes and other financial incentives that are more directed at individual professionals are also relevant;

Variations on the theme

In Denmark, quality standards have evolved from the bottom up, beginning in hospitals. This has been further developed by a national programme and includes accreditation processes of self-evaluation by the organisation and external evaluation by a professional accreditation association. Consequently, managerial and professional controls are more integrated, but the balance is shifting from the individual professional towards organisation-based criteria of quality control.

• Control is linked to integrated approaches but focuses more on the organisation than on individual doctors.

The NHS in England counts as a prime example of the implementation of new managerial regimes. Within this context, target setting and standardisation are key to improving both the quality of care and budget control. Doctors have widely adopted these strategies without significant conflict, and individual professionals and organisations may collaborate towards transformations of the content of targets and standards.

• Control focuses more on the organisation together with strong centralised controls and some individual incentives.

Managerial controls in Germany focus mainly on doctors, and in turn, doctors use the new managerialism strategically in order to reinforce their self-governing capacities. Examples of this include the introduction of clinical guidelines and continuing professional development (CPD) as a mandatory requirement by law. In this situation, existing working groups established by doctors ('quality circles') were assigned to approve CPD, which subsequently expanded rapidly. This self-governing professional control co-exists with a number of new budget controls, such as DRGs, that are more focused on the organisation.

• Control focuses more on individual doctors, but budget controls shift the focus towards the organisation. • Control is more focused on individual doctors and self-governance than on organisational innovation, but it co-exists with both market control and more centralised state controls.

Efforts towards clinical management have been reinforced in

Restructuring of hospital management in Spain primarily includes financial management, such as the management contracts linked to a DRG system. This restructuring, however, is accompanied by organisational change in the top management and the medical hierarchy as well as new efforts to rebuild medical professionalism towards leadership. There are also innovations in management, such as the introduction of a pilot scheme with more integrated management or new forms of clinical leadership that improve doctors' budget responsibility.

• Managerial and professional controls are connected and re-connected in different ways, including more integrated management and other organisational innovations.

What next in researching control?

The case study material reveals that no uniform model of control emerges across European healthcare systems. At the same time, we can observe in all countries a co-existence of selfgoverning professional controls and managerial controls that may be targeted at individuals and organisations and may also be linked with markets and hierarchical state controls. What matters in the control of clinical practice in European healthcare systems is the specific composition of a set of controls and how they are connected and re-connected and may create new more 'hybrid' patterns of controls.

These emergent patterns of control may be linked to the institutional framings of medicine and management to some degree, as shown in our examples, but other conditions, including the subject area of control and the time-specific frame, are also relevant and might even override the institutions' importance. Consequently, researching control presents new challenges. First, the new connectedness of medicine and management calls for a more dynamic and reflective theoretical approach to control that moves beyond the assumption of contradicting logics; this also brings a transformative potential of professionalism and 'hybridization' of control into perspective [START_REF] Kirkpatrick | Medicine and management in a comparative perspective: the cases of England and Denmark[END_REF][START_REF] Plochg | Transforming medical professionalism to fit changing health needs[END_REF]. Second, comparative research draws heavily on typologies and indicators that were created at the level of health systems [START_REF] Wendt | A conceptual framework of health system typologies[END_REF]. But the management of medical performance focuses on organisations and professional groups, and therefore calls for new approaches, including qualitative methods, meso-level comparison, and actor-centred dynamics.

We

  in European healthcare systems: how do they matter in the control of clinical practice?

  These examples highlight the fact that medicine and management are 'twin forces', and as such indicative of new emergent controls. In both areas, the self-governing professional controls and more individualised strategies co-exist with tighter organisational controls. What matters is the relative balance between the two and the specific composition of the toolset of controls. Some illustrative examples reveal different patterns of control in European countries.

	all countries, primarily nurturing individual approaches and the self-governing
	professional controls of doctors.
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• Control of quality and safety of patients: Examples of this type of control are diverse and may even include organisational restructuring and the creation of new institutions. But evidence-based medicine and clinical guidelines are key strategies in

  suggest exploring the emergent patterns of control more systematically by focusing on the organisational settings in different European healthcare states and the actors involved in the transformations. Organisations are the 'switchboards' of clinical practice, where 'medicine meets management' and control is made and re-made. Using cross-country comparison adds further value by filtering out how organisational settings matter in relation to the wider architecture of healthcare states. Finally, this will help to outline future avenues for 'medicine and management' that are likely to create more sustainable and integrated controls in clinical practice.

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Acknowledgements

This article draws on research carried out by Working Group 2 (Control) of the 7th EU Framework Programme COST Action IS0903 "Enhancing the Role of Medicine in the Management of European Health Systems: Implications for Control, Innovation and User Voice", chaired by Professor Ian Kirkpatrick. For further information please visit: http://www.cihm.leeds.ac.uk/new/cost/ The authors declare that they have no conflict of interest. Addresses Dr Ellen Kuhlmann University of Bath, UK Email: e.c.kuhlmann@bath.ac.uk Dr Viola Burau University of Aarhus, Denmark Email: viola@au.dk Dr Christa Larsen Goethe University Frankfurt, Germany Email: c.larsen@em.uni-frankfurt.de Prof Dr Roman Lewandowski Voivodeship Rehabilitation Hospital for Children in Ameryka, Poland Email: rlewando@wp.pl Prof Dr Christos Lionis University of Crete, School of Medicine, Greece Email: lionis@galinos.soc.med.uoc.gr Dr José Repullo Institute for Health Carlos III, Madrid , Spain Email: jrepullo@isciii.es