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Address correspondence and reprint requests to: T. Neogi, Boston University School of Medicine, 650 Albany Street, Suite X-200 Boston, MA, 02118, USA. Tel.: 617-358-9650; Fax: 617-358-9653.
Bone marrow lesions (BMLs) contribute to pain and progression of knee OA. Bisphosphonates may be a potential disease-modifier through amelioration of BMLs. We sought to determine the effect of oral bisphosphonates on BML volume over 12 months.
Design
Women in the Osteoarthritis Initiative who newly initiated an oral bisphosphonate were propensity-score matched to non-initiators. BML volume was assessed using sagittal turbo spin echo fat-suppressed intermediate-weighted MR images at the index date and 12 months later. A validated semi-automated process was used to segment subchondral OA-related BMLs to determine total volume of BMLs based on number of voxels within the outlined area of interest. Mean change in BML volume over 12 months among bisphosphonate initiators was compared with non-initiators using multiple linear regression.
Results
145 bisphosphonate initiators were identified, who were well-matched to their comparators. The difference in mean change in total BML volume between the two groups, regardless of presence of baseline BMLs, was not significant (P = 0.4, 95% CI -156.6 to +354.2). The proportion of participants with decreased, increased, or unchanged BML volumes over the 12 months were similar in both groups. Among those with baseline BMLs, bisphosphonate initiators had a greater proportion with a decrease in BML volume compared with stable or increased BML volume than non-initiators (P = 0.03).
Conclusions
In this ‘real-world’ setting of women starting bisphosphonates, we found no clear evidence of benefit on BML volume over a 12-month period, though a trend towards a decrease in BML volume was noted.
Structural abnormalities detected by knee magnetic resonance imaging are common in middle-aged subjects with and without risk factors for osteoarthritis.
that can be visualized on magnetic resonance imaging (MRI) as areas of increased signal intensity within the bone marrow.
The clinical importance of Bone marrow lesions (BMLs) lies in the fact that these lesions are strongly associated with joint pain in OA, with fluctuation in BMLs paralleling fluctuation in knee pain
Development of bone marrow lesions is associated with adverse effects on knee cartilage while resolution is associated with improvement-a potential target for prevention of knee osteoarthritis: a longitudinal study.
. Because there is a lack of effective structure-modifying therapies that can also provide symptomatic benefit in OA, BMLs have garnered much attention as a potential target for intervention to achieve both clinical improvement in pain and halting disease progression.
Bisphosphonates have been studied as a therapeutic option in OA in part for their potential to ameliorate BMLs. Bisphosphonates have also been shown to have chondroprotective effects in animal models of OA and in vitro
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.
Arthritis Rheum: Official J Am Coll Rheumatol.2004; 50: 1193-1206
Correlation between bone lesion changes and cartilage volume loss in patients with osteoarthritis of the knee as assessed by quantitative magnetic resonance imaging over a 24-month period.
. However, results from randomized trials have been mixed. In two randomized trials of risedronate, there was no significant improvement in symptoms or slowing of radiographic OA progression, though there was reduction in levels of cartilage degradation
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.
Arthritis Rheum: Official J Am Coll Rheumatol.2006; 54: 3494-3507
. One concern about these trials was the lack of sensitivity in using radiography for structural endpoints. Subsequently, a randomized controlled trial of IV zoledronic acid using MRI-based BML volume as a structural endpoint demonstrated beneficial effects of on symptoms and BML volume at 6 months, though this effect was no longer significant at 12 months
. Whether benefits to BML volume may be observed with oral bisphosphonates is not known. Further, there is a concern that long-term suppression of bone turnover may be detrimental to healing of BMLs.
We therefore sought to determine the relation of commonly prescribed oral bisphosphonates to BML volume over 12 months in a large cohort of individuals with or at risk of knee OA.
Methods
Participants and study sample
The Osteoarthritis Initiative (OAI) is a longitudinal cohort of 4,796 adults aged 45–79 at baseline with or at risk of knee OA. Participants were recruited from four clinical sites (Memorial Hospital of Rhode Island, the Ohio State University, University of Maryland and Johns Hopkins University and the University of Pittsburgh) between 2004 and 2006. For the current study, we limited our sample to women since bisphosphonates are primarily prescribed to women. Women who reported concurrent use of other bone-active agents such as parathyroid hormone, calcitonin, or raloxifene were excluded. We also excluded individuals who did not have MRIs obtained at the index date and 12 months later, and those who missed the clinic visit prior to the index date.
Exposure: bisphosphonate use
Oral bisphosphonate users were identified by self-report. We identified incident bisphosphonate users as women who did not report use of an oral bisphosphonate at baseline but did so at a subsequent visit. The visit at which new bisphosphonate initiators were identified was considered as the index visit. Women who did not report bisphosphonate use at the visit a bisphosphonate initiator was identified were considered for inclusion as a non-user comparator.
Outcome: BML volume
MRIs were acquired annually with one of four identical Siemens (Erlangen, Germany) Trio 3-T MR systems at each clinical site. For this study, we used data from 0 to 48 months. BML volume was measured in the identified study sample (described below) at the index date and 12 months later. BML quantitative measurements were performed using a sagittal intermediate-weighted, turbo spin echo, fat-suppressed MR sequence (slice thickness 3 mm). A validated, semi-automated process was used to segment the subchondral OA-related BMLs in the distal femur and proximal tibia to determine the total volume of BMLs based on the number of voxels (0.382 mm2) within the outlined region of interest
. The software presents hyperintense areas in green based on gray-scale thresholding, which changes to red when the reader selects areas of subchondral OA-related BML (Fig. 1(a); the final segmented BML is shown in Fig. 1(b)). Intra- and inter-reader reliability were 0.96 and 0.97, respectively.
Fig. 1Bone marrow lesion assessment on MRI. a: Example of BML identification; b: Example of final segmented BML.
We conducted a propensity score-matched study to examine the relation of initiating oral bisphosphonate with BML volume over time. Variables in the propensity score model included age, race/ethnicity, body mass index (BMI), minimum adult weight, marital status, education, income, employment, health insurance, blood pressure, SF-12, activity limitation, smoking status, alcohol use, comorbidity score, renal disease, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, knee pain, gait speed, physical activity, Kellgren and Lawrence (KL) grade, inflammatory arthritis, prednisone use, total dietary intake, dietary calcium intake, calcium supplement use, vitamin D prescription or supplements, estrogen use, fractures, falls and oophorectomy/hysterectomy. These were measured at the visit prior to the index date. Details of these variables can be found at: https://nda.nih.gov/oai. Multiple imputation was used to address missing covariate data. We propensity score-matched each bisphosphonate initiator with a non-initiator using a greedy-matching algorithm
We evaluated the mean change in BML volume over 12 months among oral bisphosphonate initiators compared with non-initiators using multiple linear regression after assessing for normality by examining the histograms and boxplots. In the full sample and among those with BMLs at their index visit (i.e., baseline), we assessed the proportions with decrease, increase, or no change in BML volume among oral bisphosphonate initiators compared with non-initiators over the subsequent 12 months.
Results
Alendronate, risedronate, and ibandronate were the only oral bisphosphonates that were self-reported, with alendronate being the most common. A total of 145 oral bisphosphonate initiators who also had the requisite MRIs obtained at the index date and 12 months later were propensity-score matched with 145 non-initiators. The mean age of both groups was 65 and mean BMI was 26. Overall covariate data was well balanced among initiators and non-initiators, with SMDs <0.1 (Table I). Presence of BMLs at the index visit among both groups was similar (51% of initiators and 47% of non-initiators).
Table IBaseline characteristics after propensity-score matching
Baseline Participant Characteristics
Bisphosphonate Initiators N = 145
Bisphosphonate Non-Initiators N = 145
Age (years), mean (SD)
64.8 (8.0)
65.1 (7.8)
BMI (kg/m2), mean (SD)
26.3 (4.3)
26.2 (4.1)
Caucasian
83%
88%
At least college education
53%
57%
Prior fracture
26%
23%
Prior fall
32%
37%
Prior oophorectomy/hysterectomy
34%
32%
Calcium supplement use
92%
89%
Vitamin D supplement use
88%
85%
KL grade ≥ 2
50%
56%
Presence of BML at baseline
51%
47%
Baseline volume of BML (mm3), mean (SD)
392.2 (738.8)
355.6 (704.6)
SD: standard deviation, BMI: Body mass index, KL: Kellgren–Lawrence, BML: bone marrow lesion.
The mean change in total BML volume for the overall sample, regardless of presence of BMLs at baseline, was not statistically significantly different between the two groups (difference in mean change in total BML volume: 98.8 mm3, 95% CI -156.6 to +354.2, P = 0.4). In the whole sample, the proportion of participants with decreased, increased, or unchanged BML volume over our 12-month study period was similar among both groups, though, there was a trend towards a decrease in BML volume or remaining unchanged among bisphosphonate initiators (P = 0.07) (Fig. 2). Further, among those with BMLs at baseline, bisphosphonate initiators were more likely than non-initiators to have decreased BML volume (48% vs 41%, P = 0.03).
Fig. 2For the whole sample, the proportion of bisphosphonate initiators and non-initiators experiencing decreased, unchanged, or increased BML volume over 12 months was similar (0.07).
In this ‘real-world’ setting of women with or at risk of knee OA starting bisphosphonates, we found no clear evidence of benefit or harm of starting oral bisphosphonates over a 12-month period on BML volume. However, for those women with BMLs at baseline, we noted a trend towards decreased or stable BML (as opposed to worsening) volume among bisphosphonate initiators.
Several observational studies have examined the potential for bisphosphonates to improve OA outcomes. A cross-sectional study of various anti-resorptive medications found that alendronate was associated significant reduction in knee pain and decreased subchondral bone lesions among women with knee OA
. Another observational study demonstrated that risedronate 50 mg weekly may prevent increase in BML size, although this finding was not statistically significant
. Two large population-based studies using electronic health records reported a ∼25% lower risk of knee replacement surgery, a surrogate indicator of end-stage osteoarthritis, with use of bisphosphonates
Bisphosphonate use and the risk of undergoing total knee arthroplasty in osteoporotic patients with osteoarthritis: a nationwide cohort study in Taiwan.
. While not directly related to OA, in a secondary analysis from a randomized control trial, use of alendronate was associated with decrease in spinal osteophytes and less disc space narrowing
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.
Arthritis Rheum: Official J Am Coll Rheumatol.2006; 54: 3494-3507
. Using BMLs as a potential therapeutic target has also been assessed in a trial of a patellar knee brace that demonstrated benefits in symptoms and BMLs at the patella over 6 weeks
, providing proof-of-concept for pursuing treatment of BMLs in the management of OA.
A concern has been raised about potential negative effects of long-term suppression of bone turnover in OA. There is a theoretical risk of increased bone stiffness due to ongoing laying down of bone without concomitant resorption
. Our results do not indicate concerns for adverse outcomes at least over a 12 month period, though a longer follow-up would be needed to better assess potential harmful effects of long-term use.
Limitations of our study include our relatively small sample size to precisely demonstrate beneficial effects, reflecting the low numbers of bisphosphonate initiators in the OAI. Although we used propensity score-matching, there may still be residual confounding. Adherence to bisphosphonates over the course of our study period was not evaluated. Our follow-up period was also only 12 months, making us unable to assess longer term effects of bisphosphonates on BMLs. Strengths of our study include the prospective ‘real world’ setting of bisphosphonate users. We used propensity score matching to limit confounding by indication bias and used a new user design to avoid prevalent user bias. Our BML volume assessment was highly reproducible.
In conclusion, our study highlights that while there is no definite harm in use of bisphosphonates over 12 months as a disease-modifying agent in OA, there is no clear evidence of benefit, though a suggestion of benefit was noted among those with BMLs at baseline.
Contributions
PB was involved in drafting the article and critical revision. MS, CR, JD and NL were involved in data analysis and critical revision. YZ was involved in study design and critical revision. TN was involved in conception, study design, critical revision and final approval of the article.
Conflict of interest
The authors do not have any personal or financial competing interests.
Funding
This work was supported by an Arthritis Foundation Innovative Research Grant and NIH P30AR072571. TN is supported by NIHK24AR070892. Sponsors played no role in the conduct of the study or preparation of this manuscript.
Acknowledgements
None.
References
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Turkiewicz A.
Zhang F.
Englund M.
Structural abnormalities detected by knee magnetic resonance imaging are common in middle-aged subjects with and without risk factors for osteoarthritis.
Development of bone marrow lesions is associated with adverse effects on knee cartilage while resolution is associated with improvement-a potential target for prevention of knee osteoarthritis: a longitudinal study.
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.
Arthritis Rheum: Official J Am Coll Rheumatol.2004; 50: 1193-1206
Correlation between bone lesion changes and cartilage volume loss in patients with osteoarthritis of the knee as assessed by quantitative magnetic resonance imaging over a 24-month period.
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.
Arthritis Rheum: Official J Am Coll Rheumatol.2006; 54: 3494-3507
Bisphosphonate use and the risk of undergoing total knee arthroplasty in osteoporotic patients with osteoarthritis: a nationwide cohort study in Taiwan.
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