Vitamin D analogues are synthetic derivatives of vitamin D, chemically modified to enhance therapeutic benefits whilst minimising unwanted effects on calcium metabolism. These medications play a vital role in treating psoriasis and metabolic bone disorders, working by binding to vitamin D receptors to regulate cell growth, differentiation, and immune function. Commonly prescribed vitamin D analogues in the UK include calcipotriol for skin conditions and calcitriol or alfacalcidol for bone disease. Unlike native vitamin D, these analogues offer targeted action with reduced risk of hypercalcaemia when used appropriately. Understanding their applications, safety profile, and monitoring requirements ensures optimal therapeutic outcomes.

What Are Vitamin D Analogues and How Do They Work?

Vitamin D analogues are synthetic derivatives of vitamin D that have been chemically modified to enhance specific therapeutic properties whilst minimising unwanted effects. Unlike native vitamin D (cholecalciferol or ergocalciferol), these analogues have altered pharmacological profiles. The most commonly used vitamin D analogues in clinical practice include calcipotriol, tacalcitol, calcitriol, and paricalcitol.

The mechanism of action centres on binding to the vitamin D receptor (VDR), a nuclear receptor found in various tissues throughout the body. When vitamin D analogues bind to VDR, they form a complex that regulates gene transcription, influencing cellular differentiation, proliferation, and immune function. In dermatological applications, this leads to normalisation of keratinocyte proliferation and differentiation, reducing the excessive skin cell turnover characteristic of psoriasis. In metabolic bone disease, these compounds enhance intestinal calcium absorption and support bone mineralisation.

What distinguishes vitamin D analogues from native vitamin D is their modified structure, which alters their pharmacological profile. Calcipotriol, for instance, has a significantly reduced effect on calcium metabolism compared to calcitriol, making it safer for topical use over larger skin areas. This reduced calcaemic activity allows clinicians to harness the beneficial effects on skin or bone whilst minimising the risk of hypercalcaemia—a potentially serious complication of vitamin D therapy. The analogues also differ in their potency, duration of action, and tissue selectivity, allowing tailored treatment approaches for different conditions.

Conditions Treated with Vitamin D Analogues

Vitamin D analogues have established roles in treating several distinct clinical conditions, with dermatological applications being the most widespread. Psoriasis represents the primary indication for topical vitamin D analogues, particularly plaque psoriasis affecting limited body surface areas. NICE guidance (CG153) recommends topical vitamin D or vitamin D analogues as first-line treatment options for adults with trunk or limb psoriasis. For mild to moderate plaque psoriasis, a potent corticosteroid applied once daily plus a vitamin D analogue applied once daily (applied separately) for up to 4 weeks is recommended, followed by vitamin D analogue monotherapy twice daily if needed. Treatment should be reviewed at 4 weeks for combination therapy and around 8 weeks for vitamin D analogue monotherapy.

In metabolic bone disease, calcitriol (the active form of vitamin D) and alfacalcidol are used to manage conditions where vitamin D metabolism is impaired. This includes renal osteodystrophy in patients with chronic kidney disease, where the kidneys cannot adequately convert vitamin D to its active form. These vitamin D analogues help treat secondary hyperparathyroidism and maintain calcium homeostasis. Paricalcitol is specifically licensed for the treatment of secondary hyperparathyroidism in chronic kidney disease. These medications are also indicated in hypoparathyroidism, where parathyroid hormone deficiency impairs calcium regulation, and in certain cases of vitamin D-resistant rickets (hereditary hypophosphataemic rickets), though management of the latter is typically specialist-led.

Other dermatological conditions that may benefit from vitamin D analogue therapy include ichthyosis and certain forms of palmoplantar keratoderma, though these represent off-label uses with limited evidence. The anti-proliferative and immunomodulatory properties of vitamin D analogues make them valuable in conditions characterised by abnormal keratinocyte behaviour. Emerging research continues to explore potential applications in other inflammatory skin conditions, though robust evidence remains limited for indications beyond psoriasis and the established metabolic bone disorders.

Types of Vitamin D Analogues Available in the UK

Several vitamin D analogues are licensed and available through the NHS, each with distinct formulations and approved indications. Calcipotriol is the most widely prescribed topical vitamin D analogue for psoriasis. It is available as:

• Ointment and cream formulations (50 micrograms/g) for application to psoriatic plaques, typically applied twice daily

• Scalp solution for treating scalp psoriasis

• Combination products with betamethasone dipropionate (a potent corticosteroid), marketed as Dovobet® or Enstilar® foam, which provide synergistic anti-inflammatory and anti-proliferative effects and are applied once daily

Calcipotriol has specific usage restrictions: adults should not exceed 100g per week, treatment should not cover more than 30% of body surface area, and it is not recommended for children under 6 years. For children aged 6-12 years, the maximum is 50g weekly, and for 12-17 years, 75g weekly. The face, flexures, and genitals should be avoided.

Tacalcitol is another topical vitamin D analogue available as an ointment (4 micrograms/g), used for plaque psoriasis. Whilst less commonly prescribed than calcipotriol, it offers an alternative for patients who may not tolerate or respond adequately to calcipotriol. Tacalcitol is typically applied once daily, preferably at bedtime.

Calcitriol serves dual purposes in UK clinical practice. Topically, it is available as an ointment (3 micrograms/g) for mild to moderate plaque psoriasis. Systemically, calcitriol capsules (0.25 and 0.5 micrograms) are prescribed for managing renal osteodystrophy, hypoparathyroidism, and vitamin D-resistant conditions. The systemic formulation requires careful dose titration and monitoring due to its potent effects on calcium metabolism.

Alfacalcidol (One-Alpha® and generic versions) is a synthetic analogue that requires hepatic conversion to the active form. Available in capsule and oral solution forms, it is used for similar indications to systemic calcitriol, particularly in renal bone disease and hypoparathyroidism.

Paricalcitol (Zemplar®) is available in capsule and injection forms specifically for the treatment of secondary hyperparathyroidism in chronic kidney disease. The choice between these systemic agents often depends on individual patient factors, renal function, and prescriber preference.

Side Effects and Safety Considerations

The adverse effect profile of vitamin D analogues varies significantly between topical and systemic formulations. Topical preparations generally demonstrate good tolerability, with local skin reactions being the most common concern. These include:

• Skin irritation, erythema, and burning sensation at application sites

• Pruritus (itching) and dryness

• Facial or perioral dermatitis if inadvertently applied to sensitive areas

Patients should be advised to wash hands thoroughly after application and avoid contact with the face, eyes, and mucous membranes. When using combination products containing corticosteroids, additional risks include skin atrophy, telangiectasia, and striae with prolonged use, though these are primarily attributable to the steroid component.

The most significant safety concern with vitamin D analogues is hypercalcaemia (elevated blood calcium), particularly with systemic formulations or excessive topical use over large body surface areas. Symptoms of hypercalcaemia include nausea, vomiting, constipation, confusion, excessive thirst, and polyuria. Severe hypercalcaemia can lead to renal impairment, cardiac arrhythmias, and nephrocalcinosis. Maximum weekly doses for topical calcipotriol are therefore restricted (100g ointment per week for adults, 50g for children aged 6-12 years, 75g for 12-17 years), and treatment should not exceed recommended body surface area limits (typically 30%).

Systemic vitamin D analogues require particular caution in patients with:

• Pre-existing hypercalcaemia or conditions predisposing to it

• Nephrolithiasis (kidney stones)

• Concurrent use of thiazide diuretics, which reduce calcium excretion

• Cardiac disease, as hypercalcaemia may precipitate arrhythmias

• Patients taking digitalis glycosides (increased risk of arrhythmias if hypercalcaemia develops)

• Those using magnesium-containing antacids (especially in dialysis patients)

• Patients taking bile-acid sequestrants or orlistat (may reduce absorption)

For topical therapy, caution is needed with phototherapy and UV exposure. Patients should avoid excessive UV exposure and follow specific timing advice if using phototherapy alongside vitamin D analogues.

Regarding pregnancy and breastfeeding, product-specific advice should be followed. For calcipotriol, data are limited and caution is advised; application to the breasts should be avoided during breastfeeding. Systemic analogues have clearer risks and specialist advice should be sought.

Patients should be counselled to contact their GP promptly if they experience symptoms suggestive of hypercalcaemia, particularly persistent nausea, excessive thirst, or confusion. Patients should also be encouraged to report any suspected side effects via the MHRA Yellow Card Scheme.

Monitoring and Treatment Guidelines

Appropriate monitoring protocols differ substantially between topical and systemic vitamin D analogue therapy. For topical preparations used in psoriasis management, routine biochemical monitoring is generally unnecessary when treatment adheres to recommended dose limits and body surface area restrictions. However, clinicians should:

• Review treatment response at 4 weeks for combination therapy and around 8 weeks for vitamin D analogue monotherapy, as recommended by NICE

• Assess for local adverse effects and treatment adherence

• Consider stepping down to less potent preparations or reducing frequency once control is achieved

• Advise patients not to exceed maximum weekly doses (e.g., 100g calcipotriol ointment for adults, 50g for children aged 6-12 years, 75g for 12-17 years)

• Ensure treatment does not cover more than 30% of body surface area

For systemic vitamin D analogues, comprehensive monitoring is essential to prevent hypercalcaemia and associated complications. UK guidelines recommend:

• Baseline measurements of serum calcium (corrected for albumin), phosphate, parathyroid hormone (PTH), and renal function

• Calcium monitoring once to twice weekly during dose initiation and titration

• Monthly monitoring once stable doses are established (CKD patients follow UK Kidney Association schedules, e.g., calcium/phosphate monthly, PTH 1-3 monthly for dialysis patients)

• Regular assessment of renal function (eGFR) and urinary calcium excretion in high-risk patients

• PTH levels in patients with renal osteodystrophy to guide dose adjustments

Target serum calcium should remain within the normal reference range (approximately 2.20-2.60 mmol/L when corrected for albumin), though specific targets may vary based on the underlying condition. If hypercalcaemia develops, treatment should be temporarily discontinued, calcium intake reviewed, and the dose reduced upon recommencement.

Patient education forms a crucial component of safe vitamin D analogue therapy. Individuals should understand:

• The importance of adhering to prescribed doses and application instructions

• Dietary calcium intake considerations (avoiding excessive supplementation)

• Not to take additional vitamin D or calcium supplements unless specifically prescribed

• Recognition of hypercalcaemia symptoms

• The need for regular blood test monitoring with systemic preparations

• When to seek medical advice—particularly if experiencing persistent nausea, confusion, excessive thirst, or worsening skin irritation

Referral to specialist services may be necessary for patients with poor response to optimised topical therapy, difficult-to-treat sites, extensive disease, or systemic side effects. For patients with chronic kidney disease receiving systemic vitamin D analogues, integrated care with nephrology services ensures optimal management of mineral bone disorder, with treatment adjustments based on evolving biochemical parameters and disease progression.

Frequently Asked Questions