Medical Care
Medical care for hypophosphatemia is highly dependent on three factors: cause, severity, and duration. Phosphate distribution varies among patients, so no formulas reliably determine the magnitude of the phosphate deficit. The average patient requires 1000-2000 mg (32-64 mmol) of phosphate per day for 7-10 days to replenish the body stores.
When a treatable cause of the hypophosphatemia is known, then treatment of that underlying cause is of paramount importance and is often curative. Examples include the following:
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Refeeding hypophosphatemia can be anticipated in patients who have a strong history of alcoholism, starvation, or anorexia/bulimia. Adequate treatment includes phosphate supplements in addition to feeding and attention to underlying eating disorders or substance abuse.
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A likely successful therapy for treating malabsorption due to celiac disease or Crohn disease is specific therapy directed at the underlying illness, with the addition of vitamin D supplements.
Oral phosphate supplements, although not curative, are useful for the treatment of the genetic disorders of phosphate wasting and can often normalize phosphate levels and decrease bone pain. Treatment considerations are as follows:
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The patient's serum phosphate level, calcium level, bone density, and growth should be monitored frequently to ensure adequacy of treatment.
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Oral phosphate supplements are also useful for the treatment of possible oncogenic osteomalacia until the time when the tumor can be identified and surgically removed. Oral phosphate supplements are well tolerated except in high doses, which can produce diarrhea.
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For very mild hypophosphatemia, increased oral phosphate intake from diet alone may be adequate. Foods that are high in phosphate include dairy items, meats, and beans.
Parenteral phosphate supplementation is generally reserved for patients who have life-threatening hypophosphatemia or nonfunctional gastrointestinal syndromes. Treatment considerations are as follows:
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In contrast to oral phosphate supplements, parenteral phosphate administration is more likely to have complications; overly rapid administration can result in hypocalcemia, tetany, and hypotension
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Other complications that may occur include metastatic calcification, hyperkalemia associated with potassium-containing supplements, volume excess, hypernatremia, metabolic acidosis, and hyperphosphatemia
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Suggested rates of safe delivery of phosphate range from 1-3 mmol/h. Each milliliter of sodium or potassium phosphate solution has 3 mmol/mL; therefore, this translates to 0.3-1 mL/h. An easy-to-use weight-based regimen involves administering 0.08 mmol/kg (2.5 mg/kg) or 0.16 mmol/kg (5 mg/kg) over 6 hours, depending on the severity of the expected phosphate deficit.
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More rapid correction has been found to be safe, but the magnitude of the response can be unpredictable. Serum phosphate and calcium levels should be monitored every 6 hours to ensure maintenance of normal calcium levels and to prevent overcorrection of phosphate deficiency.
The management of patients with hypophosphatemia can be divided into various subgroups based on the severity of the hypophosphatemia and the need for ventilation, as follows:
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Severe hypophosphatemia (< 1.0 mg/dL [0.3 mmol/L]) in critically ill, intubated patients or in those with clinical sequelae of hypophosphatemia (eg, hemolysis) should be managed with intravenous replacement therapy (0.08–0.16 mmol/kg) over 2-6 hours
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Moderate hypophosphatemia (1.0–2.5 mg/dL [0.3–0.8 mmol/L]) in patients on a ventilator should be managed with intravenous replacement therapy (0.08–0.16 mmol/kg) over 2-6 hours
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Moderate hypophosphatemia (1.0–2.5 mg/dL [0.3–0.8 mmol/L]) in nonventilated patients should be managed with oral replacement therapy (1000 mg/d)
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Mild hypophosphatemia should be managed with oral replacement therapy (1000 mg/d)
Vitamin D supplementation
Vitamin D supplementation is appropriate for patients with vitamin D deficiency. Most patients respond to oral vitamin D-2 supplements, commonly available in over-the-counter multivitamin preparations.
Because the kidneys are responsible for the final 1-alpha hydroxylation of vitamin D, patients with significant renal insufficiency may not be able to metabolize liver-derived 24 hydroxyvitamin D-3 to its active dihydroxy form. These patients benefit from oral 1,25 dihydroxyvitamin D-3 supplements. Because vitamin D enhances calcium and phosphate absorption, frequent monitoring of both is required.
FGF23 Antibody Treatment
Fibroblast growth factor 23 (FGF23) antibody treatment has become available for individuals with some genetic forms of hypophosphatemic rickets. [61] The FDA approved the first drug of this type, burosumab (Crysvita), for X-linked hypophosphatemia (XLH) in 2018. In 2020, the FDA expanded the indications to include FGF23-related hypophosphatemia in tumor-induced osteomalacia associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized, in adults and pediatric patients aged 2 years or older. Burosumab is an IgG1 monoclonal antibody that binds excess FGF23. This action normalizes phosphorus levels, improves bone mineralization, improves rickets in children, and helps to heal fractures in adults.
Approval for children was based on 64-week, randomized, open-label study in 52 patients aged 5 to 12 years, which showed that treatment with burosumab improved rickets, increased serum phosphorus levels, decreased serum alkaline phosphatase activity, and increased growth. The indication is also supported by 40-week data from an open-label study in 13 patients aged 1 to 4 years. In these patients, burosumab improved rickets and lower-limb deformity, increased serum phosphorus levels, and decreased serum alkaline phosphatase activity. Burosumab gained FDA approval for children aged 6 months or older in September 2019. [62]
Approval in adults with XLH (n=134) was supported by a randomized, double-blind, placebo-controlled study. Burosumab treatment resulted in a higher proportion of patients achieving serum phosphorus levels above the lower limit of normal compared with placebo (p < 0.0001). A higher rate of complete healing of active fractures and pseudofractures was also observed compared with placebo. The adult indication is also supported by data from the 48-week, open-label, single-arm bone biopsy study in 14 adults, which showed healing of osteomalacia as demonstrated by decreases in osteoid volume/bone volume, osteoid thickness and mineralization lag time. [62]
Surgical Care
Patients with primary hyperparathyroidism benefit from parathyroidectomy. For patients in whom parathyroidectomy is not feasible, treatment with the new calcium mimetic agents has shown demonstrable control of hyperparathyroidism. Patients with oncogenic osteomalacia are cured by excision of the tumor that is causing the phosphate wasting and relative vitamin D deficiency.
Consultations
An endocrinologist might be helpful if the diagnosis of primary hyperparathyroidism is not readily apparent, especially to exclude the possibility of familial hypocalciuric hypercalcemia. In conjunction with a surgeon, an endocrinologist can help assess the patient for the different potential therapies for primary hyperparathyroidism and choose the best individual therapy.
A gastroenterologist may help in establishing a diagnosis of malabsorption and in pinpointing the cause. Input from this consultant can also be very useful in formulating the most effective therapy and patient education.
A nephrologist can help confirm the likelihood of phosphate wasting and can help assess the patient for causes of renal phosphate wasting.
A surgeon is required for parathyroidectomy or for removal of a tumor causing oncogenic osteomalacia.
A psychiatrist should be requested for patients with a self-imposed eating disorder such as anorexia or bulimia. These common disorders can be fatal and are often difficult to treat. Psychiatric intervention often requires years to effect a remission.
Diet
A regular diet generally provides all of the phosphate required for the day and more. For patients with phosphate wasting, high-phosphate diets (including dairy products, meats, and beans) should be encouraged, along with phosphate supplements. Cow’s milk, an excellent and accessible source of phosphate, contains 1 mg (0.032 mmol) of elemental phosphate per milliliter. Consumption of vitamin D–supplemented foods should also be encouraged.
Activity
For transient mild hypophosphatemia, no activity restrictions are necessary. For chronic phosphate wasting syndromes, the degree of bone disease is the best guide for assessing activity. Severe osteomalacia puts patients at high risk for fracture. Notably, these patients often have accompanying proximal muscle weakness and muscle pain that in and of themselves restrict activity. These patients with established osteomalacia should avoid high-impact activities and should practice fall precautions.
