Rational testing – how to investigate a case of multifocal bone pain
Rheumatologist Dr Thomas Batty and haematologist Dr Emma Conway O’Brien describe a rational approach to investigating multifocal pain in primary care, in this case of an older male patient presenting with severe back pain and some thigh and upper arm pain
The case: A 79-year-old man presents in some discomfort with a history of severe back pain. This is new to him and came on for no clear reason a few months ago. Since then it has worsened. He says the pain is there constantly, is now waking him and has not responded well to OTC analgesics. In the last few weeks he has also developed some pain in one thigh and his right upper arm. He thinks he’s lost some weight, too. He is a non-smoking rare attender with no significant past history other than some mild osteoarthritis of his knee.
Note all cases in this series are hypothetical scenarios created for educational purposes
Bone pain is a common presentation with a broad differential presenting across the whole life course. Though bone pain is frequently benign and non-specific, appropriate investigation is essential to ensure significant underlying pathology is not missed.
The case vignette describes an older patient with multi-focal bone pain with red flag symptoms suggesting a potential underlying malignancy, the approach to which will be discussed further below.
However, the majority of ‘bone pain’ presenting to primary care will not be malignant in nature. Many patients will report widespread or focal bone pain, but careful history and examination can help localise the pain to joints or other soft tissue structures. Face to face examination is crucial to aid anatomical localisation. Chronic myofascial pain or inflammatory arthritis require a very different diagnostic approach but may be initially described as bone pain by the patient.
Multi-focal bone pain
As above, the case vignette describes multiple localised sites of bone pain. The most important differentials to rule out here are metastatic bone deposits and multiple myeloma. Red flag symptoms and signs are described in box 1 – the presence of these symptoms should prompt more urgent investigation to direct prompt onward referral. History and examination should encompass screening for signs and symptoms of malignancies classically metastasising to bone (breast, prostate, thyroid, renal/urinary tract and lung).
Box 1. Red flag symptoms for cancer or other serious pathology
Red flags include:
- Severe unremitting pain that remains when the person is supine or at rest, aching night pain that prevents or disturbs sleep, pain aggravated by straining (for example, at stool, or when coughing or sneezing) and thoracic pain
- Localized spinal tenderness/point tenderness over a vertebral body
- No symptomatic improvement with therapy
- Unexplained weight loss
- Past history of cancer
- Bone swelling, focal tenderness and/or erythema
- Fever/Systemically unwell
- Drenching night sweats
Causes of focal and multi-focal back pain often overlap and the most important causes are described in table 1 along with some key discriminating features.
Table 1. Focal and multi-focal back pain – key features
Aetiology Key features Infection (osteomyelitis/discitis) Pyrexia, systemic upset, red flag features (box 1), risk factors including diabetes, IV drug use, overlying soft tissue breakdown/ulceration, previous surgery/trauma. Primary Bone Tumour Benign bone tumours often painless (and roughly 100 times more common than malignant tumours). Malignant tumour pain may be mild at first, aggravated by exercise, worse at night. Osteosarcoma most common – peak incidence second and third decade. 6th most common malignancies in children, 3rd in adolescents and young adults. Metastatic solid tumour Lung, prostate, breast, thyroid and renal tract tumours most common primary causes of bone metastases. Most common in spine, pelvis and proximal femur Multiple Myeloma Most commonly affects the axial skeleton and classically causes lytic lesions with a normal ALP. Can cause osteoporosis and present with fractures. Other haematological conditions Isolated plasmacytoma may or may not have a positive myeloma screen. Acute leukaemias and myeloproliferative neoplasms can present with more diffuse bone pain. Paget’s disease of the bone May present with focal or multifocal bone pain, sometimes associated with deformity. Commonly presents with secondary OA or fracture. Can cause nerve impingement symptoms or hearing loss and jaw malocclusion when skull is involved. Inflammatory bone disease (chronic recurrent multifocal osteomyelitis) Also known as chronic non-bacterial osteomyelitis and overlapping with the ‘SAPHO’ syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis). A rare autoinflammatory disorder presenting with episodic or chronic multifocal bone pain frequently involving the sternum or clavicles. More common in children. Osteoporotic fractures Atraumatic/low trauma fractures in can occur in spine or sacrum. Presents with acute focal pain though onset not always clear. Multiple fractures associated with kyphosis. Worse with movement. Atypical/stress fractures A diverse group usually related to overuse injury – classically in feet (excessive walking or running – higher risk with impaired foot biomechanics or inappropriate footwear) or spondylolysis/pars defect in spine (young sportspeople). Long term bisphosphonate use associated with atypical femoral fractures – focal mid thigh pain – often bilateral. Osteonecrosis Caused by disruption of the microvascular blood supply. Often associated with underlying disease such as sickle cell disease (particularly HbSC). Spontaneous osteonecrosis/avascular necrosis is otherwise most common in the femoral head where is often associated with high dose corticosteroid use, alcohol excess, severe OA or trauma or underlying rheumatic disease. This usually presents with severe hip pain/accelerated OA rather than bone pain. It frequently occurs in patients <50 and is often bilateral. Spontaneous osteonecrosis of the knee can also occur classically in Women >55 years of age. This also mimics an acute arthritis presentation.
What would be the ‘bare minimum’ set of lab tests in this situation?
The minimum first-line investigations required are described in table 2 and include basic biochemistry and blood count as well as a myeloma screen.
A myeloma screen should include both serum protein electrophoresis and serum free light chains (which has largely supplanted testing of urine Bence Jones Protein).
Around 10-15% of myeloma secrete only free light chains and therefore may be missed if serum protein electrophoresis alone is sent. NICE recommends men without a clear alternative cause for low back pain or focal bone pain with red flag features should also have a PSA test.
The main difficulty in assessing patients with multi-focal bone pain in the presence of red flag symptoms in primary care is accessing urgent cross-sectional imaging. In patients with known cancer (or a recent history of cancer) presenting clinically suspicious back pain, NICE recommends urgent MRI within 1 week (or within 24 hours if there are neurological signs or symptoms). NICE recommends there should be a local metastatic spinal cord compression service with a clear referral pathway in place. They may recommend urgent high-dose steroids in high risk patients with neurological features while awaiting the scan. Recommendations are less clear in patients without a prior cancer diagnosis but in the context of red flag features and a high index of suspicion for malignancy (such as our patient in the vignette) urgent MRI should still be considered but this will likely require discussion with acute service providers according to local arrangements.
Plain radiograph is the first-line imaging modality for the majority of cases presenting with bone in a primary care setting, mainly due to ease of access, but the sensitivity for detecting metastatic deposits is poor, picking up around 50% of metastatic lesions. It is therefore important not to be falsely reassured by a normal plain radiograph and waiting for plain radiograph results should not delay onward referral for cross sectional imaging in the highest risk patients. Testing for tumour markers (other than PSA) is not generally recommended unless advised by a specialist.
Table 2. Minimum first-line investigations and their purpose
Test Rationale Full blood count Anaemia or other cytopenias may suggest underlying malignant, inflammatory or haematological cause Electrolytes and Creatinine Impaired renal function may suggest myeloma, obstructive uropathy or CKD associated mineral bone disorder Bone Profile (Calcium, ALP, Albumin, Phosphate) Hypercalcaemia may suggest malignancy (including myeloma) or hyperparathyroidism, raised ALP can suggest recent fracture, osteomalacia or Paget’s disease, it can also be seen in metastatic bone disease. Liver Function Tests Look for alternative causes of a raised ALP Myeloma Screen (Serum Protein Electrophoresis, Serum Free Light Chains, Immunoglobulins) Essential in screening for myeloma which may present with focal or multifocal lytic lesions, osteoporotic fractures or diffuse bone pain CRP Raised in infective or inflammatory causes of bone pain ESR/Plasma viscosity Recommended by NICE as part of myeloma work up. Also raised in inflammatory/infective causes PSA (In men >50 presenting with bone pain or new back pain without clear alternative cause) Prostate cancer Plain radiographs of area of interest Vital for picking up primary bone tumours, Paget’s disease or fractures, but the sensitivity for metastatic/infective/infective disease is relatively low
What might be add-on tests and when might you consider these?
Further testing would depend on the clinical presentation and/or the results of the initial investigations outlined in table 3. More diffuse bone pain is often due to metabolic cause (though it is also important to rule out haematological disease) and requires a slightly different approach, which is beyond the scope of this article. However, the initial investigations required are similar and the following investigations are useful in exploring both diffuse and focal bone pain.
Table 3. Further tests to consider
Test Rationale PTH Test if calcium level abnormal. Classically associated with diffuse bone pain in the context of hypercalcaemia but secondary hyperparathyroidism associated with low vitamin D may cause diffuse bone pain with a normal serum calcium level Vitamin D Test if calcium or ALP abnormal. Very low vitamin D (<25 international units) can cause osteomalacia and secondary/tertiary hyperparathyroidism. Mild insufficiency (<50iu, >25iu) in the context of a normal ALP is usually incidental Magnesium Test if calcium or ALP abnormal. Hypomagnesemia can impair bone mineralisation, increase fracture risk, and impair vitamin D activation causing functional deficiency Bloods cultures/viral serology If infection suspected Blood film If FBC abnormal Gamma GT (Glutamyl-transferase) Localise source of ALP rise Thyroid Function Tests Hyperthyroidism associated with osteoporosis. Hypothyroidism can cause raised ALP. Tissue Trans-Glutaminase Coeliac disease associated with secondary osteoporosis. Malabsorption can cause low ALP. Lactate dehydrogenase (LDH) May be raised in haematological malignancy or myeloproliferative disease. Further imaging – e.g. MRI, isotope bone scan Usually best organised by secondary care, if metastatic spinal cord disease suspected must be urgent MRI (with 7 days if no neurology, within 24 hours if neurological symptoms) Urine dip To screen for urinary tract cancer Chest X-ray To screen for a primary lung lesion
What tests are often done in this scenario but not appropriate?
The following tests outlined in table 4 are not recommended as part of primary care assessment as they are costly and generate results which require specialist interpretation.
Table 4. Tests to avoid
Test Why to avoid / use with caution ALP Isoenzymes Long turnaround, expensive, technical limitations on test mean specificity is low particularly when ALP <300. GGT is preferred. Other tumour makers May be useful when the source of the primary tumour is unclear despite cross sectional imaging and initial investigations but best done following A&G/discussion with specialist to avoid misleading or difficult to interpret results Bone turnover markers (e.g. P1NP, urine CTX) While the evidence base for more specialist applications and assessment of response to osteoporosis treatment is expanding, there is no evidence to support their use in the diagnosis of bone pain.
Key points
- A thorough history and examination is required to localise pain and establish whether it is focal, multi-focal or diffuse in nature.
- Assess for red flag features associated with malignancy and consider the common primary tumour sites.
- All patients with bone pain should have basic bloods and plain radiographs which will determine further investigations.
Dr Thomas Batty is consultant rheumatologist at University Hospitals Sussex NHS Foundation Trust and Dr Emma Conway O’Brien is haematology specialist registrar at Royal Sussex County Hospital, Brighton
Sources and further reading
- Charles J. Clinical manifestations and diagnosis of Paget disease of bone – UpToDate. Last updated 2025
- Heindel W et al.The diagnostic imaging of bone metastases.Dtsch Arztebl Int 2014 2014; 111:741-7
- Hornicek F et al. Bone tumors: Diagnosis and biopsy techniques – UpToDate. Last updated 2024
- Irving M et al. Investigative algorithms for disorders affecting human plasma alkaline phosphatase: a narrative review. J Lab Precis Med 2024;9:7
- Lalani T. Osteomyelitis in the absence of hardware: Approach to diagnosis in adults – UpToDate. Last updated 2024
- National Osteoporosis Guideline Group UK. Clinical guideline for the potential and treatment of osteoporosis. Updated 2024
- NICE. Spinal metastases and metastatic spinal cord compression. [NG234] 2023
- NICE. Prostate cancer: diagnosis and management. [NG131] Last updated 2021
- NICE. Myeloma: diagnosis and management. [NG35] Last updated 2018
- NICE. Low back pain and sciatica in over 16s: assessment and management. [NG59] Last updated 2020
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READERS' COMMENTS [1]
Please note, only GPs are permitted to add comments to articles
Fair enough arranging some tests, but this patient has red flags and should be urgently referred without unnecessary delays.
Why does Cancer take so much longer to diagnose in the NHS than in comparable Healthcare Systems?