An 80-year-old gentleman independent from home presented to hospital on the 18^th April 2023 with a one-week history of acute onset, progressively worsening large joint arthralgia and musculoskeletal pain following his first dose of denosumab. This 60 mg subcutaneous injection was prescribed by his general practitioner for osteoporosis. He was previously well with no prior arthralgia or musculoskeletal pain, infective symptoms, or history of falls or trauma. There was no immediate reaction. However, approximately five hours after denosumab administration, he began developing arthralgia and cramping musculoskeletal pain of fluctuating severity, with involvement of his bilateral knees, hips, thighs and shoulders. His symptoms were severe enough to limit range of motion and function of affected joints and did not respond to self-administered paracetamol and codeine treatment. The symptoms progressively worsened over the course of one week, at which point he also developed pain in his left wrist, which prompted him to seek medical attention.

On presentation, he had persistent bilateral joint pain involving the shoulders, knees and left wrist. He also had persistent musculoskeletal pain involving the right arm and bilateral thighs. Arthralgia, pain and joint stiffness were noted to be worse in the morning and eased through the day. He did not have any localising infective symptoms, fevers or constitutional symptoms apart from some fatigue associated with the arthralgia and musculoskeletal pain. He did not have any temporal headaches, visual disturbance or jaw claudication. He did not have significant small joint arthralgia, sicca symptoms, ocular inflammation, abnormal rash or symptoms of mononeuritis multiplex.

His medical history included osteoarthritis with a left total knee replacement three years prior, and a right reverse shoulder joint replacement ten years ago following a rotator cuff injury. He had chronic obstructive pulmonary disease, hypothyroidism, ischaemic heart disease and heart failure with reduced ejection fraction, all of which were stable. He also had a T7 spinal compression fracture diagnosed five months prior, with a dual x-ray absorptiometry (DEXA) scan confirming osteoporosis.

His regular medications included aspirin 100 mg once daily, rosuvastatin 20 mg at night, sacubitril 24.3 mg + valsartan 25.7 mg twice daily, furosemide 40 mg once daily, levothyroxine 100 µg once daily, nebivolol 5 mg once daily and spironolactone 12.5 mg once daily. He did not start any of these medications recently. He did not have any drug allergies.

The patient was a retired salesman who lived at home with his wife and was previously fully independent with his activities of daily living and mobility–regularly walking unaided for several kilometres a day. He ceased smoking 20 years ago following a 30 pack-year history, and did not drink alcohol.

On examination, he was alert, orientated and comfortable at rest. Observations were within normal limits and he was afebrile. He had an average build. He had marked limitation of right shoulder abduction and range of motion to less than 30 degrees along with generalised tenderness on palpation of his shoulder girdle and deltoid muscle belly. There were no bony step deformities nor focal areas of particular tenderness. His left shoulder had similar tenderness but preserved range of motion. He had tenderness on palpation of his left wrist but no deforming polyarthropathy and no active tenosynovitis. There were no stigmata of scleroderma, endocarditis or dermatomyositis. He had limitation of hip flexion to less than 30 degrees bilaterally, along with palpation tenderness in his quadriceps. He had preserved range of motion in his knees without significant pain on anterior joint space palpation. His power and sensation was preserved in all limbs. His gait was slow and antalgic, but otherwise normal. He did not have significant spinal tenderness or limited range of motion. He had no rash or evidence of ocular inflammation. Cardiorespiratory and abdominal examination was unremarkable and he was clinically euvolaemic.

Investigations on presentation revealed elevated inflammatory markers with an erythrocyte sedimentation rate (ESR) of 140 mm/hr and C-reactive protein (CRP) of 163.8 mg/L (Table 1). CRP peaked at 235.2 mg/L on the following day. Ferritin was mildly elevated along with low transferrin saturation, in keeping with an inflammatory state.

He had a mild normocytic anaemia with a normal platelet count (Table 1). There was a mild monocytosis but otherwise normal white blood cell count and differential. Renal function, liver function and thyroid function tests were normal. There was mild hypocalcaemia with a corrected calcium of 2.08 mmol/L, and low-normal phosphate of 0.76 mmol/L in the setting of denosumab therapy. Parathyroid hormone was appropriately elevated. 25-hydroxy Vitamin D level was normal. Other serum electrolytes were unremarkable. Creatine kinase was normal at 108 U/L.

Autoimmune serology revealed an elevated rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA) (Table 1). Antinuclear antibodies were detected at a 1:320 titre with a homogenous and speckled pattern, but extractable nuclear antigen antibody screen and double-stranded DNA antibodies were negative. Complement factor 3 and 4 levels were normal.

Respiratory virus swab was negative for Influenza A/B, Adenovirus, Rhinovirus, Respiratory syncytial virus, Human parainfluenza virus 1-4 and Severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2). Blood and urine cultures were negative. Chest x-ray revealed expected emphysematous changes, but no consolidation or pleural effusions. Cervical spine x-ray revealed stable multilevel degenerative changes without fracture or malalignment. Bilateral shoulder x-ray revealed a previous right total shoulder replacement and narrowing of the left glenohumeral joint space inferiorly, but no fracture or heterotopic soft tissue ossification. Computerised tomography of the right shoulder did not show any evidence hardware migration, periprosthetic fracture or joint effusion. Ultrasound of the right shoulder revealed a supraspinatus tendon anterior portion partial-thickness tear (Figure 1a), and subscapularis insertional tendinosis with a partial thickness tear (Figure 1b). There was no significant subdeltoid subacromial bursitis (Figure 1c). Long head of biceps was surgically absent following shoulder replacement (Figure 1d).