Cystinosis-associated metabolic bone disease: pathogenesis and outcome

Cystinosis-associated metabolic bone disease (CMBD) is a severe complication in patients with infantile nephropathic cystinosis, which is a rare inherited lysosomal storage disease due to pathogenic variants in the CTNS gene that results in an accumulation of cystine in all organs. The kidneys are the organs primarily affected, resulting in renal Fanconi syndrome at around the age of 6-12 months. Without adequate treatment with the cystine-depleting agent cysteamine, this is followed by progressive chronic kidney disease (CKD) and kidney failure in the second decade of life. Patients usually present with progressive disproportionate short stature, rickets, and bone pain in the first 2 years of life. This may be followed by muscle weakness in childhood, and scoliosis and fractures in adulthood, especially if treatment is inadequate. Early diagnosis and treatment are crucial, and this is facilitated by a positive family history, screening programs and care at specialized centers. Therapeutic measures include physical activity, physiotherapy, adequate calcium and phosphate intake, vitamin D supplements, a combination of phosphate supplements and active vitamin D, correction of metabolic acidosis, and, if necessary, growth hormone therapy and surgical correction of persisting leg deformities. Unfortunately, current treatments cannot always prevent progressive bone loss and related skeletal comorbidity. There is increasing evidence for an underlying intrinsic osteoblast and osteoclast defect in cystinosis. Cystine crystal accumulation in macrophages (e.g., in bone and muscle) may result in an inflammatory state promoting increased osteoclast activity and other alterations in myokines and osteokines. Future interventions may target these factors to improve outcomes in patients with cystinosis.