Efficacy of zoledronic acid for chronic low back pain associated with Modic changes in magnetic resonance imaging

Modic changes (MC) are pathological vertebral endplate and bone marrow changes visible in magnetic resonance imaging (MRI). Three different types of MC have been described; Type I (M1) lesions, considered to be the earliest and the most active stage in the process of MC evolution, are associated with vascular granulation tissue within the subchondral bone, whereas Type II (M2) lesions reflect fatty replacement of the red bone marrow [1]. The presence of mixed-type MC such as I/II (M1/2) has also been reported [2, 3]. These are thought to reflect the conversion of MC from one type to another, representing different stages of the same pathological process [3–6].

MC are considered clinically relevant due to their association with chronic low back pain (LBP) [7–10]. This association was also found in a systematic literature review [11]. In general, M1 changes have been more frequently reported as being related to LBP than other MC types [7, 9, 12, 13]. Moreover, the persistence of the M1 component correlates with persistence of symptoms [13]. However, recently the clinical relevance of MC has been questioned, as in prospective studies, MC were not indicated as having any prognostic role in future low back symptoms [14, 15].

A limited number of therapeutic options have been evaluated for MC, as only two randomized trials on the treatment of MC have been published so far: a 100-day amoxicillin-clavulanate treatment was reported to have induced a marked improvement in LBP in chronic LBP patients with a M1 change after disc herniation [16], whereas another trial found no difference on the effects of rest and exercise on LBP with MC [17]. Bisphosphonates are considered a potential treatment option for MC as bone marrow lesions are less commonly observed in patients using alendronate [18]. Zoledronic acid (ZA) is a potent bisphosphonate, which can be administered intravenously once a year and has been shown to suppress osteoclast recruitment, differentiation and function, as well as promoting apoptosis [19]. ZA has been shown to reduce the progression of bone oedema in MRI with concordant improvement in clinical measures of disease activity among patients with psoriatic arthritis [19], and improvement in knee symptoms and bone marrow lesion size among patients with knee osteoarthritis [20]. The objective of our study was to evaluate the efficacy of a single intravenous infusion of 5 mg ZA in comparison with intravenous placebo infusion among patients with chronic LBP and MC in MRI.

A single intravenous infusion of 5 mg ZA resulted in a greater improvement in LBP intensity at one month. Furthermore, the patients receiving ZA reported NSAID use at one year significantly less often than those in the placebo group. Overall, the improvements in most of the evaluated parameters were greater in the ZA group throughout the follow-up period. Adverse events were commonly observed in our study, but as expected, the reported events mostly consisted of mild to moderate acute phase reactions, as described in the literature [24, 25].

The natural course of MC is not well known. Usually M1 lesions convert to M2 lesions with time [5], although small M1 lesions may also normalize [6]. According to the current view, the persistence of the M1 component correlates with persistence of symptoms [13, 26]. We observed in another study population that symptoms persisted in almost one third of patients over a two-year follow-up, and that this persistence of symptoms was related to the persistence of the M1 component (Järvinen, unpublished observation). It is interesting to evaluate the course of symptoms in relation to changes in the M1 component on MRI in the current study population.

The current theories on the pathomechanisms of MC include discogenic inflammation [27] and low-grade bacterial infection [28]. The bacterial infection theory was supported by a recent demonstration of the presence of anaerobic bacteria in lumbar disc herniation in 80% of the new M1 changes [29], and by the positive results of a trial with antibiotic treatment [16]. On the other hand, in another Danish study, no anaerobic bacteria were found in biopsies from vertebrae with M1 lesions [30].

The suggested role of discogenic inflammation is based on the observation that the cartilaginous endplates of patients with M1 contained more tumour necrosis factor (TNF) immunoreactive cells than those of patients with M2 changes or with normal endplates [27]. Intradiscal glucocorticoid injection is therefore a logical treatment choice in cases of inflammation and consequently published case studies on intradiscal steroids into discs with M1 show improvement in symptoms in the short term [31, 32] and even normalization of M1 changes in MRI [32]. Similarly, in some cases patients with M1 had a greater medium-term improvement in disability when treated with epidural steroid injections [33].

Segmental instability has also been claimed to cause MC [7]. Two small case studies among patients with chronic LBP showed that patients with M1 changes benefitted from instrumented fusion [4, 34]. The presence of MC did not negatively influence the outcome of total lumbar disc replacement among patients with degenerative disc disease [35].

Bisphosphonates (BPs) are synthetic analogues of the endogenous bone mineralization regulators, pyrophosphates, and have shown to be potent inhibitors of osteoclast activity [36]. Nitrogen-containing bisphosphonates, such as ZA, inhibit farnesyl diphosphonate synthase and block prenylation of guanosine triphosphate-binding protein [37], control osteoblastic proliferation and differentiation [38], modulate osteoblast production of extracellular matrix proteins, regulate the secretion of several cytokines and growth factors, and enhance the proliferation and maturation of bone marrow stromal cells into the osteoblastic lineage [39]. Bisphosphonates not only inhibit osteoclasts; it has also been demonstrated that they suppress the secretion of proinflammatory cytokines such as interleukin 1 (IL-1), TNF-α and IL-6 [40]. Clodronate, a first-generation bisphosphonate, has shown to reduce synovial levels of prostaglandin E₂[41]. The positive trends observed in our study may partially be due to the general ability of bisphosphonates to regulate bone turnover by suppressing osteoclast activity or to direct anti-inflammatory effects.

Previous studies have shown that RA patients treated with ZA presented fewer new bone-erosions and less frequently progressing bone oedema in MRI [42]. Among patients with psoriatic arthritis, ZA reduced the progression of bone oedema in MRI and clinical measures of disease activity, while ZA had no effect on the progression of erosions [19]. Similarly, pamindronate has been found to be effective in patients with ankylosing spondylitis refractory to NSAIDs [43]. Bisphosphonates are generally considered safe in various indications [37]. Our preliminary results are encouraging as, in addition to the significant effect in LBP intensity at one month, there was a noteworthy decrease in the use of NSAIDs in the ZA group at one year. The higher degree of NSAID use at one year in the placebo group probably dilutes the one-year treatment difference in the primary outcome. This is a clinically relevant finding as long-term chronic use of NSAIDs may increase the risk of gastrointestinal side-effects and cardiovascular events, which may be avoided with the use of ZA.

The strength of our study is the randomized trial design. Further strengths include complete follow-up with no drop-outs and 100% adherence as the medication was given intravenously. Moreover, intravenously administered bisphosphonates may have greater treatment effects than oral bisphosphonates [44].

However, some limitations of our study should also be discussed. The small sample size of this pilot study is inadequate to demonstrate clinically relevant changes in the outcomes. However, despite the small sample a favourable trend in the ZA group was observed for most of the outcomes. However, due to multiple testing, the significance levels of secondary outcomes must be interpreted with caution. We did no a priori power calculations due to the lack of any previous data on the efficacy of ZA in the studied indication. The patients were well informed of possible adverse effects; this may have contributed to a large amount of reports of acute phase reaction symptoms. Some of the main determinants of the risk of acute phase reactions include younger age and higher number of circulating inflammatory cytokines and lymphocytes such as gammadelta cells [24]. The patients, the study nurse, the medical team in charge of the patient, the physician performing the assessments and infusion, and the statistician performing the analyses were all blinded to the allocation. However, the high incidence of acute phase reaction symptoms in the ZA group may have revealed the concealment to some patients. Unfortunately, we did not evaluate the patients’ perception of the nature of the treatment they had received. Therefore pre-infusion prophylaxis treatment was assigned to all patients and the observed higher incidence of post-infusion symptoms was an expected finding in the ZA group. However, some patients in the control group also experienced acute phase reactions.

To our knowledge, this is the first randomized controlled trial to investigate bisphosphonates in chronic, non-specific LBP. The improvement in the intensity of LBP was greater with a single intravenous infusion of 5 mg ZA compared to placebo at one month. We believe that ZA is an interesting therapeutic alternative for this common condition, which is difficult to treat effectively with conservative treatment approaches [17]. We acknowledge that ZA should only be reserved for patients with severe disabling LBP, with confirmed MC in MRI, and when symptoms are not adequately controlled with pain medication and physiotherapy. Although the results are encouraging, larger studies are required to prove the efficacy of ZA in patients with LBP due to MC.