Three-dimensionally printed recombinant human parathyroid hormone-soaked nanofiber sheet accelerates tendon-to-bone healing in a rabbit model of chronic rotator cuff tear.

BACKGROUND: Recombinant human parathyroid hormone (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. This study was conducted to evaluate 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. METHODS: Eighty rabbits were randomly assigned to 5 groups (n = 16 each). To create the chronic RCT model, we induced complete supraspinatus tendon tears in both shoulders and left them untreated for 6 weeks. All transected tendons were repaired in a transosseous 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 performed in half of the rabbits at 4 weeks postrepair. Genetic, histologic, and biomechanical evaluations (mode of tear and load to failure) were performed in the remaining rabbits at 12 weeks. RESULTS: For genetic evaluation, group E showed a higher collagen type I alpha 1 expression level than did the other groups (P = .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 = .001, P = .001, and P = .003, respectively) at 12 weeks. For biomechanical evaluation, group E showed a higher load-to-failure rate than did the other groups (P < .001) at 12 weeks. CONCLUSION: Three-dimensionally printed rhPTH-soaked nanofiber sheet fixation can promote tendon-to-bone healing of chronic RCT.

Changes in bone mineral density and bone turnover markers during treatment with teriparatide in pregnancy- and lactation-associated osteoporosis.

CONTEXT: Teriparatide (TPTD) therapy has been proposed as a potential treatment strategy in severe cases of pregnancy- and lactation-associated osteoporosis (PLO) characterized by the occurrence of fragility fractures in the third trimester or early postpartum. OBJECTIVE: To investigate the changes in bone mineral density (BMD) and bone turnover markers in patients with PLO with and without TPTD treatment. DESIGN: Retrospective cohort study. PATIENTS: Thirty-two patients with PLO who presented with multiple vertebral fractures to a tertiary institution between 2007 and 2015 were included. MEASUREMENTS: Changes in BMD at the lumbar spine (LSBMD) and proximal femur after 12 months of daily subcutaneous injections of 20 µg TPTD (n = 27) were assessed. Subjects who rejected the TPTD treatment were used as controls (n = 5). RESULTS: LSBMD increased in both subjects treated with TPTD and controls, with greater increases in the TPTD group (15.5 ± 6.6% vs 7.5 ± 7.1%, P = .020) after adjustment for age and baseline LSBMD. During follow-up, serum levels of osteocalcin (OCN) and C-telopeptide of type I collagen (CTX) increased significantly in the TPTD group. In multivariate linear regression models, TPTD treatment (adjusted ß = 7.92, P = .032) and younger age (adjusted ß = 1.06, P = .046), but not baseline LSBMD, body mass index, serum OCN level and CTX level, were independently associated with greater increases in LSBMD. CONCLUSIONS: In patients with PLO, LSBMD at 12 months increased in both the TPTD-treated and control groups. TPTD treatment and younger age were associated with greater increases in LSMBD irrespective of baseline LSBMD.

Teriparatide therapy for severe, refractory osteoradionecrosis of the jaw.

Although osteoradionecrosis (ORN) is a serious complication of craniofacial radiotherapy, the current management methods remain suboptimal. Teriparatide (TPTD), a recombinant human parathyroid hormone (1-34), has shown beneficial effects on osseous regeneration in medication-related osteonecrosis of the jaw or periodontitis. However, TPTD therapy in irradiated bones has not been indicated yet because of the theoretical risk of osteosarcoma seen in rat models. Hence, we first report here two patients with tongue cancer with late-emerging ORN who were successfully treated with TPTD for 4-6 months with serum calcium and vitamin D supplementation. In contrast to the usual progress of ORN, the bone defect regenerated well and bone turnover markers including serum C-terminal telopeptide of type 1 collagen and osteocalcin were restored with TPTD therapy. Our experience might suggest that TPTD therapy with careful monitoring can provide an effective treatment option for patients with ORN in select refractory cases, with the benefits outweighing the potential risks.

Effect of teriparatide (rh-PTH 1-34) versus bisphosphonate on the healing of osteoporotic vertebral compression fracture: A retrospective comparative study.

BACKGROUND: Teriparatide (recombinant human parathyroid hormone 1-34) is increasingly used for the treatment of severe osteoporosis because it stimulates bone formation and may potentially enhance fracture healing. The objective of this study was to investigate the effects of teriparatide versus a bisphosphonate on radiographic outcomes in the treatment of osteoporotic vertebral compression fractures (OVCF). METHODS: A total of 98 patients undergoing non-operative treatment for recent single-level OVCF were reviewed retrospectively. Thirty-eight patients were treated by a once-daily subcutaneous injection of 20 micrograms of teriparatide (TPD group), whereas 60 patients received 35 mg of alendronate weekly (BP group). Except for these medications, the same treatment protocol was applied to both groups. The radiographic assessments included union status, vertebral kyphosis, and mid-vertebral body height. The rates of fracture site surgical intervention were also compared between the two groups. The mean follow-up period was 27 months (median 22.5, range 2 - 75 months). RESULTS: Cox regression analysis showed that TPD reduced the time-to-union (adjusted relative hazard ratio: 1.86, 95% C.I.: 1.21 - 2.83). The union rate at six months after treatment was 89% in the TPD group and 68% in the BP group; the surgical intervention rate was significantly higher in the TPD group (p = 0.026, adjusted odds ratio: 8.15, 95% C.I.: 2.02 - 43.33). The change in local kyphosis was 4.6° in the TPD group and 3.8° in the BP group (p = 0.495, paired t-test). The change of mid-vertebral body height was 4.4 mm in the TPD group and 3.4 mm in the BP group (p = 0.228, paired t-test). Fracture site surgical interventions were not required in the TPD group; however, two patients in the BP group eventually underwent surgical treatment for symptomatic non-union or vertebral collapse. CONCLUSIONS: This retrospective study suggests that teriparatide may enhance fracture healing and improve the union rate in OVCF.

Continuous Subcutaneous Delivery of rhPTH(1-84) and rhPTH(1-34) by Pump in Adults With Hypoparathyroidism.

Context: Continuous subcutaneous infusion of recombinant parathyroid hormone (rhPTH) through a pump has been proposed as a therapeutic alternative for patients with chronic hypoparathyroidism who remain symptomatic or hypercalciuric on conventional treatment (calcium and active vitamin D) or daily injections of rhPTH(1-84) or rhPTH(1-34). However, the real-world evidence of the outcome of this novel therapy is limited. Case Descriptions: We report the clinical and biochemical outcomes of 12 adults with hypoparathyroidism (11 women, age 30-70 years, and 1 man, age 30 years) from 3 different clinical sites in the United States who were transitioned from conventional therapy to daily injections of rhPTH(1-84) or rhPTH(1-34) and then switched to continuous administration of rhPTH(1-84)/rhPTH(1-34) via pump therapy. In most patients, mean serum calcium concentrations increased while on PTH pump therapy compared with both conventional therapy (in 11 patients) and single/multiple daily rhPTH injections (in 8 patients). Despite this, 10 patients had lower median 24-hour urinary calcium levels while on PTH pump therapy compared with prior therapy (mean ± SD difference: -130 ± 222 mg/24 hours). All patients reported a qualitative decrease in hypocalcemic symptoms while receiving pump therapy. Three patients had pod failure at least once, and 1 patient developed an infusion site reaction. Conclusion: In this case series of 12 patients with chronic hypoparathyroidism treated with rhPTH(1-84)/rhPTH(1-34) administered via a pump, improvement in clinical and biochemical parameters were observed in the majority of the patients. Our observations indicate benefits of pump administration of rhPTH that warrant further investigation.

Long-Term Safety and Efficacy of Recombinant Human Parathyroid Hormone (1-84) in Adults With Chronic Hypoparathyroidism.

Context: Chronic hypoparathyroidism is conventionally treated with oral calcium and active vitamin D to reach and maintain targeted serum calcium and phosphorus levels, but some patients remain inadequately controlled. Objective: To assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment. Methods: This was an open-label extension study at 12 US centers. Adults (n = 49) with chronic hypoparathyroidism were included. The intervention was rhPTH(1-84) for 6 years. The main outcome measures were safety, biochemical measures, oral supplement doses, bone indices. Results: Thirty-eight patients (77.6%) completed the study. Throughout 72 months, mean albumin-adjusted serum calcium was within 2.00 to 2.25 mmol/L (8.0-9.0 mg/dL). At baseline, 65% of patients with measurements (n = 24/37) were hypercalciuric; of these, 54% (n = 13/24) were normocalciuric at month 72. Mean serum phosphorus declined from 1.6 ± 0.19 mmol/L at baseline (n = 49) to 1.3 ± 0.20 mmol/L at month 72 (n = 36). Mean estimated glomerular filtration rate was stable. rhPTH(1-84)-related adverse events were reported in 51.0% of patients (n = 25/49); all but 1 event were mild/moderate in severity. Mean oral calcium supplementation reduced by 45% ± 113.6% and calcitriol by 74% ± 39.3%. Bone turnover markers declined by month 32 to a plateau above pretreatment values; only aminoterminal propeptide of type 1 collagen remained outside the reference range. Mean bone mineral density z score fell at one-third radius and was stable at other sites. Conclusion: 6 years of rhPTH(1-84) treatment was associated with sustained improvements in biochemical parameters, a reduction in the percentage of patients with hypercalciuria, stable renal function, and decreased supplement requirements. rhPTH(1-84) was well tolerated; no new safety signals were identified.

Osteoporosis in Renal Disease.

Introduction: Osteoporosis is a disorder characterized by decreased bone mass and skeletal fragility with increased fracture risk. Chronic kidney disease presents with wide range of bone metabolic disorders, including osteoporosis. Osteoporosis prevalence is high in early stages of CKD; whereas in late stages, it coexists with renal osteodystrophy. Risk factors: Risk factors for osteoporosis include advancing age, low bone mineral density (BMD), glucocorticoid therapy, smoking, alcohol intake, etc. Diagnosis: The diagnosis of osteoporosis in renal disease is made after assessment of BMD, in addition to exclusion of chronic kidney disease-mineral bone disorder (CKD-MBD), eliciting history of prior fragility fractures and relevant laboratory investigations. Management: The treatment of osteoporosis varies with the different stages of CKD, with management in stages 1-3 being similar to the general population. Special emphasis must be laid on prevention of fractures as well.

Initiation of Continuous rhPTH Infusion With Insulin Pump in an Inpatient Setting.

Hypoparathyroidism is one of the few remaining hormonal insufficiencies not treated with replacement of its missing hormone. Conventional therapy involves multiple daily oral doses of calcium, active vitamin D, and magnesium, which is not only cumbersome for patients, but carries risk of nephrocalcinosis and is inadequate in patients with enteral malabsorption. Subcutaneous parathyroid hormone 1-34 (PTH[1-34]) has been tested as a hormonal replacement therapy for treatment of hypoparathyroidism. PTH(1-34) delivered by continuous infusion via insulin pump decreases or eliminates the need for oral medications, stabilizes serum and urine calcium at normal levels with minimal fluctuation, and significantly reduces PTH doses. In this case report, we describe the clinical application of PTH(1-34) via insulin pump in an adolescent with autoimmune polyendocrinopathy syndrome type 1 (APS1). Transition to a PTH pump reduced hospital admissions for calcium abnormalities and allowed our patient to discontinue all scheduled daily conventional therapy.

Bone quality in an ovariectomized monkey animal model treated with two doses of teriparatide for either 18 months, or 12 months followed by withdrawal for 6 months.

Previous studies of ovariectomized (OVX) monkeys, treated with recombinant human parathyroid hormone (PTH) (1-34) at 1 or 5 µg/kg/day for 18 months or for 12 months followed by 6 months withdrawal from treatment, displayed significant changes in geometry, histomorphometry, and bone quality, but without strict tissue age criteria, of the midshaft humerus. Since bone quality significantly depends on tissue age among other factors, the aim of the present study was to establish the bone-turnover independent effects of two doses of PTH, as well as the effects of treatment withdrawal on bone quality by measuring bone material composition at precisely known tissue ages ranging from osteoid, to mineralized tissue older than 373 days. Raman microspectroscopic analysis of bone tissue from the mid-shaft humerus of OVX monkeys demonstrated that the clinically relevant dose of PTH administered for 18 months reverses the effects of ovariectomy on bone quality when compared against SHAM. Both doses investigated in this study restore the mineralization regulation mechanisms to SHAM levels. The study also showed that the beneficial effects induced by 12 months of clinically relevant PTH therapy were sustained after six months of therapy withdrawal.

Recombinant human parathyroid hormone (1-84) replacement therapy in a child with hypoparathyroidism.

First line conventional therapy of hypoparathyroidism comprises oral calcium and active vitamin D analogues. This approach may fail to correct hypocalcemia and hyperphosphatemia caused by the absence of parathyroid hormone and carries the risk of long-term complications including ectopic calcifications and renal damage. Full-length recombinant human parathyroid hormone (rhPTH[1-84]) is approved for the treatment of hypoparathyroidism in adults refractory to conventional therapy. To date, there is no data in children. Here, we report the successful use of rhPTH(1-84) in a 5-year old girl with hypoparathyroidism and concomitant chronic diarrhea manifesting as part of the autoimmune polyglandular syndrome type 1. Prior to starting rhPTH(1-84), the patient had been on conventional and later on rhPTH(1-34) continuous pump therapy. Conventional therapy failed to meet serum and urinary calcium target levels, whilst the pump therapy wasn't well tolerated and posed handling difficulties. Dose optimization for rhPTH(1-84) was informed by serum ionized calcium, spot urinary calcium-to-creatinine ratio and 24-hour urinary calcium excretion. Twice-daily subcutaneous injections of rhPTH(1-84) with a total dose of 3.35 µg/kg/d was well-tolerated, raised serum ionized calcium to target range (1.05-1.15 mmol/L) and normalized serum phosphate levels. Urinary calcium excretion was slightly above the recommended limit of 4 mg/kg/24 h, but improved compared to conventional therapy, with no evidence of nephrocalcinosis. Twice-daily administration stabilized serum calcium and phosphate levels compared to once-daily injections. rhPTH(1-84) treatment was well tolerated and the girl did not manifest any acute clinical complications of hypoparathyroidism throughout the entire observation period. Our experience with this case indicates that rhPTH(1-84) may be a physiological hormone replacement for managing hypoparathyroidism in children.

The role, efficacy and outcome measures for teriparatide use in the management of medication-related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a complex disease which can be associated with multiple morbidities and is challenging to treat. This review evaluates the literature on the role and efficacy of teriparatide (TPTD) as a treatment for MRONJ. The clinical, radiological, histopathological and serological parameters used to assess treatment response have been described. Electronic databases were searched to retrieve articles (April 2005 and April 2020) based on strict inclusion criteria. Seventeen articles were included in this review. Of the 91 patients treated; only six received TPTD as a standalone treatment. There were significant variations in defining treatment outcomes and measuring treatment response. The longest follow-up period was 26 months, and 12 studies failed to report follow-up. The overall quality of evidence is weak with potential for a high risk of bias, making it difficult to determine the efficacy of TPTD and its long-term effects. However, TPTD may play a role in the treatment of intractable MRONJ in osteoporotic patients or those unfit for surgery. Therefore, randomized clinical trials on larger patient cohorts with long-term follow-up is required to confirm efficacy, safety and inform treatment indications for TPTD in the treatment of MRONJ.

Effects of anti-osteoporosis therapy on plasma aldosterone and renin.

OBJECTIVE: This study aimed to investigate the effect of anti-osteoporosis therapy on plasma aldosterone concentration (PAC), plasma renin concentration (PRC) and the aldosterone/renin ratio (ARR) in patients with postmenopausal osteoporosis. METHODS: In 60 patients with postmenopausal osteoporosis, bone mineral density (BMD), PAC and PRC were measured before and after treatment with alendronate (70 mg/week, n=22) or recombinant human parathyroid hormone (20 µg/day, n=35) for 48 weeks. RESULTS: PAC was negatively correlated with the T-score of lumbar spine BMD and femoral neck BMD (lumbar r=-0.386, p<0.01; femoral neck r=-0.262, p<0.05). With the improvement in lumbar BMD after anti-osteoporosis treatment (T-score -3.4±0.5 vs. -3.1 ±0.4, p<0.0001), PAC decreased from 182.8±53.2 to 143.7±68.6 pg/mL (p<0.0001), PRC increased from 7.8±11.6 to 39.2±50.0 µIU/mL (p<0.0001) and the ARR decreased from 74.8±75.2 to 13.1±17.1 pg/µIU (p<0.0001). At baseline, 58% (35/60) of the patients had an ARR >37 pg/µIU, and the proportion decreased to 8% (5/57) after treatment. CONCLUSION: Treatment with alendronate or parathyroid hormone causes decreased PAC and increased PRC, resulting in a decreased ARR in postmenopausal women with osteoporosis.

Five-year Estimated Glomerular Filtration Rate in Patients With Hypoparathyroidism Treated With and Without rhPTH(1-84).

CONTEXT: Chronic hypoparathyroidism (HypoPT) is conventionally managed with oral calcium and active vitamin D. Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is a therapy targeting the pathophysiology of HypoPT by replacing parathyroid hormone. OBJECTIVE: To compare changes in the estimated glomerular filtration rate (eGFR) in patients with chronic HypoPT receiving or not receiving rhPTH(1-84) during a 5-year period. DESIGN/SETTING: A retrospective analysis of patients with chronic HypoPT treated with or without rhPTH(1-84). PATIENTS: Sixty-nine patients with chronic HypoPT from 4 open-label, long-term trials (NCT00732615, NCT01268098, NCT01297309, and NCT02910466) composed the rhPTH(1-84) cohort and 53 patients with chronic HypoPT not receiving rhPTH(1-84) from the Geisinger Healthcare Database (01/2004-06/2016) composed the historical control cohort. INTERVENTIONS: The rhPTH(1-84) cohort (N = 69) received rhPTH(1-84) therapy; the historical control cohort (N = 53) did not receive rhPTH(1-84). MAIN OUTCOME MEASURES: Changes in eGFR from baseline during a 5-year follow-up were examined in multivariate regression analyses. RESULTS: At baseline, demographic characteristics and eGFR were similar between cohorts, though the proportions with diabetes and cardiac disorders were lower in the rhPTH(1-84) cohort. At the end of follow-up, mean eGFR increased by 2.8 mL/min/1.73 m2 in the rhPTH(1-84) cohort, while mean eGFR fell by 8.0 mL/min/1.73 m2 in the control cohort. In the adjusted model, the difference in the annual eGFR change between the rhPTH(1-84) cohort and the control cohort was 1.7 mL/min/1.73 m2 per year (P = 0.009). CONCLUSIONS: Estimated glomerular filtration rate was preserved for over 5 years among patients with chronic HypoPT receiving rhPTH(1-84) treatment, contrasting with an eGFR decline among those not receiving rhPTH(1-84).

[Hypoparathyroidism - un underestimated problem?] / Hypoparathyreoidismus ­ ein unterschätztes Problem?

BACKGROUND: Hypoparathyroidism is a rare and disabilitating disorder characterized by hypocalcemia and low parathyroid hormone levels. Most of the cases occur as a result of the removal of parathyroid glands or damage to the glands during neck surgery. More rare causes include nonsurgical causes such as autoimmune or genetic diseases. METHOD: In this review, a panel of experts presents the current state of diagnosis and therapy of hypoparathyroidism and explains practical aspects of caring for the affected patients. RESULTS: Common signs and symptoms are abnormal sensations and increased excitability in the lower limbs, paresthesia of perioral areas and nocturnal leg cramps. Renal complications frequently occur, but also basal ganglia calcification. Treatment consists of administration of vitamin D analogs in combination with 0.5-1.0 g calcium daily. An adjunctive treatment with the in April 2017 approved recombinant human parathyroid hormone (1-84) is an option for patients whose hypoparathyroidism is difficult to control by conventional treatment alone. Initially and after dose changes follow-up controls should be performed at least every 2 weeks, in well-controlled patients or in the case of chronic progression every 3-6 months.

Teriparatide Replacement Therapy for Hypoparathyroidism During Treatment With Lenvatinib for Advanced Thyroid Cancer: A Case Report.

Thyroid cancer metastasizes in 4% of cases. Approximately two-thirds of these patients are refractory to radioactive iodine-131 (RAI) therapy and have a poor 10-year survival prognosis. Treatment with tyrosine kinase inhibitors (TKIs) may be administered in selected RAI-refractory patients. However, these agents are often associated with adverse events, including vomiting. We report the case of a patient affected by RAI-refractory thyroid cancer with lung and intracranial metastases undergoing treatment with the antiangiogenic TKI lenvatinib, and with teriparatide replacement therapy for postsurgical hypoparathyroidism. Due to lenvatinib-related vomiting, which did not respond to therapy, conventional oral calcium supplementation failed to maintain normal serum calcium levels and the patient had repeated episodes of hypocalcemia. Subcutaneous teriparatide injections restored serum calcium levels, and thus lenvatinib therapy could be continued. This experience indicates that hormone replacement with teriparatide is a feasible option for cancer patients affected by hypoparathyroidism not treatable with oral calcium supplementation.

Effects of recombinant human parathyroid hormone (1-34)on cell proliferation, chemokine expression and the Hedgehog pathway in keratinocytes.

Psoriasis is an autoimmune disease involving the excessive proliferation of keratinocytes mediated by T­cells. Parathyroid hormone (PTH) has been identified as an essential factor in the treatment of psoriasis. In the present study, the mechanism underlying the effect of recombinant human parathyroid hormone (rhPTH) (1­34) in keratinocytes was investigated. The effects of rhPTH (1­34) on cell proliferation, cell cycle, and the secretion and expression of C­X­C motif chemokine 11 (CXCL11) and components of the Hedgehog signaling pathway were examined in HaCaT cells by MTT assay, flow cytometric analysis, ELISA and gene chip analysis. The data showed that rhPTH (1­34) significantly inhibited keratinocyte proliferation at concentrations >8x10­7 mol/l. rhPTH (1­34) induced G1 phase arrest of the cell cycle in the keratinocytes. The secretion of CXCL11 in tumor necrosis factor (TNF)­α­induced keratinocytes was downregulated by rhPTH (1­34) in a dose­dependent manner, compared with that in keratinocytes treated with TNF­α alone. It was also found that rhPTH (1­34) inhibited the expression of CXCL11 in the HaCaT cells. rhPTH (1­34) also affected the Hedgehog signaling pathway specifically by regulating the expression of associated genes. In conclusion, these data suggested that rhPTH (1­34) inhibited cell proliferation, and the secretion and expression of CXCL11 in HaCaTs. rhPTH (1­34) also altered the expression of associated genes in the Hedgehog pathway. Therefore, rhPTH (1­34) can be considered as a novel therapeutic agent for the treatment of psoriasis.

Safety and Efficacy of Recombinant Human Parathyroid Hormone in Adults With Hypoparathyroidism Randomly Assigned to Receive Fixed 25-µg or 50-µg Daily Doses.

PURPOSE: The present study examined the efficacy and safety of a lower rhPTH(1-84) dose. METHODS: RELAY was a dose-blinded, multicenter, 8-week study of patients with hypoparathyroidism randomized to fixed 25- or 50-µg/d doses of subcutaneous rhPTH(1-84). The primary end point was the percentage of patients at week 8 with supplement reductions in calcium to ≤500 mg/d and in calcitriol to ≤0.25 µg/d, while maintaining serum calcium levels between 1.875 mmol/L and the upper limit of normal. The secondary end point was the percentage of patients at week 8 with a ≥50% reduction in calcium and calcitriol doses, while maintaining serum calcium levels between 1.875 mmol/L and the upper limit of normal. FINDINGS: Forty-two patients were randomized (25-µg group, n = 19; 50-µg group, n = 23). At week 8, the primary end point was achieved by 4 (21%; 95% CI, 6%-46%) and 6 (26%; 95% CI, 10%-48%) of the patients receiving 25 and 50 µg/d of rhPTH(1-84), respectively. The secondary end point was achieved by 2 (11%; 95% CI, 1%-33%) and 6 (26%; 95% CI, 10%-48%) of the patients receiving 25 and 50 µg/d of rhPTH(1-84), respectively. Treatment-emergent adverse events were reported by 11 (58%) patients in the 25-µg group and 17 (74%) patients in the 50-µg group. IMPLICATIONS: Doses as low as 25 µg/d of rhPTH(1-84) are well tolerated and may be effective for a subset of patients. ClinicalTrials.gov identifier: NCT01268098.

Evaluation of recombinant human parathyroid hormone by CZE method and its correlation with in vitro bioassay and LC methods.

A stability-indicating capillary zone electrophoresis (CZE) method was validated to assess the content/potency of the recombinant human parathyroid hormone (rhPTH 1-34), using ranitidine as internal standard (IS). A fused-silica capillary, (i.d. of 50µm; effective length of 40cm) was used at 25°C; the applied voltage was 20kV. The background electrolyte solution consisted of 50mmolL-1 sodium dihydrogen phosphate solution at pH 3.0. Injections were performed using a pressure mode at 50 mbar for 45s, with detection by photodiode array (PDA) detector set at 200nm. Separation was obtained with a migration time of 5.3min, and was linear over the concentration range of 0.25-250µgmL-1 (r2 =0.9992). Specificity and stability-indicating capability were established in degradation studies, which also showed that there was no interference of the excipients. The accuracy was 100.28% with bias lower than 0.85%. Analyses of the same batches showed mean differences of the estimated content/potencies of 0.61%, 1.31% higher and 0.86% lower as compared to the validated reversed-phase and size exclusion liquid chromatography methods, and to the UMR-106 cell culture bioassay, respectively, with non-significant differences (p>0.05). Degraded forms were also subjected to the in vitro cytotoxicity test. The results obtained showed the capabilities of each one of the methods, and constitute an alternative strategy to monitor stability, improve the quality control and ensure the batch-to-batch consistency of bulk and finished biotechnology-derived medicine.

Comparison between recombinant human parathyroid hormone (1-34) and elcatonin in treatment of primary osteoporosis.

OBJECTIVE: To evaluate the efficacy and safety of rhPTH (1-34) vs. elcatonin. METHODS: Sixty patients with primary OP were randomly divided into two groups according to the ratio of 3:1. rhPTH (1-34) group (PTH group) was treated with subcutaneous injection of rhPTH (1-34) 20 µ g daily for 18 months, and the elcatonin group (CT group) was treated with intramuscular injection of elcatonin 20 U weekly for 12 months. Bone mineral density (BMD) of the lumbar spine 2-4 (L2-4) and femoral neck, serum calcium and phosphorus, urinary calcium, serum bone specific alkaline phosphatase (BSAP), and urinary c-terminal telopeptides of type I collagen/creatinine (uCTX-I/Cr) were tested at baseline, and 6, 12, and 18 months after treatment. RESULTS: In PTH group, BMD of L2-4 at 6, 12, and 18 months, BDM of femoral neck at 18 month, BSAP at 6 and 12 months and uCTX- I/Cr at 6, 12 and 18 months were all significantly raised. In CT group, BMD of L2-4 at 12 month and that of femoral neck at 12 and 18 months were significantly elevated, while BSAP was significantly decreased at 12 and 18 months, and no significant difference on CTX- I/Cr was observed. When BMD growth and growth rate between two groups were compared, PTH group had better improvement in L2-4 BMD and growth rate than CT group at 6, 12, and 18 months. BMD growth and growth rate of femoral neck at 12 month and its growth at 18 month in CT group were higher than in PTH group, but there was no significant difference between two groups regarding the growth rates at 18 month. Besides, there were no significant differences regarding the rates of adverse reactions between two groups. CONCLUSIONS: rhPTH (1-34), is safe and effective in the treatment of primary OP. It is superior to elcatonin in improving vertebral BMD at onset time, growth rate and growth range, but inferior to elcatonin at BMD of femoral neck.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of recombinant human parathyroid hormone (1-34) in healthy Chinese subjects.

BACKGROUND: The recombinant human parathyroid hormone (1-34) (rhPTH[1-34]) teriparatide is the first anabolic agent approved by the US Food and Drug Administration for the treatment of osteoporosis in men and women. This study was conducted to provide support for marketing authorization of an agent biosimilar to teriparatide in China. OBJECTIVE: The main aim of the present study was to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic parameters of rhPTH(1-34) after single and multiple subcutaneous doses in healthy Chinese subjects. METHODS: Two open-label, randomized, single-center, dose-escalation studies were performed. In study 1, subjects were randomized to receive a single dose of rhPTH(1-34) (10, 20, 30, 40, 50, or 60 µg) or a multiple dose of rhPTH(1-34) (10 and 20 µg once daily for 7 consecutive days) to determine the safety profile and tolerability, as reflected by the incidence, intensity, and seriousness of the observed adverse events. In study 2, a single dose of rhPTH(1-34) (10, 20, or 40 µg) and a multiple dose of rhPTH(1-34) (20 µg) were administrated subcutaneously to investigate the pharmacokinetic and pharmacodynamic parameters. RESULTS: Forty-two subjects completed study 1, and 30 subjects completed study 2. rhPTH(1-34) was well tolerated during the investigated single (10-60 µg) and multiple (10-20 µg once daily for 7 consecutive days) dose ranges. The most generally reported adverse events were erythema at the injection site and gastrointestinal reactions. After single and multiple subcutaneous administration of rhPTH(1-34), the drug was rapidly absorbed, with a Tmax of 20 to 30 minutes, and rapidly cleared from the plasma, with a t½ of 47.2 to 60.6 minutes. The mean Cmax, AUC0-t, and AUC0-∞ increased in proportion to the doses, whereas the t½, total clearance, and Tmax values were independent of the administered dose. No significant differences in pharmacokinetic parameters were noted by sex except for Tmax in the 10-µg and 20-µg single-dose groups. Compared with the baseline levels, no significant changes or dose-related significant effects were observed in serum calcium and phosphate levels. CONCLUSIONS: All rhPTH(1-34) doses appeared to be well tolerated in the population studied. Linear pharmacokinetic characteristics were displayed in the dose range studied. Chinese ClinicalTrials.gov identifier: ChiCTR-ONC-12002874.