Research Review Corner: September 2013

Bone edema in vertebrae may be referred to as Modic changes (MC), a phrase coined by Dr. Michael Modic, chair of the Neurological Institute at Cleveland Clinic in Ohio, who first described the condition in 1988.

Background information

Bone edema in vertebrae may be referred to as Modic changes (MC), a phrase coined by Dr. Michael Modic, chair of the Neurological Institute at Cleveland Clinic in Ohio, who first described the condition in 1988. Studies have shown MCs are commonly observed in, and strongly associated with, low back pain. In fact, Modic changes have been reported in 46 per cent of patients with non-specific low back pain (LBP) versus six per cent in the general population.

Although three types of MCs have been described (Types 1–3), this study dealt only with Type 1. Type 1 MCs involve vertebral endplate disruption and fissuring with regions of degeneration, regeneration, reactive bone formation, endplate edema and vascular granulation tissue.  

MCs can readily be seen on magnetic resonance images (MRI). The inter- and intra-observer reliability of reporting Modic changes by MRI has been shown to be excellent — even better than for disc herniations.  

The authors of this paper previously reported that out of 61 patients undergoing lumbar disc surgery, 46 per cent had nuclear material that was infected with anaerobic bacteria. On follow-up, 80 per cent of the patients with anaerobic bacterial infections of the disc developed new MCs in the vertebrae adjacent to the disc herniations, compared to 44 per cent in patients with no infection or anaerobic bacterial infection.

Yet another recently published study by this group of researchers was an uncontrolled pilot study involving 32 chronic LBP patients with pain following a lumbar disc herniation and associated Type 1 MCs. The patients were treated with antibiotics for 90 days and monitored for various outcome measures. There were clinically important and statistically significant improvements in all outcome measures, which support the hypothesis that bacterial infection may play a role in the development of LBP with Modic changes.

This study aimed to test the efficacy of Modic antibiotic spine therapy in patients with chronic low back pain and new Modic type 1 changes in the vertebrae adjacent to a previously herniated disc.  A further goal was to determine whether a dose–response relationship could be identified.

Results

• Out of 162 patients participating in the study, 147 completed the end of treatment questionnaires and 144 fulfilled the one-year follow-up MRI, questionnaire and physical examination.
• All primary outcome measures were improved in the antibiotic group from the 100 days follow-up until one-year follow-up. The antibiotic group’s improvements on all outcome measures were superior to the placebo group at one-year follow-up. These improvements were both statistically significant and clinically important in terms of the relative magnitude of improvement.
• For most patients, pain relief and disability improvement began gradually (i.e. six to eight weeks after starting antibiotics). These improvements continued long after the end of the treatment period, with some patients reporting continuing improvement at one-year follow-up.
•   Modic changes were present on the MRIs of 130 out of a possible 134 adjacent endplates in the placebo group, and 142 out of 154 in the antibiotic group.
• Ten patients in each group demonstrated no MCs at one-year follow-up. There was a significant decrease in volume in the antibiotic group, where volume 2–4 MCs were reduced to volume 1, which was not observed in the placebo group.
• Patients receiving double-dose antibiotics appeared to improve more than the single-dose patients, although the difference was not statistically significant — probably because the trial was not powered to test for this comparison.  At any rate, the researchers’ hypothesis of a dose-response relationship was not supported.
• Sixt-five per cent of participants in the antibiotic group reported adverse events, compared with 23 per cent in the placebo group. Adverse events were mainly low-grade gastroenterological complaints. Middle-grade events were also more common in the antibiotics group (27 per cent versus 11 per cent, respectively), and considerable adverse events in 21 per cent and six per cent, respectively. One serious adverse event, involving severe vomiting with blood, was reported in the placebo group but none in the antibiotic group.

Conclusions and practical applications

Based on the results of this study and their prior work, the authors suggested a substantial course of antibiotics could be considered as a treatment option for the subgroup of patients with chronic LBP and Modic type 1 changes, but only after all other treatment options have failed.

The well-known adverse effects of antibiotic should be considered when referring patients with chronic LBP and MCs for possible treatment. According to the authors of this study, “High-dose long-term antibiotics should not be prescribed without due consideration.” 

This is the only randomized controlled trial (RCT) that has been done on this topic thus far. Additional studies involving other populations should be conducted to confirm the results and investigations on the background science should be done.

Study methods        

Participants were recruited from two secondary spine centres in southern Denmark.

The initial inclusion criteria were:

• 18 to 65 years of age,
•  lumbar disc herniation confirmed by MRI within the preceding six to 24 months, and
•  lower back pain of  more than six months duration that was  greater or equal to a six rating on a zero to 10 scale.

Patients were included even if they had sciatica and/or neuropathic pain and regardless of whether they had been treated conservatively or surgically.

The exclusion criteria were:

•  allergy to antibiotics,
• current pregnancy or lactation,
• any kidney disease, and
• pending litigation.

Participants that met the inclusion criteria were consecutively recruited into the study if their repeat MRI showed Modic type 1 changes adjacent to the herniated disc.

Patients were randomly assigned to four groups:

1. A (n = 45) one Bioclavid tablet,
2. B (n = 36) one placebo tablet,
3. C (n = 45) two Bioclavid tablets,
4. D (n = 36) two placebo tablets.

An experienced research radiologist graded the size and volume of MCs according to the Nordic Modic Protocol as follows:

• 1 = endplate only,
• 2 = up to 25 per cent,
• 3 = up to 50 per cent,
• 4 = above 50 per cent of the vertebrae.

Patients and the assessor were blinded to randomization until after the one-year follow-up.

The primary outcome measures were the Roland Morris Questionnaire (RMDQ) and lumbar pain (LBP Rating Scale), with clinically important change defined as a 30 per cent reduction of the baseline RMDQ score and two LBP rating scale points.

Secondary outcome measures were global perceived effect, leg pain, hours with LBP during the last 4 weeks, EQ-5D Thermometer, days with sick leave, bothersomeness, constant pain, MRI Modic grading, serum analysis, and four physical examination tests.

Study strengths and weaknesses

Significantly more patients in the placebo group had small volume grade 1 MCs at baseline, which would lead one to expect a more favorable outcome in this group. However, since the antibiotic group had better outcomes, this dissimilarity further emphasizes the supremacy of the effect that was seen in the antibiotic group.

Small volume grade 1 MCs frequently disappear without treatment. One study reported that 52 per cent of observed small volume grade 1 MCs were no longer visible over a four-year period. However, the current study is bolstered by the fact patients that received placebo treatment experienced little or no improvement. 

According to the authors, this is the first RCT to investigate the effect of antibiotic treatment in chronic LBP. The reported effects were in Modic type 1 patients with  chronic LBP, but it is uncertain whether the results can be generalized to Modic types 2 and 3.  However, some evidence points to Types 1 through 3 Modic changes simply being different stages in the same pathological process, so results in these subgroups should be similar.

Additional limitations of this study that should be kept in mind include:

• There may have been blinding failure as 65 per cent of those in the antibiotic group experienced side effects. It is possible the participants knew they were taking an active treatment and therefore may have reported the subjective scores differently from the placebo group.
• Dropout rate was uneven: 14 per cent in the active arm compared to 7 per cent in the placebo arm.
• A potential confounding factor was the fact that subjects had access to anti-inflammatory and analgesic medications and medical consults.
• There is potential (unreported) financial conflict of interest (many of the authors involved in the research have already founded an organization with the apparent intent of widely disseminating and commercializing their discoveries — mastmedical.com).

Additional references:

• Modic MT, Steinberg PM, Ross JS, Masaryk TJ, Carter JR. Degenerative disk disease: assessment of changes in vertebral body marrow with MR imaging. Radiology 1988; 166: 193–9.
• Albert HB, Lambert P, Rollason J, et al. Does nuclear tissue infected with bacteria following disc herniations lead to Modic changes in the adjacent vertebrae? Eur Spine J 2013; 22(4): 690-6.
• Albert HB, Manniche C, Sorensen JS, Deleuran BW. Antibiotic treatment in patients with low-back pain associated with Modic changes Type 1 (bone oedema): a pilot study. Br J Sports Med 2008; 42: 969–73.
• Dancer S. How antibiotics can make us sick: the less obvious adverse effects of antimicrobial chemotherapy. Lancet Infect Dis 2004; 4: 611–19.
• Jensen TS, Bendix T, Sorensen JS et al. Characteristics and natural course of vertebral endplate signal (Modic) changes in the Danish general population. BMC Musculoskeletal Disorders 2009; 3(10): 81.

SHAWN THISTLE, BKIN (HONS), DC, CSCS, practises full time in Toronto. He is the founder and president of Research Review Service Inc., an online, subscription-based service designed to help busy practitioners integrate current, relevant, scientific evidence into their practice (www.researchreviewservice.com ).