OBJECTIVE: Calcinosis is a manifestation of systemic sclerosis with a severe negative impact on quality of life. Efforts to find a treatment for calcinosis have been hindered by our limited understanding of the underlying pathomechanism. We propose that extracellular pyrophosphate deficiency may have a causal role in the formation of these mineralized deposits, because pyrophosphate inhibits the deposition of hydroxyapatite-the major constituent of calcinosis-and supplementing pyrophosphate may have therapeutic potential in the treatment of calcinosis. METHODS: Systemic sclerosis patients were treated with a single dose of 50 mg/kg disodium pyrophosphate (cohort 1, n = 10), or a daily dose of 25 mg/kg disodium pyrophosphate for seven consecutive days (cohort 2, n = 10). Safety of oral pyrophosphate treatment was assessed with special focus on gastrointestinal tolerance, serum phosphate and calcium levels, and potential electrocardiography abnormalities. Absorption kinetics and peak plasma pyrophosphate concentrations were measured by the adenosine triphosphate sulfurylase method. RESULTS: Gastrointestinal adverse effects associated with oral pyrophosphate treatment were rare and mild. The only consistent abnormality among the serum parameters studied was a transient elevation of serum phosphate levels (change: 0.2 to 0.62 and 0.15 to 0.44 mmol/L in cohorts 1 and 2, respectively). Based on electrocardiography results, both doses can be regarded as safe in terms of corrected QT interval prolongation in short-term treatment. Serum pyrophosphate levels increased significantly in both cohorts. CONCLUSION: Oral pyrophosphate treatment was found to be safe in patients with systemic sclerosis and resulted in elevated plasma concentrations comparable to results obtained in healthy volunteers. This provides rationale to test the therapeutic potential of pyrophosphate against calcinosis.