Understanding Parathyroid Gland Function and Disorders
The parathyroid glands, four tiny glands in the neck, are crucial for regulating calcium levels in the body [1.7.1]. They produce parathyroid hormone (PTH), which controls calcium, phosphorus, and vitamin D levels [1.7.1]. When these glands malfunction, it can lead to two primary conditions: hyperparathyroidism (too much PTH) and hypoparathyroidism (too little PTH).
Hyperparathyroidism is the more common disorder, with an estimated prevalence of one to four per 1,000 people [1.7.1]. It leads to high levels of calcium in the blood (hypercalcemia) and is most often caused by a benign tumor (adenoma) on one of the glands [1.7.1]. While many patients are asymptomatic, it can cause kidney stones and bone disease [1.7.1].
Hypoparathyroidism is a rare disease characterized by insufficient PTH production, leading to low blood calcium (hypocalcemia) and high blood phosphorus [1.2.3]. The most frequent cause is accidental damage to or removal of the glands during neck surgery [1.7.1]. Symptoms can range from tingling and muscle cramps to seizures [1.2.3].
Conventional Treatments for Parathyroid Disorders
Standard therapy for hypoparathyroidism has traditionally involved lifelong supplementation with oral calcium and active vitamin D (like calcitriol) to manage blood calcium levels [1.6.1, 1.6.4]. While effective for many, this approach doesn't replace the missing hormone and can lead to complications like kidney stones and renal impairment due to high urinary calcium excretion [1.6.2, 1.6.4]. Management aims to keep serum calcium in the low-normal range to minimize symptoms and long-term risks [1.6.5].
For primary hyperparathyroidism, treatment often involves surgery to remove the overactive gland(s). For patients who are not surgical candidates, medications like Cinacalcet (Sensipar) may be used. Cinacalcet is a calcimimetic, meaning it mimics calcium's action on the calcium-sensing receptor (CaSR) in the parathyroid gland, tricking it into producing less PTH [1.8.4, 1.8.5].
A New Era in Hypoparathyroidism Treatment: Yorvipath (Palopegteriparatide)
A significant recent development is the FDA's August 2024 approval of Yorvipath (palopegteriparatide) for adults with hypoparathyroidism [1.2.3, 1.3.4]. Developed by Ascendis Pharma, Yorvipath is a long-acting prodrug of PTH administered as a once-daily injection [1.3.1]. It is the first and only FDA-approved therapy that replaces the deficient hormone, addressing the underlying cause of the disease rather than just managing symptoms [1.2.4, 1.3.1].
In clinical trials, Yorvipath demonstrated significant success. In a 26-week study, 69% of patients treated with Yorvipath were able to maintain normal calcium levels without needing active vitamin D and with a significantly reduced need for calcium supplements (≤ 600 mg/day), compared to just 5% of patients on placebo [1.2.3]. Long-term data has shown these benefits are sustained, with 96% of participants becoming independent from conventional therapy after three years [1.2.4]. This breakthrough offers patients a way to achieve better calcium control, reduce their pill burden, and potentially lower the risk of long-term kidney complications associated with conventional treatment [1.2.4]. The drug is expected to be commercially available in the U.S. in the first quarter of 2025 [1.2.2, 1.3.3].
On the Horizon: Encaleret for a Genetic Form of Hypoparathyroidism
Another promising medication in development is Encaleret, being developed by BridgeBio Pharma for Autosomal Dominant Hypocalcemia Type 1 (ADH1) [1.9.1]. ADH1 is a rare, genetic form of hypoparathyroidism caused by a mutation that makes the calcium-sensing receptor (CaSR) overly sensitive [1.5.1]. This leads to inappropriately low PTH secretion even when blood calcium is low [1.5.1].
Encaleret is a 'calcilytic'—an orally administered small molecule that works as a negative allosteric modulator of the CaSR [1.5.1, 1.9.4]. In essence, it desensitizes the receptor, allowing the parathyroid glands to secrete PTH more appropriately and restore normal calcium balance in both blood and urine [1.9.4]. Phase 2 trials showed it was well-tolerated and effective at normalizing calcium and PTH levels [1.5.4, 1.9.2]. The Phase 3 CALIBRATE study is fully enrolled, with topline results expected in the second half of 2025 [1.4.1, 1.4.6]. If successful, Encaleret could become the first approved therapy specifically targeting the root cause of ADH1 [1.4.1].
Comparison of Parathyroid Medications
| Feature | Yorvipath (Palopegteriparatide) | Encaleret (Investigational) | Cinacalcet (Sensipar) |
|---|---|---|---|
| Mechanism | Long-acting PTH replacement (prodrug) [1.3.1] | CaSR Antagonist (Calcilytic) [1.5.1] | CaSR Agonist (Calcimimetic) [1.8.5] |
| Primary Indication | Hypoparathyroidism (adults) [1.2.3] | Autosomal Dominant Hypocalcemia Type 1 (ADH1) [1.9.1] | Secondary Hyperparathyroidism (dialysis patients), Parathyroid Carcinoma [1.8.4] |
| Effect on PTH | Replaces and maintains normal PTH levels [1.3.1] | Increases secretion of natural PTH [1.9.4] | Decreases PTH secretion [1.8.4] |
| Administration | Once-daily subcutaneous injection [1.3.1] | Oral tablet [1.5.3] | Oral tablet [1.8.4] |
| Regulatory Status | FDA Approved (Aug 2024) [1.2.3] | Phase 3 Clinical Trial [1.4.5] | FDA Approved (Mar 2004) [1.8.5] |
Conclusion
The landscape for treating parathyroid disorders, particularly the rare condition of hypoparathyroidism, is rapidly evolving. The FDA approval of Yorvipath marks a pivotal shift from merely managing symptoms with supplements to true hormone replacement therapy, offering patients a more physiological and potentially safer long-term treatment option. Furthermore, the development of targeted drugs like Encaleret for specific genetic subtypes like ADH1 highlights the progress of precision medicine in endocrinology. These innovations provide new hope for improved quality of life and better health outcomes for individuals living with these challenging conditions.
For more information from an authoritative source, you can visit the HypoPARAthyroidism Association, Inc..
