Palopegteriparatide Treatment Improves Renal Function in Adults with Chronic Hypoparathyroidism: 1-Year Results from the Phase 3 PaTHway Trial.

INTRODUCTION: Individuals with chronic hypoparathyroidism managed with conventional therapy (active vitamin D and calcium) have an increased risk for renal dysfunction versus age- and sex-matched controls. Treatments that replace the physiologic effects of parathyroid hormone (PTH) while reducing the need for conventional therapy may help prevent a decline in renal function in this population. This post hoc analysis examined the impact of palopegteriparatide treatment on renal function in adults with chronic hypoparathyroidism. METHODS: PaTHway is a phase 3 trial of palopegteriparatide in adults with chronic hypoparathyroidism that included a randomized, double-blind, placebo-controlled 26-week period followed by an ongoing 156-week open-label extension (OLE) period. Changes in renal function over 52 weeks (26 weeks blinded + 26 weeks OLE) were assessed using estimated glomerular filtration rate (eGFR). A subgroup analysis was performed with participants stratified by baseline eGFR < 60 or ≥ 60 mL/min/1.73 m2. RESULTS: At week 52, over 95% (78/82) of participants remained enrolled in the OLE and of those, 86% maintained normocalcemia and 95% achieved independence from conventional therapy (no active vitamin D and ≤ 600 mg/day of calcium), with none requiring active vitamin D. Treatment with palopegteriparatide over 52 weeks resulted in a mean (SD) increase in eGFR of 9.3 (11.7) mL/min/1.73 m2 from baseline (P < 0.0001) and 43% of participants had an increase ≥ 10 mL/min/1.73 m2. In participants with baseline eGFR < 60 mL/min/1.73 m2, 52 weeks of treatment with palopegteriparatide resulted in a mean (SD) increase of 11.5 (11.3) mL/min/1.73 m2 (P < 0.001). One case of nephrolithiasis was reported for a participant in the placebo group during blinded treatment; none were reported through week 52 with palopegteriparatide. CONCLUSION: In this post hoc analysis of the PaTHway trial, palopegteriparatide treatment was associated with significantly improved eGFR at week 52 in addition to previously reported maintenance and normalization of serum and urine biochemistries. Further investigation of palopegteriparatide for the preservation of renal function in hypoparathyroidism is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT04701203.

Chronic hypoparathyroidism is caused by inadequate parathyroid hormone (PTH) levels. Hypoparathyroidism is managed with conventional therapy (active vitamin D and calcium), but over time the disease itself and conventional therapy can increase the risk of medical complications including kidney problems. This study looked at how a new treatment for chronic hypoparathyroidism, palopegteriparatide (approved in the European Union under the brand name YORVIPATH^®), affects kidney function in adults in the PaTHway clinical trial. Participants were randomly assigned to receive palopegteriparatide or a placebo injection once daily along with conventional therapy. For both groups, clinicians used a protocol to eliminate conventional therapy while maintaining normal blood calcium levels. After 26 weeks, participants on placebo switched to palopegteriparatide. Ninety-five percent of participants were still enrolled in the PaTHway trial after 52 weeks. Of those, 86% had normal blood calcium levels and 95% did not need conventional therapy (not taking vitamin D and not taking therapeutic doses of calcium [> 600 mg/day]). After 52 weeks of treatment with palopegteriparatide, significant improvements were seen in a measure of kidney function called estimated glomerular filtration rate (eGFR). Improvements in eGFR from the beginning of the trial to week 52 were considered clinically meaningful for over 57% of participants. In participants with impaired kidney function at the beginning of the trial, eGFR improvements were even greater, and 74% of participants had a clinically meaningful improvement. These results suggest that palopegteriparatide treatment may be beneficial for kidney function in adults with chronic hypoparathyroidism, especially those with impaired kidney function.

Intermittent administration of PTH for the treatment of inflammatory bone loss does not enhance entheseal pathological new bone formation.

OBJECTIVE: To investigate the effect of intermittent parathyroid hormone (iPTH) administration on pathological new bone formation during treatment of ankylosing spondylitis-related osteoporosis. METHODS: Animal models with pathological bone formation caused by hypothetical AS pathogenesis received treatment with iPTH. We determined the effects of iPTH on bone loss and the formation of pathological new bone with micro-computed tomography (micro-CT) and histological examination. In addition, the tamoxifen-inducible conditional knockout mice (CAGGCre-ERTM; PTHflox/flox, PTH-/-) was established to delete PTH and investigate the effect of endogenous PTH on pathological new bone formation. RESULTS: iPTH treatment significantly improved trabecular bone mass in the modified collagen-induced arthritis (m-CIA) model and unbalanced mechanical loading models. Meanwhile, iPTH treatment did not enhance pathological new bone formation in all types of animal models. Endogenous PTH deficiency had no effects on pathological new bone formation in unbalanced mechanical loading models. CONCLUSION: Experimental animal models of AS treated with iPTH show improvement in trabecular bone density, but not entheseal pathological bone formation，indicating it may be a potential treatment for inflammatory bone loss does in AS.

PTH treatment before cyclic joint loading improves cartilage health and attenuates load-induced osteoarthritis development in mice.

Osteoarthritis (OA) treatment is limited by the lack of effective nonsurgical interventions to slow disease progression. Here, we examined the contributions of the subchondral bone properties to OA development. We used parathyroid hormone (PTH) to modulate bone mass before OA initiation and alendronate (ALN) to inhibit bone remodeling during OA progression. We examined the spatiotemporal progression of joint damage by combining histopathological and transcriptomic analyses across joint tissues. The additive effect of PTH pretreatment before OA initiation and ALN treatment during OA progression most effectively attenuated load-induced OA pathology. Individually, PTH directly improved cartilage health and slowed the development of cartilage damage, whereas ALN primarily attenuated subchondral bone changes associated with OA progression. Joint damage reflected early transcriptomic changes. With both treatments, the structural changes were associated with early modulation of immunoregulation and immunoresponse pathways that may contribute to disease mechanisms. Overall, our results demonstrate the potential of subchondral bone-modifying therapies to slow the progression of OA.

Treatment of Hypoparathyroidism by Re-Establishing the Effects of Parathyroid Hormone.

The conventional treatment of hypoparathyroidism (HypoPT) includes active vitamin D and calcium. Despite normalization of calcium levels, the conventional treatment is associated with fluctuations in calcium levels, hypercalciuria, renal impairment, and decreased quality of life (QoL). Replacement therapy with parathyroid hormone (PTH)(1-84) is an option in some countries. However, convincing beneficial effects have not been demonstrated, which may be due to the short duration of action of this treatment. Recently, palopegteriparatide (also known as TransCon PTH) has been marketed in Europe and is expected also to be approved in other countries. Palopegteriparatide is a prodrug with sustained release of PTH(1-34) designed to provide stable physiological PTH levels for 24 hours/day. A phase 3 study demonstrated maintenance of normocalcemia in patients with chronic HypoPT, with no need for conventional therapy. Furthermore, this treatment lowers urinary calcium and improves QoL. Another long-acting PTH analog with effects on the parathyroid hormone receptor (eneboparatide) is currently being tested in a phase 3 trial. Furthermore, the treatment of autosomal dominant hypocalcemia type 1 with a calcilytic (encaleret) is also being tested. All in all, improved treatment options are on the way that will likely take the treatment of HypoPT to the next level.

Effect of Osteoporosis Treatments on Osteoarthritis Progression in Postmenopausal Women: A Review of the Literature.

PURPOSE OF REVIEW: The purpose of this literature review was to determine if medications used to treat osteoporosis are also effective for treating osteoarthritis (OA). RECENT FINDINGS: A total of 40 relevant articles were identified. Studies were categorized into those (1) discussing estrogen and selective estrogen receptor modulators (SERMs), (2) bisphosphonates, (3) parathyroid hormone (PTH) analogs, and (4) denosumab, and (5) prior review articles. A large amount of evidence suggests that estrogen and SERMs are effective at reducing OA symptoms and disease progression. Evidence suggests that bisphosphonates, the most common medications used to treat osteoporosis, can reduce OA symptoms and disease progression. In vivo studies suggest that PTH analogs may improve the cartilage destruction associated with OA; however, few human trials have examined its use for OA. Denosumab is approved to treat osteoporosis, bone metastases, and certain types of breast cancer, but little study has been done with respect to its effect on OA. The current evidence indicates that medications used to treat osteoporosis are also effective for treating OA. Estrogen, SERMs, and bisphosphonates have the most potential as OA therapies. Less is known regarding the effectiveness of PTH analogs and denosumab in OA, and more research is needed.

[Hypercalcemia: a practical review]. / Hypercalcémie : revue pratique.

Hypercalcemia, defined as an abnormal elevation of serum calcium, is a common electrolyte anomaly in primary care, affecting almost 1% of the worldwide population. Clinical manifestations concern the neuromuscular, cardiovascular, gastrointestinal, renal and skeletal systems. Among the causes, the main ones are primary hyperparathyroidism, and malignancies. Le initial workup should include the measurement of parathyroid hormone (PTH), and the discontinuation of any medication likely to be involved in iatrogenic hypercalcemia. The chosen treatments and their speed of introduction depend mainly on the severity of hypercalcemia. They include intravenous rehydration, and antiresorptive agents such as bisphosphonates, denosumab or calcitonin.

L'hypercalcémie, définie comme une élévation anormale du taux de calcium sérique, est un trouble électrolytique courant en médecine de premier recours, touchant presque 1 % de la population mondiale. Les manifestations cliniques affectent les systèmes neuromusculaire, cardiovasculaire, gastrointestinal, rénal et ostéoarticulaire. Les causes les plus fréquentes sont l'hyperparathyroïdie primaire et l'hypercalcémie paranéoplasique. Le bilan diagnostique initial nécessite la mesure de l'hormone parathyroïdienne et l'exclusion de tout médicament susceptible d'induire une hypercalcémie. Les traitements choisis et leur rapidité d'introduction dépendent surtout de la sévérité de l'hypercalcémie et comprennent l'hydratation intraveineuse et les inhibiteurs de la résorption osseuse (biphosphonates, dénosumab, calcitonine, etc.).

Abaloparatide is more potent than teriparatide in restoring bone mass and strength in type 1 diabetic male mice.

This study investigated the efficacy of the two FDA-approved bone anabolic ligands of the parathyroid hormone receptor 1 (PTH1R), teriparatide or human parathyroid hormone 1-34 (PTH) and abaloparatide (ABL), to restoring skeletal health using a preclinical murine model of streptozotocin-induced T1-DM. Intermittent daily subcutaneous injections of equal molar doses (12 pmoles/g/day) of PTH (50 ng/g/day), ABL (47.5 ng/g/day), or vehicle, were administered for 28 days to 5-month-old C57Bl/6 J male mice with established T1-DM or control (C) mice. ABL was superior to PTH in increasing or restoring bone mass in control or T1-MD mice, respectively, which was associated with superior stimulation of trabecular and periosteal bone formation, upregulation of osteoclastic/osteoblastic gene expression, and increased circulating bone remodeling markers. Only ABL corrected the reduction in ultimate load, which is a measure of bone strength, induced by T1-DM, and it also increased energy to ultimate load. In addition, bones from T1-DM mice treated with PTH or ABL exhibited increased ultimate stress, a material index, compared to T1-DM mice administered with vehicle. And both PTH and ABL prevented the increased expression of the Wnt antagonist Sost/sclerostin displayed by T1-DM mice. Further, PTH and ABL increased to a similar extent the circulating bone resorption marker CTX and the bone formation marker P1NP in T1-DM after 2 weeks of treatment; however, only ABL sustained these increases after 4 weeks of treatment. We conclude that at equal molar doses, ABL is more effective than PTH in increasing bone mass and restoring the cortical and trabecular bone lost with T1-DM, due to higher and longer-lasting increases in bone remodeling.

Cost-Effectiveness and Clinical Outcomes of Secondary Hyperparathyroidism Treatments in Patients with Chronic Kidney Disease.

The study addresses the challenge of treating secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients, focusing on the cost-effectiveness of surgical versus pharmacological interventions. Conducting a retrospective analysis on 152 CKD patients with SHPT at the Third People's Hospital of Chengdu, the study matched 80 patients into two groups: 40 undergoing parathyroidectomy with autotransplantation (PTX + AT) and 40 treated with calcimimetics. PTX + AT was more effective in alleviating symptoms, particularly bodily pain, and demonstrated greater cost-effectiveness over a long-term period compared to calcimimetics. This was especially significant in patients with PTH levels > 1800 pg/mL and hyperphosphatemia. Despite similar initial costs, PTX + AT led to a substantial decrease in expenses during the 2-5 years post-treatment period, PTX + AT results in an ICER of -RMB 26.71/QALY for the first post-treatment year and -RMB-111.9k/QALY for the 2-5 year period, indicating cost-effectiveness with reduced long-term costs. The study also found an increased economic burden in managing patients with hyperphosphatemia. Surgical intervention (PTX + AT) is advocated as the primary treatment strategy for severe SHPT in CKD patients, owing to its long-term economic and clinical advantages. The results underscore the need for a severity-based approach in treating SHPT.

Editorial Commentary: Biocomposite Implant Combined With Local Human Recombinant Parathyroid Hormone Enhances the Histological Quality and Biomechanical Strength of Rotator Cuff Repairs.

Rates of rotator cuff repair retear remain unacceptably high and are frequently the source of diminished shoulder function and patient dissatisfaction. Endocrinopathies have been implicated in these processes. Parathyroid hormone (PTH) activates chondrogenesis and angiogenesis at the enthesis and prevents fatty infiltration and atrophy in rotator cuff musculature. These facts have spurred interest in the therapeutic benefits of PTH as a means to enhance tendon healing and strengthen the bone in and around tendon repairs. New research demonstrates that recombinant human PTH delivered locally through a process of coupling it to a bioengineered scaffold "sheath" may be beneficial. The growth factor, encased within polycaprolactone (PCL), is slowly released as the PCL degrades to extend drug delivery time. The augmentation of rotator cuff repairs with this biocomposite material improves short-term structural tissue integrity and promotes the formation of more organized and stronger tendon-to-bone interface in a rabbit model.

Effect of Paricalcitol Combined with Cinacalcet on Calcium and Phosphorus Metabolism in Patients Receiving Maintenance Hemodialysis.

This study was designed to compare the beneficial effects of paricalcitol combined with or without cinacalcet on calcium and phosphorus metabolism in patients undergoing maintenance hemodialysis (MHD). A total of 140 patients who received MHD in our hospital from March 2021 to March 2022 were randomly divided into a control group (intravenous paricalcitol, n = 70) and a test group (intravenous paricalcitol combined with oral cinacalcet, n = 70). Clinical baseline data and relevant laboratory parameters before treatment were compared. Additionally, calcium, phosphorus, intact parathyroid hormone in serum were measured and compared between the 2 groups before treatment and 1, 2, 3, 4, 5, 6, 9, 10, and 12 months after treatment. As a result, comparison before treatment demonstrated no significant difference in baseline data such as age, sex, and most laboratory parameters between the 2 groups (P > .05), but there was a significant difference in mean corpuscular volume (P < .001). The serum phosphorus level decreased and calcium level increased significantly in the 2 groups after treatment, while the intact parathyroid hormone level showed no significant change within 12 months of treatment (P > .05). In addition, the combined treatment for 6-12 months caused a much lower phosphorus level (P < .05) and higher calcium level (P < .05) than the treatment with paricalcitol alone, and the difference increased with the extension of treatment time. Collectively, paricalcitol combined with cinacalcet, which is more effective than paricalcitol alone, has a positive effect on calcium and phosphorus metabolism in patients receiving MHD.

Parathyroid hormone and trabectedin have differing effects on macrophages and stress fracture repair.

Stress fractures occur as a result of repeated mechanical stress on bone and are commonly found in the load-bearing lower extremities. Macrophages are key players in the immune system and play an important role in bone remodeling and fracture healing. However, the role of macrophages in stress fractures has not been adequately addressed. We hypothesize that macrophage infiltration into a stress fracture callus site promotes bone healing. To test this, a unilateral stress fracture induction model was employed in which the murine ulna of four-month-old, C57BL/6 J male mice was repeatedly loaded with a pre-determined force until the bone was displaced a distance below the threshold for complete fracture. Mice were treated daily with parathyroid hormone (PTH, 50 µg/kg/day) starting two days before injury and continued until 24 h before euthanasia either four or six days after injury, or treated with trabectedin (0.15 mg/kg) on the day of stress fracture and euthanized three or seven days after injury. These treatments were used due to their established effects on macrophages. While macrophages have been implicated in the anabolic effects of PTH, trabectedin, an FDA approved chemotherapeutic, compromises macrophage function and reduces bone mass. At three- and four-days post injury, callus macrophage numbers were analyzed histologically. There was a significant increase in macrophages with PTH treatment compared to vehicle in the callus site. By one week of healing, treatments differentially affected the bony callus as analyzed by microcomputed tomography. PTH enhanced callus bone volume. Conversely, callus bone volume was decreased with trabectedin treatment. Interestingly, concurrent treatment with PTH and trabectedin rescued the reduction observed in the callus with trabectedin treatment alone. This study reports on the key involvement of macrophages during stress fracture healing. Given these observed outcomes on macrophage physiology and bone healing, these findings may be important for patients actively receiving either of these FDA-approved therapeutics.

Recombinant Human Parathyroid Hormone Biocomposite Promotes Bone-to-Tendon Interface Healing by Enhancing Tenogenesis, Chondrogenesis, and Osteogenesis in a Rabbit Model of Chronic Rotator Cuff Tears.

PURPOSE: To investigate the effect of recombinant human parathyroid hormone (rhPTH) biocomposite on bone-to-tendon interface (BTI) healing for surgical repair of a chronic rotator cuff tear (RCT) model of rabbit, focusing on genetic, histologic, biomechanical and micro-computed tomography (CT) evaluations. METHODS: Sixty-four rabbits were equally assigned to the 4 groups: saline injection (group A), nanofiber sheet alone (group B), rhPTH-soaked nanofiber sheet (nanofiber sheet was soaked with rhPTH, group C), and rhPTH biocomposite (rhPTH permeated the nanofiber sheet by coaxial electrospinning, group D). The release kinetics of rhPTH (groups C and D) was examined for 6 weeks in vitro. Nanofiber scaffolds were implanted on the surface of the repair site 6 weeks after the induction of chronic RCT. Genetic and histologic analyses were conducted 4 weeks after surgery. Furthermore, genetic, histologic, biomechanical, micro-CT, and serologic analyses were performed 12 weeks after surgery. RESULTS: In vivo, group D showed the highest collagen type I alpha 1 (COL1A1), collagen type III alpha 1 (COL3A1), and bone morphogenetic protein 2 (BMP-2) messenger RNA (mRNA) expression levels (all P < .001) 4 weeks after surgery; however, there were no differences between groups at 12 weeks postsurgery. After 12 weeks postsurgery, group D showed better collagen fiber continuity and orientation, denser collagen fibers, more mature bone-to-tendon junction, and greater fibrocartilage layer formation compared with the other groups (all P < .05). Furthermore, group D showed the highest load-to-failure rate (28.9 ± 2.0 N/kg for group A, 30.1 ± 3.3 N/kg for group B, 39.7 ± 2.7 N/kg for group C, and 48.2 ± 4.5 N/kg for group D, P < .001) and micro-CT outcomes, including bone and tissue mineral density, and bone volume/total volume rate (all P < .001) at 12 weeks postsurgery. CONCLUSIONS: In comparison to rhPTH-soaked nanofiber sheet and the other control groups, rhPTH biocomposite effectively accelerated BTI healing by enhancing the mRNA expression levels of COL1A1, COL3A1, and BMP-2 at an early stage and achieving tenogenesis, chondrogenesis, and osteogenesis at 12 weeks after surgical repair of a chronic RCT model of rabbit. CLINICAL RELEVANCE: The present study might be a transitional study to demonstrate the efficacy of rhPTH biocomposites on BTI healing for surgical repair of chronic RCTs as an adaptable polymer biomaterial in humans.

Extended Treatment With Recombinant Human Parathyroid Hormone (1-84) in Adult Patients With Chronic Hypoparathyroidism.

OBJECTIVE: Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is efficacious in patients with hypoparathyroidism but additional data supporting its prolonged use are needed. We evaluated whether efficacy, safety, and tolerability are maintained during long-term rhPTH(1-84) treatment of patients with chronic hypoparathyroidism. METHODS: This was a phase 4, single-center, open-label, single-arm, 3-year extension (NCT02910466) of the phase 3 Hypo Extended (HEXT) study (NCT01199614). Patients self-administered rhPTH(1-84) once daily by subcutaneous injection, with doses individualized based on clinical parameters. Albumin-adjusted serum calcium levels (primary outcome measure), other disease biomarkers, health-related quality of life, and safety of rhPTH(1-84) were assessed using descriptive statistics. RESULTS: All patients (n = 39) had been exposed to rhPTH(1-84) (mean exposure [SD] 8.5 [3.5] years) before the start of the study, resulting in a mean exposure of 10.8 years including the present study. Mean patient age was 51.9 years, 79.5% were female, and 97.4% were White. Mean albumin-adjusted serum calcium concentrations were within the target range, and mean serum phosphate, serum calcium-phosphate product, and 24-hour urinary calcium excretion levels were within reference ranges at end of treatment. Mean doses of supplemental calcium and active vitamin D were maintained throughout the study. Bone turnover marker levels were maintained from baseline to end of treatment. No clinically relevant changes in bone mineral density were observed. Patient-reported health-related quality-of-life scores were generally maintained throughout the study. Four adverse events were considered treatment related and no new safety signals were identified. CONCLUSION: The effects of rhPTH(1-84) on biochemical, skeletal, and health-related quality-of-life parameters did not wane with extended use.

The effects of adequate dietary calcium intake in patients with hypoparathyroidism non-adherent to treatment: a prospective randomized controlled trial.

OBJECTIVE: A significant problem that compels clinicians in the conventional treatment of hypoparathyroidism is patients' non-adherence to treatment. This study aimed to evaluate the effects of adequate Ca intake with dietary recommendations among hypoparathyroidism patients who persistently use Ca supplementation irregularly on plasma Ca and phosphate levels. METHODS: This prospective, randomized, controlled study was conducted on patients diagnosed with chronic hypoparathyroidism who persistently interrupt Ca supplementation therapy and therefore have a hypocalcemic course. Patients with a total daily Ca intake below 800 mg were randomized. All patients were advised to keep the doses of active vitamin D and Ca supplements they were currently using. The patients in the study group (n=32) were advised to consume 1,000-1,200 mg of Ca daily, and the patients in the control group (n=35) were advised to continue their diet according to their daily habits. After 12 weeks of follow-up, the patients' laboratory values were compared between groups to assess treatment goals. RESULTS: The mean of the total Ca level was 8.56±0.36 mg/dL in the study group and was found to be significantly higher than that in the control group, which was 7.67±0.48 mg/dL (p<0.001). The mean serum phosphate and serum Ca-P product levels were significantly higher in the study group (p<0.001) but did not exceed the safe upper limits in any patient. CONCLUSION: A suitable increase in dietary Ca intake could effectively control hypocalcemia in patients with hypoparathyroidism who persistently interrupt the recommended calcium supplementation.

Parathyroid hormone treatment partially reverses endplate remodeling and attenuates low back pain in animal models of spine degeneration.

Low back pain (LBP) is one of the most prevalent diseases affecting quality of life, with no disease-modifying therapy. During aging and spinal degeneration, the balance between the normal endplate (EP) bilayers of cartilage and bone shifts to more bone. The aged/degenerated bony EP has increased porosity because of osteoclastic remodeling activity and may be a source of LBP due to aberrant sensory innervation within the pores. We used two mouse models of spinal degeneration to show that parathyroid hormone (PTH) treatment induced osteogenesis and angiogenesis and reduced the porosity of bony EPs. PTH increased the cartilaginous volume and improved the mechanical properties of EPs, which was accompanied by a reduction of the inflammatory factors cyclooxygenase-2 and prostaglandin E2. PTH treatment furthermore partially reversed the innervation of porous EPs and reversed LBP-related behaviors. Conditional knockout of PTH 1 receptors in the nucleus pulposus (NP) did not abolish the treatment effects of PTH, suggesting that the NP is not the primary source of LBP in our mouse models. Last, we showed that aged rhesus macaques with spontaneous spinal degeneration also had decreased EP porosity and sensory innervation when treated with PTH, demonstrating a similar mechanism of PTH action on EP sclerosis between mice and macaques. In summary, our results suggest that PTH treatment could partially reverse EP restructuring during spinal regeneration and support further investigation into this potentially disease-modifying treatment strategy for LBP.

Parathyroid hormone stimulates bone regeneration in an atrophic non-union model in aged mice.

BACKGROUND: Non-union formation still represents a major burden in trauma and orthopedic surgery. Moreover, aged patients are at an increased risk for bone healing failure. Parathyroid hormone (PTH) has been shown to accelerate fracture healing in young adult animals. However, there is no information whether PTH also stimulates bone regeneration in atrophic non-unions in the aged. Therefore, the aim of the present study was to analyze the effect of PTH on bone regeneration in an atrophic non-union model in aged CD-1 mice. METHODS: After creation of a 1.8 mm segmental defect, mice femora were stabilized by pin-clip fixation. The animals were treated daily with either 200 mg/kg body weight PTH 1-34 (n = 17) or saline (control; n = 17) subcutaneously. Bone regeneration was analyzed by means of X-ray, biomechanics, micro-computed tomography (µCT) imaging as well as histological, immunohistochemical and Western blot analyses. RESULTS: In PTH-treated animals bone formation was markedly improved when compared to controls. This was associated with an increased bending stiffness as well as a higher number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and CD31-positive microvessels within the callus tissue. Furthermore, PTH-treated aged animals showed a decreased inflammatory response, characterized by a lower number of MPO-positive granulocytes and CD68-positive macrophages within the bone defects when compared to controls. Additional Western blot analyses demonstrated a significantly higher expression of cyclooxygenase (COX)-2 and phosphoinositide 3-kinase (PI3K) in PTH-treated mice. CONCLUSION: Taken together, these findings indicate that PTH is an effective pharmacological compound for the treatment of non-union formation in aged animals.

Secondary hyperparathyroidism in chronic kidney disease: pathomechanism and current treatment possibilities.

Secondary hyperparathyroidism (SHPT) is one of the most common metabolic complications resulting from chronic kidney disease (CKD). The complexity of calcium and phosphate disorders associated with CKD is defined by the Kidney Disease Improvement Global Outcomes (KDIGO) working group as CKD-related mineral and bone disorders (CKD-MBD). The last update of the KDIGO guidelines on the conduct in CKD-MBD was published in 2017. The treatment of SHPT is based on 2 strategies: counteracting hyperphosphataemia and suppressing parathyroid hormone (PTH) secretion. Therapy should be based on optimally selected drugs, taking into account additional effects to reduce the risk of chronic complications and side effects. The creation of new drugs with a better safety profile, significant reduction of side effects, and greater efficiency in achieving target serum phosphorus and PTH values forces the gradual replacement of existing treatment with new pharmacotherapies. The aim of this study is to discuss the latest issues (in connection with the latest KDIGO guidelines) regarding the pathomechanism of secondary hyperparathyroidism and the current directions of the therapy in these disorders.

Parathyroid hormone therapy improves MRSA-infected fracture healing in a murine diabetic model.

Introduction: Diabetes mellitus (DM) impairs fracture healing and is associated with susceptibility to infection, which further inhibits fracture healing. While intermittent parathyroid hormone (1-34) (iPTH) effectively improves fracture healing, it is unknown whether infection-associated impaired fracture healing can be rescued with PTH (teriparatide). Methods: A chronic diet-induced type 2 diabetic mouse model was used to yield mice with decreased glucose tolerance and increased blood glucose levels compared to lean-fed controls. Methicillin-resistant Staphylococcus aureus (MRSA) was inoculated in a surgical tibia fracture model to simulate infected fracture, after which mice were treated with a combination of antibiotics and adjunctive teriparatide treatment. Fracture healing was assessed by Radiographic Union Scale in Tibial Fractures (RUST), micro-computed tomography (µCT), biomechanical testing, and histology. Results: RUST score was significantly poorer in diabetic mice compared to their lean nondiabetic counterparts. There were concomitant reductions in micro-computed tomography (µCT) parameters of callus architecture including bone volume/total volume, trabecular thickness, and total mineral density in type 2 diabetes mellitus (T2DM) mice. Biomechanicaltesting of fractured femora demonstrated diminished torsional rigidity, stiffness, and toughness to max torque. Adjuvant teriparatide treatment with systemic antibiotic therapy improved numerous parameters of bone microarchitecture bone volume, increased connectivity density, and increased trabecular number in both the lean and T2DM group. Despite the observation that poor fracture healing in T2DM mice was further impaired by MRSA infection, adjuvant iPTH treatment significantly improved fracture healing compared to antibiotic treatment alone in infected T2DM fractures. Discussion: Our results suggest that teriparatide may constitute a viable adjuvant therapeutic agent to improve bony union and bone microarchitecture to prevent the development of septic nonunion under diabetic conditions.

[The recombinant human parathyroid hormone, teriparatide as an alternative remedy for the medication-related osteonecrosis of the jaw]. / Humán rekombináns parathormon (teriparatid) mint alternatív megoldás a gyógyszer okozta állcsontnekrózis terápiájára.

In developed countries, osteoporosis is one of the most common debilitating conditions in the population over the age of 50. Unfortunately, the pathomechanism of the disease is still not fully understood. Nowadays, the administration of antiresorptive drugs blocking osteoclastic activity is the most commonly used medication to slow down the speed of the bone loss. One of the uncommon side effects of such drugs is the medication-related osteonecrosis of the jaw (MRONJ). Recently, a number of alternative therapeutic approaches has been tested and published, amongst them the recombinant human parathyroid hormone (rhPTH, teriparatide) use, which is turning into a promising treatment modality. According to certain meta-analyses, its pharmacological effect on increasing bone mineral density and controlling pathological vertebral fractures is superior to antiresorptive drugs; however, the so-called "off-label" application of teriparatide remains controversial. As intermittent administration of teriparatide stimulates bone formation, several animal and clinical studies indicated that systemic application of teriparatide shortened fracture healing time and improved quality of the callus and the newly formed bone. Furthermore, recently several clinical studies showed the beneficial effect of the intermittent rhPTH administration in the management of MRONJ. This article reviews the history of the anabolic effect of the low-dose rhPTH discovery, provides evidence-based data from animal and human studies, summarizes its biological mechanisms and the clinical benefits of the anabolic therapy and also their possible role in the management of MRONJ. The majority of the clinical data indicates that, in the case of therapy-resistant osteonecrosis, it may be worthwhile to apply short-term intermittent teriparatide therapy. Notwithstanding, more randomized clinical trials are necessary in order to confirm the efficacy and the safety of the use of teriparatide in the treatment of MRONJ. Orv Hetil. 2023; 164(36): 1406-1415.

Daily administration of parathyroid hormone slows the progression of basic multicellular units in the cortical bone of the rabbit distal tibia.

Basic Multicellular Units (BMUs) conduct bone remodeling, a critical process of tissue turnover which, if imbalanced, can lead to disease, including osteoporosis. Parathyroid hormone (PTH 1-34; Teriparatide) is an osteoanabolic treatment for osteoporosis; however, it elevates the rate of intra-cortical remodeling (activation frequency) leading, at least transiently, to increased porosity. The purpose of this study was to test the hypothesis that PTH not only increases the rate at which cortical BMUs are initiated but also increases their progression (Longitudinal Erosion Rate; LER). Two groups (n = 7 each) of six-month old female New Zealand white rabbits were both administered 30 µg/kg of PTH once daily for a period of two weeks to induce remodeling. Their distal right tibiae were then imaged in vivo by in-line phase contrast micro-CT at the Canadian Light Source synchrotron. Over the following two weeks the first group (PTH) received continued daily PTH while the second withdrawal group (PTHW) was administrated 0.9 % saline. At four weeks all animals were euthanized, their distal tibiae were imaged by conventional micro-CT ex vivo and histomorphometry was performed. Matching micro-CT datasets (in vivo and ex vivo) were co-registered in 3D and LER was measured from 612 BMUs. Counter to our hypothesis, mean LER was lower (p < 0.001) in the PTH group (30.19 ± 3.01 µm/day) versus the PTHW group (37.20 ± 2.77 µm/day). Despite the difference in LER, osteonal mineral apposition rate (On.MAR) did not differ between groups indicating the anabolic effect of PTH was sustained after withdrawal. The slowing of BMU progression by PTH warrants further investigation; slowed resorption combined with elevated bone formation rate, may play an important role in how PTH enhances coupling between resorption and formation within the BMU. Finally, the prolonged anabolic response following withdrawal may have utility in terms of optimizing clinical dosing regimens.