Rheumatology Advance Access published May 20, 2015

RHEUMATOLOGY

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Original article

doi:10.1093/rheumatology/kev123

Intravenous neridronate in the treatment of acute painful knee osteoarthritis: a randomized controlled study

Objective. The aim of this randomized, double-blind, placebo-controlled study was to assess the efficacy of i.v. neridronate in controlling pain in patients with acute painful knee OA. Methods. Sixty-four patients with acute knee pain (50 years of age and with a recent worsening of knee pain were screened. These patients came from the orthopaedic and rheumatology outpatient services and the emergency department of our hospital, a tertiary care centre devoted to bone and joint diseases. Sixty-eight patients (31 male, 37 female) were considered eligible to be recruited when they met the following inclusion criteria: knee OA fulfilling the ACR criteria [14], a radiographic Kellgren–Lawrence (KL) grading score 52 in the tibiofemoral joint [15], a continuous worsening of knee pain for at least 2 weeks with an onset 43 months, pain intensity >30 mm on a visual analogue scale (VAS) ranging from 0 (no pain) to 100 mm (maximal pain) and a dedicated knee MRI scan showing large (>1 cm) BMLs. Exclusion criteria were hepatic, renal, endocrine, haematological, cardiac, pulmonary or neurological diseases and diabetic patients taking insulin or oral hypoglycaemic drugs; routine laboratory abnormalities (including calcaemia and glomerular filtration rate); prior treatment with BPs; an MRI scan with significant joint effusion, subchondral bone attrition and/or evidence of bursitis or tendonitis; knee pain resulting from definite knee trauma. At the time of recruitment, 58 of 68 (85.3%) patients were taking or had taken drugs to control pain in the previous 3 months. The patients were asked not to take any analgesics or NSAIDs throughout the study period. All patients were informed that they were free to leave the study whenever they wanted and that a further examination to have an alternative treatment could be arranged within a day by calling the hospital directly. All patients gave written consent. The study complied with the amended

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Knee MRI High-resolution, three-dimensional MRI of the target knee was obtained for each patient before the start of the treatment (1–7 days) and at the end of the study (day 58–69). All MRIs were evaluated by a skilled musculoskeletal radiologist who was blinded to the patient’s treatment. All MRI examinations were performed with a 1.5T scanner (Magnetom Espree, Siemens, Berlin, Germany) using a dedicated knee coil. Imaging was performed on the sagittal, coronal and transverse planes, with a field of view of 18 cm and a matrix of acquisition of 256  256. The MRI protocol included spin echo T1-weighted sequences [repetition time (TR) 580 ms, echo time (TE) 12 ms, number of signal averages 2, thickness 3.0 mm, intersection gap 0.5 mm] on the sagittal, coronal and transverse planes; spin echo T2-weighted sequences (TR 4.000 ms, TE 30/100 ms, one signal acquired, thickness 3.0 mm, intersection gap 0.5 mm) on the sagittal and transverse planes; proton density–weighted sequence with fat/suppression (TR 2800 ms, TE 40 ms, one signal acquired, thickness 3.0 mm, intersection gap 0.5 mm) on the coronal plane. Subchondral BMLs were identified as areas of increased signal intensity on fat-suppressed T2-weighted images. Scores were assigned using the whole-organ MRI score (WORMS) for knee OA for bone marrow oedema [16]. Specifically, BMLs were coded 0–3 in each of 10 subregions of the medial and lateral tibiofemoral compartments and in each of the four subregions of the patellofemoral compartments. For each subregion, the extent of the lesion was assessed following the WORMS scale: 0 = absence of oedema, 1 = 50%.

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fluctuation in size of bone marrow lesions (BMLs), has become evident [2–4]. Histological evaluation of subchondral BMLs is usually performed in advanced stages of disease, with several histological patterns and without a clear correlation with pain [5–7]. In recent years an observed efficacy of bisphosphonates (BPs) in the treatment of some diseases characterized by pain and MR signalling similar to BMLs arising in knee OA has been reported. Spondylarthritides [8], bone marrow oedema of the hip [9] and complex regional pain syndrome type I (CRPS-I) [10] have all shown a significant improvement in pain when treated with high-dose BPs administered intravenously. Furthermore, there is some evidence that BPs are effective in the treatment of OA pain when taken regularly at a lower dose [11], possibly by reducing the prevalence of BMLs [12]. Neridronate is an amino-BP that recently demonstrated further positive results in controlling pain, inflammatory signs and functional impairment in patients with CRPS-I [13]. The aim of this study was to evaluate the efficacy of neridronate administered intravenously in patients with painful knee OA following the same regimen employed in the study on CRPS-I.

Intravenous neridronate in painful knee OA

Measures

Statistical analysis Sample size calculation was performed assuming a twotailed probability of type I error equal to 0.05. In accordance with the results of a previous study exploring pain changes in knee OA patients treated with zoledronate [21], we assumed a reduction in VAS score of >20 mm in patients treated with neridronate. Assuming a maximal VAS S.D. of 25 mm as inferred by a number of studies on knee pain in OA, we calculated that a total sample of 50 patients would be able to detect a significant difference between groups with a power of 80%. To accomplish this, we planned a total sample of 65 patients, because a dropout rate of 430% was hypothesized due to the study design (60 days without analgesics). The statistical analysis was performed according to the intention-to-treat principle, including all randomized patients who received at least one dose of the study medication. As the variables were not normally distributed (Shapiro–Wilk test), non-parametric tests were used. Differences between groups were assessed by Mann–Whitney U test. The Wilcoxon signed rank test was used to evaluate intragroup differences in clinical variables at the different time points and to compare WORMS values. Predictive factors for VAS and WORMS changes were assessed using univariate and multivariate

Results Sixty-eight patients were recruited and randomized to treatment or placebo in two equal groups (34 patients). At entry, the two groups were well balanced for demographic and clinical characteristics (Table 1). Only the time elapsed since pain onset was slightly but significantly shorter in the placebo group. Fifty-six patients completed the study. One patient in the neridronate group withdrew consent because of an adverse event (acute phase reaction) after the first infusion and one patient was excluded because of analgesic resumption before the last clinical evaluation. Eight patients in the placebo group dropped out for the resumption of analgesic or NSAID treatment during the study (seven patients) and one patient refused to return to be evaluated 50 days after the treatment. Two patients (one in the neridronate group and one in the placebo group) who presented features evocative of bone attrition (flattening/depression of the femoral condyle surface) on the MRI performed at the end of the study were excluded. The disposition of patients is reported in Fig. 1. On the day of the last infusion, both groups showed a significant decrease in VAS score compared with the basal values, with a greater significant difference in the neridronate group (Fig. 2). VAS score changed from 59.0 (S.D. 14.7) to 30.4 (S.D. 15.6) in the neridronate group (P < 0.001), while in the placebo group it decreased from 64.8 (S.D. 16.9) to 55.4 (S.D. 17.4) (P = 0.04). The comparison between groups on the day of the last infusion showed a significantly greater decrease in the neridronate group (P < 0.001). On day 60 (T2), no further improvement in VAS score was observed in the placebo group (Fig. 2) and, in addition, other clinical measures did not show any significant change before and after treatment (Table 2). Instead, the

TABLE 1 Demographic, clinical and MRI characteristics of patients with painful knee OA at baseline treated with neridronate or placebo Characteristic

Neridronate (n = 34)

Placebo (n = 34)

P-valuea

Age, years Gender (male/female), n/n BMI, kg/m2 Pain duration, weeks VAS score WOMAC score SF-36 physical component SF-36 mental component McGill WORMS

64.7 (11.8) 15/19 25.7 (3.6) 8.1 (2.2) 59.0 (14.7) 232 (79) 36.6 (10.2) 56.1 (12.4) 14.3 (7.6) 6.3 (3.0)

67.0 (7.3) 16/18 25.5 (3.9) 6.8 (2.7) 64.8 (16.9) 254 (86) 33.4 (6.7) 59.4 (13.2) 16.3 (12.5) 7.7 (3.9)

0.1 0.6 0.7 0.039 0.1 0.4 0.4 0.1 0.9 0.1

Values are mean (S.D.) unless otherwise specified. aMann–Whitney U test. SF-36: 36-Item Short Form Health Survey; VAS: visual analogue scale; WORMS: whole-organ MRI score.

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The primary outcome measure of the study was the comparative changes in pain intensity between the neridronate group and the placebo group over the study. Pain in the affected knee was measured by VAS (0–100) [17] at day 1 (T0), at the day of the last infusion (day 10; T1) and 50 days later (day 60; T2). As secondary endpoints we evaluated other clinical assessments, including the WOMAC pain questionnaire (five items) [18], the McGill pain questionnaire [19] and the 36-Item Short Form Health Survey (SF-36) [20], to assess functional status. All these instruments were administered at T0 and T2. As an additional endpoint, changes in the WORMS before the treatment and at T2 were measured.

regression analyses. Data were explored both in absolute values and in percentage changes. All statistical tests were two-sided at the 5% level and performed using SPSS software (version 17.0; SPSS, Chicago, IL, USA).

Massimo Varenna et al.

FIG. 1 Flow diagram illustrating outcomes of patients with acute painful knee OA in a randomized controlled trial of neridronate vs placebo

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decreases at T2 (after adjustment for age, sex, BMI, KL grade and pain duration) (b = 0.736, P = 0.001). When the patients were interviewed by phone 2 months after the last clinical evaluation, 18 of 25 patients treated with placebo had resumed analgesic drugs or NSAIDs (72%), while only 4 patients of 31 treated with neridronate (12.9%) had taken analgesics or NSAIDs.

Side effects During the neridronate course, no patients showed decreases in serum calcium values requiring treatment. No patients complained of serious BP-related adverse events (atypical fractures and osteonecrosis of the jaw) during the follow-up period (4 months after the treatment). As expected, the most common adverse event was an acute phase reaction (mainly polyarthralgia), which was reported by 10 patients (29%) after the first infusion. Five patients also reported fever that never exceeded 38 C. In all patients these symptoms disappeared within 2 days after the first infusion.

Discussion The results of this randomized controlled study provide evidence that a course of neridronate administered

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neridronate group showed further significant pain improvement with a VAS score that fell to 9.4 (S.D. 10.8; P < 0.001 vs both T0 and T1 values). Also, other pain and functional rating indices showed significant decreases compared with both basal values and placebotreated patients, with the exclusion of the SF-36 Mental Component Summary score, which showed no change between the neridronate and placebo groups (Table 2). The WORMS, revaluated at T2, showed a significant decrease in lesion size only in the neridronate group [from 6.3 (S.D. 3.0) to 3.7 (S.D. 4.2); P = 0.01], while no significant change was observed in the placebo-treated group (Table 2). Regression analyses showed no correlations between baseline clinical variables (age, gender, BMI, KL grade, pain duration, VAS and WOMAC) and basal WORMS. No correlations were found between WORMS changes and changes in other clinical variables evaluated both in absolute values and in percentage change. In the search for predictive variables influencing the measure of pain improvement, a univariate regression analysis showed a significant correlation between VAS decreases found at T1 and VAS decreases observed at the end of the study (b = 0.452, P = 0.01). Moreover, a multivariate regression analysis showed a significant correlation between basal WOMAC score and VAS

Intravenous neridronate in painful knee OA

FIG. 2 Pain trend at baseline and after neridronate treatment or placebo

Mean (S.D.) changes in pain measured by visual analogue scale from baseline to day 60 in patients with acute painful knee OA treated with four infusions of neridronate 100 mg or placebo. Differences between groups were analysed using the Mann–Whitney U test.

were normal, necrotic or showed an active remodelling process [25]. Trabecular microfractures were documented only at the femoral head level in patients undergoing hip arthroplasty for hip OA [26]. Poor venous drainage, a local increase in bone pressure and low local pH would be causative factors for pain [27] and the subsequent evolution towards marrow necrosis and eventually fibrosis. Two patients who showed a deformity of the condylar profile at MRI examination performed at the end of the study (T2) were excluded because the pain and bone oedema were probably related to a disease other than OA, such as bone bruise due to occult trauma or spontaneous osteonecrosis. Our choice to use a BP was based on the efficacy of these drugs in the treatment of various painful skeletal disorders all characterized by bone oedema. In these diseases, including knee OA [21], there is growing evidence derived from case reports, case series and observational and controlled studies that BPs reduce pain and improve the MRI oedema pattern. Recently neridronate used with the same schedule employed in this study has been shown to be useful in the treatment of CRPS-I [13], which frequently shows marrow oedema in the involved skeletal sites [28]. Since the pathophysiological path of BMLs is not fully known, the mechanism of action of neridronate in reducing pain remains conjectural. BPs reach a high local concentration, as demonstrated by studies that compared MRI features with bone scans employing TC99 labelled to a BP as a marker [29]. The radiotracer distribution is likely similar to an in vivo accumulation of the drug at the disease site. This large drug concentration probably accounts for mechanisms of action that are not usually active when these molecules are employed at lower dosages to treat osteoporosis. At high local concentrations, BPs are possibly able to exert an inhibitory effect on the local production of inflammatory mediators [30], which change the threshold of nociceptive fibres and perhaps the local release of some neuromediators (calcitonin gene-related peptide and substance P) involved in pain generation in patients with OA [31]. Alternatively, neridronate may reduce pain by lowering the local acidosis

TABLE 2 Clinical characteristics of patients with painful knee OA 50 days after treatment (T2) with neridronate or placebo Neridronate (n = 31) VAS score WOMAC score SF-36 physical component SF-36 mental component McGill WORMS

9.4 (10.8)* 58 (58)* 51.1 (8.7)* 62.5 (11.1)** 3.7 (4.6)* 3.7 (4.2)**

Difference from baseline, mean (%) 81.9 73.1 47.5 13.8 57.2 41.1

(22.7) (30.9) (51.8) (29.5) (71.6) (102.6)

Placebo (n = 25) 50.1 (16.9) 228 (162) 39.3 (19.1) 58.3 (13.8) 15.6 (10.8) 7.1 (3.6)

Difference from baseline, mean (%) 14.2 15.3 26.4 6.7 36.3 23.7

(37.2) (108.8) (68.6) (39.1) (136.8) (90.3)

P-valuea 0.001 0.001 0.01 0.2 0.001 0.002

Values are given as mean (S.D.). aMann–Whitney U test (neridronate group vs placebo group). *P = 0.001; **P = 0.01 vs baseline values (Wilcoxon signed rank test). SF-36: 36-Item Short Form Health Survey; VAS: visual analogue scale; WORMS: wholeorgan MRI score.

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intravenously reduces pain intensity in patients with symptomatic knee OA. We also found that the size and extent of BMLs on MRI showed a greater decrease in subjects treated with neridronate than in the placebo-treated patients. Although some studies reported no association between pain and BMLs [22, 23], overall evidence has demonstrated this relationship through cross-sectional and longitudinal studies [24]. An association between increased size of BMLs and pain worsening has been reported as well [3, 4]. More controversial are the results of histopathological studies, mostly because all were performed in patients with advanced disease who underwent replacement surgery. Heterogeneous findings involving bone marrow and bone tissue have been reported. At the bone marrow level, oedema, bleeding, necrosis, fibrosis and sometimes an inflammatory infiltration showed the same altered signal on MRI. Similarly, bone trabeculae

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oedema [38]. A further limitation would be the potential for the study not to be fully blinded due to an acute phase reaction that occurred in 30% of patients treated with neridronate. However, as outcome measures we employed self-administered tools, thus avoiding the use of clinical instruments by investigators who could link this side effect to BP administration. Furthermore, in contrast to studies that explored the effect of long-lasting BP treatment, we have no data that can support a possible effect in slowing the anatomical disease progression. Finally, we do not know if this treatment may show the same effect in patients with smaller BMLs or no BMLs and in patients with pain of longer duration. In conclusion, an i.v. neridronate course showed a clinically relevant benefit in patients with acute painful OA, reducing the extent of bone marrow oedema. Further controlled studies with a follow-up long enough to evaluate disease progression and also aimed at optimizing the dosing regimen appear worthwhile.

Acknowledgements We thank Ray Hill, an independent medical writer, who provided assistance with the English-language editing and journal styling prior to submission. This assistance was funded by Abiogen Pharma, Pisa, Italy. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: The authors have declared no conflicts of interest.

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Intravenous neridronate in painful knee OA

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