Understanding the Calcium‑Sensing Receptor
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What Is the CaSR?
The calcium-sensing receptor (CaSR) is a protein found on the surface of cells in the parathyroid glands, kidneys, and other tissues. It acts like a thermostat for blood calcium.
When calcium levels in the blood drop, the CaSR detects the change and signals the parathyroid glands to release parathyroid hormone (PTH). PTH then works to restore calcium to normal levels by increasing calcium absorption from the gut, releasing calcium from bones, and reducing calcium lost through the kidneys.
When calcium levels rise sufficiently, the CaSR senses this too and suppresses PTH release, keeping the system in balance.
The CaSR was first identified in 1993 by Professor Edward Brown and colleagues — a landmark discovery that transformed our understanding of calcium regulation and opened the door to targeted therapies for calcium disorders.
How CaSR Disorders Occur
CaSR disorders are caused by mutations in the CASR gene. The type of mutation determines the direction of the calcium imbalance.
Loss-of-Function Mutations
The receptor becomes less sensitive to calcium. The parathyroid glands don’t suppress PTH adequately, leading to higher-than-normal blood calcium levels. This causes Familial Hypocalciuric Hypercalcaemia (FHH).
Gain-of-Function Mutations
The receptor becomes over-sensitive to calcium. Even normal calcium levels trigger PTH suppression, resulting in low blood calcium. This causes Autosomal Dominant Hypocalcemia Type 1 (ADH1) and related forms of hypoparathyroidism.
Related Conditions
CaSR mutations give rise to a spectrum of calcium disorders, each with distinct clinical features and management needs.
Hypoparathyroidism
Too little PTH production leads to chronically low blood calcium. Symptoms include muscle cramps, tingling in the hands and feet, and in severe cases, seizures.
The PARADOX study found that 72% of patients experience 10 or more symptoms, revealing a disease burden far greater than previously recognised.
ADH1
Autosomal Dominant Hypocalcemia Type 1 is caused by an inherited gain-of-function mutation in the CASR gene. A systematic review (Roszko et al., JBMR 2022, n=191) found that 41% present with severe symptoms and 75% on conventional therapy develop complications.
Estimated prevalence is approximately 3.9 per 100,000 (Gorvin et al., Am J Hum Genet 2020), suggesting around 1,000 Australians may be affected.
FHH
Familial Hypocalciuric Hypercalcaemia is caused by a loss-of-function CASR mutation. Blood calcium is mildly elevated, but the condition is usually benign and most patients do not require treatment.
Accurate diagnosis is important to avoid unnecessary parathyroid surgery.
Current Treatment
Standard management relies on calcium and active vitamin D supplements. While these can improve symptoms, they do not address the underlying receptor defect.
Current therapy works by supplementing the calcium that the body fails to regulate on its own. However, pushing calcium levels higher with supplements also increases the amount of calcium filtered through the kidneys, creating a difficult trade-off between managing low calcium symptoms and risking kidney damage.
Complications of Conventional Therapy
- 38% of patients develop nephrocalcinosis (calcium deposits in the kidneys)
- 36% develop kidney stones
- 75% develop at least one complication (nephrocalcinosis, nephrolithiasis, renal impairment, or brain calcifications)
For ADH1 specifically, conventional therapy was associated with a 91% increase in hypercalciuria (excess calcium in the urine; n=27), compounding the risk of kidney complications (Roszko et al., JBMR 2022).
The Promise of Calcilytics
A new class of drugs — calcilytics — is being developed to target the CaSR directly, addressing the root cause of gain-of-function CaSR disorders for the first time.
Calcilytics work by reducing the over-sensitivity of the mutated CaSR, allowing the parathyroid glands to produce PTH at appropriate levels. Rather than simply supplementing calcium, these drugs aim to restore the body’s own calcium regulation.
Encaleret — Phase 3 CALIBRATE Trial
Encaleret, developed by BridgeBio Pharma, has shown striking results in the Phase 3 CALIBRATE trial (reported October 2025):
- Calcium normalisation: 76% of encaleret patients vs 4% placebo
- PTH normalisation: 91% of encaleret patients vs 7% placebo
BridgeBio has announced plans to submit a New Drug Application (NDA) in H1 2026. If approved, encaleret would be the first therapy to treat the underlying cause of ADH1.
