Human PTH (1–34) induces longitudinal bone growth in rats

The growth plate is a specialized structure that is responsible for longitudinal bone growth (LGR). Growth plate organization is altered with loading in rats. Parathyroid hormone (PTH) is known to induce mitogenic effect on chondrocytes in vitro. Type I PTH/PTH related peptide (rP) receptor is expressed in growth plate cartilage in rats. We therefore investigated the effect of PTH administration on the organization and longitudinal growth rate of the growth plate in rats. We also investigated the effect of PTH on the changes induced by unloading in the organization and growth of the growth plate. Thirty 6-week-old and 30 15-week-old male Sprague-Dawley rats were randomly assigned to five groups (n = 6 per group), i.e., basal controls, control (i.e., normally loaded), PTH-treated control (i.e., PTH-treated under normal loading), unloaded, and PTH-treated under unloading. PTH-treated animals received human PTH (1–34) at a dose of 80 μg/kg per day five times per week for 3 weeks, for the duration of unloading. In young loaded rats treated with the systemic administration of PTH, growth plate thickness, chondrocyte number, and LGR were increased in the proximal tibiae compared with findings in young loaded rats without PTH administration. Hindlimb unloading induced a reduction in growth plate thickness, chondrocyte number, and LGR. In young rats, systemic administration of PTH partly prevented these changes induced by unloading. These preventive effects of PTH were observed only in young rats; not in adult rats. These results show that the systemic administration of PTH stimulates longitudinal bone growth, and diminishes the reduction in growth plate growth induced by unloading in young rats. Received: August 9, 2001 / Accepted: November 9, 2001     

The Effect of Recombinant PTH(1–34) and PTH(1–84) on Serum Ionized Calcium, 1,25-Dihydroxyvitamin D,and Urinary Calcium Excretion: A Pilot Study

We investigated the frequency of hypercalcemia and/or hypercalciuria following parathyroid hormone (PTH) 1–34 and 1–84 administration in a crossover trial. Ten postmenopausal osteoporotic women previously treated with bisphosphonates were subdivided into two groups of five patients each. A 24-h urine collection to determine baseline calcium (Ca) and creatinine (Cr) the day before administration of PTH was followed by determination of serum ionized Ca (Ca²⁺), Cr, 25(OH)D, and 1,25(OH)₂D at baseline. Thereafter, 100 mcg of PTH(1–84) or 20 mcg of PTH(1–34) was administered. A 24-h urinary collection and blood samples 2, 4, and 24-h after each PTH administration were again taken. One week after the first PTH administration patients were rechallenged with the second PTH. The PTH peptides did not differ with respect to changes in Ca²⁺ at 2, 4, and 24 h postinjection; at the last time point the values were virtually identical to the initial values. There was no difference in urinary Ca on the day following PTH injection compared to baseline, in terms both of Ca/Cr and of Ca excretion. The two PTH peptides did not differ with respect to changes in 1,25(OH)₂D at 2, 4, and 24 h considering both the absolute values and the percent changes with respect to baseline (24-h 1–84 = 125.6 ± 58.6 pg/ml, 153% increase; 1–34 = 124.1 ± 64.7, 130%). Our results indicate no difference in postinjection serum Ca²⁺, 1,25(OH)₂D, or urinary Ca excretion after a single dose of either PTH(1–84) or PTH(1–34) in patients previously treated with bisphosphonates.     

De novo autoimmune hepatitis associated with PTH(1–34) and PTH(1–84) administration for severe osteoporosis in a liver transplant patient

De novo autoimmune hepatitis (AIH) is a rare graft dysfunction occurring in patients having undergone liver transplantation (LT) for causes other than AIH. We describe for the first time a case of de novo AIH associated with the administration of parathyroid hormone 1-34 [PTH(1-34)] and PTH(1-84) for severe osteoporosis. A 61-year-old woman was referred to our metabolic bone clinic due to severe osteoporosis, 3?years after LT for primary biliary cirrhosis. Initial treatment with PTH(1-34) led to asymptomatic hypertransaminasemia (two-fold the upper limit of normal), which normalized after drug discontinuation. A new flare of transaminases (three-fold the upper limit of normal) along with elevated alkaline phosphatase was observed after administration of PTH(1-84), which did not resolve after PTH(1-84) withdrawal. Subsequently, after exclusion of common causes of liver enzyme elevation, a liver biopsy was performed. Histological findings showed de novo AIH, which responded rapidly to treatment with methylprednisolone.     

Parathyroid hormone PTH(1–34) increases the volume,mineral content,and mechanical properties of regenerated mineralizing tissue after distraction osteogenesis in rabbits

Background and purpose Parathyroid hormone (PTH) has attracted considerable interest as a bone anabolic agent. Recently, it has been suggested that PTH can also enhance bone repair after fracture and distraction osteogenesis. We analyzed bone density and strength of the newly regenerated mineralized tissue after intermittent treatment with PTH in rabbits, which undergo Haversian bone remodeling similar to that in humans.

Methods 72 New Zealand White rabbits underwent tibial mid-diaphyseal osteotomy and the callus was distracted 1 mm/day for 10 days. The rabbits were divided into 3 groups, which received injections of PTH 25 µg/kg/day for 30 days, saline for 10 days and PTH 25 µg/kg/day for 20 days, or saline for 30 days. At the end of the study, the rabbits were killed and the bone density was evaluated with DEXA. The mechanical bone strength was determined by use of a 3-point bending test.

Results In the 2 PTH-treated groups the regenerate callus ultimate load was 33% and 30% higher, absorbed energy was 100% and 65% higher, BMC was 61% and 60% higher, and callus tissue volume was 179% and 197% higher than for the control group.

Interpretation We found that treatment with PTH during distraction osteogenesis resulted in substantially higher mineralized tissue volume, mineral content, and bending strength. This suggests that treatment with PTH may benefit new bone formation during distraction osteogenesis and could form a basis for clinical application of this therapy in humans.     

Differences between ‘intact’ PTH and 1–84 PTH assays in chronic renal failure and dialysis

Intact parathyroid hormone (iPTH) assays overestimate actual PTH as they cross-react with non (1–84) PTH fragments (C-PTH) that accumulate in renal failure. New assays that measure just 1–84 PTH (CAP-PTH) are now available. It has been suggested that there is a linear relationship between the two assays; however, increased C-PTH levels are found as glomerular filtration rate (GFR) declines and in patients on dialysis. We investigated the relationship between iPTH and CAP-PTH in children with chronic renal failure (CRF) managed conservatively and on dialysis. We investigated 241 children, 156 with a GFR <60 ml/min per 1.73 m² managed conservatively, 49 post renal transplant (and GFR <60 ml/min per 1.73 m²) and 36 on dialysis, by measuring PTH levels by iPTH and CAP-PTH assays. Multiple regression analysis comparing differences between PTH levels in each patient group was performed. Correlation slopes between iPTH and CAP-PTH assays differed between CRF and dialysis patients (P=0.001). These assays perform differently in CRF and dialysis patient groups. Studies investigating the correlation between newer assays and bone histology are required to determine whether these more-specific PTH assays are superior surrogate markers of bone turnover.     

PTH and FGF23 Exert Interdependent Effects on Renal Phosphate Handling: Evidence From Patients With Hypoparathyroidism and Hyperphosphatemic Familial Tumoral Calcinosis Treated With Synthetic Human PTH 1–34

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) both influence blood phosphate levels by regulating urinary phosphate reabsorption. Clinical data suggest that adequate renal phosphate handling requires the presence of both FGF23 and PTH, but robust evidence is lacking. To investigate whether the phosphaturic effects of PTH and FGF23 are interdependent, 11 patients with hypoparathyroidism, which features high blood phosphate in spite of concomitant FGF23 elevation, and 1 patient with hyperphosphatemic familial tumoral calcinosis (HFTC), characterized by deficient intact FGF23 action and resulting hyperphosphatemia, were treated with synthetic human PTH 1–34 (hPTH 1–34). Biochemical parameters, including blood phosphate, calcium, intact FGF23 (iFGF23), nephrogenic cAMP, 1,25(OH)₂ vitamin D (1,25D), and tubular reabsorption of phosphate (TRP), were measured at baseline and after hPTH 1–34 treatment. In patients with hypoparathyroidism, administration of hPTH 1–34 increased nephrogenic cAMP, which resulted in serum phosphate normalization followed by a significant decrease in iFGF23. TRP initially decreased and returned to baseline. In the patient with HFTC, hPTH 1–34 administration also increased nephrogenic cAMP, but this did not produce changes in phosphate or TRP. No changes in calcium were observed in any of the studied patients, although prolonged hPTH 1–34 treatment did induce supraphysiologic 1,25D levels in the patient with HFTC. Our results indicate that PTH and FGF23 effects on phosphate regulation are interdependent and both are required to adequately regulate renal phosphate handling. Published 2021. This article is a U.S. Government work and is in the public domain in the USA.     

Significance of Bio-intact PTH(1–84) assay in hemodialysis patients

The aim of the present study was to examine whether the newly developed bio-intact parathyroid hormone (Bio-PTH) assay, which exclusively measures the intact PTH(1–84) molecule, provides a better assay for estimating parathyroid function in hemodialysis (HD) patients, and to evaluate the factors associated with serum PTH levels measured by Bio-PTH assay and by second-generation intact PTH (I-PTH) assay. The study also examined whether Bio-PTH/I-PTH ratio, an index of the active fraction of PTH, could provide information not obtainable from simple PTH results. Serum levels of PTH were measured in 177 male HD patients, together with the bone formation markers bone alkaline phosphatase (BAP), intact osteocalcin (iOC), N-midfragment osteocalcin (N-Mid OC), and N-terminal propeptide of type I collagen (PINP), and the bone resorption markers deoxypyridinoline (DPD), pyridinoline (PYD), and -CrossLaps (-CTx). Bone mineral density (BMD) was determined twice at distal radius one-third by dual-energy X-ray absorptiometry. Serum Bio-PTH was significantly elevated in HD patients compared to normal controls. Serum Bio-PTH and I-PTH correlated significantly in a positive manner with serum bone formation markers (BAP, iOC, N-Mid OC, PINP), and resorption markers (DPD, PYD, -CTx), and in a negative manner with BMD and annual change therein at distal radius one-third. The degree of correlation of Bio-PTH was not significantly different from that of I-PTH. The Bio-PTH/I-PTH ratio was significantly lower in HD patients than in normal individuals, due probably to accumulation of N-truncated PTH fragments in the former. The Bio-PTH/I-PTH ratio correlated significantly in a negative manner with serum calcium (Ca) (r=–0.251, P<0.001) and nutritional marker serum urea nitrogen, protein catabolic rate and serum creatinine. Multiple regression analysis further revealed that serum I-PTH, but not Bio-PTH, was significantly associated with each of these nutritional markers, and that the Bio-PTH/I-PTH ratio was negatively associated with serum Ca. It was also found that I-PTH, but not Bio-PTH, was influenced by nutritional state. It is concluded that serum Bio-PTH assay could be of similar value to I-PTH assay in evaluating parathyroid function in HD patients and that their combined use in the form of the Bio-PTH/I-PTH ratio could provide information not obtainable from simple PTH results.     

Effect of intermittent PTH (1–34) on posterolateral spinal fusion with iliac crest bone graft in an ovariectomized rat model

Summary

Intermittent treatment with high-dose parathyroid hormone (PTH) enhances the quantity and quality of the fusion callus and reduces healing time of posterolateral spinal fusion with autologous iliac bone grafts in ovariectomized osteoporotic female Sprague–Dawley rats. Intermittent PTH (1–34) could be an appropriate adjunctive therapy for osteoporotic patients undergoing posterolateral intertransverse process fusion.

Introduction

The study was designed to test the hypothesis that intermittent administration of PTH improves spinal fusion rates in a randomized controlled, ovariectomized osteoporotic rat spinal fusion model.

Methods

Thirty-six 10-week-old Sprague–Dawley rats were ovariectomized and underwent bilateral posterolateral L4–L5 spinal fusion with autologous iliac bone graft 6 weeks later. The experimental (PTH) group (18 rats) received daily subcutaneously administered injections of PTH (1–34) at 30 μg/kg/day starting on the day of operation. The control group (18 rats) received a subcutaneously administered injection of normal saline of the same volume. Nine rats from each group were sacrificed at 4 and 6 weeks. After sacrifice, the L4–L5 vertebral segments were removed and analyzed by plain radiographs, μ-CT, histomorphometry, and serum bone metabolism marker.

Results

The PTH group had a significantly higher fusion rate and X-ray fusion score than the control group at 4 and 6 weeks (p?<?0.05). μ-CT and histological analysis showed that the fusion bone volume and cortical thickness for the PTH group were significantly higher than those for the control group at 4 and 6 weeks (p?<?0.05). Metabolic marker analysis also showed significant difference between the two groups. The serum osteocalcin was significantly higher in the PTH group at 4 and 6 weeks, and levels of N-terminal peptide of type I collagen were significantly higher at 4 weeks (p?<?0.05).

Conclusion

Intermittent treatment with high-dose PTH enhances the quantity of the fusion callus and reduces the healing time of posterolateral spinal fusion with autologous iliac bone grafts in ovariectomized osteoporotic female Sprague–Dawley rats.     

Amino terminal cleavage of PTH(1–84) to PTH(7–84) is regulated by serum calcium concentration via calcium-sensing receptor in hemodialysis patients

Background  

Secondary hyperparathyroidism is one of the critical complications of end-stage renal disease patients. Conventionally intact parathyroid hormone (iPTH) was used to assess secondary hyperparathyroidism, but this assay measures both PTH(1–84) (full-length parathyroid hormone) and PTH(7–84) (amino (N)-terminal-cleaved parathyroid hormone). PTH(7–84) is biologically inactive or antagonistic for PTH. In this study, we examined the relationship between serum calcium concentration and PTH(7–84)/PTH(1–84) ratio and the effect of calcimimetics on the ratio in hemodialysis (HD) patients.     

Parathyroid hormone PTH(1�C34) increases the volume, mineral content, and mechanical properties of regenerated mineralizing tissue after distraction osteogenesis in rabbits

Background and purpose Parathyroid hormone (PTH) has attracted considerable interest as a bone anabolic agent. Recently, it has been suggested that PTH can also enhance bone repair after fracture and distraction osteogenesis. We analyzed bone density and strength of the newly regenerated mineralized tissue after intermittent treatment with PTH in rabbits, which undergo Haversian bone remodeling similar to that in humans.Methods 72 New Zealand White rabbits underwent tibial mid-diaphyseal osteotomy and the callus was distracted 1 mm/day for 10 days. The rabbits were divided into 3 groups, which received injections of PTH 25 µg/kg/day for 30 days, saline for 10 days and PTH 25 µg/kg/day for 20 days, or saline for 30 days. At the end of the study, the rabbits were killed and the bone density was evaluated with DEXA. The mechanical bone strength was determined by use of a 3-point bending test.Results In the 2 PTH-treated groups the regenerate callus ultimate load was 33% and 30% higher, absorbed energy was 100% and 65% higher, BMC was 61% and 60% higher, and callus tissue volume was 179% and 197% higher than for the control group.Interpretation We found that treatment with PTH during distraction osteogenesis resulted in substantially higher mineralized tissue volume, mineral content, and bending strength. This suggests that treatment with PTH may benefit new bone formation during distraction osteogenesis and could form a basis for clinical application of this therapy in humans.     

Impact of a Phone Follow-Up Program on Persistence with Teriparatide or PTH(1–84) Treatment

A follow-up program to help patients suffering from severe osteoporosis during their therapy with teriparatide or PTH(1–84) has been designed and performed. The objective of this study was to evaluate the 18-month persistence on these therapies in patients participating in the program. We enrolled 382 patients who started teriparatide or PTH(1–84) following this program and compared them with a historical cohort of 398 patients treated with the same therapies but who did not participate in any follow-up program. At the beginning of the therapy, nurses trained patients on self-injection. Patients received one phone call per week during the first month, then one phone call per month and per 3 months during the following 5 and 12 months, respectively. In every call, nurses helped patients to resolve any possible issues and collected adverse event information. The persistence rate of the group following the program was 85.6%, 8.2% higher than that of the group not following any program (77.4%). The log-rank test on persistence rates on therapy in patients enrolled and not enrolled in the program was performed; the difference was statistically significant (P = 0.006). Discontinuation in the follow-up program group occurred mainly at early stages of the treatment due to adverse events. Our results show that patients suffering from severe osteoporosis treated with teriparatide or PTH(1–84) and enrolled in a follow-up program have higher persistence rates than patients not following the program.     

Parathyroid hormone (1–34) increases attachment of PMMA cement to bone

The attachment of an implant material to bone is related to the surface of the implanted material and the ability of the bone to form around the implant. Intermittent parathyroid (PTH) administration increases bone formation by stimulating osteoblastic activity. Little is known about the effect of PTH administration on orthopedic implant incorporation. The present study determined how PTH (1–34) administration influenced bone bonding, i.e., the bone-cement interfacial tensile strength, of vacuum-mixed polymethylmethacrylate (PMMA) bone cement (surface roughness; Ra, 4.8 μm). Bone bonding was evaluated by a detachment test. We used unloaded cement surfaces, which could be detached from the bone. Titanium plates were developed such that a cement fill was contained within a plate that was contained within a titanium holder. Thus, a flat cement surface came into contact with traumatized bone only, and the rest of the plate had no contact with tissue. After implantation of the plate in the left tibia, 20 adult male rats were injected daily with human PTH (1–34) at 60 μg/kg per injection (n = 10) or vehicle (n = 10); the animals were killed after 4 weeks. The plates were detached from the bone by a perpendicular force. PTH treatment increased the median pull-away strength (0.21 MPa), compared with that in the vehicle-treated rats, (0.04 MPa) (P = 0.02). The results suggest that PTH treatment may have the potential to enhance the incorporation of cemented orthopedic implants. Received: September 18, 2000 / Accepted: June 6, 2001     

ILCOR- Konsensuskonferenz in Dallas, 1.–4.2.2010

The consensus conference for elaboration of the International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations (CoSTR) of the International Liaison Committee on Resuscitation (ILCOR) took place from 1^st–4^th February 2010 in Dallas. The American Heart Association (AHA) and European Resuscitation Council (ERC) presided over the development of this consensus. The new guidelines for resuscitation 2010 are anticipated to be published in October 2010. The official German language translation document, which is ratified by the German Resuscitation Council (GRC), is planned to be published by the end of 2010.     

The effects of PTH,loading and surgical insult on cancellous bone at the bone–implant interface in the rabbit

Enhancing the quantity and quality of cancellous bone with anabolic pharmacologic agents may lead to more successful outcomes of non-cemented joint replacements. Using a novel rabbit model of cancellous bone loading, we examined two specific questions regarding bone formation at the bone–implant interface: (1) does the administration of intermittent PTH, a potent anabolic agent, and mechanical loading individually and combined enhance the peri-implant cancellous bone volume fraction; and, (2) does surgical trauma enhance the anabolic effect of PTH on peri-implant bone volume fraction. In this model, PTH enhanced peri-implant bone volume fraction by 30% in loaded bone, while mechanical loading alone increased bone volume fraction modestly (+ 10%). Combined mechanical loading and PTH treatment had no synergistic effect on any cancellous parameters. However, a strong combined effect was found in bone volume fraction with combined surgery and PTH treatment (+ 34%) compared to intact control limbs. Adaptive changes in the cancellous bone tissue included increased ultimate stress and enhanced remodeling activity. The number of proliferative osteoblasts increased as did their expression of pro-collagen 1 and PTH receptor 1, and the number of TRAP positive osteoclasts also increased. In summary, both loading and intermittent PTH treatment enhanced peri-implant bone volume, and surgery and PTH treatment had a strong combined effect. This finding is of clinical importance since enhancing early osseointegration in the post-surgical period has numerous potential benefits.     

High serum levels of a non-(1–84) parathyroid hormone (PTH) fragment in pediatric haemodialysis patients

The measurement of serum intact parathyroid hormone (PTH) is routinely made in haemodialysed (HD) patients to diagnose and monitor secondary hyperparathyroidism. We measured pre- and post-dialysis serum ionized calcium (Ca²⁺) and PTH in 12 HD children (7 boys) aged 13.8±3.6 years. A group of 27 normal short-statured children served as controls. Serum PTH was assessed by a new assay (CAP) recognizing only the (1–84) molecule and an older one (Allegro) recognizing both the 1–84 and a non-(1–84) PTH equally. The concentrations obtained with the CAP assay were lower than those obtained with the Allegro assay both in controls and in HD patients. They were still lower in HD patients when expressed as multiples of the median of the control group. The Allegro/CAP ratio, was highly variable from one subject to another and was lower (P<0.0001) in controls (1.46±0.26) than in HD patients, both before (3.06±1.60) and after dialysis (2.94±0.65). During dialysis, Ca²⁺ increased significantly (P<0.0001) and PTH decreased significantly (P<0.0001) with both the CAP and the Allegro assays, but was more often normal or low with the CAP than with the Allegro assay. Although the two assays correlate well, they may provide different clinical information in some HD children which could lead to different therapeutic decisions. Received: 13 March 2001 / Revised: 12 July 2001 / Accepted: 12 July 2001