Available online http://arthritis-research.com/content/7/3/R625
`
`Vol 7 No 3Research article
`Open Access
`Effect of risedronate on joint structure and symptoms of knee
`osteoarthritis: results of the BRISK randomized, controlled trial
`[ISRCTN01928173]
`Tim D Spector1, Philip G Conaghan2, J Christopher Buckland-Wright3, Patrick Garnero4,
`Gary A Cline5, John F Beary5, David J Valent5 and Joan M Meyer5
`
`1Twin Research & Genetic Epidemiology Unit, St Thomas' Hospital, London, UK
`2Academic Unit of Musculoskeletal Disease, University of Leeds, UK
`3King's College London, School of Biomedical Sciences, London, UK
`4SYNARC, Lyon, France
`5Procter & Gamble Pharmaceuticals, Mason, OH, USA
`
`Corresponding author: Tim D Spector, tim.spector@kcl.ac.uk
`
`Received: 20 Dec 2004 Revisions requested: 20 Jan 2005 Revisions received: 1 Feb 2005 Accepted: 15 Feb 2005 Published: 24 Mar 2005
`
`Arthritis Research & Therapy 2005, 7:R625-R633 (DOI 10.1186/ar1716)
`This article is online at: http://arthritis-research.com/content/7/3/R625
`© 2005 Spector et al.; licensee BioMed Central Ltd.
`This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/
`2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
`
`Abstract
`
`To determine the efficacy and safety of risedronate in patients
`with knee osteoarthritis (OA), the British study of risedronate in
`structure and symptoms of knee OA (BRISK), a 1-year
`prospective, double-blind, placebo-controlled study, enrolled
`patients (40–80 years of age) with mild to moderate OA of the
`medial compartment of the knee. The primary aims were to
`detect differences in symptoms and function. Patients were
`randomized to once-daily risedronate (5 mg or 15 mg) or
`placebo. Radiographs were taken at baseline and 1 year for
`assessment of
`joint-space width using a standardized
`radiographic method with fluoroscopic positioning of the joint.
`Pain, function, and stiffness were assessed using the Western
`Ontario and McMaster Universities (WOMAC) OA index. The
`patient global assessment and use of walking aids were
`measured and bone and cartilage markers were assessed. The
`intention-to-treat population consisted of 284 patients. Those
`receiving risedronate at 15 mg showed improvement of the
`
`WOMAC index, particularly of physical function, significant
`improvement of the patient global assessment (P < 0.001), and
`decreased use of walking aids relative to patients receiving the
`placebo (P = 0.009). A trend towards attenuation of joint-space
`narrowing was observed in the group receiving 15 mg
`risedronate. Eight percent (n = 7) of patients receiving placebo
`and 4% (n = 4) of patients receiving 5 mg risedronate exhibited
`detectable progression of disease (joint-space width ≥ 25% or
`≥ 0.75 mm) versus 1% (n = 1) of patients receiving 15 mg
`risedronate (P = 0.067). Risedronate (15 mg) significantly
`reduced markers of cartilage degradation and bone resorption.
`Both doses of risedronate were well tolerated. In this study,
`clear trends towards improvement were observed in both joint
`structure and symptoms in patients with primary knee OA
`treated with risedronate.
`
`Introduction
`Osteoarthritis (OA) is a chronic, progressive disease that par-
`ticularly affects weight-bearing joints such as hips and knees.
`The entire joint is affected by a complex combination of degra-
`dative and reparative processes, which alter the anatomy and
`function of articular cartilage, subchondral bone, and other
`joint tissues. Of the joints affected, knee OA in particular is a
`
`major cause of morbidity, often resulting in knee replacement
`[1-3]. Moreover, costs associated with OA are high – in the
`USA alone in 1991, the annual cost of knee replacements was
`estimated to be more than one billion dollars [4]. OA is nor-
`mally the result of an interplay between systemic (e.g. age,
`obesity) and local (e.g. sports injury) factors that affect the
`joints of the body. Radiographic evidence has shown that joint-
`
`AE = adverse event; BRISK = British Study of Risedronate in Structure and Symptoms of Knee OA; CTX-II = C-terminal crosslinking telopeptide of
`type II collagen; GI = gastrointestinal; ITT = intention-to-treat; JSW = joint-space width; NTX-I = N-terminal crosslinking telopeptide of type I collagen;
`OA = osteoarthritis; PGA = patient global assessment; VAS = visual analogue scale; WOMAC = Western Ontario and McMaster Universities [OA
`index].
`
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`space narrowing (a surrogate marker for articular cartilage
`[5]), sclerosis of the subchondral bone, and the presence of
`osteophytes are typical structural features of OA.
`
`Current therapies for OA are largely aimed at providing symp-
`tom relief, and include a wide range of analgesics (e.g. nons-
`teroidal anti-inflammatory drugs and cyclooxygenase-2
`agents). In contrast, only limited data are available about ther-
`apies that modify the course of the disease or affect joint struc-
`ture. Historically, OA has been considered a disease of the
`cartilage, but more recent evidence suggests that subchron-
`dral bone is also involved in the pathogenesis, in both disease
`initiation and progression. For example, increased local bone
`turnover, decreased bone mineral content and stiffness, and
`decreased trabecular numbers have been observed in OA
`subchondral bone structure compared with normal bone [6-8].
`There is an increased level of interest in subchondral bone as
`a therapeutic OA target, and, in particular, the possibility that
`drugs affecting bone metabolism might alter the progression
`of knee and hip OA.
`
`The Duncan-Hartley guinea pig model is a widely used spon-
`taneous model of OA progression [9]. Several recent OA
`studies have evaluated this model for the effects of the antire-
`sorptive agents bisphosphonates. For example, a comparative
`analysis of multiple bisphosphonates showed that only the
`group of nitrogen-containing bisphosphonates with pyridinyl
`sidechains demonstrated significant effects on the cartilage,
`although not all of these proved effective [10]. In a separate
`study using the guinea pig OA model, the pyridinyl bisphos-
`phonate risedronate was shown to slow disease progression,
`as measured by the size and severity of cartilage lesions and
`the size of osteophytes, by up to 40% [11]. Based upon these
`preclinical studies, a clinical trial was performed in order to
`evaluate the effects of risedronate in patients with mild to mod-
`erate knee OA. The primary end points were changes in symp-
`toms and function, with secondary end points of changes in
`joint structure or in markers of joint structure.
`
`Materials and methods
`Study design and selection of patients
`The British Study of Risedronate in Structure and Symptoms
`of Knee OA (BRISK) was a 1-year prospective, double-blind,
`placebo-controlled study conducted in 10 centres in the UK.
`Male and female subjects aged 40 to 80 years with mild to
`moderate medial-compartment knee OA, diagnosed accord-
`ing to the clinical and radiological criteria of the American Col-
`lege of Rheumatology [12], were recruited into the trial.
`
`OA in at least one knee, designated the signal knee, was
`required to meet the following clinical and radiographic inclu-
`sion criteria. Clinical inclusion criteria were the presence of
`daily knee pain for at least 1 month out of the 3 months pre-
`ceding the study, with at least one of the following: age >50
`years, morning knee stiffness of <30 minutes, or knee crepitus.
`
`The radiographic criteria for inclusion were a joint-space width
`(JSW) of 2 to 4 mm in the medial tibiofemoral compartment in
`the semiflexed anterior–posterior (AP) view of the signal knee
`and a narrower width than in the lateral compartment of the
`same knee. Patients were also required to have at least one
`osteophyte in either the medial or the lateral compartment of
`the tibiofemoral joint. Major exclusion criteria were the pres-
`ence of rheumatic diseases that could be responsible for sec-
`ondary OA; use of intra-articular hyaluronic acid in the signal
`knee; knee injury or diagnostic arthroscopy of the signal knee
`in the 6 months preceding enrollment; a history of knee sur-
`gery (including arthroscopy requiring an incision of internal
`joint components) in the signal knee at any time; intra-articular
`corticosteroids in the 3 months preceding enrollment; the
`presence of non-OA causes of knee pain in the signal knee
`(e.g. anserine bursitis, fibromyalgia, or osteonecrosis); and the
`use of bisphosphonates within the 12 months preceding
`enrollment.
`
`The subjects gave their written, informed consent before
`entering the study, which was conducted in accordance with
`the International Conference on Harmonization (ICH) guide-
`lines for Good Clinical Practice (GCP) and was approved by
`the UK Multicentre Research Ethical Committee (MREC).
`
`Treatment assignment
`The subjects were randomly assigned in a 1:1:1 ratio to one of
`three arms to receive risedronate at 5 mg or 15 mg or placebo
`once daily for 1 year. Before randomization, patients were
`stratified according to their current use of oestrogen or a
`selective oestrogen receptor modulator.
`
`The subjects were instructed to take their study medication
`with at least 120 mL of water, 30 minutes before breakfast, or,
`if the medication was taken later in the day, at least 2 hours
`before or after food intake and at least 30 minutes before bed-
`time. They were instructed to take their study medication while
`they were upright and not to lie down for at least 30 minutes
`afterwards.
`
`Symptom outcome measures
`The outcome instrument for evaluation of risedronate efficacy
`on symptoms of OA was the Western Ontario and McMaster
`Universities (WOMAC) OA index [13]. The visual analogue
`scale (VAS) of the index was used, in which patients assessed
`each question using a 100-mm scale, with a higher score rep-
`resenting greater symptom severity. The total index score for
`the signal knee corresponded to the weighted composite of
`the 24 question scores standardized to a 100-point scale.
`Scores were also determined for the subscales of pain (5
`questions), stiffness (2 questions), and physical function (17
`questions). Other symptom outcome measures included the
`patient global assessment (PGA) of disease, consumption of
`pain medication, and the use of walking aids. For the PGA,
`patients answered the following question using a VAS:
`
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`"Considering all the ways your OA affects you, how have you
`been in the last 48 hours?" Patients marked values on a scale
`from 0 to 100 mm.
`
`A step-down reduction in the use of pain medication was
`effected 5 days before all symptom evaluations. Patients were
`provided with approximately 30 tablets each of paracetamol
`(500 mg) and diclofenac (50 mg) to be used as the only pain
`medication 3 to 5 days before the baseline assessment and at
`visits at months 3, 6, and 12 (the exit visit). No pain medica-
`tions were to be used 2 days before the scheduled evaluation
`date or on the day itself, with the exception of low-dose acetyl-
`salicylic acid (<350 mg/day) for cardiac protection. Rescue
`analgesia was permitted during the study except for the 2-day
`washout period before each visit.
`
`Structure outcome measures
`The outcome measure for assessment of joint structural
`changes was the mean change from baseline values in mini-
`mum JSW of the medial compartment of the knee. Radio-
`graphs of the knee were taken at baseline and at 1 year using
`a standardized radiographic method with fluoroscopic posi-
`tioning of the joint in a semiflexed position [14,15]. By the use
`of this technique, the anterior and posterior rims of the tibia
`were aligned (to within 1 mm) for reproducible positioning.
`Radiographs were subjected to extensive quality control at the
`radiographic facility before dispatch to the Central Analysis
`Center [15]. Radiographs were read centrally and their quality
`control was rechecked before computer software was used to
`obtain the radiographic magnification. This was determined
`from measurement of a metal ball placed at the head of the fib-
`ula at the time of radiography and was used to adjust the com-
`puterized measurement obtained of the minimum medial
`compartment JSW [15]. The test–retest standard deviation of
`the difference between radiographs taken 2 days apart for this
`technique was approximately 0.2 mm, based upon repeat
`measurements in 199 subjects [15]. A retrospective analysis
`was performed taking into account the precision of the instru-
`ment. Retrospectively, clinically meaningful disease progres-
`sion was defined as joint-space narrowing of ≥ 0.75 mm or a
`≥ 25% loss from baseline values. The ≥ 0.75-mm value is
`almost four times the 0.2-mm standard deviation observed for
`the x-ray method.
`
`Structure–symptom relation
`The relation between knee OA symptoms and radiographic
`joint-space narrowing was assessed retrospectively; the mean
`change in symptom scores between baseline to month 12 of
`the total WOMAC score and pain and function subscales was
`compared with the magnitude of change in JSW over the
`study period.
`
`Bone and cartilage markers
`Early-morning fasting urine and serum samples were collected
`at baseline and at months 3, 6, and 12 for assessment of mark-
`
`Available online http://arthritis-research.com/content/7/3/R625
`
`ers of bone and cartilage turnover. Bone resorption was
`assessed by measurement of urinary levels of the N-terminal
`crosslinking telopeptide of type I collagen (NTX-I, Osteomark;
`OrthoClinical Diagnostics, High Wycombe, Bucks, UK) [16].
`Bone formation was assessed by measurement of bone-spe-
`cific serum alkaline phosphatase (Ostase, Beckman-Coulter,
`San Diego, CA, USA) [17] and cartilage degradation was
`assessed by measurement of urinary levels of C-terminal
`crosslinking telopeptide of type II collagen (CTX-II, Cartilaps,
`Nordic Bioscience, Herlev, Denmark) [18]. The intra-assay
`and interassay coefficients of variation were lower than 10%.
`
`Evaluation of safety
`recorded
`(AEs) were
`Patient-reported adverse events
`throughout the study. AEs were categorized using the Coding
`Symbols for Thesaurus of Adverse Reaction Terms (COS-
`TART®) coding dictionary. Clinical laboratory measurements
`for safety monitoring were made throughout the study. Serious
`AEs were defined as any that resulted in death; were life
`threatening; resulted in hospitalization; resulted in persistent
`or significant disability or incapacity; or were judged to be
`medically significant.
`
`Upper-GI AEs included the following symptoms and condi-
`tions: substernal chest pain; duodenitis; dyspepsia; dys-
`phagia; oesophagitis; gastritis; bleeding gastritis; gastro-
`oesophageal reflux; oesophageal bleeding; GI bleeding; hae-
`matemesis; melena; abdominal pain; ulcers (duodenal,
`oesophageal, peptic, gastric); bleeding ulcers (duodenal, pep-
`tic, gastric); perforated ulcers (duodenal, peptic, gastric); per-
`forated and bleeding ulcers (duodenal, peptic, gastric); and
`reactivated ulcers (duodenal, peptic, gastric).
`
`Statistical analysis
`To ensure 80% power to detect a 20% effect of risedronate
`treatment versus placebo with respect to pain modification
`(quantified according to the WOMAC pain subscale, assum-
`ing a standard deviation of 70 mm on a 0- to 500-mm scale),
`a 1-year dropout rate of 20%, and a type I error rate of 5%
`without adjustment for two comparisons with placebo control,
`the sample size requirement was 100 patients per treatment
`group.
`
`Analyses were undertaken on the intention-to-treat (ITT) pop-
`ulation. This was defined as all randomized patients who
`received at least one dose of study medication. All statistical
`analyses were performed using a two-sided statistical test
`with a type-I-error rate of 0.05. Baseline characteristics were
`compared using Fisher's exact test for categorical variables
`and the Kruskal–Wallis test for continuous variables. Extended
`Mantel–Haenszel tests with pooled centres as strata were
`used for end points with categorical responses. Analysis of
`variance (ANOVA) methods were used. Symptom analyses
`were adjusted for baseline value (PGA < WOMAC total or
`subscale value, as appropriate), pooled study centres,
`
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`Arthritis Research & Therapy Vol 7 No 3 Spector et al.
`
`Figure 1
`
`Assessed for eligibility
`(n = 1140)
`
`Randomized (n = 285)
`
`Did not meet inclusion criteria (n = 748)
`Refused to participate (n = 29)
`Other (n = 78)
`
`Placebo
`(n = 99)
`Received study
`dose (n = 98)
`
`Risedronate 5 mg/d
`(n = 96)
`Received study
`dose (n = 96)
`
`Risedronate 15 mg/d
`(n = 90)
`
`Received study
`dose (n = 90)
`
`Lost to follow up (n = 1)
`Adverse event (n = 12)
`Noncompliance with protocol (n = 1)
`Patient reconsidered/withdrew
`consent (n = 5)
`
`Lost to follow up (n = 2)
`Did not meet enrollment (n = 2)
`Adverse event (n = 7)
`Noncompliance with protocol (n = 2)
`Patient reconsidered/withdrew
`consent (n = 3)
`
`Lost to follow up (n = 1)
`Adverse event (n = 10)
`Noncompliance with protocol (n = 2)
`Patient reconsidered/withdrew
`consent (n = 6)
`
`Placebo
`completed
`(n = 80)
`
`Risedronate 5 mg/d
`completed
`(n = 80)
`
`Risedronate 15 mg/d
`completed
`(n = 71)
`
`
`
`Disposition of patients with knee osteoarthritis in a controlled, randomized trial of risedronateDisposition of patients with knee osteoarthritis in a controlled, randomized trial of risedronate.
`
`baseline use of oestrogen or selective oestrogen receptor
`modulators, gender, age, body mass index, and baseline JSW.
`Mean JSW analyses were adjusted for pooled study centres,
`baseline use of oestrogen or selective oestrogen receptor
`modulators, gender, age, body mass index, and baseline JSW
`as covariates. Each risedronate group was compared with the
`placebo group. For walking aids, the percentages were com-
`pared with placebo using the Cochran–Mantel–Haenszel test
`after adjusting for pooled centres. Individual AEs and the pro-
`portion of clinically meaningful JSW progressors were ana-
`lysed using Fisher's exact test.
`
`The WOMAC scores were calculated in accordance with the
`WOMAC User's Guide [19]. The total scores were composed
`of subscales weighted as follows: pain = 42%, stiffness =
`21%, and function = 37% [19]. For each subscale, the
`reported response was the patient's average. If at least two
`pain items, both stiffness items, or more than four physical
`function items were omitted, or if the patient's response was
`unclear, the items were regarded as invalid and the relevant
`subscale was not included.
`
`Results
`Patients
`Two hundred and eighty-five patients were considered eligible
`for the study and were randomized to treatment. Of these, 284
`received at least one dose of study medication and were
`included in the ITT population, and 231 (81%) completed the
`study (placebo, n = 80; risedronate at 5 mg, n = 80; risedro-
`nate at 15 mg, n = 71) (Fig. 1). The number of patients who
`completed the study and the reasons for withdrawal were sim-
`ilar across treatment groups. Table 1 shows the baseline char-
`acteristics for the ITT population. These were similar between
`
`treatment groups; the average age of the patients was 63.3
`years. There were no significant differences in the use of con-
`comitant analgesics between treatment groups. Patients'
`compliance during study treatment, based on pill counts, was
`≥ 83% and was comparable in the three treatment groups.
`
`Symptom outcome measures
`There was an improvement from baseline values in the symp-
`tom outcome measure of total WOMAC scores (weighted and
`unweighted) (unweighted not shown) and the subscales for all
`treatment groups (Fig. 2). The group given risedronate at 15
`mg showed a trend towards improvement from baseline val-
`ues, although the differences were not statistically significant
`(P values from 0.10 to 0.33).
`
`Assessment of PGAs revealed a statistically significant
`improvement with risedronate at 15 mg compared with pla-
`cebo at 1 year (-19.4 for risedronate at 15 mg versus -5.7 for
`placebo, P < 0.001) (Fig. 3). Although all treatment groups
`showed a significant improvement from baseline values at 3
`months, the improvement in the group receiving risedronate at
`15 mg continued to increase with time, whereas the level of
`improvement with placebo or risedronate at 5 mg did not show
`any further improvement after 6 months.
`
`Analysis of the use of walking aids during study treatment
`showed a statistically significant difference in the proportion of
`patients who used walking aids in patients treated with risedr-
`onate at 15 mg (7 patients, 4% reduction) compared with pla-
`cebo (21 patients, 8% increase) (P = 0.009) at 12 months
`compared with the proportion of patients that had reported
`using a walking aid during the previous year.
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`
`Table 1
`
`Baseline characteristics of the intention-to-treat (ITT) population with osteoarthritis of the knee
`
`Characteristic
`
`Age (years)
`
`Height (cm)
`
`Body mass index (kg/m2)
`
`Sex (no. (%))
`
`Male
`
`Female
`
`Post-menopausal (no. (%))
`
`Years since menopause
`
`Oestrogen or SERM use (no. (%))
`
`Race (no.)
`
`Asian Oriental
`
`Asian Indian
`
`Placebo (n = 98)
`
`5 mg/day (n = 96)
`
`15 mg/day (n = 90)
`
`Risedronate
`
`63.2 (0.82)
`
`164.3 (0.90)
`
`29.2 (0.38)
`
`34 (35%)
`
`64 (65%)
`
`54 (84%)
`
`14.4 (1.22)
`
`18 (28%)
`
`1
`
`1
`
`96
`
`62.9 (0.90)
`
`165.3 (0.97)
`
`29.0 (0.40)
`
`40 (42%)
`
`56 (58%)
`
`49 (88%)
`
`16.5 (1.57)
`
`15 (27%)
`
`0
`
`0
`
`96
`
`63.8 (0.88)
`
`165.1 (0.93)
`
`29.2 (0.42)
`
`41 (46%)
`
`49 (54%)
`
`43 (88%)
`
`17.4 (1.42)
`
`10 (20%)
`
`0
`
`2
`
`88
`
`P
`
`0.652a
`
`0.614a
`
`0.799a
`
`0.307b
`
`0.985b
`
`0.273a
`
`0.380b
`
`0.385b
`
`Caucasian
`
`Joint-space width (mm)
`
`WOMAC – weighted total score
`
`Use of walking aids (no. (%))
`
`uCTX-II (ng/mmol creatinine)
`
`uNTX-I (nmol/mmol creatinine)
`
`3.03 (0.05)
`
`50.3 (2.0)
`
`16 (16)
`
`312.5 (19.9)
`
`40.3 (2.8)
`
`2.95 (0.05)
`
`46.1 (2.0)
`
`22 (23)
`
`328.9 (29.7)
`
`42.3 (4.5)
`
`3.01 (0.06)
`
`49.4 (2.4)
`
`12 (13)
`
`340.1 (24.0)
`
`38.6 (2.2)
`
`0.577a
`
`0.281a
`
`0.224b
`
`0.748a
`
`0.954a
`
`Unless indicated otherwise, values are means (standard errors of the mean). aKruskal–Wallis test; bFisher exact test. SERM, selective oestrogen
`receptor modulator; uCTX-II, urinary C-terminal crosslinking telopeptide of type II collagen; uNTX-I, urinary N-terminal crosslinking telopeptide of
`type I collagen; WOMAC, Western Ontario and McMaster Universities osteoarthritis index.
`
`Table 2
`
`Summary of adverse events (no. (%)) in patients with osteoarthritis who received risedronate or placebo
`
`Patients with AEs
`
`Dropouts due to AEs
`
`Overall GI AEs
`
`Abdominal pain
`
`Dyspepsia
`
`Gl disorder
`
`Placebo
`
`(n = 98)
`
`94 (96%)
`
`12 (12%)
`
`15 (15%)
`
`6 (6%)
`
`7 (7%)
`
`3 (3%)
`
`Risedronate
`
`5 mg/day (n = 96)
`
`15 mg/day (n = 90)
`
`95 (99%)
`
`7 (7%)
`
`16 (17%)
`
`7 (7%)
`
`7 (7%)
`
`1 (1%)
`
`84 (93%)
`
`10 (11%)
`
`7 (8%)
`
`3 (3%)
`
`3 (3%)
`
`1 (1%)
`
`AE, adverse event; GI, gastrointestinal.
`
`Structure outcome measures
`Assessment of the mean change from baseline values in mini-
`mum JSW in the medial compartment of the tibiofemoral joint
`at 1 year showed that there was a trend for patients receiving
`risedronate at 5 mg (JSW -0.08 ± 0.44 mm) or 15 mg (JSW -
`0.06 ± 0.25 mm). The change was greater in patients receiv-
`
`ing placebo (JSW -0.12 ± 0.42 mm) compared with baseline
`values. Overall, the difference between treatment groups in
`loss of JSW at 12 months was not statistically significant (P =
`0.275). The loss in JSW from baseline values was statistically
`significant only in the placebo group (P < 0.05).
`
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`Arthritis Research & Therapy Vol 7 No 3 Spector et al.
`
`Figure 2
`
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`1!
`c
`0
`E
`N
`1il
`Q)
`.!:
`"3l
`"' .0
`E
`_g
`gi,
`C "' .r:
`
`(.)
`
`0
`
`-5
`
`- 10
`
`- 15
`
`-20
`
`- 25
`
`Placebo
`
`Ris 5 mg/day
`
`Ris 15 mg/day
`
`mWeighted
`•Pain
`~ Function
`• Stittness
`
`• P = 0.185 vs baseline
`t P = 0.28 vs baseline
`* P = 0.104 vs baseline
`§ P = 0.326 vs baseline
`
`Changes in mean values at 12 months from baseline measures in patients with osteoarthritisChanges in mean values at 12 months from baseline measures in
`
`
`patients with osteoarthritis. Patients were given risodronate (Ris) or pla-
`cebo. Scores were the weighted composite of the 24 question scores
`on the visual analogue scale (1 to 100 mm) of the Western Ontario and
`McMaster Universities (WOMAC) osteoarthritis index or its subscales
`for pain, stiffness, and physical function. Vertical lines represent stand-
`ard errors of the mean. P values refer to risedronate (15 mg) vs base-
`line values.
`
`In terms of detectable progression (i.e. loss of JSW ≥ 25% or
`≥ 0.75 mm), the analysis of the distribution of change from
`baseline values in JSW at 1 year showed a greater presence
`of detectable progression in the placebo (8%) and risedronate
`(5 mg) (4%) (P = 0.36) groups than in the risedronate (15 mg)
`group (1%) (P = 0.067). The patients with JSW loss of >0.75
`mm included none of the patients treated with risedronate at
`15 mg and 6% of the patients treated with placebo (P =
`0.060). Similarly, only 1% of the patients treated with risedro-
`nate at 15 mg but 7% of the patients treated with placebo had
`>25% loss of JSW (P = 0.12).
`
`Structure–symptom relation
`Figure 4 shows the relation between structure and symptoms
`for this population of patients. The mean WOMAC total score
`and the scores on the pain and function subscales increased
`(i.e. symptom severity increased) with increasing loss of JSW.
`In the group of patients with any loss of JSW, the mean
`changes of the WOMAC total score and the scores on the
`pain and function subscales at 1 year were -5.9 mm, -4.6 mm,
`and -6.3 mm, respectively, indicating that these symptoms
`were not increasing overall. In contrast, for the subset of
`patients with a loss in JSW of 40% or more, the corresponding
`mean changes were +1.4 mm, +6.0 mm, and +2.3 mm,
`indicating increased symptom severity in these patients con-
`current with narrowing of their knee-joint space.
`
`Markers of biochemical turnover
`Risedronate treatment significantly reduced markers of carti-
`lage degradation (Fig. 5) and bone resorption compared with
`placebo. At 1 year, treatment with risedronate at 15 mg signif-
`
`icantly decreased mean urinary CTX-II values, by -22.8% ±
`5.35; urinary NTX-I was reduced by -32.9% ± 4.92 relative to
`baseline values (P < 0.05). Dose-dependent effects were also
`observed with the 5-mg dose compared with placebo, but to
`a lesser magnitude. This finding is consistent with the known
`pharmacologic effect of risedronate on bone turnover. At 1
`year, CTX-II and NTX-I values in the placebo group were sig-
`nificantly higher than those in the risedronate 15-mg group
`(14.5% ± 5.4 and 17.2% ± 4.9 higher, respectively). Signifi-
`cant decreases in bone alkaline phosphatase were observed
`in the risedronate groups compared with placebo. At 1 year,
`the mean decreases in the groups receiving risedronate at 15
`mg and 5 mg were 29.1% ± 2.6 and 19.5% ± 2.5, respec-
`tively, compared with a mean decrease of 2.7% ± 2.5 in the
`placebo group (P < 0.001).
`
`Safety
`The frequencies of AEs were similar in the two treatment
`groups (Table 2). There were no clinically meaningful
`differences between groups in the percentage of patients with
`AEs in any body system and there were no significant differ-
`ences in routine clinical chemistry parameters between the
`risedronate groups and the placebo group. The numbers of
`patients who dropped out of the study because of AEs were
`similar. Overall, 34 patients reported a total of 53 serious AEs.
`Investigators considered four serious AEs as possibly related
`to study treatment; two of these (rash and diarrhea) were in
`patients treated with placebo and two (anaemia and increased
`general joint pain) were in patients treated with risedronate at
`5 mg.
`
`Table 2 provides a summary of adverse events for the ITT pop-
`ulation and the frequency of the overall GI AEs and the most
`common upper-GI AEs. Forty-seven upper-GI events were
`reported in 38 patients, of which abdominal pain and dyspep-
`sia were the most frequently reported. The majority of the
`upper-GI AEs occurred in patients with a history of GI disease;
`there were no significant differences between the groups
`given risedronate and the group given placebo in the inci-
`dence of upper-GI AEs in these patients.
`
`Discussion
`Increased evidence of the role of bone in both the initiation and
`progression of OA has resulted in an interest in drugs that
`affect bone metabolism and might slow or even halt the proc-
`ess of joint degeneration [6]. The early findings reported here
`suggest that the bisphosphonate risedronate may have dis-
`ease-modifying effects in patients with knee OA. A recent
`cross-sectional study also suggests an association between
`antiresorptive treatments (oestrogen or bisphosphonate) and
`improved symptoms and/or decreased bone marrow abnor-
`malities [20].
`
`Positive trends were observed with risedronate treatment with
`regard to symptomatic improvement, as assessed by the
`
`R630
`
`

`

`Available online http://arthritis-research.com/content/7/3/R625
`
`Placebo
`
`Ris 5 mg/day
`
`Ris 15 mg/day
`
`* P < 0.05 vs baseline
`† P <0.001 vs placebo
`
`I
`·-- ·-... ·-.. ·-.. ·-
`
`*
`
`**
`*
`
`*
`
`---
`
`*
`
`*
`
`Baseline
`
`Month 3
`
`Month 6
`Time (Month)
`
`* †
`
`Month 12
`
`1.8
`
`–2.2
`
`–6.2
`
`–10.2
`
`–14.2
`
`–18.2
`
`–22.2
`
`Meanchangefrombaseline(mm)
`
`Figure 3
`
`Changes in mean patient global assessment after risedronate or placebo in osteoarthritisChanges in mean patient global assessment after risedronate or placebo in osteoarthritis. Vertical lines represent standard errors of the mean. Ris,
`
`risedronate.
`
`0% –10% –20% –30% –40% –50%
`n = 5
`n = 146 n = 50 n = 16 n = 7
`n = 5
`
`Minimum JSW % change
`
`---
`
`WOMAC total mean
`
`WOMAC pain mean
`
`Figure 4
`
`10
`
`8 6 4 2 0
`
`–2
`
`–4
`
`–6
`
`–8
`
`Changefrombaseline(mm)
`
`WOMAC function mean
`
`*
`
`Relation between WOMAC scores and minimum percentage change in JSW after 1 year in patients with osteoarthritisRelation between WOMAC scores and minimum percentage change in
`
`
`JSW after 1 year in patients with osteoarthritis. Scores were the
`weighted composite (1 to 100 mm) of the Western Ontario and
`McMaster Universities (WOMAC) osteoarthritis index or its subscales
`for pain and physical function. JSW, joint-space width.
`
`defined as a decrease in JSW ≥ 2 mm, in comparison with
`subjects in the lowest quartile [22]. This suggests that an
`enriched population of subjects with an elevated rate of carti-
`
`R631
`
`WOMAC index. Treatment with risedronate at 15 mg resulted
`in a consistent trend in improvement in WOMAC scores,
`whereas the group receiving placebo showed less improve-
`ment. The group receiving risedronate at 15 mg showed a sig-
`nificant improvement in the PGA of OA compared with
`placebo. Similarly, the percentage of patients who used a
`walking aid during the study decreased in the group treated
`with risedronate at 15 mg, contrasting with an increase in the
`placebo group. While the differences in JSW among the
`groups were not significant, there was a trend for less loss in
`the risedronate (15 mg) than in the placebo group. When the
`data were analysed in a post hoc manner to identify patients
`with detectable progression (i.e. approximately four times the
`precision of the measurement), 8% of patients receiving
`placebo and 1% of patients receiving 15 mg risedronate were
`found to exhibit this degree of progression. Additionally, rise-
`dronate significantly reduced levels of bone resorption and
`cartilage degradation, as assessed by NTX-I and CTX-II mark-
`ers, respectively.
`
`Despite these encouraging results, they were not confirmed in
`multicentre studies of risedronate treatment for 2 years using
`a similar protocol [21]. The following provides perspectives
`comparing the two studies. In our study, there was a dose-
`dependent trend for improvement in the WOMAC score. In the
`2-year North American study, which enrolled 1,232 patients
`with knee OA, the placebo effect was approximately twice that
`observed in our study, and was comparable to the magnitude
`of change observed in the group given 15 mg risedronate in
`our study. Both studies showed significant decreases in CTX-
`II, the marker of cartilage degradation, but these were not
`associated with an attenuation of joint-space loss This lack of
`association may be related to the length of observation in
`these studies. Reijman and colleagues [22] observed 1,235
`men and women with OA, followed up over an average period
`of 6.6 years. The subjects with baseline CTX-II levels in the
`highest quartile had a sixfold risk of progression of knee OA,
`
`

`

`Arthritis Research & Therapy Vol 7 No 3 Spector et al.
`
`Figure 5
`
`-~~~------+-----+-------------
`l ·-- ·-- +- --- --- --- --- ---1
`
`*
`
`**
`
`'\,
`
`*
`
`**
`
`-
`--- ·-
`
`Placebo
`
`Ris 5 mg/day
`
`Ris 15 mg/day
`* P < 0.05 vs placebo
`** P < 0.001 vs placebo
`
`50
`
`0
`
`–50
`
`–100
`
`–150
`
`–200
`
`CTX–IIng/mmolcreatinine
`
`3
`
`**
`6
`
`Time (Month)
`
`12
`
`
`
`Changes in urinary CTX-II levels after treatment of