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Chronic osteomyelitis – a review

By Sarfaraz S, Janjua S, I O’Keeffe, and Harney S - 12th Jun 2025


Reference: June 2025 | Issue 6 | Vol 11 | Page 34


Chronic non-bacterial osteomyelitis (CNO) is an auto-inflammatory, chronic, sterile condition in children, primarily affecting bones, and can cause bone destruction if left untreated.1 Chronic recurrent multifocal osteomyelitis (CRMO) is considered a severe form of the same disease. SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is an adult disease with similar features.

CNO is a diagnosis of exclusion. In the following sections, epidemiology, clinical and laboratory features, pathophysiology, and treatment of CNO will be discussed.

Epidemiology

CNO is a rare disease with an incidence of four cases per million children. There are approximately 500 existing cases worldwide.2 It is likely an under-diagnosed and an under-reported condition due to multiple factors which include lack of awareness among the general population, difficulty getting data from countries with no national registry, and the absence of validated diagnostic criteria. S

pecialists in adult rheumatology come across patients who are already diagnosed for ongoing management, but initially these patient are seen by different specialties, so close collaboration between orthopaedics, paediatric rheumatology, infectious disease, oncology, and radiology services is crucial for timely diagnosis of this condition, with the aim of preventing complications and avoiding unnecessary exposure to prolonged antibiotics and cytotoxic medications.3

The condition has been reported in all races and ethnicity, with peak onset between seven and 12 years of age and a slightly higher prevalence in European countries.4 Other causes of bone pain should be investigated if the presentation is before three years of age, such as an isolated bone tumour.

Pathogenesis

The exact pathogenesis of CNO is still not known. CNO/CRMO share features with monogenic auto-inflammatory conditions, though no single gene has yet been identified as a cause of CNO. Recent data suggest CNO is a genetically complex disorder with dysregulated TLR4/MAPK/ inflammasome signalling cascades resulting in an imbalance between pro- and anti-inflammatory cytokine expression, leading to osteoclastic activation and osteolytic lesions.5,6

There is no proven infectious aetiology, as prolonged courses of antibiotics are ineffective in treating CNO. Any organisms identified on biopsy were felt to be contaminants.7

Presentation

The cardinal feature of CNO/CRMO is insidious onset of bone pain, which may be associated with local warmth and swelling. It can affect any part of the bone but the metaphysis of long bones of the lower extremities is the most common site, followed by the pelvis, vertebrae, clavicle, and long bones of the upper extremities. It can present with unifocal or multifocal lesions. Silent asymptomatic lesions are usually detected on full body imaging.8

Diagnosis

The diagnosis of CNO/CRMO is generally a diagnosis of exclusion. There are no existing diagnostic biomarkers. Routine laboratory tests, including markers of inflammation, are normal or slightly elevated. The results of microbiological and serological markers for bacterial, viral, and fungal organisms are negative. Additionally autoantibodies for specific connective tissue disorders are also negative.

Bone biopsy is required to rule out infectious osteomyelitis and malignancies, both of which can have similar presentations. Histopathological examinations show non-specific findings, with infiltration of bone by neutrophils, plasma cells, lymphocytes, macrophages, and histiocytes.

Imaging remains crucial for diagnosis of CNO/CRMO. Plain x-ray is normal in most cases. Computed tomography has limited value due to difficulty in differentiating between acute and chronic lesions. Bone scintigraphy and positron emission tomography (PET)-CT are generally avoided in children due to the risk of exposure to radiation.

Bone scintigraphy is also difficult to interpret in children due to increased physiological uptake at the growth plate, the site commonly affected by CNO/CRMO. Given the lack of exposure to ionising radiation and its ability to detect asymptomatic (silent) lesions, whole body MRI is considered the gold standard investigation.

No definitive diagnostic criteria have been identified so far. The most commonly used are the Jansson and Bristol criteria.9,10 Jansson’s algorithm includes four major and six minor criteria. The major criteria are:

  • Radiologically proven osteolytic bone lesion;
  • Multiple bone lesions;
  • Palmoplantar pustulosis (PPP) or psoriasis;
  • Sterile bone biopsy with signs of inflammation.

The six minor criteria are:

  • Normal blood count and general health;
  • Mild to moderately raised
    CRP and ESR;
  • Observation time >6 month;
  • Hyperostosis;
  • Associated with other autoimmune diseases apart from PPP or psoriasis;
  • Grade 1 or 2 relatives with autoimmune or auto-inflammatory disease, or with non-bacterial osteomyelitis.

The Bristol diagnostic criteria require the presence of typical clinical findings (bone pain +/- localised swelling without significant local or systemic features of inflammation or infection and radiological findings – MRI showing bone marrow oedema,+/- bone marrow expansion, lytic areas and periosteal reaction, or plain radiography showing a combination of lytic areas, sclerosis, and new bone formation) plus one of the following:

  • ≥1 bone (or clavicle alone) involved without significantly raised CRP;
  • Unifocal disease other than clavicle or CRP >30g/L with bone biopsy showing inflammatory changes and no bacterial growth whilst not on antibiotic therapy.

As there are lots of limitations to these diagnostic criteria, CNO remains a diagnosis of exclusion.

Treatment

The initial therapy for CNO is non-steroidal anti-inflammatory medication at a standard dose. Duration of therapy depends on initial response and monitoring by MRI. Children should be closely monitored for recurrence of disease.

Episodic flares can be managed by retreatment with NSAIDs for a few months. CNO/CRMO involving the spine has shown a favourable outcome with the addition of bisphosphonate.11

Use of disease modifying anti-rheumatic medication, tumour necrosis factor inhibitor, and/or bisphosphonate is reported in literature for refractory cases to induce remission and prevent bone destruction.

References

  1. Yongdong Zhao M, PhD, Fatma Dedeoglu, MD. Chronic nonbacterial osteomyelitis (CNO)/chronic recurrent multifocal osteomyelitis (CRMO) UpToDate; 2022 [02/06/2024]. Available at: www.uptodate.com/contents/chronic-nonbacterial-osteomyelitis-cno-chronic-recurrent-multifocal-osteomyelitis-crmo-in-children.
  2. Roderick MR, Sen ES, and Ramanan AV. Chronic recurrent multifocal osteomyelitis in children and adults: Current understanding and areas for development. Rheumatology (Oxford). 2018;57(1):41-8.
  3. Zhao DY, McCann L, Hahn G, et al. Chronic nonbacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO). J Transl Autoimmun. 2021;4:100095.
  4. Jansson AF and Grote V. Nonbacterial osteitis in children: Data of a German incidence surveillance study. Acta Paediatrica. 2011;100(8):1150-7.
  5. Ferguson PJ and Laxer RM. New discoveries in CRMO: IL-1β, the neutrophil, and the microbiome implicated in disease pathogenesis in Pstpip2-deficient mice. Semin Immunopathol. 2015;37(4):407-12.
  6. Greenhill CJ, Jones GW, Nowell MA, et al. Interleukin-10 regulates the inflammasome-driven augmentation of inflammatory arthritis and joint destruction. Arthritis Res Ther. 2014;16(4):419.
  7. Girschick HJ, Raab P, Surbaum S, et al. Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis. 2005;64(2):279-85.
  8. Roderick MR, Shah R, Rogers V, et al. Chronic recurrent multifocal osteomyelitis (CRMO) – advancing the diagnosis. Paediatr Rheumatol Online J. 2016;14(1):47.
  9. Jansson A, Renner ED, Ramser J, et al. Classification of non-bacterial osteitis: Retrospective study of clinical, immunological, and genetic aspects in 89 patients. Rheumatology (Oxford). 2007;46(1):154-60.
  10. Roderick MR, Shah R, Rogers V, et al. Chronic recurrent multifocal osteomyelitis (CRMO) – advancing the diagnosis. Paediatric Rheumatology. 2016;14(1):47.
  11. Yamashita K, Calderaro C, Labianca L, et al. Chronic recurrent multifocal osteomyelitis (CRMO) involving spine: A case report and literature review. J Orthop Sci. 2021;26(2):300-5.

Author Bios

Sarfaraz S, Rheumatology SPR; Janjua S, Paediatrics Registrar; I O’Keeffe, Rheumatology SHO; and Harney S, Consultant Rheumatologist; Cork University Hospital
Credit: iStock.com/wildpixel

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