Continuing Education Activity

Calcitriol is a hormonally active, synthetic vitamin D analog prescribed to treat hypocalcemia, osteoporosis, and the prevention of corticosteroid-induced osteoporosis. Systemic calcitriol is FDA indicated to control hypocalcemia in patients on chronic renal dialysis, secondary hyperparathyroidism in those with chronic kidney disease not yet on dialysis, and hypocalcemia in patients with hypoparathyroidism and pseudohypoparathyroidism. There are also other approved indications. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of calcitonin, pertinent for clinicians and all interprofessional team members to ensure proper utilization of calcitriol therapy.

Objectives:

• Review the mechanism of action of calcitriol.

• Identify the FDA-approved and off-label indications of calcitriol.

• Summarize the contraindications and risks associated with calcitriol therapy.

• Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with calcitriol.

Indications

Calcitriol is a hormonally-active, synthetic vitamin D analog prescribed to treat hypocalcemia, osteoporosis, and the prevention of corticosteroid-induced osteoporosis.[1] Systemic calcitriol is FDA indicated to control hypocalcemia in patients on chronic renal dialysis, secondary hyperparathyroidism in those with chronic kidney disease not yet on dialysis, and hypocalcemia in patients with hypoparathyroidism and pseudohypoparathyroidism. In 2009, the FDA approved topical calcitriol ointment for the management of mild to moderate plaque psoriasis.[2] Off-label uses for systemic calcitriol include type 1, vitamin D-dependent rickets, and pseudo-vitamin D deficiency rickets. Off-label use of topical calcitriol ointment includes psoriasis in children and adolescents.

Mechanism of Action

Systemically, calcitriol binds to vitamin-D receptors in the kidneys, parathyroid glands, intestines, and bones to increase serum blood calcium levels by promoting absorption in the intestines, renal tubular reabsorption in the kidneys, and release from bone. Calcitriol serves as a transcription factor to encode a calcium-binding protein, which simultaneously transports calcium and phosphate ions across intestinal epithelial cells.[3] Along with parathyroid hormone, calcitriol stimulates bone resorption by activating osteoclasts through the release of receptor activator of nuclear factor kappa-B ligand (RANKL) from osteoblasts. Topically, studies have found that calcitriol significantly inhibits the proliferation of normal human epidermal keratinocytes and T lymphocytes by inducing apoptosis, as well as inhibiting gene expression of relevant chemokines and epidermal proteins involved in psoriasis.[4]

Administration

Calcitriol is administered intravenously through a catheter, orally without regard to meals, and topically for external use only. For intravenous administration, no dilution is necessary, and a bolus dose is given at the end of a hemodialysis session. During the initial titration period, serum calcium and phosphorous levels should be monitored twice weekly. Calcitriol capsules and oral solutions may be taken with or without meals but should be protected from prolonged light exposure. Topical administration is performed by applying a thin film to the affected area with gentle rubbing, being careful not to apply to the face or eyes.

Adverse Effects

Hypercalcemia is the most common adverse reaction reported in at least one-third of patients taking systemic calcitriol. Early signs of hypercalcemia include fatigue, weakness, nausea, vomiting, abdominal pain, constipation, diarrhea, vertigo, tinnitus, ataxia, arthralgia, and irritability.[5] Late signs of hypercalcemia include polyuria, polydipsia, cardiac arrhythmias, sensory disturbances, apathy, nephrocalcinosis, urinary tract infections, and hypertension.

Less than 10% of reported adverse reactions include headache, skin rash, polydipsia, nausea, abdominal pain, and urinary tract infection. Less than 1% of reported adverse reactions include hypertension, increased hematocrit, increased hemoglobin, drowsiness, hyperthermia, lymphocytosis, increased neutrophils, anorexia, constipation, and ophthalmic conditions, such as conjunctivitis and photophobia.

Hypercalciuria and nephrolithiasis have been confirmed in patients receiving systemic calcitriol treatment, and further laboratory abnormalities associated with late signs of hypercalcemia include elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood urea nitrogen (BUN) levels. Because calcitriol also increases the intestinal absorption of phosphorous, hyperphosphatemia can occur in patients with renal failure and may further contribute to elevated serum creatinine levels, ectopic calcification, secondary hyperparathyroidism, and renal osteodystrophy.

Hypersensitivity reactions, including pruritus, rash, and urticaria, may occur in susceptible patients, and studies of intravenous calcitriol have found rare cases of anaphylactoid reactions attributed to systemic calcitriol.[6] Less than 1% of post-marketing case reports have found pruritus, erythema, acute generalized exanthematous pustulosis, psoriasis, and contact dermatitis to be associated with calcitriol ointment.

Contraindications

Hypercalcemia, vitamin D toxicity, and hypersensitivity to calcitriol or any vitamin D analog are relative contraindications to taking systemic calcitriol. Further contraindications to calcitriol are patients with increased sensitivity to calcium dysregulation, including arteriosclerosis, cardiac disease, hyperphosphatemia, renal failure, and sarcoidosis. Patients with cardiac disease, especially those taking digoxin, are at an increased risk for cardiac arrhythmias from hypercalcemia and should be dosed conservatively.[7] Patients with renal failure are susceptible to increased risk for vitamin D-induced hypercalcemia, and chronic hypercalcemia may lead to soft tissue calcification, nephrocalcinosis, and other toxicities.

From a preventative lifestyle perspective, accidental exposure, prolonged ultraviolet (UV) sunlight absorption, occlusive dressing use, ocular exposure, and dehydration are contraindications to calcitriol use, as they may increase serum calcium to toxic levels. Photosensitizing agents and UV sunlight may increase the risk of skin tumor formation when combined with topical calcitriol. The topical ointment should not be applied to the face and may lead to skin irritation. For patients with recent injuries and wounds, increased calcium levels may also occur with topical administration due to the enhanced absorption of calcitriol from occlusive dressings.

Pregnancy and breastfeeding are also contraindications to calcitriol administration. Calcitriol is considered in the FDA Pregnancy Category C, meaning there are no well-controlled studies on the adverse effects of calcitriol on pregnant women. In cases where calcitriol is necessary for pregnant women, close monitoring of serum calcium levels is required since pregnancy is associated with alterations in calcium production, metabolism, and excretion.[8] Further adverse effects of mental retardation and congenital aortic stenosis in the neonate must be considered as potential outcomes of hypercalcemia during pregnancy. After pregnancy, lactating mothers must also be closely monitored for hypercalcemia due to post-partum and potential lactation-induced alterations in calcium metabolism.[9]

Further contraindications and considerations to calcitriol administration include major drug interactions that are known to induce hypercalcemia. For example, many patients who benefit from calcitriol may also be taking thiazide diuretics and serum calcium concentrations must be monitored closely. Concomitant use of thiazides and calcitriol can worsen hypercalcemia as thiazides help reabsorb calcium at the distal tubule. Patients with chronic renal failure who take aluminum-containing antacids for hyperphosphatemia must also be monitored closely, as the calcium-phosphate product may affect serum calcium and phosphate levels. Other drugs, such as phenytoin and phenobarbital, accelerate systemic calcitriol metabolism, and drugs, such as ketoconazole, may inhibit catabolic enzymes of calcitriol and cause unintentional hypercalcemia.

Monitoring

Monitoring parameters for calcitriol involve measurements of serum calcium, creatinine, BUN, intact PTH, and phosphate. During titration periods, all patients must be monitored with serum calcium levels twice weekly. According to the KDIGO 2009 guidelines, the corrected total serum calcium and phosphorous levels should be in the normal range for all stages of chronic kidney disease (CKD).[10] For patients with CKD stage 3, serum calcium and phosphorous levels should be monitored every 6 to 12 months. For CKD stage 4, serum calcium and phosphorous levels should be monitored every 3 to 6 months and PTH every 6 to 12 months. For CKD stage 5, serum calcium and phosphorous levels should be monitored every 1 to 3 months and PTH every 3 to 6 months. The literature is unclear of the optimal range for PTH levels in CKD, but in patients with CKD stage 5D, the careful maintenance of intact PTH levels should be within 2 to 9 times the upper limit of normal values.

If hypercalcemia develops, the drug is discontinued immediately until serum calcium levels normalize, at which point treatment can resume at a lower initial dose. In dialysis patients, serum calcium, phosphorous, magnesium, and alkaline phosphatase must be monitored periodically. In hypoparathyroidism patients, serum calcium, phosphorous, and 24-hour urinary calcium levels must be monitored periodically. In predialysis patients, serum calcium, phosphorous, alkaline phosphatase, creatinine, and intact PTH are compared at baseline then monthly for 6 months. Therapeutic effectiveness requires a minimum of 600 mg of calcium intake daily, with the recommended dietary allowance for calcium in adults being 800 to 1200 mg.[11]

Toxicity

The median lethal dose for oral administration in rats is 620 micrograms/kg. The median lethal dose for intraperitoneal administration in rats is greater than 5 mg/kg. Overdose symptoms of hypercalcemia include anorexia, nausea, vomiting, polyuria, polydipsia, and weakness.

Treatment for calcitriol overdose includes general supportive measures. Immediate discontinuation of calcitriol and a low calcium diet is recommended. In cases of persistent, elevated calcium levels, drugs such as phosphates and corticosteroids may help induce excretion and forced diuresis.

Enhancing Healthcare Team Outcomes

Calcitriol is a widely prescribed agent by the primary care provider, nurse practitioner, endocrinologist, and internist. However, therapy with the drug requires the efforts of an entire interprofessional healthcare team, including clinicians (MDs, DOs, NPs, PAs), nurses, and pharmacists. While calcitriol is relatively safe, it has to be monitored for adverse effects, of which the most common is hypercalcemia. Patients may present with hypertension, renal stones, behavior alterations, and severe constipation. At each clinic visit, the healthcare provider should ask for symptoms of hypercalcemia. In some patients, regular monitoring of calcium levels may be required.[12] Utilizing the interprofessional model, with collaborative activity and open communication when treating patients with calcitriol, will drive improved patient outcomes and help preclude adverse events. [Level 5]