Rickets

Symptomatic hypocalcemia is a medical emergency and requires hospitalization. Hypocalcemic seizures and/or cardiovascular instability require an intensive care environment and intravenous calcium infusion.

Most patients respond well to calcium supplements and oral vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol). Vitamin D2 is the Food and Drug Administration (FDA)-approved treatment for vitamin D deficiency, although studies have shown that vitamin D3 is more effective. Vitamin D3 is substantially less expensive than vitamin D2.

Alternative treatment protocols include: high dose of oral vitamin D2 given as a single dose (Stoss therapy); or a single high dose of vitamin D2 given intramuscularly (a practical alternative if malabsorption makes oral vitamin D2 ineffective). However, parenteral vitamin D2 is not currently available in the US.

Oral calcium and vitamin D2 at recommended daily values are used to treat calcium-deficiency rickets.[26]Munns CF, Shaw N, Kiely M, et al. Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab. 2016 Feb;101(2):394-415. https://academic.oup.com/jcem/article/101/2/394/2810292 http://www.ncbi.nlm.nih.gov/pubmed/26745253?tool=bestpractice.com ​[27]Drezner MK. Osteomalacia and rickets. In: Goldman L, Ausiello D, eds. Cecil textbook of medicine, 22nd ed. Philadelphia, PA: Saunders Publishing; 2004:1555-62.​​

Occurs due to a defect in 1-alpha hydroxylase, the enzyme that is responsible for the conversion of 25-hydroxyvitamin D into the active metabolite. A physiologic dose of calcitriol generally promotes complete healing of the bone disease and resolution of the biochemical abnormalities. Treatment is continued at this dose until the bone is healed.

The aim of therapy is to maintain serum levels of calcium, phosphorus, and alkaline phosphatase within normal limits.[27]Drezner MK. Osteomalacia and rickets. In: Goldman L, Ausiello D, eds. Cecil textbook of medicine, 22nd ed. Philadelphia, PA: Saunders Publishing; 2004:1555-62. Where available, alfacalcidol can be used instead of calcitriol (outside the US) with the same dosing range.

Every patient receives a 6-month trial of therapy with supplemental calcium and vitamin D2 or, in more severe cases, calcitriol.

Treatment recommended for SOME patients in selected patient group

In patients for whom the abnormalities of the syndrome do not normalize in response to oral calcium and vitamin D, clinical remission might be achieved by administering high-dose oral calcium or a long-term intravenous infusion of calcium into a central vein (intracaval infusion). Long-term intravenous administration is via an indwelling intracaval catheter.

Regimen includes a period of titration to achieve a maximum dose of calcitriol and phosphate salts. Where available, alfacalcidol (1a-hydroxyvitamin D) can be used in place of calcitriol (outside the US) with the same dosing range.

A second-line therapeutic option for patients with X-linked hypophosphatemia (XLH). In the US, burosumab is approved for the treatment of XLH in children 6 months of age and older.

Burosumab is given subcutaneously. Adverse effects include hypersensitivity reactions, injection site reactions, extremities pain, and headaches.[28]Haffner D, Emma F, Eastwood DM, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019 Jul;15(7):435-55. https://www.doi.org/10.1038/s41581-019-0152-5 http://www.ncbi.nlm.nih.gov/pubmed/31068690?tool=bestpractice.com Hyperphosphatemia and nephrocalcinosis are potential adverse effects, but were not seen in the children in the clinical trials.

Although patients with XLH may benefit from burosumab, there are many patients who can be treated successfully with phosphate salts and calcitriol. Consensus guidelines recommend considering burosumab for patients with XLH who have radiographic evidence of overt bone disease that is refractory to conventional therapy, or for patients who experience complications or are unable to adhere to conventional therapy.[28]Haffner D, Emma F, Eastwood DM, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019 Jul;15(7):435-55. https://www.doi.org/10.1038/s41581-019-0152-5 http://www.ncbi.nlm.nih.gov/pubmed/31068690?tool=bestpractice.com

In children, burosumab increases serum phosphate levels, reduces alkaline phosphatase levels, and improves the radiologic features of rickets.[29]Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019 Jun 15;393(10189):2416-27. http://www.ncbi.nlm.nih.gov/pubmed/31104833?tool=bestpractice.com In adults, it normalizes phosphate levels in 94% of patients and improves fracture healing and histomorphometric signs of osteomalacia.[30]Carpenter TO, Imel EA, Ruppe MD, et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest. 2014 Apr;124(4):1587-97. https://www.jci.org/articles/view/72829 http://www.ncbi.nlm.nih.gov/pubmed/24569459?tool=bestpractice.com [31]Zhang X, Imel EA, Ruppe MD, et al. Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) in the first multiple ascending-dose trial treating adults with X-linked hypophosphatemia. J Clin Pharmacol. 2016 Feb;56(2):176-85. https://accp1.onlinelibrary.wiley.com/doi/full/10.1002/jcph.570 http://www.ncbi.nlm.nih.gov/pubmed/26073451?tool=bestpractice.com [32]Imel EA, Zhang X, Ruppe MD, et al. Prolonged correction of serum phosphorus in adults with X-linked hypophosphatemia using monthly doses of KRN23. J Clin Endocrinol Metab. 2015 Jul;100(7):2565-73. https://academic.oup.com/jcem/article/100/7/2565/2829602 http://www.ncbi.nlm.nih.gov/pubmed/25919461?tool=bestpractice.com

Treatment is with high-dose phosphate salts.

Surgical removal of the tumor can cure rickets.

Treatment recommended for SOME patients in selected patient group

In patients for whom tumor resection is not possible because of recurrence or metastasis, calcitriol alone (or combined with phosphate salt supplementation) completely heals the attendant bone disease or significantly improves the biochemical and histologic abnormalities.