Presenting Complaint:

• Bone pain

Symptoms:

• Site: Lower back, pelvis and generalised bone pain
• Onset: Gradual, worsening over the past 2 months – “It’s been 2 months and it still hurts”
• Character: Deep, aching pain – “I feel like it’s in my bones”
• Associated symptoms: Fatigue, constipation, increased thirst, polyuria, occasional confusion – “I feel all the time tired, thirsty and confused sometimes for no reason”
• Exacerbating/alleviating factors: Pain worse at night, not relieved by paracetamol – “I can’t sleep when it hurts. Not even paracetamol helps the pain”
• Severity: Severe – “I can’t do anything because of the pain”

Systemic Symptoms (answer only if specifically asked for):

• Urinary: Dilute urine, increased frequency, no obvious blood, no retention, no dysuria 
• Bowels: No bowel movements today, recent constipation, normal coloured stools noted previously, no PR bleeding noticed, no faecal incontinence
• Saddle anaesthesia: None
• Leg weakness or sensory disturbance: None
• Fever: No fever
• Eyes: No scleral icterus
• Cough: Long-standing smoker’s cough, recently more persistent with occasional streaks of blood
• Chest pain: None
• Shortness of breath: Dyspnoea with minimal exertion
• Weight loss: Lost around 6 kg unintentionally over 3 months, poor appetite
• Night sweats: Occasional night sweats
• Vomiting and nausea: No vomiting episodes, intermittent nausea
• Fatigue: Persistent tiredness, low mood
• Pruritus: None

Past Medical History:

• COPD (mild)
• Hypertension

Past Surgical History:

• None

Drug History:

• Amlodipine
• Salbutamol inhaler PRN

Allergies:

• NKDA

Family History:

• Father had COPD
• Mother had hypertension and a stroke

Social History:

• BMI: 17
• Smoker: Currently smokes 15 cigarettes a day (40 pack-year history)
• Alcohol: One pint of beer a day
• Occupation: Retired builder
• Diet: Admits diet includes fatty foods

Ideas, Concerns and Expectations:

• Thinks the pain might just be “old age” or arthritis
• Worried about cancer (friend died of bone cancer)
• Wants pain relief and an explanation for symptoms

Observations:

• Respiratory rate: 18
• Oxygen sats: 97% RA
• Pulse: 96
• Blood pressure: 150/90
• Alert but slightly drowsy
• Temperature: 37.0

NEWS: 1

Examination:

General Inspection:

• Appears fatigued
• Slim body habitus
• Mildly dehydrated
• Not grossly jaundiced

Musculoskeletal back:

Inspection:

• Normal spinal alignment and curvature
• No visible deformity, swelling, or muscle wasting
• No bruising, erythema, or scars

Palpation:

• Marked bony tenderness over the thoracic and lumbar spine
• Tenderness also present over the posterior iliac crests and pelvis
• No paraspinal muscle spasm
• No step deformities

Movement:

• Reduced range of motion in lumbar flexion and extension due to pain
• Thoracic rotation limited by discomfort
• Cervical spine normal

Special Tests:

• Straight leg raise: Negative bilaterally
• No pain radiating down the legs
• No evidence of nerve root irritation
  

Neurology for completion:

• Alert and oriented to person, place, and time
• Tone, power, and reflexes normal and symmetrical in all limbs
• Sensation intact to light touch and pinprick
• Coordination normal (finger–nose, heel–shin)
• Gait normal, Romberg’s negative
• No focal neurological deficit or signs of spinal cord compression
• Normal speech and facial symmetry
• Cranial nerves II–XII intact

Investigations Provided:

• Corrected calcium 3.25 mmol/L (Normal corrected calcium range: 2.2-2.6 mmol/L)
• Urea 9.8 mmol/L (Normal urea range: 2.5-7.0 mmol/L)
• Creatinine 125 µmol/L (Normal creatinine range: 45-90 µmol/L)
• Hb 11.0 g/dL (Normal Hb range 13.0–17.0 g/dL)
• WCC 7.0 ×10⁹/L (Normal WCC range: 4.0–11.0 ×10⁹/L)
• ALP 250 U/L (Normal ALP range: 40–130 U/L)
• PTH 0.8 pmol/L (Normal PTH range: 1.6–6.9 pmol/L)
• CRP 95 mg/L (Normal CRP range: < 5 mg/L)

Chest X-ray: 

Case courtesy of Frank Gaillard, Radiopaedia.org, rID: 10552

Examiner questions:

1. What are your main differential diagnoses, and why are these more likely than other differentials?

Answer: Hypercalcaemia of malignancy likely secondary to either paraneoplastic PTHrP secretion from squamous cell carcinoma of the lung), or lung cancer with bone metastases

• Persistent bone pain, fatigue, constipation and confusion are suggestive of hypercalcaemia.
• Markedly raised corrected calcium (3.25 mmol/L) with suppressed PTH (0.8 pmol/L) indicates a PTH-independent hypercalcaemia.
• Significant smoking history, unintentional weight loss, haemoptysis, and night sweats are indicative of malignant causes such as lung cancer. The chest radiograph shows a central mass. All of these factors, combined with the symptomatic hypercalcaemia are suggestive of squamous cell lung carcinoma with paraneoplastic hypercalcaemia.
• Squamous cell carcinoma (SCC) of the lung commonly secretes parathyroid hormone–related peptide (PTHrP), which mimics PTH action and causes paraneoplastic hypercalcaemia with or without bone metastases.
• Metastatic lung cancer should also be considered due to the clinical findings of bone pain, thoracic spine tenderness, constitutional symptoms and hypercalcaemia, which it causes through bony invasion, in addition to the release of osteoclast-activating factors, increasing bone turnover.
• In humoral hypercalcaemia of malignancy due to PTHrP secretion, bone pain tends to be dull, diffuse, and generalised, reflecting widespread osteoclastic bone resorption rather than local invasion. Examination may reveal mild or generalised spinal tenderness, but imaging is usually normal or shows osteopenia rather than discrete lesions. In contrast, osteolytic metastases cause focal, severe, and progressive pain, often worse at night or on weight bearing, with localised bony tenderness and radiological evidence of lytic or mixed lesions. Thus, PTHrP-mediated hypercalcaemia produces diffuse bone discomfort without structural bone destruction, whereas metastatic disease causes localised, destructive bone pain.
• Raised ALP (250 U/L) may reflect increased bone turnover, but may also be mildly elevated due to the systemic effects of malignancy.
• Multiple myeloma can also cause hypercalcaemia and bone pain, but is less likely here given normal renal function, absence of anaemia or back-dominant pain, CXR findings and haemoptysis with smoking history; however, serum protein electrophoresis should be checked to exclude it.
• The suppressed PTH level excludes primary hyperparathyroidism.
• Other causes such as vitamin D intoxication, sarcoidosis, or prolonged immobility, are less likely based on history.

2. Further blood tests show PTHrP is 8.5 pmol/L (normal PTHrP levels: < 2.0 pmol/L). How would you differentiate the diagnosis between squamous cell carcinoma of the lung and metastatic lung cancer? 

Answer: Raised PTHrP levels are suggestive of squamous cell carcinoma of the lung. Normal PTHrP levels are suggestive of metastatic lung cancer.

• In PTHrP-mediated hypercalcaemia, the PTHrP level is elevated while endogenous PTH is suppressed (here, 0.8 pmol/L).
• This pattern differentiates paraneoplastic hypercalcaemia from osteolytic metastatic hypercalcaemia or primary hyperparathyroidism (unless there is metastatic SCC also secreting PTHrP).

3. Describe the management of this condition

Possible answer:

• Initial A-E assessment, including ECG, full set of bloods including Amylase/Lipase, FBC, U&Es, LFTs, Lactate, CRP, Glucose, Calcium profile, Coagulation screen and G&S, IV access, ABG/VBG
• IV fluids (normal saline 3-4 L/day) for rehydration and as first-line treatment for hypercalcaemia
• IV bisphosphonate (zoledronic acid) after rehydration if required. Consider calcitonin if severe or symptomatic hypercalcaemia persists
• Urine dip to assess for UTI (increased frequency)
• Urinary Bence-Jones proteins and serum protein electrophoresis
• Chest X-ray to examine for masses and lesions:

Case courtesy of Frank Gaillard, Radiopaedia.org, rID: 10552

Chest x-ray demonstrates increased density in the right upper medial hemithorax with loss of volume, and shift of the trachea to the right. A mass is present at the right hilum. 

‘Golden S sign’ – Right hilar mass (orange) obstructing the right upper lobe bronchus results in collapse of the right upper lobe (green arrow). This results in a reverse S shape to the pleural edge. 

• Lumbar and thoracic spine radiographs
• Treat underlying cause – refer patient urgently to the Respiratory team for suspected lung cancer
• CT chest for suspected malignancy
• Arrange pain management and MDT input from oncology, respiratory, and palliative medicine if appropriate

4. Name some possible complications of hypercalcaemia of malignancy

Possible answer:

• Cardiac arrhythmias
• AKI, renal failure and urinary tract calculi
• Neurocognitive impairment (confusion, coma)
• Severe dehydration
• Bone fractures from metastases or osteolysis from PTHrP
• Constipation and abdominal pain
• Low mood and depression