A 62-year-old woman presented with worsening osteoporosis, calcinosis universalis and hypocalcaemia. She had amyotrophic dermatomyositis with biopsy-proven panniculitis and extensive dystrophic calcinosis, and was on immunosuppressive therapy (prednisone, cyclophosphamide, hydroxychloroquine).
Despite two doses of zoledronic acid, her BMD decreased and bone turnover markers increased. Current investigations revealed hypocalcaemia (corr Ca 2.11 mmol/L, iCa 1.06 mmol/L), secondary hyperparathyroidism (PTH 18.3 pmol/L), high-normal phosphate (1.3-1.5 mmol/L), normal 25-(OH)D3 (68 nmol/L) and markedly elevated 1,25-(OH)2D3 (966 pmol/L); 24-hour urinary calcium and phosphate were low, bone turnover markers were elevated and trending upwards (CTx 2320 ng/L, P1NP 379 ug/L). Investigations for malignancy or granulomatous disease, including FDG-PET/MRI and CT, were unremarkable.
Dystrophic calcinosis cutis occurs as a result of local tissue injury in the context of normal biochemistry. Deposits consist of hydroxyapatite, calcium phosphate and calcium carbonate crystals. Markedly elevated levels of 1,25-(OH)2D3 may reflect either extra-renal production or dysregulation of the vitamin D activation pathway. FGF23 is a hormone produced by osteoblasts and osteocytes; its major actions are inhibition of both renal phosphate reabsorption and 1α- hydroxylation of 1,25-(OH)2D3. Klotho is a membrane-bound co-receptor required for FGF23 function. Impaired signalling through this pathway causes elevated 1,25-(OH)2D3, hyperphosphatemia and soft tissue calcification.
Although our patient's extremely elevated 1,25-(OH)2D3 would be expected to cause hypercalcaemia, this may be buffered by her extensive subcutaneous calcinosis, resulting in intermittent hypocalcaemia (triggering secondary hyperparathyroidism) and high-normal, although not frank, hyperphosphataemia. The elevated 1,25-(OH)2D3 also contributes to bone resorption through osteoclast activation and to demineralisation by increased production of osteopontin and pyrophosphate, resulting in worsening osteoporosis and possible osteomalacia.
Therefore we hypothesise that impaired signalling through the FGF23/Klotho pathway may be responsible for the clinical and biochemical picture in our patient. Serum FGF23 assay is pending and tetracycline-labelled bone biopsy and repeat calcinosis biopsy are planned.