Recombinant Human Parathyroid Hormone (Natpara)

Number: 0894

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of Natpara is required of all Aetna participating providers and members in applicable plan designs.  For precertification of Natpara, call (866) 752-7021, or fax (866) 267-3277.

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 all of the following criteria are met:

  • Member has hypocalcemia and concomitant serum parathyroid hormone concentrations below the lower limit of normal for the laboratory reference range on at least 2 separate dates at least 21 days apart within the last 12 months; and
  • Member is receiving vitamin D metabolite/analog therapy with calcitriol greater than or equal to 0.25 mcg per day or alphacalcidol greater than or equal to 0.5 mcg/day (or equivalent); and
  • Member is receiving supplemental calcium treatment greater than or equal to 1000 mg/day over and above normal dietary calcium intake; and
  • Serum magnesium levels is within normal laboratory limits; and
  • Serum 25-hydroxyvitamin D concentration is above the lower limit of normal laboratory range; and
  • Serum calcium is greater than 7.5 mg/dL prior to initiating therapy with the requested medication.

Aetna considers continuation of rhPTH(1-84) (Natpara) medically necessary for members requesting reauthorization for an indication listed above who are experiencing benefit from therapy as evidenced by having an increase in calcium and parathyroid hormone level from baseline.

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:

  • Fracture healing
  • Prevention of breast cancer skeletal metastases
  • Treatment of osteoporosis
  • Treatment of acute post-surgical hypoparathyroidism (within 6 months of surgery) and expected recovery from the hypoparathyroidism.

Dosing Recommendations

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 2020

Background

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.
  • Limitations of Use:
    • 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.
    • Natpara was not studied in patients with hypoparathyroidism caused by calcium-sensing receptor mutations.
    • Natpara was not studied in patients with acute post-surgical 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.

The most common adverse reactions associated with Natpara and occurring in greater than 10 % of individuals were: paresthesia, hypocalcemia, headache, hypercalcemia, nausea, and hypoesthesia, diarrhea, vomiting, arthralgia, hypercalciuria and pain in extremity (Shire-NPS, 2020).

Natpara can cause some people to have hypercalcemia. serum calcium should be monitored prior to initiating therapy with Natpara and during treatment (FDA, 2015).

People who stop using or miss a dose of Natpara may have an increased risk of hypercalcemia (FDA, 2015).

Natpara contains a Boxed Warning citing the potential risk of osteosarcoma.  During animal drug testing, Natpara caused some rats to develop osteosarcoma (Shire-NPS, 2020).  It is not known if people who take Natpara will have a higher chance of getting osteosarcoma.  Natpara will be made available through a Risk Evaluation and Mitigation Strategy (REMS) Program to mitigate the potential risk of osteosarcoma.

It is not known if Natpara is safe and effective for children 18 years of age and younger.  Natpara should not be used in children and young adults who are skeletally immature (Shire-NPS, 2020).

Warnings and Precautions (Shire-NPS, 2020):

  • Potential Risk of Osteosarcoma: Prescribe Natpara only to patients who cannot be well-controlled on calcium and active vitamin D. Avoid use of in patients who are at increased risk for osteosarcoma.
  • Severe Hypercalcemia: Monitor serum calcium when starting or adjusting Natpara dose and when making changes to co-administered drugs known to raise serum calcium.
  • Severe Hypocalcemia can occur with interruption or discontinuation of Natpara treatment. Monitor serum calcium and replace calcium and vitamin D.
  • Digoxin Toxicity: Hypercalcemia increases the risk of digoxin toxicity. In patients using Natoara concomitantly with digoxin, monitor serum calcium more frequently and increase monitoring when initiating or adjusting Natpara dose.
  • Hypersensitivity reactions (anaphylaxis, dyspnea, angioedema, urticaria, rash) have been reported. If signs or symptoms of a serious hypersensitivity reaction occur, discontinue treatment with Natpara and treat patient according to the standard of care.

Fracture Healing

Zhang et al (2014) stated that human PTH is known to be effective in the treatment of osteoporosis and reduction of risk of vertebral and non-vertebral fractures; however, its role in the enhancement of human fracture healing is controversial.  These investigators conducted a systematic literature review on the use of recombinant PTH in human fracture healing to
  1. evaluate the evidence for recombinant PTH in human fracture healing and
  2. examine if there are notable differences between previous case reports and prospective trials.
These researchers performed a literature search in PubMed, EMBASE, Web of Science, and the Cochrane Database of Systematic Reviews for "teriparatide", "PTH (1-84)", "fracture" and "healing".  References of retrieved articles were screened for additional studies, and exclusion criteria were applied.  Due to the limited publications on the subject, case reports and case series were included in data analysis.  The authors concluded that this review yielded 16 publications on the use of recombinant PTH in human fracture healing with 2 randomized controlled trials (RCTs) with 1 retrospective subgroup analysis.  They stated that there were discrepancies in study design in the RCTs and the majority of case reports; additional prospective studies are needed.

Campbell et al (2015) reviewed current literature regarding possible mechanisms and effectiveness for PTH and teriparatide (PTH 1-34, TPTD) to improve the healing process in the setting of various types of fractures.  This review focused first on the role of PTH in normal bone.  These researchers then discussed mechanisms of normal bone healing as well as delayed and impaired fracture healing.  They summarized pertinent animal data and then reviewed human studies utilizing PTH or TPTD for fracture healing.  In particular, the authors examined unique situations including osteoporotic fractures, diabetes, stress fractures, delayed or poor healing and combination with bisphosphonate therapy.  They concluded that available data indicated there is likely an important role for TPTD and PTH in promoting fracture healing in selected patients, but more clinical trial data are needed.

Management of Medication-Related Osteonecrosis of the Jaw

Taysi and colleagues (2019) stated that treatment of patients with bisphosphonate usage is a significant concern for oral surgeons because it interferes with jaw bone turnover and regeneration . In case of adverse effects manifesting related to bisphosphonate use, oral surgeons are usually treating and keep the patient's symptoms under control.  These investigators examined a new treatment protocol for medication-related osteonecrosis of the jaw (MRONJ).  This treatment protocol consisted of administering hPTH loaded chitosan microspheres that were prepared by ionotropic gelation method and/or the prepared microspheres were suspended in a poloxamer gel.  After in-vitro optimization studies, the efficacy of the chosen formulations was evaluated in-vivo studies.  Zoledronic acid was administered daily to 48 adult female Sprague-Dawley rats, divided into 4 experimental groups, at a daily concentration of 0.11 mg/kg over 3 weeks to induce the MRONJ model.  At the end of this period, maxillary left molar teeth were extracted.  In the first group, the subjects received no treatment.  In the negative control group, poloxamer hydrogel containing empty microspheres were immediately applied to the soft tissues surrounding the extraction socket.  The treatment group-1 was treated with local injections of poloxamer hydrogel containing hPTH.  The treatment group-2 was treated with a single local injection of poloxamer hydrogel containing hPTH-loaded chitosan microspheres.  Both treatment groups received a total of 7 µg of hPTH at the end of the treatment protocol.  The authors concluded that the findings of this study demonstrated successful attenuation of MRONJ via a local drug delivery system combined with hPTH, as opposed to previously attempted treatment strategies.  These researchers stated that, to the best of their knowledge, this was the first study to examine the efficacy of local application method with the sustained-release microspheres to attenuate of MRONJ.  Moreover, they stated that the limitations of the study included small sample size and the lack of analysis with immunohistochemistry technique; and future research is needed with larger sample size with immunohistochemical observation. 

Management of Post-Thyroidectomy Hypoparathyroidism

Edafe and colleagues (2019) noted that post-surgical hypoparathyroidism is a common complication following thyroid surgery.  The incidence is likely to increase given the rising trend in the annual number of thyroid surgeries being carried out.  Measures to prevent post-thyroidectomy hypoparathyroidism including different surgical techniques and prophylactic calcium and vitamin D supplements have been extensively studied; however, the management of post-thyroidectomy hypoparathyroidism has not been extensively studied.  Routine use of calcium and vitamin D supplements in the post-operative period may reduce the risk of symptoms, temporary hypocalcemia and hospital stay.  However, this may result in over-treatment and has no effect on long-term hypoparathyroidism.  Current recommendations on the management of post-thyroidectomy hypoparathyroidism is based on low-quality evidence.  Existing guidelines do not often distinguish between surgical and non-surgical hypoparathyroidism, and transient and long-term disease.  In a Cochrane review, these researchers examined the evidence on the use of calcium, vitamin D and rhPTH in the management of post-thyroidectomy hypoparathyroidism.  Furthermore, they highlighted deficiencies in the current literature and stimulated further work in this field.  These investigators searched CENTRAL, Medline, PubMed, Embase as well as ICTRP Search Portal and ClinicalTrials.gov.  The date of the last search for all data-bases was December 17, 2018 (except Embase, which was last searched on December 21, 2017).  No language restrictions were applied.  They planned to include RCTs or controlled clinical trials (CCTs) examining the effects of calcium, vitamin D or rhPTH in individuals with temporary and long-term post-thyroidectomy hypoparathyroidism.  Two review authors independently screened titles, abstracts and full texts for relevance.  Data-base searches yielded a total of 1751 records.  These investigators retrieved potentially relevant full texts and excluded articles on the following basis: not a RCT or CCT; intervention, comparator or both did not match pre-specified criteria; non-surgical causes of hypoparathyroidism, and studies on prevention.  None of the articles was eligible for inclusion in the systematic review.  The authors concluded that the findings of this systematic review highlighted a gap in the current literature and the lack of high-quality evidence in the management of post-thyroidectomy temporary and long-term hypoparathyroidism.  They stated that further research focusing on clinically relevant outcomes is needed to examine the effects of current treatments in the management of temporary and long-term post-thyroidectomy hypocalcemia.

Prevention of Breast Cancer Skeletal Metastases

Swami and associates (2017) noted that advanced breast cancer is frequently associated with skeletal metastases and accelerated bone loss.  Recombinant PTH [teriparatide, PTH(1-34)] is the first anabolic agent approved in the US for treatment of osteoporosis.  While signaling through the PTH receptor in the osteoblast lineage regulates bone marrow hematopoietic niches, the effects of anabolic PTH on the skeletal metastatic niche are unknown.  These researchers demonstrated, using orthotopic and intra-tibial models of 4T1 murine and MDA-MB-231 human breast cancer tumors, that anabolic PTH decreases both tumor engraftment and the incidence of spontaneous skeletal metastasis in mice.  Micro-computed tomography and histomorphometric analyses revealed that PTH increased bone volume and reduced tumor engraftment and volume.  Trans-well migration assays with murine and human breast cancer cells revealed that PTH altered the gene expression profile of the metastatic niche, in particular VCAM-1, to inhibit recruitment of cancer cells.  While PTH did not affect growth or migration of the primary tumor, it elicited several changes in the tumor gene expression profile resulting in a less metastatic phenotype.  The authors concluded that PTH treatment in mice altered the bone microenvironment, resulting in decreased cancer cell engraftment, reduced incidence of metastases, preservation of bone micro-architecture and prolonged survival.  They stated that anabolic PTH clearly warrants further investigation in preventing breast cancer metastasis.

Treatment of Osteoporosis

Farahmand and colleagues (2016) stated that osteoporosis in men is an important public health problem with more than 1 million cases in Germany.  Although osteoporotic fractures have a much higher mortality in men than in women, male patients are still under-diagnosed and under-treated.  These investigators reviewed the epidemiology of male osteoporosis and current treatment situation, pathophysiological aspects at the hormonal level, risk factors, diagnostic work-up and therapeutic options.  They provided an overview of data concerning male osteoporosis, recommendations for diagnostic work-up and presentation of the study situation on pharmaceutical therapies.  As risk factors for osteoporosis are present in 50 to 70 % of male patients, a detailed patient history is necessary for assessment of the risk factors.  Radiological imaging of the spine is primarily recommended to identify individuals with prevalent vertebral fractures, as approximately 10 % of men over the age of 50 years have suffered a vertebral fracture.  Laboratory testing of relevant parameters helps to rule out other metabolic bone diseases.  In Germany, specific medications available for the treatment of male osteoporosis comprise the active vitamin D analog alfacalcidol, the oral bisphosphonates alendronate and risedronate, the intravenous bisphosphonate zoledronic acid, the anti-receptor activator of NF-κB ligand (RANKL) antibody denosumab, which can be given as intravenous injection and strontium ranelate, a drug with a complex mode of action.  Teriparatide, a recombinant form of the 34 N-terminal amino acid sequence of PTH is the only anabolic agent approved for male osteoporosis.  The authors concluded that osteoporosis in men is increasingly being recognized as an important public health problem and affected patients need to be adequately diagnosed and treated.  Nowadays, a broad spectrum of well-proven therapeutic options with different modes of action allow individual treatment strategies for male osteoporosis patients.

The use of rhPTH[1-84] in the treatment of osteoporosis (male or female) is considered an off-label use.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

There is no specific code for recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) (Natpara):

Other CPT codes related to the CPB:

96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

Other HCPCS codes related to the CPB:

S0169 Calcitrol, 0.25 microgram

ICD-10 codes covered if selection criteria are met:

E20.0 - E20.9 Hypoparathyroidism [(for adults 18 years of age or older with hypocalcemia)]

ICD-10 not codes covered if selection criteria are met:

C50.011 - C50.929 Malignant neoplasm of breast [prevention of breast cancer skeletal metastases]
E89.2 Postprocedural hypoparathyroidism
M81.1 - M81.8 Osteoporosis without current pathological fracture [treatment of]

The above policy is based on the following references:

  1. Bilezikian JP, Clarke BL, Mannstadt M, et al. Safety and efficacy of recombinant human parathyroid hormone in adults with hypoparathyroidism randomly assigned to receive fixed 25-μg or 50-μg daily doses. Clin Ther. 2017;39(10):2096-2102.
  2. Calvert GT, Randall RL, Jones KB, et al. At risk populations for osteosarcoma: The syndromes and beyond. Sarcoma. 2012;2012:152382.
  3. Campbell EJ, Campbell GM, Hanley DA. The effect of parathyroid hormone and teriparatide on fracture healing. Expert Opin Biol Ther. 2015;15(1):119-129.
  4. Edafe O, Mech CE, Balasubramanian SP. Calcium, vitamin D or recombinant parathyroid hormone for managing post-thyroidectomy hypoparathyroidism. Cochrane Database Syst Rev. 2019;5(5):CD012845.
  5. Farahmand P, Spiegel R, Ringe JD. Male osteoporosis. Z Rheumatol. 2016;75(5):459-465.
  6. Khan MI, Waguespack SG, Hu MI. Medical management of postsurgical hypoparathyroidism. Endocr Pract. 2011;17(Suppl 1): 18-25. 
  7. Linglart A, Rothenbuhler A. From synthesis to replacement of parathyroid hormone. Lancet Diabetes Endocrinol. 2013;1(4):260-261.
  8. Mannstadt M, Clarke BL, Vokes T, et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): A double-blind, placebo-controlled, randomised, phase 3 study. Lancet Diabetes Endocrinol. 2013;1(4):275-283.
  9. NPS Pharmaceuticals, Inc. FDA approves Natpara (parathyroid hormone) for injection as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism. Press Release. Bedminster, NJ: NPS Pharma; January 23, 2015.
  10. NPS Pharmaceuticals, Inc. Natpara (parathyroid hormone) for injection. Recombinant human parathyroid hormone. BLA 12551. Risk Evaluation and Mitigation Strategy (REMS). Initial REMS Approval: 01/2015. Bedminster, NJ: NPS Pharmaceuticals; January 2015.
  11. NPS Pharmaceuticals, Inc. Natpara (parathyroid hormone) for injection, for subcutaneous use. Prescribing Information. Bedminster, NJ: NPS Pharmaceuticals; January 2015. 
  12. Shire-NPS Pharmaceuticals, Inc. Natpara (parathyroid hormone) for injection, for subcutaneous use. Prescribing Information. Lexington, MA: Shire-NPS: revised July 2020. 
  13. Swami S, Johnson J, Bettinson LA, et al. Prevention of breast cancer skeletal metastases with parathyroid hormone. JCI Insight. 2017;2(17):e90874.
  14. Tay YD, Tabacco G, Cusano NE, et al. Therapy of hypoparathyroidism with rhPTH(1-84): A prospective eight year investigation of efficacy and safety. J Clin Endocrinol Metab. 2019;104(11):5601-5610.
  15. Taysi AE, Cevher E, Sessevmez M, et al. The efficacy of sustained-release chitosan microspheres containing recombinant human parathyroid hormone on MRONJ. Braz Oral Res. 2019;33:e086.
  16. U.S. Food and Drug Administration (FDA). FDA approves Natpara to control low blood calcium levels in patients with hypoparathyroidism. FDA News Release. Silver Spring, MD: FDA: January 23, 2015.
  17. Vokes TJ, Mannstadt M, Levine MA, et al. Recombinant human parathyroid hormone effect on health-related quality of life in adults with chronic hypoparathyroidism. J Clin Endocrinol Metab. 2018;103(2):722-731. 
  18. Zhang D, Potty A, Vyas P, Lane J. The role of recombinant PTH in human fracture healing: A systematic review. J Orthop Trauma. 2014;28(1):57-62