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Center for Treatment Comparison and Integrative Analysis (CTCIA), Division of Rheumatology, Tufts Medical Center, 800 Washington Street, 02111 Boston, MA, USA
Center for Treatment Comparison and Integrative Analysis (CTCIA), Division of Rheumatology, Tufts Medical Center, 800 Washington Street, 02111 Boston, MA, USA
Center for Treatment Comparison and Integrative Analysis (CTCIA), Division of Rheumatology, Tufts Medical Center, 800 Washington Street, 02111 Boston, MA, USA
Center for Treatment Comparison and Integrative Analysis (CTCIA), Division of Rheumatology, Tufts Medical Center, 800 Washington Street, 02111 Boston, MA, USA
Address correspondence and reprint requests to: R.R. Bannuru, Center for Treatment Comparison and Integrative Analysis (CTCIA), Division of Rheumatology, Tufts Medical Center, Box 406, 800 Washington Street, 02111 Boston, MA, USA. Fax: 1-617-636-1542.
Center for Treatment Comparison and Integrative Analysis (CTCIA), Division of Rheumatology, Tufts Medical Center, 800 Washington Street, 02111 Boston, MA, USA
To clarify the effects of bisphosphonates in knee osteoarthritis (OA) using an up-to-date meta-analysis of randomized controlled trials (RCTs).
Design
The protocol is registered in PROSPERO (CRD42017073449). We searched MEDLINE, EMBASE, Google Scholar, Web of Science, and Cochrane Database from inception until August 2017. We included only RCTs comparing any bisphosphonates vs placebo in knee OA patients and reporting validated pain and function scales, radiographic progression, and adverse events (AEs) outcomes. We excluded studies using active comparators or concomitant medications besides non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. We calculated standardized mean differences (SMDs) to account for variation in outcome scales. Random effects meta-analyses were performed.
Results
We included seven RCTs (3013 patients, 69% female); most patients (N = 2767) received oral risedronate. No pain or function outcomes, regardless of dose, route, time point or measuring instrument, revealed statistically significant results (end of trial pain SMD = −0.16 [95% confidence interval (CI): −0.34, 0.02]). Similarly, we found no statistically significant effect on radiographic progression (risk ratio = 0.98 [95% CI: 0.77, 1.26]). One small RCT in patients with bone marrow lesions (BMLs) suggested a reduction in BML size at 6 months. Bisphosphonates displayed good tolerability, with no statistically significant differences in AE outcomes vs placebo.
Conclusions
Contrary to prior reviews, our analysis showed that bisphosphonates neither provide symptomatic relief nor defer radiographic progression in knee OA. However, these agents may still be beneficial in certain subsets of patients who display high rates of subchondral bone turnover. Future studies should be directed at defining such OA subsets and investigating the effects of bisphosphonates in those patients.
. Symptomatic knee OA, perhaps the most prevalent form of the disease, has been recently estimated to impact 14 million US adults, and in over 50% of the cases it is diagnosed before the age of 65
. Growing prevalence and a relatively early average age of disease onset necessitate the search for new therapies to avoid the exacerbation of pain and development of disability in a large share of the aging population
Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
. For patients who do not respond to all other treatments, the only remaining option is total knee replacement. Unsurprisingly, total knee replacement utilization rates have been steadily increasing over the past decades, outpacing trends in obesity and population growth
The dramatic increase in total knee replacement utilization rates in the United States cannot be fully explained by growth in population size and the obesity epidemic.
. Despite increasing demand, expanding the criteria for total knee arthroplasty would amplify the economic burden of OA while leading to greater failure rates and lower patient satisfaction
. It manifests in the altered architecture and flexibility with simultaneous hypomineralization of subchondral cancellous bone; sclerosis of the subchondral plate; thickening of the calcified cartilage layer and its invasion with blood vessels; osteophyte development due to the proliferation of periosteal cells at the joint margin and endochondral ossification; and the formation of microfractures, cysts, and bone marrow lesions (BMLs)
. These changes occur as a result of biochemical crosstalk between the subchondral bone's osteoblasts and osteoclasts and the articular cartilage's chondrocytes
. Mechanical stress is thought to first induce osteoblasts to express pro-inflammatory and angiogenic factors, which in turn reach chondrocytes and alter their phenotype in addition to promoting cartilage angiogenesis and calcification
. The hypertrophic chondrocytes then produce more angiogenic factors (such as vascular endothelial growth factor, or VEGF), matrix metalloproteinases (MMP), and receptor activator of nuclear factor kappa-B ligand (RANKL)
. The up-regulation of angiogenic and nerve-growth factors within the number of cells in the subchondral bone and in the articular chondrocytes precipitates the growth of blood vessels and sensory nerves from subchondral bone to cartilage (at osteochondral junction), contributing to OA pain
. Osteoclastic activity also plays a significant role in pain generation in OA. First, osteoclasts promote the expansion of microchannels from subchondral marrow spaces into the articular cartilage, resulting in the exposure of subchondral nerves to pro-inflammatory and algogenic cytokines from synovial fluid
Bisphosphonates are a class of drugs commonly prescribed for fracture prevention due to their inhibitory effects on the osteoclast-mediated bone resorption, which accompanies osteoporosis and some other conditions
. These drugs have also been proposed as a possible disease-modifying treatment for OA because of their ability to limit the excessive bone remodeling, impede synovitis, and block osteoclast-mediated pain pathways
Pre-emptive, early, and delayed alendronate treatment in a rat model of knee osteoarthritis: effect on subchondral trabecular bone microarchitecture and cartilage degradation of the tibia, bone/cartilage turnover, and joint discomfort.
The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model.
Enhancement of subchondral bone quality by alendronate administration for the reduction of cartilage degeneration in the early phase of experimental osteoarthritis.
The effects of bone remodeling inhibition by alendronate on three-dimensional microarchitecture of subchondral bone tissues in guinea pig primary osteoarthrosis.
. Likewise, studies in humans had conflicting findings, with some of the randomized controlled trials (RCTs) reporting lack of efficacy of bisphosphonates and others reporting positive results
Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.
. To interpret the evidence derived from the primary studies and to guide future investigative efforts, the Evidence-Based Research Network calls for up-to-date high quality systematic reviews and meta-analyses
. Consistent with the Evidence-Based Research Network approach, we searched for existing systematic reviews on this topic and assessed the available systematic reviews for their scope, quality, and currency
. Prior meta-analyses on the efficacy of bisphosphonates in OA indicated that bisphosphonates may have a positive, albeit limited effect on symptomatology of OA
. However, the aforementioned analyses had numerous, major methodological flaws, such as overlooking the lack of statistical significance of their assessments or confounding their results with the inclusion of non-randomized trials, patient populations with assorted OA sites, active comparators, and less common outcomes. With our study, in accordance with the principles of evidence-based research, we aimed to update the existing body of evidence on the topic and to identify the effects of bisphosphonates in a more homogenous population of knee OA patients, using a meta-analysis of RCTs with well-validated study outcomes and a placebo comparator.
Methods
Our meta-analysis was conducted as a part of a larger literature review project, which was undertaken to inform clinical practice guidelines. Although we had pre-specified most of the methods within the parent project, we did not individually publish a formal written protocol specific to this review. The protocol was registered in PROSPERO (CRD42017073449) before the completion of data extraction.
Data sources/searches
We searched Medline, EMBASE, Google Scholar, Web of Science, and the Cochrane Database from inception to August 2017 (Appendix Table AI) and hand searched reference lists of relevant systematic review and meta-analyses. We also searched published supplements of relevant conference proceedings from inception to August 2017. The search was limited to RCTs in human subjects with knee OA. There were no limitations in terms of publication date or publication status, and foreign language papers were translated.
Study selection
We included RCTs involving participants with clinically and radiographically confirmed knee OA that compared any bisphosphonate against a matching placebo. We excluded studies that utilized active comparators or any concomitant medications, except for non-steroidal anti-inflammatory drugs (NSAIDs) and/or acetaminophen if those were used as a rescue medication or initiated before study baseline and continued in stable doses throughout the study. We included studies that used validated pain and function scales, radiographic progression measures, and adverse event (AE) outcomes. The following interventions and comparators were included in this study: bisphosphonates administered via any route, including intra-articular (IA) (e.g., clodronate), intravenous (IV) (zoledronic acid, neridronate), or oral (alendronate, risedronate); vs placebo (oral, IA, or IV). Two reviewers (MCO, M-CM) independently screened all abstracts recovered by the search according to the above stated inclusion and exclusion criteria. Full manuscripts of abstracts considered to be potentially relevant were gathered and independently assessed for eligibility. Conflicts were resolved by consensus or adjudicated by a third reviewer (RRB or EEV).
Data extraction and quality assessment
Two reviewers (MCO, M-CM) independently extracted data from included RCTs into RevMan software
. Data extraction and quality ratings were reviewed for consistency, and any discrepancies were resolved by a third reviewer (RRB or EEV). Extracted data included study and population characteristics; intervention dosage and frequency of administration; use of rescue medication; pain, function, and radiographic progression outcomes; and relevant safety data. For continuous outcomes (pain and function) we extracted the mean change from baseline. When mean change values were not available, we calculated them using baseline and time-point-of-interest values; when the outcomes were presented only as graphs, we converted graphical data into numerical data using Engauge Digitizer software, and values extracted from graphs were verified by a second reviewer (EEV)
We extracted data on pain, function, proportion of patients experiencing radiographic progression, rates of discontinuation due to AEs, incidence of serious AEs (SAEs), and incidence of gastrointestinal (GI) AEs at the last available follow-up time point. For pain, we also extracted values within 6 months, by 12 months, and/or by 24 months, wherever possible.
We considered pain and functional outcomes that were assessed by validated scales, including but not limited to the pain and function subscales of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee injury and Osteoarthritis Outcome Score (KOOS), the Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP), visual analog scale (VAS) for pain, and the Lequesne algofunctional index for function
Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.
. Radiographic progression was defined as joint space narrowing (JSN) of ≥0.6 mm within a given period of time. Though this is not a conventional definition of radiographic progression, we used it because it was utilized by the only two studies that reported the outcome
Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.
. Withdrawals due to AEs were defined as the number of participants who discontinued study medication or withdrew from the study due to any AE, regardless of its association with the study medication. SAEs were defined as the number of patients reporting at least one AE that was classified by study authors as a “Serious Adverse Event” within the timeframe of the study. We collected GI AEs from studies involving oral bisphosphonates, because upper GI AEs, such as reflux, esophagitis, and esophageal ulcers, are commonly associated with oral bisphosphonates.
As we expected methodological and clinical heterogeneity among the studies, meta-analyses were performed using random effects models. Dichotomous outcomes (radiographic progression and safety outcomes) were analyzed using the Mantel–Haenszel method
and were reported as risk ratios (RRs) with 95% confidence intervals (CIs). Continuous outcomes (pain and function) were analyzed using the DerSimonian and Laird method and reported as standardized mean differences (SMDs) with 95% CIs
. We conducted sensitivity analyses on pain outcomes to assess any potential impact of treatment duration (≤6 months, 12 months, or 24 months) on effect sizes. Additional sensitivity analyses evaluated the influence of administration route (oral vs parenteral) and measurement scales (i.e., VAS vs WOMAC pain, Lequesne index vs WOMAC function). Publication bias was assessed using funnel plots and Egger's test
Our initial search yielded 201 references; we excluded 186 references during abstract screening. Of 15 potentially relevant RCTs, 8 were excluded during full text screening, and 7 RCTs (N = 3013) met inclusion criteria and were eligible for analysis (Fig. 1). The included trials were published between 2005 and 2015, with duration ranging from 2 to 24 months. Two of the RCTs were reported within one manuscript
Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.
. The patients' mean age ranged from 47.6 to 66.4 years (median: 62.9), and the proportion of females ranged from 42% to 85%. The majority of the studies involved participants with mild to moderate knee OA. One RCT additionally required the magnetic resonance imaging (MRI) presence of at least one BML at baseline
Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.
. Four RCTs (N = 2581) permitted continuation of stable doses of NSAIDs and/or cyclooxygenase-2 (COX-2) inhibitors in patients who had been taking these medications at baseline
Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.
Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.
Risk of bias was assessed using Cochrane risk of bias tool.
Spector, 2005; BRISK study
284
63.3
60%
Risedronate 5 or 15 mg/day vs oral placebo
ND; rescue analgesia with acetaminophen and diclofenac
12 months
WOMAC pain; WOMAC function; mean JSW change (mm); AEs
Unclear
Bingham, 2006; KOSTAR: efficacy data; E.U. trial
1251
63.6
79%
Risedronate 5 or 15 mg/day or 35 mg/week vs oral placebo
57%; from day 5 to day 3 preceding the baseline, 6-, 12-, 18-, and 24-month visits, only rescue analgesia with acetaminophen and diclofenac was permitted
24 months
WOMAC pain; WOMAC function; proportion of patients experiencing radiographic progression, defined as ≥0.6 mm of JSN over 24 months (%); AEs
Unclear
Bingham, 2006; KOSTAR: efficacy data; N.A. trial
1232
60.5
61%
Risedronate 5 or 15 mg/day or 50 mg/week vs oral placebo
72%; from day 5 to day 3 preceding the baseline, 6-, 12-, 18-, and 24-month visits, only rescue analgesia with acetaminophen and diclofenac was permitted
24 months
WOMAC pain; WOMAC function; proportion of patients experiencing radiographic progression, defined as ≥0.6 mm of JSN over 24 months (%); AEs
Unclear
Adami, 2005; KOSTAR study: pooled safety data
2483
62.1
70%
Risedronate 5 or 15 mg/day or 35/50 mg/week vs oral placebo
65%; from day 5 to day 3 preceding the baseline, 6-, 12-, 18-, and 24-month visits,nly rescue analgesia with acetaminophen and diclofenac was permitted
24 months
AEs
Unclear
Jokar, 2010
39
47.6
85%
Alendronate 70 mg/week vs oral placebo
82%; continuation of current analgesic regimen was permitted
. Although Egger's test showed no evidence of publication bias (P = 0.22), we cannot completely rule it out because we may not have had sufficient power to detect this
Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.
. Overall, the mean change in pain from baseline to study end point was not statistically significantly different between bisphosphonate and placebo (SMD = −0.16 [95% CI: −0.34, 0.02]). Pain within 6 months was reported in three RCTs (N = 193), two of which involved IV and one – IA bisphosphonates
. Though the effect of bisphosphonates on pain was larger within 6 months compared to other time points, it was not statistically significant (SMD = −0.88 [95% CI: −2.02, 0.27]). Function scores were reported in four RCTs (N = 2845) with trial duration ranging from 4 to 24 months; bisphosphonates did not have a statistically significant benefit over placebo (SMD = −0.02 [95% CI: −0.11, 0.06])
Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.
1Spector et al., 2005; 2Bingham et al., 2006 (Europe); 3Bingham et al., 2006 (N. America); 4Adami et al., 2005 (AE data from two RCTs reported by Bingham et al., 2006); 5Jokar et al., 2010; 6Laslett et al., 2012; 7Rossini et al., 2015; 8Varenna et al., 2015.
∗ Data available only from studies with parenteral (IV, IA) route of administration of bisphosphonates.
† Combined data from the North American and European Union RCTs reported by Bingham 2006.
Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.
. By 24 months, there was no statistically significant difference between bisphosphonate and placebo with regard to the proportion of patients experiencing radiographic progression (RR = 0.98 [95% CI: 0.77, 1.26]).
. The event rate in the bisphosphonate group was 3.5%. There was no statistically significant difference between bisphosphonates and placebo with regard to the number of patients experiencing at least one SAE (RR = 1.83 [95% CI: 0.38, 8.75]).
Seven RCTs (N = 3013) reported on withdrawals due to AEs
. The rate of discontinuation in bisphosphonate groups was 9.9%. There was no statistically significant difference between groups (RR = 0.88 [95% CI: 0.70, 1.12]).
. The rate of GI AEs in the bisphosphonate group was 18.7%. Our analysis revealed no statistically significantly greater risk of GI AEs in patients given oral bisphosphonates vs those given placebo (RR = 1.04 [95% CI: 0.87, 1.24]).
Sensitivity analyses, performed to assess whether administration route, short (≤6 months) vs medium (12 months) vs long (24 months) study duration, and measurement scales would affect outcomes, did not produce significant changes to any of our findings (Appendix Table AII, Table II).
Discussion
Our analysis has demonstrated that bisphosphonates provide no significant benefit over placebo in patients with knee OA with regard to pain relief, functional improvement, or prevention of radiographic progression. This conclusion has aligned itself with the results of the largest RCTs to date on the topic (Bingham 2006 and Spector 2005, both contributing over 90% of patients to our analysis), which found no notable effect of bisphosphonates on pain, function or structural outcomes in knee OA
Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.
. It is worth noting that, notwithstanding the lack of efficacy, bisphosphonates displayed good tolerability, with no statistically significant differences in AE outcomes in comparison with placebo despite relatively high doses used by some RCTs.
The reason for poor performance of bisphosphonates in knee OA RCTs may lie in the changing balance of bone-resorptive and bone-formative processes within subchondral bone over the course of the disease. In the early stage of OA, osteoresorptive mechanisms prevail, with high rate of bone remodeling
. This is the phase during which the disease could be receptive of the effects of bisphosphonates. Later in OA, bone remodeling slows down, and the balance tips in favor of bone formation – the process not amenable to the mechanism of action of bisphosphonates
. It is possible that the patients recruited in RCTs comprising our review were in stages too advanced for bisphosphonates to work. Most of the RCTs accepted patients with “mild” to “moderate” (stages 2–3) knee OA, whereas those with the earliest stages of the disease were all but absent. We concede, however, that patient recruitment in the initial OA stages may be challenging and truly feasible only in cases of secondary, post-traumatic OA
. In addition to the biphasic nature of bone remodeling in OA, the rates of bone remodeling even at the early OA stages may differ between individuals; a novel diagnostic approach may be required to assess those rates and predict whether a patient would be a good candidate for the treatment with antiresorptive agents
. The first publication, by Davis et al., 2013 reviewed both RCTs and observational studies performed in the knee, hip or spine OA patients but used only three RCTs in its meta-analyses (Spector 2005 and North American and European cohorts from Bingham et al., 2006, all studying oral risedronate in knee OA)
. The authors performed separate analyses for risedronate daily doses of 5 and 15 mg and did not reach statistical significance for any of the outcomes. However, this lack of statistical significance was not communicated in the review's abstract; instead the conclusion stated that the authors found “limited evidence that bisphosphonates are effective in the treatment of OA pain”. Considering that many providers who consult literature on a medical topic would read only an abstract and not delve into the manuscript's details, such presentation of findings could give the misleading impression that bisphosphonates are a viable option for OA treatment. Moreover, Davis et al. made several data extraction errors that exacerbated the ambiguity: the results from Spector 2005, presented as graphs, were not transcribed into correct values and, most strikingly, for all three RCTs the standard errors of the mean were inputted as standard deviations without conversion, resulting in extremely narrow CIs and presenting a picture of statistically significant results for WOMAC scores within the individual RCTs, which, in fact, were all non-significant.
The second, most recent meta-analysis on the topic, by Xing et al., 2016 also arrived at a positive verdict on the efficacy of bisphosphonates in OA
. However, this study had major methodological flaws. First, the review suffered from the same data extraction errors seen in the paper by Davis et al., such as an incorrect transcription of graphical into numerical data from Spector 2005 study or the failure to convert standard errors of mean into standard deviations. Second, Xing et al. inappropriately combined data from observational studies with those from RCTs in the same meta-analyses. Third, the review calculated mean differences, and not SMDs (which would account for the variation in measurement scales), skewing the final effect sizes. In addition, the analyses combined disparate studies performed in patients with varying OA sites and using both active and inactive (placebo) comparators and active concomitant medications. Consequently, the meta-analyses by Xing et al. were characterized by extremely high heterogeneity, as measured by the I2 statistic, which in some analyses reached 95–99% – a level that severely limits the interpretability of the results.
There were certain limitations to our study as well. Although we were able to reduce heterogeneity by restricting inclusion criteria to patients with OA of the knee, placebo comparators only, and no concomitant medications besides the conventional “rescue” analgesics such as acetaminophen or NSAIDs, the included RCTs still varied with regard to types or routes of delivery for bisphosphonates; as a result, the heterogeneity for our end-of-study pain outcome reached 76% (I2 statistic). However, heterogeneity estimates fell to 0% after we removed one study outlier that, in contrast to all other studies, reported a very large and statistically significant effect for pain (Varenna 2015); removing this outlier resulted in no changes to the final findings. We performed a number of other sensitivity analyses to investigate the possible influence of the route of administration, dose (for risedronate), treatment duration or measuring instrument (e.g., VAS vs WOMAC pain) on the outcomes; these analyses brought no significant changes to our conclusions.
Though our results suggest an apparent lack of clinical effect of bisphosphonates in patients with knee OA, these agents may still be beneficial in certain subsets of patients who display high rates of subchondral bone turnover. One of the RCTs included in our analysis, by Laslett et al., 2012, focused on such patients by restricting the inclusion criteria to those who presented with BMLs at baseline
. The authors reported a limited effect of IV zoledronic acid on VAS pain by 6, but not 3 or 12 months, and only when data were adjusted for baseline medication use, age, sex, and baseline pain score. No statistically significant benefit on pain was observed for the original, unadjusted data. Similarly, the study reported some reduction in BML area (mm2) by 6 months, with the effect losing significance by 12 months. However, the lack of effect in this study could be explained by the failure to correctly define the OA phenotype susceptible to therapy by antiresorptive agents. BMLs are thought to have heterogeneous pathogenesis mechanisms and histologic findings and may represent varying OA phenotypes
. Laslett et al. identified BMLs using proton density-weighted fat saturation (PDFS) MRI; however, it has been suggested that BMLs detected by both PDFS and T1-weighed sequences might have more degenerative structural changes and represent a phenotype different from that with BMLs detected only with PDFS (although it was theorized that BMLs detected with only PDFS had a greater potential for resolution)
Semiquantitative assessment of subchondral bone marrow edema-like lesions and subchondral cysts of the knee at 3T MRI: a comparison between intermediate-weighted fat-suppressed spin echo and Dual Echo Steady State sequences.
. A different approach for identifying the subgroups of OA patients who might benefit from bisphosphonates could involve forgoing the BML metric, since BML size reduction may arguably be a poor surrogate end point for predicting OA progression and cartilage loss, as reflected by JSN advancement
Evaluation of bone marrow lesion volume as a knee osteoarthritis biomarker–longitudinal relationships with pain and structural changes: data from the Osteoarthritis Initiative.
Change in MRI-detected subchondral bone marrow lesions is associated with cartilage loss: the MOST Study. A longitudinal multicentre study of knee osteoarthritis.
. The medial-to-lateral tibial bone mineral density (M:L BMD) ratio, acquired from subchondral bone dual-energy X-ray absorptiometry (DXA), has been suggested as a prognostic biomarker for knee OA structural progression and may aid in defining patients amenable to treatment with antiresorptives
Development of a clinical prediction algorithm for knee osteoarthritis structural progression in a cohort study: value of adding measurement of subchondral bone density.
. Simultaneous use of scintigraphy and subchondral bone DXA has also been proposed to capture the presence of high subchondral bone turnover and low subchondral bone density
In conclusion, our analysis showed that bisphosphonates neither provide symptomatic relief nor defer radiographic progression in patients with knee OA. Future RCTs should be directed at defining subsets of OA patients who display high rates of subchondral bone turnover and investigating the effects of bisphosphonates in those patients.
Contributions
EEV and MCO made substantial contributions to all of the following: conception and design; acquisition of data; analysis and interpretation of the data; drafting of the article; critical revision of the article for important intellectual content; and final approval of the article.
RRB made substantial contributions to: conception and design; acquisition of data; analysis and interpretation of the data; statistical expertise; drafting of the article; critical revision of the article for important intellectual content; and final approval of the article.
M-CM made substantial contributions to: acquisition of data; drafting of the article; critical revision of the article for important intellectual content; and final approval of the article.
TEM made substantial contributions to: conception and design; analysis and interpretation of the data; critical revision of the article for important intellectual content; and final approval of the article.
Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
The dramatic increase in total knee replacement utilization rates in the United States cannot be fully explained by growth in population size and the obesity epidemic.
Pre-emptive, early, and delayed alendronate treatment in a rat model of knee osteoarthritis: effect on subchondral trabecular bone microarchitecture and cartilage degradation of the tibia, bone/cartilage turnover, and joint discomfort.
The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model.
Enhancement of subchondral bone quality by alendronate administration for the reduction of cartilage degeneration in the early phase of experimental osteoarthritis.
The effects of bone remodeling inhibition by alendronate on three-dimensional microarchitecture of subchondral bone tissues in guinea pig primary osteoarthrosis.
Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.
Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.
Semiquantitative assessment of subchondral bone marrow edema-like lesions and subchondral cysts of the knee at 3T MRI: a comparison between intermediate-weighted fat-suppressed spin echo and Dual Echo Steady State sequences.
Evaluation of bone marrow lesion volume as a knee osteoarthritis biomarker–longitudinal relationships with pain and structural changes: data from the Osteoarthritis Initiative.
Change in MRI-detected subchondral bone marrow lesions is associated with cartilage loss: the MOST Study. A longitudinal multicentre study of knee osteoarthritis.
Development of a clinical prediction algorithm for knee osteoarthritis structural progression in a cohort study: value of adding measurement of subchondral bone density.
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