By: 13 November 2015
Part 2: The Genetics of metabolic bone diseases which influence back pain

Part 2: The Genetics of metabolic bone diseases which influence back pain

Osteoporotic vertebral fractures

Vertebral insufficiency fractures are a major cause of chronic low back pain. In the year 2000, there were approximately 1.4 million people suffering with vertebral fractures secondary to osteoporosis [51]. There are known genetic factors which influence the onset of osteoporosis, mostly related to oestrogen function. Erdogan et al. [52] found that ERα gene polymorphisms correlated with bone density in 126 postmenopausal Turkish females, which concurred with the findings of Gennari et al. [53]. There may be an advantage conferred to the intervertebral discs by having low bone mineral density, according to Wang and colleagues [54]. An MRI (magentic resonance imaging) and DEXA (dual-energy X-ray absorptiometry) study of 359 people’s lumbar spines showed a significant inverse correlation between bone mineral density and lumbar disc degeneration in females, and a positive trend in males, again supporting the hypothesis that osteoporosis has a protective effect on disc integrity [54].

Whereas low bone density increases the risk of painful insufficiency fractures, it appears that high bone mineral density correlates with disc degeneration. A recent cadaveric study showed that when CT scans calculated vertebral body bone mineral density, i.e. excluding the posterior elements and endplates, there was a significant association with increasing bone density, correlating with more severe adjacent disc degeneration, as seen on discography. Unfortunately, being a cadaveric study, there was no available information relating to associated symptoms [55]. Conflicting evidence comes from Adams et al., who performed mechanical studies of cadaveric lumbar spines. The spines were compressed and the load distribution assessed in the three spinal columns (anterior half vertebral body, posterior half vertebral body and neural arch). The neural arch accepted more load according to the degree of disc degeneration, with approximately two-thirds of total compressive load transferred through the facet joints in spines with severe disc degeneration. They found that the bone mineral density of the anterior vertebral body was reduced in those vertebrae that were effectively stress-shielded by the posterior load transfer. The team hypothesised that this may increase the risk of anterior insufficiency fractures in the flexed position [56]. More research is required to conclude whether there is truly an inverse relationship between vertebral body bone mineral density and disc degeneration.


The genetics of vertebral fractures from other metabolic bone diseases

The most common lysosomal storage disease, Gaucher disease, is due to a genetic deficiency in lysosomal glucocerebrosidase. One study found a 15 per cent prevalence of vertebral fractures in 105 patients with Gaucher disease type 1 [57]. Osteogenesis imperfecta (OI) is a group of inherited diseases affecting collagen type 1, which result in osteopenia. Patients with OI have increased incidence of fractures including vertebral fractures. Paget’s disease is the second most prevalent metabolic bone disease after osteoporosis. There are subsets of Paget’s disease which are caused by genetic mutations of the sequestosome gene (SQSTM1); however, not all types of Paget’s disease have been definitively associated with genetic deficiences [58]. Close associations have been found between four genes and the development of Paget’s disease, implying that patients with this disease are likely to have a genetic mutation which predisposes them to developing the illness [59].

The inherited disorders of renal phosphate wasting result in hypophosphataemia and rickets. This group of disorders results in skeletal deformities as well as an increased risk of fractures.


The genetics of rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune condition which manifests itself as a chronic symmetrical polyarthritis due to synovitis in around one per cent of the population. It mainly affects women and genetics are believed to account for around 60 per cent of susceptibility to RA [60] – there is an increased incidence of RA in first-degree relatives of those with the condition, and 15 per cent concordance is seen in monozygotic twins. Rheumatoid factors are present in the majority of patients with RA, and these comprise circulating autoantibodies against the Fc portion of IgG that aggregate into complexes to trigger inflammation via the activation of complement. The disease process in RA affects the lumbar spine causing symptomatic backache of at least three months in one-third of patients [61]. As the facet joints are synovial joints, rheumatoid synovitis can create synovial cysts which can cause both backache and sciatica [62]. Although most literature refers to cervical spine instability as a consequence of RA, there are several reports which explore histopathological manifestations of the disease in the lumbar spine [63]. There is a significant correlation between disease activity and radiological changes in the lumbar spine, which can be seen on both plain radiography and MRI [64].

The association of RA with the inheritance of certain type-II HLA (human leukocyte antigen) genes is now well described; HLA-DR4 is found in at least 50 per cent of patients with RA and is known to correlate with a more severe form of RA, as does possession of the HLA-DRB1* 0404/0401 haplotype. The development of anti-citrullinated cyclic peptide (anti-CCP) antibodies in patients with RA can help distinguish early RA from other arthropathic processes, and also identifies those patients most likely to develop joint erosions. Anti-CCP positivity has been linked to the loci near the HLA-DRBI gene (which is involved in autoantigen presentation) and PTPN22 (protein tyrosine phosphatase, non-receptor type 22; which has a role in T-cell receptor signal transduction) in European populations. There are also reported associations between RA and tumour necrosis factor receptor-associated factor (TRAF1).

RA is managed with combinations of disease-modifying anti-rheumatic drugs (DMARDs) – such as methotrexate, sulphasalazine, leflunamide and ciclosporin – to achieve cytokine inhibition, although anti-TNF agents such as etanercept and adalimumab are now being used for patients whose disease fails to respond to DMARDs alone. Alongside DMARDs, the management of RA often involves multiple courses of corticosteroids for acute exacerbations, which can lead to osteoporosis and consequent back pain, particularly where vertebral body collapse occurs. Many patients who have had RA treated with corticosteroids for a number of years will be on prophylactic treatment to prevent and slow the onset of osteoporosis (e.g. using bisphosphonates alongside calcium and vitamin D supplementation, with encouragement to the patient to increase physical activity), but osteoporosis unfortunately remains an important cause of back pain in patients with RA.


The genetics of the seronegative spondyloarthropathies

The seronegative spondyloarthropathies are a group of inflammatory arthropathies in which no rheumatoid factors are found (nor, usually, anti-CCP antibodies), and includes psoriatic arthritis, ankylosing spondylitis, reactive arthritis, and the enteropathic arthritis found in inflammatory bowel disease. The seronegative spondyloarthropathies affect the spine along with peripheral joints, in contrast to RA in which the spine is a relatively minor component of the disease process in the majority of patients. The genetic association of these disorders with HLA-B27 is well known and is particularly marked in patients with ankylosing spondylitis, of whom over 90 per cent will be HLA-B27 positive. The role of HLA-B27 in triggering seronegative arthropathies has been postulated to be due to molecular mimicry, in which structural similarities between infectious organisms and the HLA molecule leads to the formation of antibodies that react against self antigens. HLA-B27 molecule is also known to have an unusually large tendency to fold itself incorrectly, but the relevance of this to the disease process in the seronegative spondyloarthropathies is unclear [65]. People who express HLA-B27 have between a one and 5 per cent chance of developing ankylosing spondylitis, whereas most people who suffer with the disease are positive for HLA-B27. A genetic study involving 1,787 patients with ankylosing spondylitis and 4,800 controls has recently found that in those patients with HLA-B27-positive ankylosing spondylitis, there is also expression of the gene ERAP1, suggesting that ERAP1 influences the risk of developing the disease in normal people who are HLA-B27 positive. This finding also suggests that inhibition of ERAP1 in HLA-B27-positive patients may help to cure the disease itself [4].


The genetics of autoimmune rheumatic disorders

The spine may rarely be involved in autoimmune disease processes such as systemic lupus erythematosus (SLE). Back pain may be experienced in such patients where the disease process has triggered major joint deformities (e.g. of hip or knee in the Jaccoud’s arthropathy of large joints sometimes seen in SLE). SLE is known to have a genetic component in its aetiology; concordance in monozygotic twins is around 25 per cent, and HLA-A1, -B8 and -DR3 are all linked to its development. The risk of developing SLE is known to be greatly increased in homozygotes for complement deficiencies of C1q, C3 and C4 [68].


Backache and crystal deposition arthropathies

Gout and pseudogout are rarely associated with backache. Crystals have been aspirated from the lumbar facet joints of a backache patient [69].


Spondyloarthropathies and back pain

Ankylosing spondylitis (sacroiliitis a diagnostic criterion)

Psoriatic arthritis (5 per cent have sacroiliitis with male predominance) [66]

Spondyloarthropathy related to inflammatory bowel disease (IBD) (30 per cent of IBD patients) [67]


Coming next…

The role of genetics in the causes and perception of back pain. Part III: The genetics of disc degeneration and lumbar disc herniation will be published in the Winter 2015 issue of Spinal Surgery News.



Iona Collins is a consultant orthopaedic spinal surgeon at Morriston Hospital in Swansea.

Suzanne Docherty is a haematology SpR at Norfolk and Norwich University Hospitals NHS Foundation Trust.

Ray Iles is chief executive officer at MAP Diagnostics.

Masood Shafafy is a consultant orthopaedic spinal surgeon at Queens Medical Centre in Nottingham.

All authors contributed equally to this work.



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