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Management of bone disease in cystinosis


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Review on Bone disease in cyrtinosis

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Management of bone disease in cystinosis

  2. 2. ► 1- The metabolic consequences of Fanconi syndrome include hypophosphatemic rickets and growth failure ► 2- Mineral and bone disorders related to chronic kidney disease (CKD-MBD), including renal osteodystrophy
  3. 3. ► a complex bone phenotype termed cystinosis metabolic bone disease (CMBD)
  4. 4. Clinical characteristics 1-Rickets: ► bone deformities ► delay ambulation ► widening of the wrist ► rachitic rosary ► Harrison's groove ► reduced bone density ► widening of the metaphyses ► fraying of the epiphyses
  5. 5. Clinical characteristics 2-CKD-MBD: manifested by one or a combination of the following: ►abnormalities of Ca, P, iPTH , or vitamin D metabolism ► abnormalities in bone turnover, mineralization, volume, linear growth, or strength (renal osteodystrophy) ► vascular or other soft-tissue calcification
  6. 6. Other causes:  A primary osteoblast and osteoclastic defect
  7. 7.  knockout of Ctns in mice did not result in full-blown Fanconi syndrome  yet these animals showed osteopenia with decreased mineralization  raising the hypothesis of a specific underlying bone defect in cystinosis
  8. 8.  mutations in CTNS may reduce the ability of osteoblast precursor cells to transform into mature osteoblasts capable of synthesizing osteoid, Further contributing to defective mineralization and rickets
  9. 9. Pathogenesis of CMBD  Muscle and bone form a functional unit  impaired muscle function leads to disturbances of bone development  reduced plasma and muscle levels of carnitine in pretransplant patients with cystinosis may impair the functionality of the muscle/bone unit
  10. 10. Pathogenesis of CMBD ► GH, LH, FSH, androgens/estrogens, insulin-like growth factor (IGF)-1, insulin, amylin, and TSH/thyroxine all contribute to maintaining normal bone ► This balance is disrupted in cystinosis
  11. 11. Pathogenesis of CMBD  hypothyroidism often appears in the first decade of life and can contribute to growth retardation  poor nutrition may result in reduced IGF-1 serum levels  in advanced CKD, lack of sensitivity to endogenous GH and IGF-1 can further impede growth
  12. 12. Pathogenesis of CMBD  Cystine crystals in bone may also impair growth  Treatment with glucocorticoids limits catch up growth after renal transplantation and may cause osteoporosis
  13. 13. Pathogenesis of CMBD * low doses of cysteamine in vitro stimulate osteoblastic differentiation and mineralization * an inhibitory effect at higher doses * explaining the bone toxicity observed in patients receiving high doses of cysteamine
  14. 14. Pathogenesis of CMBD
  15. 15. Assessing CMBD  Serum mineral and enzyme values  In children with hypophosphatemic rickets, serum phosphate, bicarbonate, and potassium reflect renal losses and the efficacy of replacement therapy  alkaline phosphatase (ALP) is a biomarker of rickets and CKD-MBD  Measurement of serum PTH, calcium, 25(OH) vitamin D, and phosphate also serve as the mainstays of monitoring for CKD-MBD
  16. 16. Management of CMBD ▀ The treatment of Fanconi syndrome largely involves oral replacement of urinary losses plus nutrition that provides the recommended daily requirements of protein and calories
  17. 17. Management of CMBD Phosphate repletion:  Starting dose is 30 to 40 mg/kg/d in 3 to 5 doses  up to 80 mg/kg/d  Phosphate should not be administered at the same time as calcium, since this can lead to precipitation  providing phosphate with milk products is acceptable  Phosphate administration can contribute to nephrocalcinosis, but is still required.  Oral phosphate supplements may be reduced or stoped in patients with advanced CKD  Some patients with cystinosis and ESKD may only require a low dose of oral phosphate binders, if any, due to the ongoing renal phosphate wasting
  18. 18. Management of CMBD ▀ Calcitriol, can treat and prevent deficiency of active vitamin D and hypocalcemia ▀ improve phosphate reabsorption from the gut ▀ prevent phosphate-driven secondary hyperparathyroidism ▀ initial dose of 0.1 to 1 μg ▀ High doses of active vitamin D may increase hypercalciuria and nephrocalcinosis, and can Promote extraskeletal (vascular) calcifications
  19. 19. Management of CMBD ► For most patients, calcium requirements can be met by adequate nutrition and vitamin D administration ► calcium supplementation can serve as “insurance” against daily losses of calcium that eventually lower bone density ► should be within the recommended daily allowance as recommended for other patients with CKD
  20. 20. Management of CMBD  Orthopedic surgery  during puberty is preferred, with metabolic control optimized prior to surgery  Active vitamin D may be paused during prolonged immobilization to prevent hypercalcemia
  21. 21. Management of CMBD ► Initiation of GH treatment may be considered at any stage of CKD in the presence of persistent short stature (<3rd percentile) and low height velocity (<25th percentile), despite adequate nutritional intake, metabolic control, and cysteamine treatment
  22. 22. Management of CMBD * In patients on renal replacement therapy, persistent Fanconi syndrome may impair bone health, and native kidney nephrectomy might be considered