Recombinant Human Parathyroid Hormone (Natpara)

Number: 0894

Table Of Contents

Policy Applicable CPT / HCPCS / ICD-10 Codes Background References

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Policy

Note: 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 Specialty Pharmacy Precertification.

1. 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 all of the following criteria are met:

   1. 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
   2. 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
   3. Member is receiving supplemental calcium treatment greater than or equal to 1000 mg/day over and above normal dietary calcium intake; and
   4. Serum magnesium levels are within normal laboratory limits; and
   5. Serum 25-hydroxyvitamin D concentration is above the lower limit of normal laboratory range; and
   6. Serum calcium level is greater than 7.5 mg/dL prior to initiating therapy with the requested medication.

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

2. 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: Takeda Pharmaceuticals, 2023b

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:

• Charcot neuro-osteoarthropathy
• Enhancement of tendon-to-bone healing in rotator cuff tear
• Fracture healing
• Hungry bone syndrome
• Prevention of breast cancer skeletal metastases
• Treatment of acute osteoporotic vertebral compression fracture
• Treatment of acute post-surgical hypoparathyroidism (within 6 months of surgery) and expected recovery from the hypoparathyroidism
• Treatment of osteoporosis.

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

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

Other CPT codes related to the CPB:

82310 Calcium; total 82330 Calcium; ionized 83970 Parathormone (parathyroid hormone) 96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

HCPCS codes covered if selection criteria are met:

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Recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) (Natpara) – no specific code

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 codes not covered for indications listed in the CPB:

C50.011 – C50.929 Malignant neoplasm of breast [prevention of breast cancer skeletal metastases] E83.81 Hungry bone syndrome E89.2 Postprocedural hypoparathyroidism M14.60 Charcot’s joint, unspecified site M14.611- M14.619 Charcot’s joint, shoulder M14.621- M14.629 Charcot’s joint, elbow M14.631- M14.639 Charcot’s joint, wrist M14.641- M14.649 Charcot’s joint, hand M14.651- M14.659 Charcot’s joint, hip M14.661- M14.669 Charcot’s joint, knee M14.671- M14.679 Charcot’s joint, ankle and foot M14.68 Charcot’s joint, vertebrae M14.69 Charcot’s joint, multiple sites M75.100 – M75.102 Unspecified rotator cuff tear or rupture, not specified as traumatic M75.110 – M75.112 Incomplete rotator cuff tear or rupture not specified as traumatic M75.120 – M75.122 Complete rotator cuff tear or rupture not specified as traumatic M80.88XA – M80.88XS Other osteoporosis with current pathological fracture, vertebra(e) [acute osteoporotic vertebral compression] M81.1 – M81.8 Osteoporosis without current pathological fracture [treatment of]

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.

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.

In September 2019, Takeda issued a US recall for all doses of Natpara. Since then, Takeda has been providing access to Natpara to select patients through a special use program (SUP). In April 2022, the manufacturer indicated Natpara’s commercial return to the US market has been indefinitely delayed. In October 2022, Takeda announced that it will discontinue global manufacturing of Natpara at the end of 2024 due to the ongoing manufacturing issues (Takeda Pharmaceuticals, 2022).

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.

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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

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.

Hungry Bone Syndrome

Ahmed and colleagues (2020) reported the findings of the case of a 35-year-old woman with end-stage renal disease (ESRD) on hemodialysis for 9 years. She was diagnosed with secondary hyperparathyroidism complicated with a brown tumor in the mandible. After medical therapy failed, she underwent total parathyroidectomy (PTX), which was complicated by severe and prolonged hypocalcemia (hungry bone syndrome). Post-surgery, she needed prolonged and frequent intravenous (IV) calcium and a high dose of vitamin D resulting in frequent admission with symptomatic hypocalcemia. Her serum magnesium was noted to be in the normal range. She continued to be hypocalcemic for nearly 8 months post-surgery despite the intensive treatment. Recombinant PTH (teriparatide; 20-mg daily) resulted in normalization of calcium within 2 weeks. The authors concluded that the use of PTH proved to be an effective therapeutic approach in this case. Moreover, these researchers stated that proper pre-operative preparation and subtotal PTX with an adequate dose of vitamin D and calcium supplement may have been a rational option for this case. This was a single-case report.

Furthermore, an UpToDate review on “Hungry bone syndrome following parathyroidectomy in end-stage kidney disease patients” (Berkoben and Quarles, 2021) does not mention recombinant human PTH as a management / therapeutic option.

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 Acute Osteoporotic Vertebral Compression Fracture

Gou et al (2022) noted that although widely used in clinical practice, vertebral augmentation procedure (VAP) for osteoporotic vertebral compression fracture (OVCF) is not supported. Recently, the effect of rhPTH has been paid great attention for its effectiveness in anti-osteoporosis and bone union. In a retrospective study, these researchers examined the outcome of rhPTH on acute OVCF and compared it with VAP to clarify its therapeutic advantages. This trial included 71 acute OVCF patients from January 2015 to March 2020: 22 received rhPTH treatment (rhPTH group) and 49 underwent VAP (VAP group). The rhPTH group comprised 15 women and 7 men with an average of 76.18 years, and the VAP group comprised 35 women and 14 men with an average of 73.63 years. The thoracic/lumbar vertebrae were 14/8 in the rhPTH group and 29/20 in the VAP group. The average follow-up period was 14.05 months in the rhPTH group and 13.82 months in the VAP group. The 2 groups were evaluated regarding the visual analog score (VAS), Oswestry Disability Index (ODI), OVCF bone union, bone mineral density (BMD), kyphotic angle (KA), anterior and posterior border height (ABH and PBH, respectively), adverse events (AEs) and the health-related quality of life (HR-QOL) assessed by short form-36 health survey scores (SF-36). Categorical variables were analyzed by Chi-square test and continuous variables between groups were analyzed by independent samples t-test or Mann-Whitney U test according to the normality. During the follow-up, the VAS was significantly lower in the rhPTH group than in the VAP group at month 3 (0.39 ± 0.6 versus 0.68 ± 0.651) (p = 0.047), month 6 (0.45 ± 0.60 versus 2.18 ± 1.22) (p < 0.001), and month 12 (0.45 ± 0.60 versus 2.43 ± 1.49) (p < 0.001). At month 12, the ODI was significantly lower in the rhPTH group (18.59 ± 3.33 %) than in the VAP group (28.93 ± 16.71 %) (p < 0.001). Bone bridge was detected on sagittal computed tomography images of all fractured vertebrae in the rhPTH group. The BMD was significantly higher in the rhPTH group (87.66 ± 5.91 Hounsfield units [HU]) than in the VAP group (68.15 ± 11.32HU) (p < 0.001). There were no significant differences in the changes in KA, ABH, and PBH between groups (all p > 0.05). The incidence of new OVCF was significantly lower in the rhPTH group than in the VAP group (p = 0.042). All scores of SF-36 were significantly higher in the rhPTH group than in the VAP group (all p < 0.05). The authors concluded that in acute OVCF patients, rhPTH was better than VAP in increasing spinal BMD to promote OVCF healing, reduced new OVCF, and improve back pain, physical ability, and HR-QOL.

These researchers stated that this trial had several drawbacks. First, this study showed the clinical outcomes of rhPTH for acute OVCF, especially in boosting OVCF union; however, multi-centric randomized trials are needed for future studies. Second, although vital for early treatment, these investigators only focused on patients with acute OVCF in this study, further investigations are needed to examine the effectiveness of rhPTH on subacute and chronic OVCF. Third, high-density bone cement within the vertebral bodies affects the evaluation of bone bridge. These researchers did not examine the fracture union of the affected vertebrae in the VAP group. Furthermore, the subsequent anti-osteoporosis therapy with other anti-osteoporotic medications should also be considered in the future.

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.

References

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