Expanding Care for Hypoparathyroidism with Parathyroid Hormone Therapy

The standard of care for hypoparathyroidism has been calcium and vitamin D replacement, making it the last endocrine deficiency for which hormone replacement is the treatment of choice.

with Michael Mannstadt, MD, and Tamara Wexler, MD, PhD

Hypoparathyroidism, albeit uncommon, is characterized by low or absent concentrations of parathyroid hormone often owing to removal of, or injury to, the parathyroid glands typically as the result of neck or thyroid surgery. The standard of care has been oral calcium and active vitamin D (eg, calcitriol).

Since this treatment is not curative and is associated with short-term adverse consequences including hypo- or hypercalcemia and increased urinary calcium excretion and long-term complications such as nephrocalcinosis, kidney stones, and brain calcifications.


“Hypoparathyroidism is one of the last endocrine deficiencies to have a corresponding parathyroid hormone (PTH) for replenishment,” said Michael Mannstadt, MD, chief of endocrinology at Massachusetts General Hospital, and associate professor in medicine at the Harvard Medical School, in Boston Massachusetts.

Advancing Hypoparathyroidism Management

While patients may lack sufficient PTH, many have been treated with the goal of restoring serum calcium levels, not to replenish PTH. As such, the standard of care has remained oral calcium/vitamin D. However, for patients with hypoparathyroidism who require lifelong parathyroid replenishment, it is important to ascertain the long-term benefits and consequences of rhPTH(1-84).1

Safety and effectiveness of parathyroid hormone (PTH) replacement with human PTH (1-34) or PTH (1-84) has been demonstrated in clinical trials lasting up to 6 years.2-4

  • REPLACE trial: A phase 3 randomized. double-blind, placebo-controlled study to assess the efficacy and safety of recombinant human parathyroid hormone (rhPTH[1–84]) in hypoparathyroidism; a registration trial.2
  • RELAY study: A phase 3, randomized, fixed dose-blinded trial in patients with hypoparathyroidism conducted at 11 sites in the United States. investigate the safety and efficacy of NPSP558, a rhPTH(1-84), at fixed doses of 25 µg and 50 µg for the treatment of adults with hypoparathyroidism.3
  • REPEAT study: A phase 3, 24-week, open-label, flexible dose extension of the REPLACE study conducted in 25 patients across three outpatient clinics in Hungary.4

Full-length recombinant human (rh)PTH (1-84) is now approved in both the United States and Europe as an adjunctive therapy for hypoparathyroidism. However, initial placebo-controlled and open-label trials were of short duration (through 24 weeks) and no long-term studies had been performed for efficacy and safety.

In the pivotal 24-week placebo-controlled REPLACE study (n=134), 53% of patients receiving rhPTH(1-84) at 50 μg versus one patient who was getting the placebo achieved a > 50% reduction from baseline in oral calcium and calcitriol doses with maintenance of normal albumin-corrected serum calcium. Patients receiving the rhPTH (1-84) also demonstrated significant reductions in serum phosphorus.2

While urinary calcium excretion was reduced in the patients receiving placebo as well as those taking rhPTH(1-84), excretion rates in patients in the rhPTH (1-84) group remained at or above the upper limit of normal at 24 weeks.2 The subsequent open-label 8-week RELAY trial expanded rhPTH (1-84) dosing to also include doses of 25 μg.3

Findings from the long anticipated, 5-year RACE trial,5 which was open to any patient who had participated in either the REPLACE and/or RELAY trials, supported continued benefit of rhPTH (1-84) up to the five years follow-up with results similar to results of the shorter-duration studies, with no change in efficacy over time. 

As with earlier trials with rhPTH,2,3 patients in the RACE trial received self-administered rhPTH (1-84) once daily in the morning by subcutaneous injection; most patients were receiving either 25 or 50 μg at study outset and were titrated in 25 μg increments to a maximum of 100 μg/day. Starting doses were determined by baseline serum calcium concentrations and whether the participants were taking supplemental calcium and/or calcitriol.

The RACE study included 49 patients with a mean age of 48 years, mostly women (n=40); and 40 of the 49 enrolled patients completed 60 months of treatment. Five (5) patients withdrew for reasons not related to adverse effects; investigators withdrew another 2 patients, 1 person chose not to continue after the initial 12 months, and 1 patient withdrew owing to an adverse effect.5

Confirming rhPTH as a Viable Alternative to Ca/D

In an interview with EndocrineWeb, Tamara L. Wexler, MD, PhD, a neuroendocrinologist with expertise in novel therapeutic development, and a clinical associate professor at New York University School of Medicine said: “I am particularly interested in the reduction of urinary calcium seen over 60 months, as elevated urine calcium (and the resultant sequelae, which include kidney stones) is a problem that is related to both hypoparathyroidism and the oral calcium and vitamin D (Ca/D) used as treatment. Of note, there was better calciuria control seen over the longer 5-year observation period than in the initial 2-month REPLACE trial.“

Mean albumin-corrected serum calcium remained between 8.2 and 8.7 mg/dL at 60 months. Serum phosphorus decreased as did calcium phosphorus product; serum creatinine and estimated glomerular filtration rate (GFR) remained unchanged.5

“My primary considerations were whether the effectiveness was maintained—which it was—and whether the 60-month data would identify any new safety issues,” said Dr. Wexler.

Furthermore, “while nearly all patients reported adverse events, there was no comparator group, and it would not be unreasonable to anticipate a similar AE rate for rhPTH, particularly as all of patients in the comparator group in the randomized REPLACE study experienced AEs," she said.

All but one of the patients (48/49; 98%) reported a treatment-emergent adverse event; the most common adverse events (AEs) included hypocalcemia (37%), muscle spasms (33%), paresthesia, sinusitis, and nausea (all 31%). Few of the AEs were serious, and none were considered to be related to rhPTH(1-84). At the end of the trial, 70% of patients achieved the composite efficacy outcome.5

Dr. Mannstadt said, “four of the 12 patients who failed to achieve the composite outcome were not on the maximal dose of rhPTH(1-84). In addition, bone turnover markers peaked at 12 months, but then dropped slightly below normal.”

As such, clinicians should be cognizant of an increased risk for osteosarcoma.5.  

“There aren’t many changes for clinicians regarding how often patients require monitoring when on rhPTH(1-84) compared with conventional therapies,” said Dr. Mannstadt. However, patients who cease taking rhPTH(1-84) will need to return to their normal calcitriol and calcium doses—and may need much higher doses of PTH replacement as there is a risk that they will become extremely hypocalcemic.

Dr. Wexler added: "the question now becomes—for which patients rhPTH(1-84) is most appropriate. Likely considerations will include quality of health and quality of life (QoL) on oral calcium/vitamin D alone, and whether patients report similar or better QoL on rhPTH than the mineral/vitamin supplement. Also, relative costs also need to be factored into new treatment plans for anyone with hypoparathyroidism.”

Better Approach for Parathyroid Hormone Deficiency

Parathyroid hormone (PTH) stimulates renal reabsorption of calcium, enhances absorption of calcium and phosphate from the gastrointestinal tract via conversion of 25[OH]D to 1,25[OH]2D, and is a potent regulator of bone turnover.

Hypoparathyroidism affects about 70,000 people in the US, equally affecting males and females. Many patients in this study were perimenopausal or postmenopausal women with hypoparathyroidism, who are generally not as likely to have osteoporosis as their cohort without hypoparathyroidism. According to Dr. Mannstadt, given the benefits of PTH in preserving bone density, PTH(1-34) is advisable for osteoporosis in at-risk patients; however, rhPTH(1-84) is not approved for use in treatment of osteoporosis in the United States.

A phase 2, randomized, double blind, placebo-controlled, parallel trial of four treatment groups (1:1:1:1) to receive a daily combination product (Transcon PTH) at three different dosages: 15 mcg, 18 mcg, 21 mcg or placebo is currently underway with results expected in March 2023.6

Neither Dr. Manstardt nor Dr. Wexler had any relevant financial conflicts regarding this study. Funding for the RACE trial was provided by Shire Human Genetic Therapies, Inc.,a member of the Takeda group of companies.

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