Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

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vitamin D deficient

1st line – calcium plus vitamin D

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vitamin D deficient
1st line – 

calcium plus vitamin D

In patients with malabsorptive states and osteomalacia, vitamin D dosing and duration of treatment are dependent upon the vitamin D absorptive capacity of the individual patient.

High doses may be necessary to replete stores in patients with severe malabsorptive states, such as gastrectomy, small bowel disease, bariatric surgery, or resection. In the presence of steatorrhoea, the daily dose of vitamin D may need to be increased.

Studies have suggested that colecalciferol (D3) increases serum 25-hydroxyvitamin D more efficiently than does ergocalciferol (D2);[63] however, subsequent studies suggest that vitamin D2 and D3 are equally effective for bone health.[64]

Patients taking anticonvulsant medications, glucocorticoids, or other drugs that activate steroid and xenobiotic receptors require higher doses of vitamin D. The goal is to achieve concentrations of 25-hydroxyvitamin D at about the 75-150 nmol/L (30-60 ng/mL) range.[18]

Dose of calcium supplements depends on the clinical condition and the serum calcium level. Higher doses may be necessary in patients with malabsorptive disorders. Calcium citrate preparations are preferred in patients with achlorhydria, those on proton-pump inhibitors, and older patients due to better absorption.

Primary options

ergocalciferol: 50,000 units orally once or twice weekly for 6-12 weeks; or 5000 to 10,000 units orally once daily for 6-12 weeks

or

colecalciferol: 50,000 units orally once or twice weekly for 6-12 weeks; or 5000 to 10,000 units orally once daily for 6-12 weeks

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calcium carbonate: 1-2 g/day orally given in 3-4 divided doses

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or

calcium citrate: 1-2 g/day orally given in 3-4 divided doses

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2nd line – calcium plus vitamin D analogue

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vitamin D deficient
2nd line – 

calcium plus vitamin D analogue

Vitamin D analogues (e.g., calcitriol) are utilised in patients who remain hypocalcaemic after treatment with vitamin D or who have renal disease. They are also used in those with vitamin D-dependent rickets types 1 and 2.

Of note, these medicines have a faster onset of action, within hours, but a shorter half-life (<5-8 hours), compared with ergocalciferol and cholecalciferol. Adequate dietary or supplemental calcium is necessary for an optimal clinical response to vitamin D therapy.

Patients initiated on phenobarbital or phenytoin may require an increase in their calcitriol dose, as both drugs can increase catabolism of vitamin D.

Dose of calcium supplements depends on the clinical condition and the serum calcium level. Higher doses may be necessary in patients with malabsorptive disorders. Calcium citrate preparations are preferred in patients with achlorhydria, those on proton-pump inhibitors, and older patients due to better absorption.

Primary options

calcitriol: 0.25 to 1 microgram orally once daily

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calcium carbonate: 1-2 g/day orally given in 3-4 divided doses

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or

calcium citrate: 1-2 g/day orally given in 3-4 divided doses

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inherited or acquired disorders of phosphate wasting

1st line – burosumab

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inherited or acquired disorders of phosphate wasting
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X-linked hypophosphataemia or oncogenic osteomalacia
1st line – 

burosumab

Inherited or acquired disorders of phosphate wasting may include X-linked hypophosphataemia and oncogenic osteomalacia (also known as tumour-induced osteomalacia).

In skeletally mature patients, the goal of therapy is to prevent symptoms of hypophosphataemia such as muscle weakness and paraesthesias. For most patients, treatment of the underlying disorder causing the low phosphorus is adequate.

Burosumab, a monoclonal antibody that increases renal tubular phosphate reabsorption and increases serum 1,25-dihydroxyvitamin D levels through inhibition of fibroblast growth factor 23 (FGF23), is approved in the US for the treatment of X-linked hypophosphataemia and FGF23-related hypophosphataemia in tumour-induced osteomalacia associated with phosphaturic mesenchymal tumours that cannot be curatively resected or localised. Burosumab is also approved for both of these indications in Europe.

Burosumab is contraindicated in patients with severe renal impairment/end-stage renal disease or hyperphosphataemia, and must not be used with oral phosphate and/or active vitamin D analogues (e.g., calcitriol).

One 24-week randomised trial in symptomatic adults reported improvement in stiffness, as well as improved fracture healing compared to placebo.[59]​ Initial results from phase 2 trials suggest that burosumab improved serum phosphate levels in adults with tumour-induced osteomalacia.[60][61]

Primary options

burosumab: X-linked hypophosphataemia: 1 mg/kg subcutaneously every 4 weeks initially, adjust dose according to serum phosphate levels, maximum 90 mg/dose; oncogenic osteomalacia: 0.5 mg/kg subcutaneously every 4 weeks initially, adjust dose according to serum phosphate levels (may administer every 2-4 weeks), maximum 2 mg/kg/dose up to 180 mg/dose every 2 weeks

2nd line – calcium plus vitamin D analogue plus phosphate

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inherited or acquired disorders of phosphate wasting
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X-linked hypophosphataemia or oncogenic osteomalacia
2nd line – 

calcium plus vitamin D analogue plus phosphate

Calcium plus a vitamin D analogue (e.g., calcitriol) plus phosphate supplementation is an alternative treatment option in patients with X-linked hypophosphataemia or oncogenic osteomalacia, and may be used if burosumab is not available or contraindicated.

Phosphate supplementation is indicated only in patients who are symptomatic, have very low serum phosphate levels, or have a renal tubular defect leading to chronic phosphate loss. These patients often need additional calcium and vitamin D analogue supplementation.[57][58]​​​ Symptoms of hypophosphataemia are rare, unless the plasma phosphate level is <0.64 mmol/L (<2 mg/dL). Long-term administration of phosphate supplements can stimulate parathyroid activity (secondary hyperparathyroidism), leading to a further fall in phosphate levels.

To minimise parathyroid stimulation, one of the active metabolites of vitamin D, calcitriol, is given in conjunction with phosphate therapy. There is a risk of hypercalcaemia with supraphysiological calcitriol replacement; therefore, 24-hour urinary calcium excretion rates or spot urine calcium:creatinine ratios are recommended to determine the adequacy of treatment.

In patients with X-linked hypophosphataemic rickets, replacement of phosphate is confined to those patients with symptomatic bone disease, as there is some evidence that treatment might accelerate new bone formation. In addition, over-replacement of phosphate in X-linked hypophosphataemic rickets can be associated with renal tubular acidosis and can lead to nephrocalcinosis.[65]

Patients with oncogenic osteomalacia have similar clinical, biochemical, and radiological characteristics to X-linked hypophosphataemic rickets, but often require more aggressive treatment until the tumour is localised and surgically removed.[57]

Patients initiated on phenobarbital or phenytoin may require an increase in their calcitriol dose, as both drugs can increase catabolism of vitamin D.

Dose of calcium supplements depends on the clinical condition and the serum calcium level. Higher doses may be necessary in patients with malabsorptive disorders. Citrate preparations are preferred in patients with achlorhydria, those on proton-pump inhibitors, and older patients due to better absorption.

Primary options

calcitriol: X-linked hypophosphataemia: 0.5 to 0.75 micrograms/day orally given in 2 divided doses initially, adjust dose according to response; oncogenic osteomalacia: 0.75 to 3 micrograms/day orally given in 2-3 divided doses initially, adjust dose according to response

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sodium phosphate/potassium phosphate: X-linked hypophosphataemia: 250-1000 mg/day orally given in 3-4 divided doses initially, adjust dose according to response; oncogenic osteomalacia: 1-3 g/day orally given in 4-5 divided doses initially, adjust dose according to response

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calcium carbonate: 1-2 g/day orally given in 3-4 divided doses

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or

calcium citrate: 1-2 g/day orally given in 3-4 divided doses

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1st line – calcium plus vitamin D analogue plus phosphate

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inherited or acquired disorders of phosphate wasting
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other disorders (e.g., types 1 and 2 vitamin D-dependent rickets, Fanconi's syndrome)
1st line – 

calcium plus vitamin D analogue plus phosphate

Inherited or acquired disorders of phosphate wasting may include types 1 and 2 vitamin D-dependent rickets and Fanconi's syndrome, among others.

In skeletally mature patients, the goal of therapy is to prevent symptoms of hypophosphataemia such as muscle weakness and paraesthesias. For most patients, treatment of the underlying disorder causing the low phosphorus is adequate.

Phosphate supplementation is indicated only in patients who are symptomatic, have very low serum phosphate levels, or have a renal tubular defect leading to chronic phosphate loss. These patients often need additional calcium and vitamin D analogue supplementation.[57][58]​​ Symptoms of hypophosphataemia are rare, unless the plasma phosphate level is <0.64 millimol/L (2 mg/dL). Long-term administration of phosphate supplements can stimulate parathyroid activity (secondary hyperparathyroidism), leading to a further fall in phosphate levels.

To minimise parathyroid stimulation, one of the active metabolites of vitamin D, calcitriol, is given in conjunction with phosphate therapy. There is a risk of hypercalcaemia with supraphysiological calcitriol replacement; therefore, 24-hour urinary calcium excretion rates or spot urine calcium:creatinine ratios are recommended to determine the adequacy of treatment.

Patients initiated on phenobarbital or phenytoin may require an increase in their calcitriol dose, as both drugs can increase catabolism of vitamin D.

Dose of calcium supplements depends on the clinical condition and the serum calcium level. Higher doses may be necessary in patients with malabsorptive disorders. Citrate preparations are preferred in patients with achlorhydria, those on proton-pump inhibitors, and older patients due to better absorption.

Primary options

calcitriol: 2 micrograms orally once daily initially, adjust dose according to response

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sodium phosphate/potassium phosphate: 250-500 mg orally four times daily initially, adjust dose according to response

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-- AND --

calcium carbonate: 1-2 g/day orally given in 3-4 divided doses

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or

calcium citrate: 1-2 g/day orally given in 3-4 divided doses

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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