Approach
Symptomatic hypocalcemia is a medical emergency and requires hospitalization. Hypocalcemic seizures and/or cardiovascular instability require an intensive care environment and intravenous calcium infusion.
Calcitriol may be useful in vitamin D deficiency with hypocalcemia until calcium levels are normalized. Calcitriol is also recommended for type I vitamin D-deficient rickets, type II vitamin D-resistant rickets, and familial or X-linked hypophosphatemic rickets.[4][27]
Calcium-deficient rickets (sometimes referred to as hypocalcemic rickets)
Vitamin D deficiency
The mainstay of treatment for infants and children with nutritional rickets is to correct vitamin D deficiency and to ensure adequate calcium intake.[1]
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. Patients who do not respond should be evaluated for vitamin D-resistant rickets. Many successful dosing regimens exist.
Alternative treatment protocols include:
A high dose of oral vitamin D2 given as a single dose (Stoss therapy)
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.
Serum calcium, phosphorus, alkaline phosphatase, and urinary calcium/creatinine ratio are measured periodically in children who are being treated for vitamin D deficiency. Radiographs are used to document the healing of rachitic lesions.[4][27]
Calcium deficiency
Oral calcium and vitamin D2 at recommended daily values are used to treat calcium-deficiency rickets.[26][27]
Pseudovitamin D-deficient rickets
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]
Vitamin D resistance
Severe vitamin D-resistant rickets presents in the first few weeks of life with symptomatic hypocalcemia, requiring intravenous calcium support.
Every patient receives a 6-month trial of therapy with supplemental calcium and vitamin D2 or calcitriol.
If the abnormalities of the syndrome do not normalize in response to this treatment, 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).
Patients undergoing therapy are evaluated initially at least once a week.
Serum calcium, phosphorus, alkaline phosphatase, creatinine, 1,25-dihydroxyvitamin D, parathyroid hormone, and the urinary calcium-to-creatinine ratio are measured.[27]
Hypophosphatemic rickets
Treatment varies according to cause.[25]
Hypophosphatemic rickets (X-linked, autosomal dominant, autosomal recessive, McCune-Albright syndrome)
The treatment of hypophosphatemic rickets is complex and has serious potential adverse effects. Patients should be managed by experienced practitioners.
Oral phosphate salts are used to replace renal phosphate losses and heal the rickets. The goal of treatment is not to normalize serum phosphate, but rather to heal the rickets.
High-dose oral phosphate salts can inhibit gastrointestinal absorption of calcium, resulting in an increase of parathyroid hormone (PTH) and worsening of the phosphate losses.
Calcitriol is used to counteract the decrease in calcium absorption. Underdosing results in hyperparathyroidism. Overdosing can cause hypercalciuria, nephrocalcinosis, and, in the long term, renal failure.
Burosumab, a fibroblast growth factor-23 (FGF-23) blocking monoclonal antibody, is 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] 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]
Treatment monitoring requires frequent determinations of serum calcium, phosphorus, PTH, alkaline phosphatase, and urine calcium-to-creatinine ratio.
Renal ultrasounds are needed to screen for nephrocalcinosis.
X-rays are used to monitor the rickets.
In children, burosumab increases serum phosphate levels, reduces alkaline phosphatase levels, and improves the radiologic features of rickets.[29] In adults, it normalizes phosphate levels in 94% of patients and improves fracture healing and histomorphometric signs of osteomalacia.[30][31][32]
Hereditary hypophosphatemic rickets with hypercalciuria
Treatment is with high-dose oral phosphate salts alone.
Tumor-induced osteomalacia
Primary treatment is the resection of the associated tumor. However, incomplete resection, recurrence or metastases of tumors can preclude definitive therapy.
In such cases, calcitriol alone or combined with phosphate salts completely heals or significantly improves the attendant bone disease and biochemical and histological abnormalities. This is because patients with oncogenic osteomalacia have similar clinical, biochemical, and radiologic characteristics to patients with X-linked hypophosphatemic rickets.
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