U.S. Food and Drug Administration (FDA)-Approved Indications

Natpara is indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism.

Recombinant human parathyroid hormone for injection is available as Natpara (Shire-NPS Pharmaceuticals, Inc). Parathyroid hormone raises serum calcium by increasing renal tubular calcium reabsorption, increasing intestinal calcium absorption (i.e., by converting 25-OH vitamin D to 1,25-OH2 vitamin D) and by increasing bone turnover which releases calcium into the circulation (Shire, 2022).

Natpara carries a black box warning for potential risk of osteosarcoma. In male and female rats, parathyroid hormone caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. A risk to humans could not be excluded. Because of the potential risk of osteosarcoma, it is recommended that healthcare providers prescribe Natpara only to patients who cannot be well-controlled on calcium and active forms of vitamin D and for whom the potential benefits are considered to outweigh the potential risk. The label also recommends avoiding use in patients who are at increased baseline risk for osteosarcoma (including those with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses, patients with hereditary disorders predisposing to osteosarcoma or patients with a history of prior external beam or implant radiation therapy involving the skeleton). Becuase of the risk, Natpara is only available through a restricted program called the NATPARA REMS Program.

In addition to the potential risk of osteosarcoma, other warnings and precautions include severe hypercalcemia, severe hypocalcemia (which can occur with interruption or discontinuation of Natpara), digoxin toxicity (hypercalcemia increases this risk), and hypersensitivity reactions such as anaphylaxis, dyspnea, angioedema, urticaria, and rash.

The most common adverse reactions associated with Natpara and occurring in greater than 10% of individuals included paresthesia, hypocalcemia, headache, hypercalcemia, nausea, hypoesthesia, diarrhea, vomiting, arthralgia, hypercalciuria and pain in extremity.

It is recommended to monitor infants exposed to parathyroid hormone through breast milk for symptoms of hypercalcemia or hypocalcemia. Monitoring of serum calcium in the infant should be considered. The safety and efficacy in pediatric patients have not been established. No dose adjustment is recommended in patients 65 years of age and older, or in patients with mild to moderate renal or hepatic impairment.

Hypoparathyroidism

Hypoparathyroidism is a rare endocrine disorder in which the parathyroid glands fail to produce sufficient amounts of parathyroid hormone (PTH) or where the hormone lacks biologic activity (NPS, 2015). PTH plays a central role in a variety of critical physiological functions in the body. Insufficient levels of PTH lead to low levels of calcium and high levels of phosphate in the blood, and an inability to convert native vitamin D into its active state, which helps the body properly absorb oral calcium. Parathyroid hormone increases serum calcium by increasing renal tubular calcium reabsorption, increasing intestinal calcium absorption (i.e., by converting native vitamin D (25 OH) into its active form (1,25 OH2 vitamin D)) and by increasing bone turnover which releases calcium into the circulation.

Hypoparathyroidism occurs most commonly as a result of surgical removal of the parathyroid glands and more rarely as a result of autoimmune or congenital diseases (NPS, 2015). Patients with hypoparathyroidism can experience numbness, tingling, muscle twitching, spasms or cramps, abnormal heart rhythm, and seizures as a consequence of hypocalcemia. Hypoparathyroidism is also associated with long-term complications such as kidney damage, kidney stones, development of cataracts and calcification of soft tissues.

The U.S. Food and Drug Administration (FDA) has approved Natpara (recombinant human parathyroid hormone) as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism (FDA, 2015). Natpara received orphan drug status for the treatment of hypoparathyroidism from the FDA in 2007 as it is intended to treat a rare disease.

Because of the potential risk of osteosarcoma, Natpara is recommended only for patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone (FDA, 2015). Natpara was not studied in patients with hypoparathyroidism caused by calcium-sensing receptor mutations or in patients with acute post-surgical hypoparathyroidism.

The FDA approval of Natpara was supported by 12 pharmacology studies and 4 company-sponsored efficacy and safety studies (NPS, 2015). In clinical studies, Natpara has been shown to increase serum calcium levels while reducing the need for oral calcium and active vitamin D and, in some cases, eliminate the need for active vitamin D altogether.

The pivotal Phase 3 study, known as REPLACE (Mannstadt et al, 2013), was a randomized, double-blind, placebo-controlled study in 124 patients with hypoparathyroidism who were randomly assigned to receive Natpara or a placebo. The trial was designed to determine whether Natpara can be used as a substitute for, or be used to help reduce the amount of, active forms of vitamin D or oral calcium taken by participants. Results showed 42 % of Natpara-treated participants achieved normal blood calcium levels on reduced doses of calcium supplements and active forms of vitamin D, compared to 3 % of placebo-treated participants.

Mannstadt et al (2013) reported on the efficacy, safety, and tolerability of Natpara, a once-daily recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) in adults with hypoparathyroidism. In this double-blind, placebo-controlled, randomized phase III study (REPLACE), investigators recruited patients with hypoparathyroidism (greater than or equal to 18 months duration) aged 18 to 85 years from 33 sites in 8 countries. Hypoparathyroidism was defined as hypocalcemia (calcium concentration below the lower limit of normal) and documented PTH concentrations below the lower limit of the normal range, recorded on at least 2 occasions within the previous 12 months. Additional eligibility criteria were: a requirement for active vitamin D and oral calcium (greater than or equal to 1,000 mg daily) treatment, normal thyroid-stimulating hormone concentrations if not on thyroid hormone replacement therapy (or if on therapy, the dose had to have been stable for greater than or equal to 3 months), and normal magnesium and serum 25-hydroxyvitamin D concentrations. Creatinine clearance needed to be either greater than 30 ml/min on 2 separate measurements, or greater than 60 ml/min (1 measurement) with an accompanying serum creatinine concentration of less than 132.6 μmol/L. Patients with a known activating mutation in the calcium-sensing receptor gene were excluded.

After an optimization period, during which calcium and active vitamin D doses were adjusted to achieve consistent albumin-corrected serum calcium, patients were randomly assigned (2:1) via an interactive voice response system to 50 μg per day of rhPTH(1-84) or placebo for 24 weeks (Mannstadt et al, 2013). Active vitamin D and calcium were progressively reduced, while rhPTH(1-84) could be titrated up from 50 μg to 75 μg and then 100 μg (weeks 0 to 5). The primary end-point was the proportion of patients at week 24 who achieved a 50 % or greater reduction from baseline in their daily dose of oral calcium and active vitamin D while maintaining a serum calcium concentration greater than or the same as baseline concentrations and less than or equal to the upper limit of normal, analyzed by intention to treat. Between June 23, 2009, and Feb 28, 2011, 134 eligible patients were recruited and randomly assigned to rhPTH(1-84) (n = 90) or placebo (n = 44); 6 patients in the rhPTH(1-84) group and 7 in the placebo group discontinued before study end. A total of 48 (53 %) patients in the rhPTH(1-84) group achieved the primary end-point compared with 1 (2 %) patient in the placebo group (percentage difference 51.1 %, 95 % confidence interval [CI]: 39.9 to 62.3; p < 0.0001). The proportions of patients who had at least 1 adverse event were similar between groups (84 [93 %] patients in the rhPTH[1-84] group versus 44 [100 %] patients in the placebo group), with hypocalcaemia, muscle spasm, paraesthesias, headache, and nausea being the most common adverse events. The proportions of patients with serious adverse events were also similar between the rhPTH(1-84) group (10 [11 %] patients) and the placebo group (4 [9 %] patients). The investigators concluded that 50 μg, 75 μg, or 100 μg per day of rhPTH(1-84), administered subcutaneously in the out-patient setting, is effective and well-tolerated as a PTH replacement therapy for patients with hypoparathyroidism.

An accompanying editorial (Linglart and Rothenbuhler, 2013) noted that, by reducing serum phosphate, rhPTH(1-84) has the potential to prevent of calcium-phosphate precipitation within the kidney and other tissues, the study by Mannstadt et al (2013) had only short-term follow-up. The editorialist noted that children aged younger than 18 years and patients with a known activating mutation in the calcium-sensing receptor gene did not take part in the study, and stated that further studies should assess the efficacy and safety of rhPTH in these patients.

Other Indications

Charcot Neuro-Osteoarthropathy

Petrova and colleagues (2021) noted that fractures in Charcot neuro-osteoarthropathy (CNO) often fail to heal despite prolonged immobilization with below-knee casting. In a double-blind, placebo-controlled study, these researchers examined the efficacy of rhPTH in reducing time to resolution of CNO and healing of fractures. Patients with diabetes and acute (active) Charcot foot were randomized (double-blind) to either full-length PTH (1-84) or placebo therapy, both in addition to below-knee casting and calcium and vitamin D3 supplementation. The primary outcome was resolution of CNO, defined as a skin foot temperature difference greater than 2°C at 2 consecutive monthly visits. Median time to resolution was 5 months (95 % CI: 4 to 12) in intervention and 6 months (95 % CI: 2 to 9) in control. There was no significant difference in time to resolution between the groups (mixed-effects logistic regression; p = 0.64). The hazard ratio (HR) of resolution was 0.84 (95 % CI: 0.41 to 1.74; p = 0.64), and the odds ratio (OR) of resolution by 12 months was 1.22 (0.90, 1.67; p = 0.20) (intervention versus control). On linear regression analysis, there were no significant differences in the effect of treatment on fracture scores quantitated on magnetic resonance imaging (MRI) scans (coefficient 0.13 [95 % CI: -0.62 to 0.88]; p = 0.73) and on foot and ankle X-rays (coefficient 0.30 [95 % CI: -0.03 to 0.63]; p = 0.07). The authors concluded that they observed no added benefit from PTH (1-84) in achieving earlier resolution of CNO as compared with below-knee casting. Daily intervention with PTH (1-84) did not reduce time to resolution or enhance fracture healing of the active Charcot foot. This study used, for the first time, MRI and X-ray scores, in addition to skin foot temperature, to quantitate resolution and fracture healing, and these new efficacy measures should be considered in further clinical trials in CNO.

The authors stated that this study had several drawbacks. First, annual recruitment was slower than anticipated. Second, during the 2nd year of the trial, the research team was made aware of an unprecedented global shortage of the investigational medicinal product. Nevertheless, with the 48 patients recruited, the study achieved the 30 resolutions called by the power requirement to detect the sought HR of 2.77. Third, withdrawal rate was high; however, missing data analysis indicated the withdrawal mechanism to be “missing at random” since it was not related to skin foot temperature or total MRI fracture score, variables that were significantly associated with the likelihood of clinical resolution by 12 months. Furthermore, findings of the multiple imputation model and the sensitivity analysis were consistent with the findings of the complete-case analysis. This confirmed that the high withdrawal rate did not affect the study results. Fourth, only 73 % in the control group and 65 % in the intervention group were managed in non-removable casts. Nevertheless, this rate was significantly higher than the previously reported rate of the use of non-removable off-loading for the acute Charcot foot in the United Kingdom. (35.4 %). In addition, the type of off-loading was similar between the groups and had no significant effect on resolution.

Enhancement of Tendon-To-Bone Healing in Rotator Cuff Tear

Han et al (2022) stated that rhPTH promotes tendon-to-bone healing in humans and animals with rotator cuff tear (RCT); however, problems regarding repeated systemic rhPTH injections in humans exist. These researchers examined the effect of topical rhPTH administration using 3-dimensionally (3D)-printed nanofiber sheets on tendon-to-bone healing in a rabbit RCT model compared to that of direct topical rhPTH administration. A total of 80 rabbits were randomly assigned to 5 groups (n = 16 each). To create the chronic RCT model, these investigators induced complete supraspinatus tendon tears in both shoulders and left them untreated for 6 weeks. All transected tendons were repaired in a trans-osseous manner with saline injection in group A, hyaluronic acid (HA) injection in group B, 3D-printed nanofiber sheet fixation in group C, rhPTH and HA injection in group D, and 3D-printed rhPTH- and HA-soaked nanofiber sheet fixation in group E. Genetic (messenger RNA expression evaluation) and histologic evaluations (hematoxylin and eosin and Masson trichrome staining) were carried out in 50 % of the rabbits at 4 weeks post-repair. Genetic, histologic, and biomechanical evaluations (mode of tear and load to failure) were carried out in the remaining rabbits at 12 weeks. For genetic evaluation, group E showed a higher collagen type I alpha 1 expression level than did the other groups (p = 0.008) at 4 weeks. However, its expression level was downregulated, and there was no difference at 12 weeks. For histologic evaluation, group E showed greater collagen fiber continuity, denser collagen fibers, and more mature tendon-to-bone junction than did the other groups (p = 0.001, p = 0.001, and p = 0.003, respectively) at 12 weeks. For biomechanical evaluation, group E showed a higher load-to-failure rate than did the other groups (p < 0.001) at 12 weeks. The authors concluded that 3D-printed rhPTH-soaked nanofiber sheet fixation could promote tendon-to-bone healing of chronic RCT. This was a basic science study using a rabbit model; these findings need to be further investigated in human studies.

Fracture Healing

: Requires Precertification:

Precertification of recombinant human parathyroid hormone (Natpara) is required of all Aetna participating providers and members in applicable plan designs. For precertification of Natpara, call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see

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Criteria for Initial Approval

Aetna considers initiation of recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) (Natpara) medically necessary for the treatment of hypocalcemia associated with hypoparathyroidism when

of the following criteria are met:

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

Continuation of Therapy

Aetna considers continuation of rhPTH(1-84) (Natpara) therapy medically necessary for members requesting reauthorization for an indication listed in Section I who are experiencing benefit from therapy as evidenced by maintenance or normalization of calcium levels compared to baseline.

Dosage and Administration

Natpara (parathyroid hormone) for subcutaneous injection is supplied as a multiple-dose, dual-chamber glass cartridge containing a sterile lyophilized powder and a sterile diluent for reconstitution in four dosage strengths (25 mcg, 50 mcg, 75 mcg, or 100 mcg).

According to the Full Prescribing Information, Natpara should be individualized based on total serum calcium (albumin-corrected) and 24-hour urinary calcium excretion. The recommended Natpara dose is the minimum dose required to prevent both hypocalcemia and hypercalciuria. This dose will generally be the dose that maintains total serum calcium (albumin-corrected) within the lower half of the normal range (i.e., between 8 and 9 mg/dL) without the need for active forms of vitamin D and with calcium supplementation sufficient and individualized to meet the individual’s daily requirements. Doses of active forms of vitamin D and calcium supplements will need to be adjusted when using Natpara.

Natpara is self-administered once-daily by subcutaneous injection in the thigh. The starting dose of Natpara is 50 mcg once-daily. The dose of Natpara (parathyroid hormone) for injection may be increased in increments of 25 mcg every 4 weeks up to a maximum daily dose of 100 mcg if serum calcium cannot be maintained above 8 mg/dL without an active form of vitamin D and/or oral calcium supplementation. The dose of Natpara (parathyroid hormone) for injection may be decreased to as low as 25 mcg per day if total serum calcium is repeatedly above 9 mg/dL after the active form of vitamin D has been discontinued and calcium supplement has been decreased to a dose sufficient to meet daily requirements.

The maintenance dose should be the lowest dose that achieves a total serum calcium (albumin-corrected) within the lower half of the normal total serum calcium range (i.e., approximately 8 and 9 mg/dL), without the need for active forms of vitamin D and with calcium supplementation sufficient to meet daily requirements. Monitor serum calcium and 24-hour urinary calcium per standard of care once a maintenance dose is achieved.

Source: Shire-NPS 2022

Experimental and Investigational

Aetna considers rhPTH(1-84) experimental and investigational for all other indications including the following (not an all-inclusive list) because its effectiveness for these indications has not been established: