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`Clinical and epidemiological research
`
`10.1136/annrheumdis-2011-200970
`
`1Menzies Research Institute
`Tasmania, University of
`Tasmania, Hobart, Tasmania,
`Australia
`2Clinical Effectiveness Cluster,
`Flinders University, Adelaide,
`South Australia, Australia
`
`Correspondence to
`Laura Louise Laslett, University
`of Tasmania, Menzies Research
`Institute Tasmania, Private
`Bag 23, Hobart, Tasmania,
`Australia, 7000;
`Laura.Laslett@utas.edu.au
`
`Received 27 October 2011
`Accepted 21 December 2011
`
`ExTENDED REPORT
`Zoledronic acid reduces knee pain and bone marrow
`lesions over 1 year: a randomised controlled trial
`Laura Louise Laslett,1 Dawn A Doré,1 Stephen J Quinn,2 Philippa Boon,1 Emma Ryan,1
`Tania Maree Winzenberg,1 Graeme Jones1
`
`AbstrACt
`Objectives To compare the effect of a single infusion of
`zoledronic acid (ZA) with placebo on knee pain and bone
`marrow lesions (BMLs).
`Methods Adults aged 50–80 years (n=59) with clinical
`knee osteoarthritis and knee BMLs were randomised to
`receive either ZA (5 mg/100 ml) or placebo. BMLs were
`determined using proton density-weighted fat saturation
`MR images at baseline, 6 and 12 months. Pain and
`function were measured using a visual analogue scale
`(VAS) and the knee injury and osteoarthritis outcome
`score (KOOS) scale.
`results At baseline, mean VAS score was 54 mm and
`mean total BML area was 468 mm2. VAS pain scores
`were significantly reduced in the ZA group compared
`with placebo after 6 months (−14.5 mm, 95% CI −28.1
`to −0.9) but not after 3 or 12 months. Changes on the
`KOOS scales were not significant at any time point.
`Reduction in total BML area was greater in the ZA group
`compared with placebo after 6 months (−175.7 mm2,
`95% CI −327.2 to −24.3) with a trend after 12 months
`(−146.5 mm2, 95% CI −307.5 to +14.5). A greater
`proportion of those in the ZA group achieved a clinically
`significant reduction in BML size at 6 months (39% vs
`18%, p=0.044). Toxicity was as expected apart from
`a high rate of acute phase reactions in treatment and
`placebo arms.
`Conclusions ZA reduces knee pain and areal BML size
`and increases the proportion improving over 6 months.
`Treatment of osteoarthritis may benefit from a lesion
`specific therapeutic approach.
`Clinical trial registration number: ACTRN
`12609000399291.
`
`IntrOduCtIOn
`Knee osteoarthritis (OA) is a leading cause of
`chronic disability. While there are therapies for
`symptoms, there are currently no approved dis-
`ease-modifying OA drugs available which modify
`structural progression in OA. Bone marrow lesions
`(BMLs) are regions of increased signal intensity
`within the bone marrow and appear to be a prom-
`ising target. They are the first sign of OA after
`experimental ligament damage and precede carti-
`lage erosion and degeneration in an animal model
`of OA,1 and strongly correlate with knee pain in
`humans.2–4 Incident2 and progressing4 5 BMLs have
`been shown to be associated with development of
`knee pain. Further, a reduction in BML size is asso-
`ciated with pain improvement.5 Importantly, BMLs
`are also associated with structural changes. They
`
`predict joint space loss on x-ray,6 cartilage defect
`progression7 and cartilage loss on MRI8–10 as well
`as knee replacement surgery.5 11 12
`Despite this, there are no therapies in use. Meizer
`et al report on uncontrolled studies of patients
`treated with the prostacyclin analogue iloprost,13 14
`and a study compares iloprost with core decom-
`pression.15 BML end points have been reported
`in a pilot study of chondroitin sulphate on carti-
`lage volume loss.16 However, the sample size was
`small and differences in pain and function between
`treatment and placebo groups were not significant.
`Bisphosphonates are a potential therapeutic candi-
`date as there is observational evidence that BMLs
`are less common in persons taking alendronate.17 A
`study investigating the effect of risedronate on car-
`tilage loss in knee OA suggested that risedronate 50
`mg weekly may prevent an increase in BML size,18
`although this was not statistically significant. While
`the effect of bisphosphonates on BMLs could be a
`class effect, bisphosphonates given intravenously
`appear to have greater treatment effects, at least,
`for osteoporosis.19
`Therefore, this study aimed to compare the
`effect of a single infusion of zoledronic acid (ZA)
`5 mg with placebo on knee pain and BMLs over 12
`months in participants with a pain intensity score
`>40 mm on a visual analogue scale (VAS) and a
`prevalent knee BML.
`
`PAtIents And MethOds
`trial design
`This study was a single centre, double blind, par-
`allel group, placebo controlled, randomised trial of
`intravenous ZA (5 mg) versus placebo with a 1:1
`allocation ratio.
`
`setting and participants
`Participants were recruited from May to December
`2009 through advertising in local print media.
`Participants were eligible for inclusion if they were
`≥50 years of age with significant knee pain on most
`days (VAS ≥40 mm) and at least one BML on MRI.
`Participants were screened for eligibility by a
`rheumatologist (GJ) to confirm clinical knee OA as
`defined by the American College of Rheumatology
`criteria20 and enrolled into the study by a nurse
`(PB). Participants supplied a blood specimen for
`serum chemistry, renal function and 25 hydroxy-
`calciferol; provided a urine specimen; and had a
`semiflexed knee x-ray.
`Major exclusion criteria were abnormal blood
`tests (serum calcium >2.75 mmol/l (11.0 mg/dl) or
`
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`Clinical and epidemiological research
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`Figure 1 Participant flow diagram. BML, bone marrow lesion; JSN, joint space narrowing; ZA, zoledronic acid.
`
`<2.00 mmol/l (8.0 mg/dl), or creatinine clearance <35 ml/min),
`prior diagnosis of cancer (metastatic cancer or cancer diagnosed
`<2 years with ongoing treatment), use of bisphosphonates
`(except according to a washout schedule), history of non-trau-
`matic iritis or uveitis, or severe knee OA (joint space narrow-
`ing (JSN) on x-ray of grade 3 using the Osteoarthritis Research
`Society International atlas).21 Participants then had a screening
`MRI. The ‘study knee’ was either the knee in which the patient
`was experiencing the most pain or difficulty or the remaining
`knee if the most painful knee had grade 3 JSN.
`Use of other medications was allowed but kept constant
`through the trial period where possible. Participants who had
`serum vitamin D levels of <50 nmol/l were prescribed vitamin
`D supplements. All participants provided written consent. The
`study was approved by the Tasmanian Human Research Ethics
`Committee and conducted at the Menzies Research Institute
`Tasmania, Hobart, Australia.
`
`randomisation and interventions
`Participants were randomly allocated to one of two treatment
`arms (ZA or placebo) using computer generated block ran-
`domisation in blocks of thirty. The random allocation sequence
`was automatically generated, and a security protected central
`
`automated allocation procedure was used to allocate partici-
`pants to treatment arm 1 or 2. This was then used by one
`author (LL) to dispense the allocated medication to another
`(EB) who administered medication to each individual patient.
`Participants and staff involved in patient care (PB, EB, GJ) and
`assessment of MRI (DD) remained blinded to treatment alloca-
`tion throughout the trial.
`Participants (n=59) received an identical intravenous infu-
`sion of 100 mg of fluid, containing ZA (5 mg in normal saline)
`or placebo (normal saline), given by one nurse at the Menzies
`Institute. All participants were advised to take paracetamol as a
`prophylaxis for any acute phase reactions; these were recorded
`3 days later by phone interview.
`
`Outcomes
`Primary outcomes were pain intensity (assessed using a VAS)
`and maximal area of BML as assessed by MRI at 6 months.
`Secondary outcomes were pain intensity at 3 and 12 months;
`knee pain and symptoms at 3, 6 and 12 months (using the knee
`injury and osteoarthritis outcome score (KOOS) questionnaire);
`and BML size at 12 months and safety outcomes (including any
`adverse or serious adverse event, and acute phase reactions).
`Outcomes were assessed using change between baseline and the
`
`Ann Rheum Dis 2012;71:1322–1328. doi:10.1136/annrheumdis-2011-200970
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`Clinical and epidemiological research
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`table 1 Characteristics of study participants at baseline, by treatment
`received
`
`
`
`Age
`Sex (% male)
`BMI (kg/m2)
`Baseline pain score (0–100)
`Total bone marrow lesion area (mm2)
` Medial tibial area
` Medial femoral area
` Lateral tibial area
` Lateral femoral area
`Radiographic OA (%)
` OARSI grade 0
` OARSI grade 1
` OARSI grade 2
` OARSI grade 3*
`Medication use
` Fish oil (%)
` Glucosamine (%)
` Paracetamol (%)
` COX-2 inhibitors (any/none) (%)
`Number of pain medications
` 0
` 1
` 2
` 3
`Creatinine
`eGFR
`
`Zoledronic acid (n=31)
`mean (sd)
`
`Placebo (n=28)
`mean (sd)
`
` 64.2 (8.2)
` 61
` 29.6 (4.4)
` 49.5 (20.3)
`483.9 (410.2)
`160.9 (250.4)
`190.2 (249.6)
` 66.3 (140.7)
` 66.6 (164.3)
`
`26
`23
`39
`3
`
`26
`29
`32
`35
`
` 60.4 (7.3)
` 54
` 29.8 (5.8)
` 55.1 (17.3)
`449.4 (339.3)
` 98.8 (126.6)
`190.0 (265.1)
` 54.4 (99.2)
`106.1 (157.2)
`
`29
`25
`36
`11
`
`14
`21
`43
`46
`
`26
`35
`32
`7
` 71.6 (11.3)
` 83.2 (7.7)
`
`21
`43
`25
`11
` 69.2 (13.9)
` 83.7 (8.6)
`
`*OARSI grade 3 features are osteophytes, as participants with grade 3 joint space
`narrowing were excluded.
`BMI, body mass index; COX-2, cyclooxygenase-2; eGFR, estimated glomerular filtration
`rate; OA, osteoarthritis; OARSI, Osteoarthritis Research Society International.
`
`relevant time point. Baseline questionnaires were completed in
`the clinic. Subsequent questionnaires were completed by mail.
`
`Pain and function
`Knee pain intensity and function were measured on four occa-
`sions (baseline, 3, 6 and 12 months). Knee pain intensity was
`measured using a 100 mm VAS and subjects were asked ‘on this
`line, where would you rate your pain today? Zero represents no
`pain and 100 represents extreme pain.’.
`Knee pain and symptoms were also assessed using the KOOS
`questionnaire.22 These two subscales have nine (pain) and seven
`(symptoms) questions, each with five response levels scored from
`0 to 4. Subscales were transformed according to instructions in
`the original manuscript.22 The transformed scale had possible val-
`ues from 0 to 100 with zero representing extreme knee pain or
`symptoms, and 100 representing no knee pain or symptoms.
`
`MrI
`MRIs of the study knee were obtained at baseline, 6 and
`12 months with a 1.5T whole body MR unit (GE-Signa; GE
`Healthcare, Buckinghamshire, UK). using a dedicated 8-chan-
`nel knee coil. All MRIs were performed using proton density-
`weighted fat saturation two-dimensional fast spin echo sequence
`in the sagittal plane (repetition time 3875 ms, echo time 42 ms,
`slice thickness 3–5 mm, interslice gap 0–3 mm, field of view
`16 cm, 224×448-pixel matrix, number of excitations 2).
`A BML was defined as an ill-defined hyperintensity in the
`subchondral bone. One trained observer (blinded to treatment
`allocation and clinical data) scored lesions using Osiris software
`
`Figure 2 Pain scores (visual analogue scores) over the study time
`frame using unadjusted data and 95% CI of the point estimates. ZA,
`zoledronic acid.
`
`(University of Geneva, Geneva, Switzerland). To maximise
`sensitivity, chronological order was known to the observer.23 24
`The maximum size was measured in mm2 using software cur-
`sors applied to the greatest area of each lesion as previously
`described.5 The lesion with the highest score was used if more
`than one was present at the same site. The intraobserver repeat-
`ability for this method of measurement is excellent with an
`intraclass correlation coefficient (ICC) of 0.97.5 Participants were
`given a BML score (mm2) at each of the four sites (medial tibial,
`medial femoral, lateral tibial and lateral femoral sites) and these
`were summed to create a total BML score (mm2).
`A clinically significant reduction in BML size was classified as
`a reduction of 140 mm2.5
`BMLs were also scored using an ordinal scale at each of
`the four sites, where 0=normal; 1=mild, <25% of the region;
`2=moderate, 25–50% of the region; and 3=severe, >50% of the
`region. If the lesion was depicted in multiple slices, the one with
`the largest extent was chosen.25
`
`sample size
`Sample size for change in BML size was based on prelimi-
`nary results from an in-house observational study (Tasmanian
`Older Adult Cohort Study) in which participants with exist-
`ing BMLs had a mean BML area at baseline of 83 mm2 and an
`SD for change in area of 16 mm2, and thus a 20% reduction
`(or 16 mm2) in lesion area required 16 per group with α=0.05
`and β=0.20.
`Sample size for pain intensity using VAS was based on dem-
`onstrating a 20 mm greater reduction compared with placebo
`with an SD of 25 mm,26 27 which required 25 per group; thus,
`we aimed to enrol 60 participants to allow for dropouts.
`
`Other
`Information on medication use (particularly change in analgesia),
`hospital admissions and newly diagnosed medical conditions
`was recorded at baseline, 3, 6 and 12 months. Blood samples
`were taken to assess safety at 3 and 6 months.
`
`statistical analysis
`Primary hypotheses were tested using intent to treat analysis.
`Statistical significance was determined using a p value ≤0·05
`(two-tailed). Due to an error in treatments given where one
`
`1324
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`table 2 Change in pain and knee symptoms between treatment groups (per protocol analysis)
`
`
`
`baseline to 3 months
`β Coefficient (95% CI) n=59
`
`baseline to 6 months
`β Coefficient (95% CI) n=59
`
`baseline to 12 months
`β Coefficient (95% CI) n=59*
`
`Clinical and epidemiological research
`
`Pain score (visual analogue scale)
`Knee injury and osteoarthritis outcome score
`Pain scale
`3.3 (−6.3 to 12.9)
`0.24
`5.1 (−3.4 to 13.6)
`Symptom scale
`Visual analogue score 0–100 where 0=no pain; 100=extreme pain. Negative change indicates improvement.
`Knee injury and osteoarthritis outcome score pain and symptom scales: 100=no problems; 0=extreme problems. Positive change indicates improvement.
`Adjusted for baseline medication use, age, sex and baseline pain score.
`*n=53 original data, n=5 imputed using the MICE system of chained equations.
`
`−6.5 (−20.8 to 7·8)
`2.6 (−8.6 to 13.7)
`
`0.37
`0.65
`
`−14.5 (−28.1 to −0.9)
`6.2 (−2.5 to 14.9)
`
`0.04
`0.16
`
`0.50
`
`−6.8 (−21.9 to 8.4)
`3.2 (−8.3 to 14.7)
`
`7.0 (−4.5 to 18.5)
`
`0.24
`0.58
`
`0.23
`
`table 3 Change in bone marrow lesion size between treatment groups (per protocol analysis)
`
`
`
`baseline to 6 months
`β Coefficient (95% CI) n=59
`
`Total area (mm2)
`Ordinal scale
`
`−175.7 (−327.2 to −24.3)
`−0.63 (−1.28 to +0.01)
`
`p Value
`
`0.024
`0.05
`
`baseline to 12 months
`β Coefficient (95% CI) n=59*
`
`−146.5 (−307.5 to +14.5)
`−0.7 (−1.6 to 0.1)
`
`p Value
`
`0.07
`0.104
`
`Adjusted for baseline medication use, age, sex and baseline pain score.
`The ordinal scale measures the extent of bone size involved in the lesion.
`*n=51 original data, n=8 using imputed data.
`
`subject randomised to placebo received ZA (figure 1), all subse-
`quent analyses used per protocol analysis. Groups were com-
`pared for change in the pain and BML area between the two
`time points of interest using linear regression, ordered logistic
`regression for the BML ordinal scale and logistic regression
`for the clinical improvement analyses as log binomial mod-
`els did not converge. Groups were compared for safety end
`points using log binomial and Poisson regression. Analyses
`were adjusted for factors which were clinically significantly
`different between the two groups: baseline medication use
`(glucosamine, fish oil, paracetamol and non-steroidal anti-
`inflammatory medications), age, sex and baseline pain score.
`Missing data (n=8 at 12 months) were imputed using multivar-
`iate imputation by chained equations (MICE). We used Stata
`V.10.0 (StataCorp LP) for statistical analyses.
`
`results
`Participants
`A total of 88 participants were screened for the study (figure 1).
`Twenty-nine participants were excluded as they failed to meet
`inclusion criteria (n=26), failed to attend appointments (n=2)
`or declined to participate further (n=1). Fifty-nine participants
`received infusions of either ZA (n=31) or placebo (n=28).
`Follow-up was 100% at 6 months and 89% (n=53) for the
`questionnaire and 86% (n=51) for MRI at 12 months.
`Table 1 and figure 1 show the characteristics of study partici-
`pants at baseline by treatment received. Participants (n=59) had
`a mean age of 62.4 years, mean body mass index of 29.7, mean
`VAS score of 54.4 mm and mean total BML area of 468 mm2 at
`baseline. Most had radiographic OA (defined as any score ≥1 for
`JSN or osteophytes).
`
`Pain and symptom scores
`Pain reduced in both groups between baseline and 3 months
`(figure 2). Intent to treat analysis for change in pain intensity
`between the groups receiving ZA and placebo after 6 months
`was borderline (β coefficient -13.3, 95% CI -26.8 to 0.3; p=0.055),
`after adjustment for age, sex, baseline pain score and baseline
`medication use. Table 2 displays the per protocol analysis.
`
`Effect sizes were similar in per protocol and intent to treat
`analyses after 6 months but the per protocol analysis reached
`statistical significance (β=−14.5, p=0.04). Changes in pain inten-
`sity between baseline and the other time points were not statis-
`tically significant.
`There were no differences in change in pain and symptom scales
`from the KOOS questionnaire in either group at any time point.
`Few participants reported major changes in use of pain medi-
`cations; therefore, analysis was adjusted for only baseline medi-
`cation data.
`
`bMl scores
`The intent to treat analysis for change in BML area over 6 months
`was significant (β coefficient −163.8, 95% CI −314.3 to −13.2,
`p=0.03) after adjustment for age, sex, baseline pain score and
`baseline medication use. Table 3 demonstrates the change over
`6 months was also statistically significant in per protocol analysis,
`and the effect size was similar (β coefficient −175.7, p=0.02). After
`12 months of follow-up, change in BML area was lower in mag-
`nitude and of borderline significance (β coefficient −146.5, p=0.07
`(table 3, figure 3)). Results were consistent but of borderline sig-
`nificance using the ordinal scale.
`In post hoc analysis, a larger proportion of participants in the
`ZA group had improvements in BMLs which should equate to
`a 1 unit improvement in pain (140 mm2),5 as measured by the
`Western Ontario and McMaster Universities Osteoarthritis Index
`(WOMAC) (39% vs 18%, OR 5.0, p=0.044) after 6 months, but
`this was no longer significant after 12 months (OR 2.7, p=0.13)
`(table 4).
`
`Adverse events
`Adverse events were common during the study period and
`occurred more frequently in the ZA group (table 5). The most
`common adverse events were acute phase reactions: primarily
`cold or flu-like symptoms and headaches.
`Serious adverse events were primarily non-elective hospital
`admissions, which included admissions related to the cancer
`diagnoses of two patients, admissions for angina and fractures.
`The two cases of cancer were bladder cancer and non-Hodgkin’s
`lymphoma. No participants died during the study.
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`dIsCussIOn
`In this proof of principle study, a single infusion of intravenous
`ZA was effective in reducing pain intensity and areal BML size
`after 6 months of observation. This study is therefore an impor-
`tant step in identifying treatments which may slow the progres-
`sion of knee OA, as we have demonstrated improvement in
`pain and structure. We also demonstrate that the proportion of
`BMLs improving is more frequent in ZA treated patients than
`those receiving placebo after 6 months, whereas risedronate is
`reported, at best, to halt progression.18
`Pain improvement compared with baseline was clinically
`and statistically significant in both groups (using the VAS) after
`3 months, as expected from an infusion therapy. However, by
`6 months the improvement was numerically and statistically
`greater in the ZA group. This was in addition to the use of exist-
`ing pain medicines and occurred regardless of the high preva-
`lence of co-pathologies such as effusions, meniscal tears and
`cartilage defects (data not shown). The effect size was smaller
`than the 20 mm we had hypothesised, but is comparable with
`effect sizes seen in pharmacotherapy28 and was in addition to
`the effect of existing pain medicines.
`By 12 months, pain had returned to baseline levels in the
`placebo group but remained 10 mm better than baseline in the
`ZA group. This suggests some residual effect, but also indicates
`that more frequent infusions may be required for BMLs than for
`osteoporosis. There were no significant changes in the pain scale
`from the KOOS questionnaire, suggesting that this scale may
`be less sensitive to change than pain intensity from the VAS in
`these participants.
`
`Figure 3 Total bone marrow lesion area (mm2) by treatment group
`over 12 months, and 95% CI of the point estimates. BML, bone marrow
`lesion; ZA, zoledronic acid.
`
`Previous studies have shown conflicting findings on the nat-
`ural history of BMLs. In participants with existing knee OA,
`one study reported that <1% of patients showed a decrease in
`BML size over 30 months9; while, in contrast, another study
`found that 20% of BMLs decreased over 2 years.29 Roemer
`et al30 found that in participants with prevalent knee OA or
`at risk for OA, half of pre-existing BMLs decreased in size
`after 30 months follow-up,30 while Dore et al5 found that in
`a community cohort, similar proportions both worsened and
`improved. The reasons behind these variations are unclear, but
`might be related to the use of different definitions of BMLs or
`imaging protocols. In our study, around one in five patients in
`the placebo arm experienced clinical improvement; suggesting
`improvement is common in this sample, but more frequent in
`participants receiving ZA.
`Some patients’ BMLs continued to enlarge despite ZA treat-
`ment and use of other medications. This could be due to normal
`fluctuation in BMLs, progression of the underlying clinical con-
`dition or BML resolution may occur in some histological profiles
`but not others. BML histology is heterogeneous and consists of
`several abnormalities including bone marrow necrosis, abnormal
`trabeculae, bone marrow fibrosis, bone marrow bleeding, bone
`marrow oedema and sclerosis.31 32 The challenge is to identify
`which of these types are responsive to therapy.
`The proportion of our participants who had BMLs on their
`screening MRI was very high at 88% and more prevalent than
`the 43% in our community cohort with existing knee pain.25
`This suggests that BMLs are almost ubiquitous in adults of this
`age with significant knee pain and less than grade 3 JSN. Thus,
`MRI has a high yield as a screening tool for BMLs in this popu-
`lation for deciding if targeted therapy is appropriate.
`Adverse events were common in this study, and types of
`events observed were consistent with previous trials.19 33
`However, the rate of acute phase reactions was markedly
`higher than previous studies in placebo and ZA arms, and most
`likely reflects advising subjects on this potential side effect but
`could also be due to these reactions being more common in
`participants taking non-steroidal anti-inflammatory drugs,34
`which comprised 40% of our cohort. There was a trend to a
`higher rate of serious adverse events in the ZA group but these
`were disparate in nature and none were considered causally
`related to ZA.
`The strengths of our study are the complete follow-up after
`6 months of observation and high follow-up after 12 months
`(89%), and assessment of change in BMLs using several dif-
`ferent methods. Limitations include the smaller effect size
`detected for pain scores than expected, reducing the actual
`power of the study to detect differences between groups and
`the dispensing error requiring primarily per protocol analyses.
`Residual confounding was still apparent despite the randomi-
`sation, but this was dealt with by multivariate methods. Much
`
`table 4 Change in bone marrow lesion area corresponding to clinically important improvement (≥140 mm2)
`
`
`
`Zoledronic acid n=31
`
`Placebo n=28
`
`Or
`
`p Value
`
`Baseline to 6 months
`Worsen or no change
`Improve
`Baseline to 12 months*
`Worsen or no change
`Improve
`
`19 (61%)
`12 (39%)
`
`17 (55%)
`14 (45%)
`
`23 (82%)
` 5 (18%)
`
`20 (73%)
` 8 (27%)
`
`5.0 (1.0 to 24.1)
`
`0.044
`
`2.7 (0.7 to 9.9)
`
`
`0.132
`
`
`Results obtained using logistic regression and adjusted for age, sex, baseline pain score and baseline medication use.
`A significant change is an increase or decrease of ≥140 mm2, corresponding to a one unit change in WOMAC score.5
`*Missing data at 12 months imputed using the MICE system of chained equations.
`
`1326
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`Ann Rheum Dis 2012;71:1322–1328. doi:10.1136/annrheumdis-2011-200970
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`Downloaded from http://ard.bmj.com/ group.bmj.com on March 24, 2017 - Published by
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`table 5 Adverse events
`
`
`
`Adverse events
`Participants with at least one adverse event
`Number of adverse events
`Acute phase reaction
` Cold or ‘flu’ symptoms
` Uveitis
` Increased knee pain
`Abnormal blood results*
` Low creatinine
` Low eGFR
` Low corrected calcium
`Knee replacements
`Elective surgery (excluding knee replacements)
`Serious adverse events
`Prevalence of at least one serious adverse event
`Number of serious adverse events
` Cancer
` At least one non-elective hospital admission†
` Death
`
`Clinical and epidemiological research
`
`Zoledronic acid (n=31) n (%)
`
`Placebo (n=28) n (%)
`
`p Value
`
`31 (100%)
`42
`28 (90%)
`22
`2
`3
`10 (32%)
`4
`8
`3
`2 (6%)
`2 (6%)
`
`6 (19%)
`8
`1 (3%)
`6 (19%)
`0 (0%)
`
`19 (68%)
`25
`12 (43%)
`7
`0
`0
`12 (43%)
`3
`7
`2
`2 (7%)
`1 (4%)
`
`1 (4%)
`2
`1 (4%)
`1 (4%)
`0 (0%)
`
`0.001
`0.10
`0.001
`
`0.40
`
`0.80
`0.40
`
`0.11
`0.10
`0.94
`0.09
`-
`
`*Results of blood tests pooled for 3 and 6 month tests.
`†Non-elective admissions included removal of lymph node (in a patient with lymphoma), insertion of heart stent, heart valve repair,
`colonoscopy and cystoscopy (two operations in a patient with bladder cancer), knee pain, fractured pelvis and fractured elbow.
`eGFR, estimated glomerular filtration rate.
`
`larger, longer studies are required to assess whether these
`decreases in BML size will translate to reductions in cartilage
`loss or rates of knee replacement over time. However, this can
`be hypothesised from the observational studies, given that
`presence and severity of BMLs predict cartilage loss and knee
`replacement surgery.5 11
`In conclusion, a single infusion of ZA reduces knee pain, areal
`BML size, and proportion experiencing clinically significant
`reduction in BML size after six months.
`
`Contributors GJ designed the study and obtained funding. LLL and PB recruited
`patients. GJ and PB screened patients. EB and PB collected data. DAD read and
`interpreted MR images. SJQ provided statistical advice. GJ and LLL wrote the draft
`manuscript. GJ, LLL, DAD, SJQ and TMW participated in data interpretation. All
`authors critically reviewed and edited the manuscript and approved the final version.
`Acknowledgements We thank Mr Tim Albion (Senior Database Administrator
`Health IT, Menzies Research Institute Tasmania) for generating the random allocation
`sequence and Associate Professor Changhai Ding (Principal Research Fellow, Menzies
`Research Institute Tasmania) for his contributions to the sample size calculations.
`Funding Funding is provided by Novartis Pharmaceuticals Australia; Australian
`Government; National Health and Medical Research Council; and Osteoporosis
`Australia. LLL is supported by an Australian Government Australian Postgraduate
`Award. DAD is supported by a Tasmanian Postgraduate Research Scholarship and
`a Heald Fellowship from Arthritis Australia. GJ is supported by a National Health
`and Medical Research Council practitioner fellowship. TMW is supported by an
`Osteoporosis Australia/Australian and New Zealand Bone and Mineral Society/Amgen
`Fellowship.
`Competing interests GJ has participated in advisory boards, given talks and acted
`as a clinical investigator for Novartis.
`ethics approval Tasmanian Human Research Ethics Committee.
`Provenance and peer review Not commissioned; externally peer reviewed.
`
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`Ann Rheum Dis 2012;71:1322–1328. doi:10.1136/annrheumdis-2011-20097