Background
Up to 80% of people experience low back pain (LBP) at some point in their lifetime [
1], which can cause notable physical and psychological impairment. This results in substantial direct and indirect expenses for the healthcare industry and the economy as a whole [
2]. According to a study conducted between 1990 and 2019, the global burden of LBP resulted in 63.7 million disability-adjusted life years [
3].
Over 90% of LBP cases are considered non-specific, making it difficult to determine the exact cause of the pain, thereby posing a challenge for effective management [
4]. In recent decades we have discovered that radiological alterations in the vertebral endplate and surrounding bone marrow, visible on MRI, are linked to LBP [
5,
6]. These changes, known as Modic changes (MCs), were first described by Michael Modic [
7] and are classified into three types based on T1 and T2-weighted signal intensity. They are most commonly found at the L4/5 and L5/S1 vertebral levels [
8]. The correlation between these specific radiological changes and LBP has led to the identification of a subgroup of patients with LBP who may be treated with therapeutic agents that target bony metabolism.
Previous studies have demonstrated that potent anti-resorptive drugs such as intravenous zoledronic acid reduce LBP in patients with MCs [
9]. A decrease in pain scores was associated with a conversion of MC type, as well as decrease in area and volume affected by MCs. Towards ease of administration, a recent clinical trial administered oral zoledronic acid and found a similar reduction in both MCs as well as LBP [
10]. However, this study drug did not proceed towards commercialization. Alendronic acid is approximately 20-fold less potent than zoledronic acid [
11] and ingested orally as either a daily (10 mg) or weekly (70 mg) regimen that is recommended as a cost-effective first-line treatment option for post-menopausal osteoporosis [
12]. Continuous treatment is advocated for up to 5 years, after which a drug holiday is recommended in view of risks of cumulative bisphosphonate exposure. The use of such nitrogen-containing oral bisphosphonates of milder potency is commonplace in the treatment of osteoporosis and has long been reported to reduce back pain [
13,
14]. Nevertheless, it remains unknown how treatment affects MCs. Here, we characterized MCs in patients receiving long-term oral alendronic acid in comparison to matched controls not receiving anti-resorptive drugs.
Discussion
In this case control study, patients receiving oral alendronic acid treatment for at least 1-year demonstrated a lower prevalence of MCs over the lumbar spine. Treatment also resulted in a reduced area and volume of type 2 MCs in comparison to matched controls. Our results reveal that MCs, and potentially LBP, may be attenuated by oral alendronic acid intake.
Modic changes are proposed to occur following damage to the disc and endplate which results in an immune response from adjacent bone marrow [
22]. Nitrogen-containing bisphosphonate such as alendronic acid reduce bony resorption by osteoclasts via selective inhibition of farnesyl pyrophosphate synthase [
11]. Prior studies investigating the effects of anti-resorption drugs on MCs have favoured more potent formulations such as oral and intravenous zolendronic acid [
10,
23]. Denosumab given subcutaneously has also been found to have a comparable result to IV zoledronic acid in treating MC-associated LBP at 6-months, whist being associated with less adverse effects [
9]. Alendronic acid intake of 6-months has been reported to improve pain scores and quality of life measures in postmenopausal osteoporotic females [
13] which was associated with a reduction in biochemical markers of bony turnover. Remarkably, the reduction of pain in accordance with facial scale score (FSS) was 55% at 6-months post treatment with weekly oral alendronic acid as compared to weekly elcatonin injection, with the FSS declining from 6.1/10 to 2.7/10 in the alendronic acid group [
13], and others have similarly reported significant reductions in limited-activity and bed-disability days following the use of oral alendronic acid [
14]. As a pathophysiological correlate, a post-menopausal animal model receiving alendronic acid demonstrated reduced degenerative changes in the nucleus pulposus and annulus fibrosis [
24]. Here, we describe for the first time a radiological difference in MCs in patients receiving long-term alendronic acid treatment in comparison to matched controls not on bisphosphonates, which may be an underlying mechanism by which LBP and functional measures improved in related clinical trials [
13,
14].
Our study found type 2 MCs to predominate amongst the cohort. Others have similarly reported on the abundance of type 2 changes amongst the general population [
25] as well as patient subgroup attending the spine clinic [
10], and an increased prevalence has been reported with aging [
26]. The association between MC and LBP is clearest with type 1 changes [
8,
27] which are thought to represent bony edema and inflammation [
28]. Conversion of type 1 changes to type 2 or type 3 changes is well-correlated with a decrease in LBP. Although fewer in number, prior studies have also demonstrated a correlation between a reduction in type 2 MCs and LBP [
27,
29]. Additionally, a recent histological study has indicated type 2 MCs to represent fibroinflammatory changes with complement system activation, features consistent with a pain generator. Regardless of MC type, the extent of reduction in MC area and volume compared favourably to studies utilizing more potent anti-osteoporotic medications [
9,
10,
30]. In combination with prior findings on the effect of oral alendronic acid on improving LBP and function, our findings suggest that oral bisphosphonates should be prescribed in osteoporotic patients not only to improve bony turnover, but to alleviate LBP especially in patients with pre-existing MCs.
Limitations to the study include the cross-sectional study design whereupon we were unable to establish a temporal link between alendronic acid intake and conversion in MC type and reduction of MC area / volume since there were no serial MRIs for comparison, nor of routinely available MRIs prior to the initiation of bisphosphonate treatment as compared to after. Another important omission from our study was patient reported outcome measures and functional scores, as these were not routinely assessed at the time of imaging. There was also significant heterogeneity in the dosing period of alendronic acid, and recruitment of larger sample sizes may have enabled for better subgroup analysis of dosing duration in relation to MCs, which this study found to be insignificant.
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