No effective drugs for "parathyroidism" so far

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◆ Professor Xie Zhongjian, chief physician of the Department of Metabolic Endocrinology, Xiangya Second Hospital, Central South University, introduced that it is projected that there are about 400,000 patients with parathyroidism in China. Patients who have parathyroid glands damaged or removed due to anterior neck surgery account for 78%, and a small percentage is due to genetic or autoimmune diseases.

◆In addition to the unstable blood calcium indicators, patients with parathyroidism also face frequent fluctuations of several indicators in the blood such as magnesium, phosphorus and potassium. From time to time, some patients have sudden and severe hypocalcemia causing crooked mouth, slanted eyes and atrial fibrillation and are resuscitated by 120; some have epileptic-like seizures due to long-term failure to supplement calcium; some have calcification of the basal ganglia of the brain due to high phosphorus over the years.

◆ For hypothyroid patients, they need to take eugenol to replenish thyroid hormone, but a day or two off the medication hardly affects their lives, while for hypoparathyroid patients, one meal of calcium tablets not taken can cause serious problems such as twitching of the hands and feet, heart twitching and epilepsy.

(Health Times reporter Qiu Yue) "I have had thyroid cancer for 35 years, and in 2010 I had all my parathyroid glands removed during a total thyroidectomy and lymphatic dissection, resulting in hypoparathyroidism, which I have had for 12 years now. I feel that hypoparathyroidism has caused even more pain in my life than thyroid cancer." Haitang (a pseudonym) told the Health Times on March 31.

Hypoparathyroidism, or hypoparathyroidism, is a rare endocrine disorder in which patients suffer from systemic disorders of calcium and phosphorus metabolism due to low secretion and/or insufficient effect of parathyroid hormone (PTH), leading to short-term symptoms and long-term complications, mainly hypocalcemia, such as kidney stones, renal calcinosis, renal insufficiency, intracranial calcification, and cataracts. There are no targeted and effective therapeutic drugs available.

No effective drugs for "parathyroidism" so far

Every day is like the edge of life and death

The day after her total thyroidectomy, Haitang learned that the surgery had removed not only the thyroid gland, but also four parathyroid glands. From that day on, she needed to take calcium supplements for life.

"After the operation, in order to replenish calcium, I had more than 200 days of continuous infusion, and I could not break a day, to the point that the blood vessels of my hands and feet were rotten by the needles, and the backs of my hands and feet still had large bruises." Haitang said.

After that, Haitang had to switch to oral calcium tablets, but after several iodine 131 treatments, her gastrointestinal function was severely impaired, resulting in the amount of 8 capsules of osteopontin and 8 calcium tablets a day still not allowing her to maintain her blood calcium at a normal level and frequent episodes of low blood calcium.

"During hypocalcemia, I often had tingling in my limbs, a severe walking ant feeling, and in severe cases, I couldn't even walk on my feet, so I went to the emergency room overnight several times. In addition, due to the lack of parathyroid hormone regulation, my blood calcium fluctuated greatly, and I was once rescued in an emergency due to hypercalcemia crisis. It feels like I am on the edge of life and death at any time, and it is very painful." This is how Haitang describes her life now.

In addition to unstable blood calcium indicators, patients with parathyroidism also face frequent fluctuations in several indicators in the blood such as magnesium, phosphorus, potassium and carbon dioxide. Haitang told the Health Times, "In our patient group, we often have patients with sudden onset of severe hypocalcemia causing crooked mouth, slanted eyes and atrial fibrillation, and are rescued by 120; some have frequent seizures due to long-term calcium supplementation; some have calcification of the basal ganglia of the brain due to high phosphorus over the years; more commonly, patients who have had the disease for a long time suffer from kidney stones, cataracts and organ calcification. "

Professor Xie Zhongjian, chief physician of the Department of Metabolic Endocrinology at the Second Xiangya Hospital of Central South University and director of the Institute of Metabolic Endocrinology of Central South University, introduced that there is no large-scale epidemiological data on parathyroidism in China. According to a population study in the United States, the prevalence of parathyroidism in the United States is about 37/100,000, and another study shows that the prevalence of parathyroidism in Japan is about 26/100,000. Among the known parathyroid patients in China, 78% are due to damage or removal of parathyroid glands during anterior neck surgery, and a small percentage are due to genetic or autoimmune diseases.

"In recent years, with the elevated incidence of thyroid cancer, patients with parathyroidism are also on the rise. Acute clinical manifestations of parathyroidism include convulsions, laryngeal spasms, wheezing, convulsions or epileptiform seizures, and in the long term, patients also experience anxiety, depression, cataracts, high urinary calcium, kidney stones, and central nervous system calcification." Professor Xie Zhongjian said.

No solution to the treatment dilemma so far

"The current treatment for parathyroidism worldwide is mainly active vitamin D combined with calcium supplementation to maintain the patient's blood calcium level, but this treatment plan is only a symptomatic treatment. Hormone replacement therapy is the optimal choice for endocrine glandular hypofunction, but no ideal hormone replacement drug has been developed worldwide." Professor Xie Zhongjian said.

Without medication for the cause, patients can only passively and temporarily relieve their symptoms. Haitang has witnessed a number of patients who had sudden seizures or cardiac tamponade because they could not control their blood calcium through medication and were finally pulled away by emergency vehicles for resuscitation.

"Even if we bring our blood calcium indicators up to standard through calcium supplementation, it doesn't necessarily make our bodies feel truly comfortable, and it doesn't necessarily ensure that we can cope with life's unexpected situations, such as mood swings, changes in temperature or experiencing physiological periods, which can cause sudden low blood calcium." Haitang said.

According to Haitang's recollection, one summer, due to the heat and the lack of ventilation in her environment at the time, she sweated a lot. Although she had just taken the medicine for less than half an hour, she still had convulsions. She immediately realized that there was a problem with her blood calcium and quickly supplemented the medication with 2 consecutive doses, and the convulsions gradually subsided after an hour.

"Since the body has absolutely no ability to self-regulate blood calcium, encountering some special circumstances can lead to sudden hypocalcemia. There is no way to anticipate these environments, we can only be prepared at all times. I now go out with a 3-day supply of medication to deal with unexpected situations." Haitang said.

No effective drugs for "parathyroidism" so far

According to Professor Xie Zhongjian, the human body has a sophisticated regulation system for blood calcium. Once the body senses a drop in blood calcium concentration, the parathyroid glands will accelerate the synthesis and secretion of parathyroid hormone, which will act on the bones, kidneys and intestines. The combination of active vitamin D and calcium is a powerful mechanism for blood calcium regulation. The combination of active vitamin D and calcium only works in the intestinal tract and has a short half-life and a short duration of efficacy, which is not comparable to the regulatory function of parathyroid hormone.

"Currently, there are four major therapeutic dilemmas in the treatment of parathyroidism." Professor Xie Zhongjian pointed out that, first, it is difficult to stabilize patients' blood calcium levels, and among patients treated with active vitamin D combined with calcium, only about half of such patients' blood calcium can be stabilized in the normal range; second, it is difficult to balance patients' blood calcium and urine calcium levels, and often blood calcium meets the standard but urine calcium exceeds it, leading to a much higher risk of renal complications; third, it is difficult to improve patients' ectopic calcification, especially Fourth, even if all indicators are controlled within the normal range, patients still often experience anxiety and depression, which seriously affect the quality of life.

Several hormone replacement drugs approved abroad, but not as effective

"For hypothyroid patients, they need to take eugenol to replenish their thyroid hormones, but a day or two off the medication hardly affects their lives, whereas for parathyroid patients, a meal of calcium tablets not taken can cause serious problems such as twitching of the hands and feet, heart twitches and seizures." Haitang said.

Research and development on parathyroid hormone has actually been carried out for many years. Currently, some foreign parathyroid hormone drugs for the treatment of osteoporosis have been approved for the treatment of hypoparathyroidism, such as recombinant human parathyroid hormone (1~34) and new recombinant parathyroid hormone (1~84), but these drugs have never been widely used.

In 2015, the US FDA approved novel recombinant parathyroid hormone (1~84) for the treatment of refractory hypoparathyroidism. The phase III clinical trial of the drug, the REPLACE study, showed that 50-100 mcg/day, once/day subcutaneous injections of novel recombinant parathyroid hormone (1~84) were effective in reducing calcium and vitamin D requirements in adult hypoparathyroid patients, with 43% of patients able to discontinue vitamin D and calcium requirements was also reduced to less than 500 mg per day.

"Since both drugs fail to solve the bottleneck of half-life, they fall far short of maintaining the balance of calcium and phosphorus metabolism throughout the body, thus most patients using the drug still need to continue to take calcium and active vitamin D, which instead increases the medication burden of patients, and the new recombinant parathyroid hormone (1~84) has poor improvement on urinary calcium, and because long-term Because of the potential risk of osteosarcoma, domestic and international guidelines only recommend it as a complementary treatment option when conventional treatment is difficult to control." Professor Zhongjian Xie said.

Xie Zhongjian told Health Times that the treatment needs of patients with endocrine diseases are very simple, that is, whatever hormone is needed is supplemented with whatever hormone, but recombinant human parathyroid hormone (1~34) and new recombinant parathyroid hormone (1~84) are both drugs mainly used for the treatment of osteoporosis, and the mechanism of action is not the same as that for the treatment of hypoparathyroidism. Drugs for the treatment of hypoparathyroidism require sustained stabilization of their blood levels in the range of normal physiological levels, but none of the currently approved drugs can do this.

"I heard that there are now long-acting parathyroid hormone drugs in clinical trials, and we are very much looking forward to the advances in technology that will bring light to our lives and will allow us to truly be free from the pain of disease torment and live a better quality of life." Haitang said.

Mannstadt M, Clarke BL, Vokes T, et al. Efficacy and safety ofrecombinant human parathyroid hormone (1-84) inhypoparathyroidism (REPLACE): a double-blind, placebocontrolled, randomised, phase 3 study. Lancet DiabetesEndocrinol,2013,1(4):275-283。

Update: Parathyroidism long-acting treatment drug has entered phase III clinical trials in China

TransCon PTH is a long-acting parathyroid hormone treatment for adult patients with hypoparathyroidism. The drug was developed by AscendisPharma, a Danish biopharmaceutical company, and Shanghai Vison Pharmaceuticals, China, is responsible for the development and promotion of the treatment regimen in Greater China, where it is currently in Phase III clinical trials.

Although TransCon PTH has not yet been approved for marketing both domestically and internationally, the results from the foreign Phase III clinical data are very good," said Lu Anbang, CEO and Director of Vital Pharmaceuticals, adding that positive data were obtained from the foreign Phase III clinical trial in March: compared to the control group, the TransCon PTH group showed statistically significant improvements in the primary composite endpoint and all key secondary endpoints , 78.7% of treated patients met the primary endpoint, compared to 4.8% of control patients.

The drug normalizes blood and urine calcium levels, serum phosphate levels, bone turnover, and may address short-term symptoms and long-term complications in patients with hypoparathyroidism, according to Luang Pang. TransCon PTH has also been granted orphan drug status by the U.S. Food and Drug Administration (FDA).

Based on good clinical trial data from abroad, the phase III clinical trial of the drug in China was approved in May 2021 and the first patient was successfully enrolled in that year. Lu Anbang told reporters that recruitment for the Phase III clinical trial in China is still underway. It is planned to start in 16 hospitals in China, and 76 volunteers are to be recruited. "If the phase III clinical trial in China goes well, perhaps in the future, hypoparathyroidism patients can resume their lives as ordinary people with one injection of hormone per day." Lu Anbang said. (Qiu Yue collated)

Related reading: Parathyroid adenoma that was almost spared

I had a parathyroid tumor removed on December 12, 2013 at Tampa General Hospital in Tampa, Florida, USA. The tumor was 1.6 cm x 0.7 cm in size. Insomnia, hyperactivity, and weakness ...... This tumor tormented me for 6 years and even "eluded" some doctors' diagnosis for a while.

In 2007, I began to suffer from insomnia, hyperactivity, and trouble sleeping. The neurologist advised me to increase my exercise. However, I already had no energy without exercising. I would lie down at 10:30 p.m. and wake up from a deep sleep at 12:00 p.m. Sometimes after walking half of a 500-meter road, I suddenly had no energy to finish the next half.

During this time, a parathyroid hormone test was also performed and the results showed values within normal limits. After seeing an endocrinologist, a complete set of parathyroid tests was done and the results showed that blood calcium was below the high normal limit, blood VD was below the low normal limit, parathyroid hormones were normal, 24-hour urine calcium was near the high normal limit, and no tumors or nodules were seen on the isotope scan. The diagnosis was not parathyroid disease and the treatment was VD and calcium supplementation. However, after treatment, blood pressure was higher, heart rate disturbance became more severe, and the pain in the hips made it difficult to sleep and walk.

Finally, I thought to check the Internet. The diagnostic criteria for parathyroid disorders were a revelation: "calcium in the blood was ever higher than the normal high limit" was enough to diagnose parathyroid disorders. Immediately, I opted to have the surgery.

A more advanced isotope scan clearly showed the tumor on the left side of my parathyroid gland! Eventually the symptoms finally went into remission.

According to Health Times, June 6, 2014, issue 1126, page 20, Chen Keqing, Maryland, USA