Parathyroid Hormone Analogs Research Articles

Enhancing bone regeneration and osseointegration using rhPTH(1-34) and dimeric R25CPTH(1-34) in an osteoporotic beagle model.

This study investigates the effects of two parathyroid hormone (PTH) analogs, rhPTH(1-34) and dimeric R25CPTH(1-34), on bone regeneration and osseointegration in a postmenopausal osteoporosis model using beagle dogs. Twelve osteoporotic female beagles were subjected to implant surgeries and assigned to one of three groups: control, rhPTH(1-34), or dimeric R25CPTH(1-34). Bone regeneration and osseointegration were evaluated after 10 weeks using micro-computed tomographic (micro-CT), histological analyses, and serum biochemical assays. Results showed that the rhPTH(1-34) group demonstrated superior improvements in bone mineral density, trabecular architecture, and osseointegration compared to controls, while the dimeric R25CPTH(1-34) group exhibited similar, though slightly less pronounced, anabolic effects. Histological and TRAP assays indicated both PTH analogs significantly enhanced bone regeneration, especially in artificially created bone defects. The findings suggest that both rhPTH(1-34) and dimeric R25CPTH(1-34) hold potential as therapeutic agents for promoting bone regeneration and improving osseointegration around implants in osteoporotic conditions, with implications for their use in bone-related pathologies and reconstructive surgeries.

8041 Eneboparatide, A Potent Stimulator Of Urinary Calcium Reabsorption, Induces Prolonged Renal Cortex Retention And PTH1 Receptor Signaling

Abstract Disclosure: G. Ravel: Employee; Self; Amolyt Pharma. R. Datta: Consulting Fee; Self; Amolyt Pharma. S. Milano: Employee; Self; Amolyt Pharma. M. Ovize: Employee; Self; Amolyt Pharma. S. Allas: Employee; Self; Amolyt Pharma. M. Aouadi: None. M.D. Culler: Employee; Self; Amolyt Pharma. Natural parathyroid hormone (PTH) replacement therapy for chronic hypoparathyroidism (cHP) is not ideal due to both short circulating half-life and brief receptor signaling, making the effect too transient. Following agonist binding to the PTH 1 receptor (PTH1R), the magnitude and duration of the receptor signal, and consequently the biological response, appears to depend on the affinity of the ligand for a specific receptor conformation termed R0, which determines the duration of ligand binding. Eneboparatide (Enebo) is a hybrid analog of PTH and PTH-related peptide designed to strongly bind to the R0 conformation while having a short circulating half-life similar to that of PTH. When tested in cHP patients, Enebo eliminated the need for calcium (Ca) (88% patients) and Vitamin D (92% patients) supplementation, while maintaining serum Ca levels over a full 24 hours. Urinary calcium (uCa) was rapidly decreased and was normalized in 92% of patients who were hypercalciuric prior to treatment. To explore the mechanism of the potent effect of Enebo on uCa, a binding assay specific for the R0 conformation of the PTH1R confirmed the high affinity of Enebo versus natural PTH1-34, with IC50 = 1.5nM and 30.9nM, respectively. Postulating that the high-affinity binding of Enebo to R0 should result in longer tissue retention in vivo, we examined the tissue levels of PTH1-34 and Enebo in male, 200-300g rats using quantitative whole-body autoradiography (QWBA) following subcutaneous injection of 3H-labeled Enebo and PTH1-34. Tissue levels of the compounds were normalized based on the concentrations observed in cardiac blood. The highest level observed for both compounds was in the renal cortex, the major site of active PTH-induced Ca reabsorption, with peak concentrations observed 30 minutes post-injection. Six hours after injection, 96.3% of PTH1-34 had disappeared from the renal cortex, as compared with only 61.4% of Enebo, despite both compounds having similar circulating half-lives. With respect to activating the PTH1R, both compounds showed a similar increase in cAMP in human embryonic kidney (HEK293) cells transfected with the PTH1R and the Green Downward cADDis cAMP biosensor, with EC50 of 0.32 and 0.48nM for Enebo and PTH1-34, respectively. To mimic the effect of rapid elimination in vivo, the ligands were added to the cells, washed-off after 15 minutes, and cAMP production followed over the next 16 hours. After washout, the cAMP signal induced by PTH1-34 rapidly returned to baseline in less than 60 minutes, whereas the cAMP signal induced by Enebo gradually decreased and was still evident after 16 hours. Collectively, these data confirm high affinity of Enebo for the R0 conformation of the PTH1R, as well as prolonged receptor signaling and retention by the renal cortex, clearly differentiating Enebo from PTH1-34 and providing strong rationale for the efficacy of Enebo in reducing uCa in cHP patients. Presentation: 6/3/2024

Update on Atypical Femoral Fractures.

➤ Atypical femoral fractures (AFFs) are stress fractures between the lesser trochanter and the metaphyseal flare that are most commonly related to prolonged (3 to 5 years) antiresorptive medication use.➤ An important finding is a visible transverse line in the lateral cortex, known as the "dreaded black line." Complete fractures are transverse and have minimal comminution.➤ Prodromal symptoms including hip, groin, thigh, and knee pain are present in more than one-half of cases and are usually misdiagnosed.➤ Nonoperative treatment for all patients with AFF includes withdrawal of bisphosphonates, assessment for secondary causes of osteoporosis, and optimization of vitamin D and calcium.➤ Incomplete fractures without a visible line can initially be treated nonoperatively with protected weight-bearing.➤ Intramedullary nailing is indicated for complete fractures and incomplete fractures with a visible fracture line. Delayed healing after fixation should be anticipated.➤ Treatment with parathyroid hormone (PTH) analogs (teriparatide and abaloparatide) after AFF prevents other fractures in high-risk patients, but the effect on healing of the fracture is unclear.

Bone Health Optimization in Adult Spinal Deformity Patients: A Narrative Review.

Osteoporosis and low bone mineral density (BMD) pose significant challenges in adult spinal deformity surgery, increasing the risks of complications such as vertebral compression fractures, hardware failure, proximal junctional kyphosis/failure, and pseudoarthrosis. This narrative review examines the current evidence on bone health optimization strategies for spinal deformity patients. Preoperative screening and medical optimization are crucial, with vitamin D supplementation showing particular benefit. Among the pharmacologic agents, bisphosphonates demonstrate efficacy in improving fusion rates and reducing hardware-related complications, though the effects may be delayed. Teriparatide, a parathyroid hormone analog, shows promise in accelerating fusion and enhancing pedicle screw fixation. Newer anabolic agents like abaloparatide and romosozumab require further study but show potential. Romosozumab, in particular, has demonstrated significant improvements in lumbar spine BMD over a shorter duration compared to other treatments. Surgical techniques like cement augmentation and the use of larger interbody cages can mitigate the risks in osteoporotic patients. Overall, a multifaceted approach incorporating medical optimization, appropriate pharmacologic treatment, and tailored surgical techniques is recommended to improve outcomes in adult spinal deformity patients with compromised bone quality. Future research should focus on optimizing the treatment protocols, assessing the long-term outcomes of newer agents in the spine surgery population, and developing cost-effective strategies to improve access to these promising therapies.

Towards an enhanced understanding of osteoanabolic effects of PTH-induced microRNAs on osteoblasts using a bioinformatic approach.

In this study, we used a bioinformatic approach to construct a miRNA-target gene interaction network potentially involved in the anabolic effect of parathyroid hormone analogue teriparatide [PTH (1-34)] on osteoblasts. We extracted a dataset of 26 microRNAs (miRNAs) from previously published studies and predicted miRNA target interactions (MTIs) using four software tools: DIANA, miRWalk, miRDB, and TargetScan. By constructing an interactome of PTH-regulated miRNAs and their predicted target genes, we elucidated signaling pathways regulating pluripotency of stem cells, the Hippo signaling pathway, and the TGF-beta signaling pathway as the most significant pathways in the effects of PTH on osteoblasts. Furthermore, we constructed intersection of MTI networks for these three pathways and added validated interactions. There are 8 genes present in all three selected pathways and a set of 18 miRNAs are predicted to target these genes, according to literature data. The most important genes in all three pathways were BMPR1A, BMPR2 and SMAD2 having the most interactions with miRNAs. Among these miRNAs, only miR-146a-5p and miR-346 have validated interactions in these pathways and were shown to be important regulators of these pathways. In addition, we also propose miR-551b-5p and miR-338-5p for further experimental validation, as they have been predicted to target important genes in these pathways but none of their target interactions have yet been verified. Our wet-lab experiment on miRNAs differentially expressed between PTH (1-34) treated and untreated mesenchymal stem cells supports miR-186-5p from the literature obtained data as another prominent miRNA. The meticulous selection of miRNAs outlined will significantly support and guide future research aimed at discovering and understanding the crucial pathways of osteoanabolic PTH-epigenetic effects on osteoblasts. Additionally, they hold potential for the discovery of new PTH target genes, innovative biomarkers for the effectiveness and safety of osteoporosis-affected treatment, as well as novel therapeutic targets.

Injective hydrogel loaded with liposomes-encapsulated MY-1 promotes wound healing and increases tensile strength by accelerating fibroblast migration via the PI3K/AKT-Rac1 signaling pathway

Failed skin wound healing, through delayed wound healing or wound dehiscence, is a global public health issue that imposes significant burdens on individuals and society. Although the application of growth factor is an effective method to improve the pace and quality of wound healing, the clinically approved factors are limited. Parathyroid hormone (PTH) demonstrates promising results in wound healing by promoting collagen deposition and cell migration, but its application is limited by potentially inhibitory effects when administered continuously and locally. Through partially replacing and repeating the amino acid domains of PTH(1–34), we previously designed a novel PTH analog, PTH(3–34)(29–34) or MY-1, and found that it avoided the inhibitory effects of PTH while retaining its positive functions. To evaluate its role in wound healing, MY-1 was encapsulated in liposomes and incorporated into the methacryloyl gelatin (GelMA) hydrogel, through which an injectable nanocomposite hydrogel (GelMA–MY@Lipo, or GML) was developed. In vitro studies revealed that the GML had similar properties in terms of the appearance, microstructure, functional groups, swelling, and degradation capacities as the GelMA hydrogel. In vitro drug release testing showed a relatively more sustainable release of MY-1, which was still detectable in vivo 9 days post-application. When the GML was topically applied to the wound areas of rat models, wound closure as well as tensile strength were improved. Further studies showed that the effects of GML on wound repair and tensile strength were closely related to the promotion of fibroblast migration to the wound area through the controlled release of MY-1. Mechanically, MY-1 enhanced fibroblast migration by activating PI3K/AKT signaling and its downstream molecule, Rac1, by which it increased fibroblast aggregation in the early stage and resulting in denser collagen deposition at a later time. Overall, these findings demonstrated that the nanocomposite hydrogel system promoted skin wound healing and increased tensile strength, thus offering new potential in the treatment of wound healing.

The Current Status of Sequential Therapy with Commonly Used Anti-Osteoporosis Drugs

As the trend of population aging intensifies, the incidence of osteoporosis is rising correspondingly. Osteoporotic fractures are one of the primary causes of disability and death in elderly patients, placing a great burden on both families and society in terms of medical care resources. The monotherapy of osteoporosis drugs has certain limitations and sequential drug treatment should be considered under the following circumstances: (i) when bone resorption inhibitors fail to work, have been used for too long, or cause adverse reactions; (ii) when the recommended treatment course of bone formation promoters (such as parathyroid hormone analogues) has ended but the patient's fracture risk remains high and requires continued treatment; (iii) when short-acting drugs such as teriparatide or denosumab need to maintain treatment effects after discontinuation. The sequential therapy of osteoporosis drugs can be categorized according to the mechanism of action into the following schemes: (i) bone formation promoters followed by bone resorption inhibitors; (ii) bone resorption inhibitors followed by bone formation promoters; (iii) different types of bone resorption inhibitors used sequentially; (iv) other sequential drug treatments. Osteoporosis is a progressive disease, and the ageing of the human population cannot be reversed. Therefore, single-drug treatment is unlikely to achieve the goal of long-term disease prevention and control, making the exploration of long-term treatment plans for existing drugs a key aspect of osteoporosis drug treatment.

Bone health in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are prone to reduced bone mineral density and elevated overall fracture risk. Osteopenia affects up to 40% of patients with IBD (high regional variability). Besides disease activity, IBD specialists must consider possible side effects of medication and the presence of associated diseases and extraintestinal manifestations. Osteopenia and osteoporosis remain frequent problems in patients with IBD and are often underestimated because of widely differing screening and treatment practices. Malnutrition, chronic intestinal inflammation and corticosteroid intake are the major pathophysiological factors contributing to osteoporosis. Patients with IBD are screened for osteoporosis using dual-energy X-ray absorptiometry (DXA), which is recommended for all patients with a prolonged disease course of more than three months, with repeated corticosteroid administration, aged >40 years with a high FRAX risk score or aged <40 years with multiple risk factors. From a therapeutic perspective, besides good disease control, vitamin D supplementation and glucocorticoid sparing, several specific osteological options are available: bisphosphonates, receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (denosumab), parathyroid hormone (PTH) analogues and selective estrogen receptor modulators. This review provides an overview of the pathophysiology, diagnosis, prevention and treatment of IBD-associated bone loss.

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.

New forms of resistance to the action of human parathyroid hormone analogues

New forms of resistance to the action of human parathyroid hormone analogues

Advancing bone biology: The mutual promotion of biology and pioneering technologies

&lt;p&gt;Bone is a mineralized tissue that provides fundamental support for body posture and biomechanical forces. Bones have also been meticulously used by humans as fine tools for at least over 25,000 years, perpetually captivating our curiosity and driving exploration into its mysteries. In this perspective, we revisit the milestones in the history of bone biology since the 17&lt;sup&gt;th&lt;/sup&gt; century, and highlighted the transformative impact of pioneering technologies. From macroanatomical observations to microscopic cellular analyses and molecular signaling pathway explorations, each milestone has heralded groundbreaking discoveries. These include the elucidation of Wollf’s Law, the regulatory mechanisms of calcium metabolism (via osteotropic parathyroid hormone analogs and calcitonin), as well as the revelation of critical cell interactions and signaling pathways in bone remodeling. These foundational insights deepen our understanding of bone as an enigmatic and underexplored tissue, but also yield significant clinical advancements. Bone biology stands poised for an explosive expansion of knowledge as we usher in the era of systems biology, propelled by cutting-edge multi-omics approaches, including single cell RNA sequencing (scRNA-seq) and spatial transcriptomics, as well as artificial intelligence. Therefore, challenges and future directions are discussed to navigate the complexities of integrating emerging technologies and to foster interdisciplinary collaborations that will propel bone biology research towards innovative breakthroughs and holistic solutions.&lt;/p&gt;

Biologics: Teriparatide and Newer Anabolics.

The landscape of osteoporosis management has evolved significantly over the years, witnessing a paradigm shift from conventional therapies to the emergence of biologic agents. This chapter delves into the intricate mechanisms, potential applications, and future directions of biologic interventions in osteoporosis care. Biologic agents, with their targeted approach to bone health, have revolutionized the field by offering precision-driven strategies that address the underlying mechanisms of bone fragility. This chapter explores the mechanisms of action of various biologics, including Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) inhibitors, monoclonal antibodies targeting sclerostin, parathyroid hormone (PTH) analogues, and cathepsin K inhibitors. It discusses their potential benefits, limitations, and safety considerations, while shedding light on the promise of combination therapies that merge biologic agents with traditional approaches. Furthermore, the chapter delves into the potential applications of biologic agents in specific patient populations, the role of biomarkers in predicting treatment responses, and the influence of emerging biological targets. It also explores the advancements in novel targets and drug delivery systems that aim to enhance treatment convenience and effectiveness. By tailoring treatments based on patient characteristics and exploring novel therapeutic targets, the chapter envisions a future of precision medicine in osteoporosis care. As research continues to evolve, the chapter anticipates a transformative impact on bone health outcomes, fracture prevention, and overall quality of life for individuals at risk of osteoporosis-related fractures. Through comprehensive insights into the mechanisms, applications, and future directions of biologic agents, this chapter offers a holistic perspective on the evolving landscape of osteoporosis management.

Hypocalcemia in combination with hyperphosphatemia impairs muscle cell differentiation in vitro

PurposeHypoparathyroidism is a rare endocrine disorder characterized by low or absent secretion of parathyroid hormone (PTH), which leads to decreased calcium and increased phosphorus levels in the serum. The diagnosis of hypoparathyroidism is based on the identification of the aforementioned biochemical abnormalities, which may be accompanied by clinical manifestations. Symptoms of hypoparathyroidism, primarily attributed to hypocalcemia, include muscle cramps or spasms, facial, leg, and foot pain, seizures, and tingling in the lips or fingers. The treatment of hypoparathyroidism depends on the severity of symptoms and the underlying pathology. Over the long term, calcium supplements, active vitamin D analogs, and thiazide diuretics may be needed. In fact, in patient cohorts in which optimal disease control still remains elusive, replacement therapy with recombinant parathyroid hormone analogs may be contemplated. Despite the predominantly neuromuscular symptoms of hypoparathyroidism, further effects of parathyroid hormone deficiency at the muscle cell level remain poorly understood. Thus, the aim of our study was to evaluate the effects of hypocalcemia in combination with hyperphosphatemia on muscle cells differentiation in vitro.MethodsC2C12 cells, an in vitro model of muscle cells, were differentiated for 2 or 6 days in the presence of hypocalcemia (CaCl2 0.9 mmol/l) and moderate (PO4 1.4 mmol/l) or severe (PO4 2.9 mmol/l) hyperphosphatemia, or combinations of both conditions. Cell differentiation and expression of genes linked to muscle differentiation were evaluated.ResultsThe combination of hypocalcemia with hyperphosphatemia induced a significant reduction (50%) in differentiation marker levels, such as MyoD (protein 1 for myoblast determination) and myogenin on the 1st day of differentiation, and MHC (myosin heavy chains) after 6 days of differentiation compared to control. Furthermore, this condition induced a statistically significant reduction of insulin-like growth factor-1 (IGF-1) mRNA expression and inhibition of IGF signaling and decrease in ERK phosphorylation compared to control cells.ConclusionsOur results showed that a condition of hypocalcemia with hyperphosphatemia induced an alteration of muscle cell differentiation in vitro. In particular, we observed the reduction of myogenic differentiation markers, IGF-1 signaling pathway, and ERK phosphorylation in differentiated skeletal myoblasts. These data suggest that this altered extracellular condition might contribute to the mechanisms causing persistence of symptoms in patients affected by hypoparathyroidism.

THU450 Looking Beyond The Usual Suspects: A Rare Case Of Teriparatide Induced Gynecomastia

Abstract Disclosure: B.P. Ramchandani: None. F.S. Mirza: None. Introduction: Teriparatide (TP) is a parathyroid hormone analogue used as anabolic therapy for treatment of osteoporosis. Common side effects include nausea, headache and orthostatic hypotension. We hereby describe the first case of gynecomastia that developed shortly after starting treatment with TP, and resolved a couple of months after discontinuation of therapy. Clinical Case: A 61 year old male physician with severe osteoporosis presented to the endocrinology clinic with bilateral nipple tenderness and a firm lump under the left areolar region four months after starting therapy with TP. There was no associated bleeding or nipple discharge. He denied having any erectile dysfunction or decline in sexual function. His medications included vitamin D, lansoprazole and rosuvastatin. Family history was significant for osteoporosis and ductal carcinoma in situ in mother, and bilateral hip fractures after falls in his father at the age of 80. He denied any alcohol or recreational drug use. He was physically active but denied any recent weight loss. Other than the firm glandular tissue under left lateral areola, no other findings including nipple inversion or lymphadenopathy were noted on exam. Laboratory testing showed normal total and free testosterone level at 360 ng/dl and 68 pg/ml respectively, estradiol 39 pg/ml, LH 1.44 mIU/ml, FSH 4.44 mIU/ml, TSH 1.71 uIU/L, Prolactin 4.54 ng/ml and HCG &amp;lt;2 IU/ml, along with normal creatinine and liver enzymes. Mammogram showed left greater than right flame-shaped focal asymmetry contiguous with the nipple compatible with gynecomastia. Breast ultrasound showed left greater than right retroareolar dendritic slightly hypoechoic soft tissue correlating with the mammographic findings. Due to significant discomfort associated with gynecomastia, a decision was made to stop TP and treatment with risedronate was initiated. Following the discontinuation of the drug, the patient reported that his symptoms gradually improved and the nipple sensitivity and the palpable swelling of the left breast completely resolved at his follow up visit four months later. Conclusion: The temporal association between the initiation of teriparatide treatment and onset of gynecomastia, and improvement of the symptoms and physical findings upon discontinuation of the drug suggests that teriparatide was the likely cause of gynecomastia in our patient. Presentation: Thursday, June 15, 2023

Osteogenic Effects of KY-054, a Novel Coumarin Derivative on Femur Cortical Bone in Ovariectomized Female Rats.

Osteoporosis is treated with oral and parenteral bone resorption inhibitors such as bisphosphonates, and parenteral osteogenic drugs including parathyroid hormone (PTH) analogues and anti-sclerostin antibodies. In the present study, we synthesized KY-054, a 4,6-substituted coumarin derivative, and found that it potently promoted osteoblast differentiation with an increase in alkaline phosphatase (ALP) activity at 0.01-1 µM in mouse-derived mesenchymal stem cells (ST2 cells) and rat bone marrow-derived mesenchymal stem cells (BMSCs). In the ovariectomized (OVX) rats, KY-054 (10 mg/kg/d, 8 weeks) increased plasma bone-type ALP activity, suggesting in vivo promoting effects on osteoblast differentiation and/or activation. In dual-energy X-ray absorption (DEXA) scanning, KY-054 significantly increased the distal and diaphyseal femurs areal bone mineral density (aBMD) that was decreased by ovariectomy, indicating its beneficial effects on bone mineral contents (BMC) and/or bone volume (BV). In micro-computed tomography (micro-CT) scanning, KY-054 had no effect on metaphysis trabecular bone loss and microarchitecture parameters weakened by ovariectomy, but instead increased metaphysis and diaphysis cortical bone volume (Ct.BV) and cortical BMC (Ct.BMC) without reducing medullary volume (Med.V), resulting in increased bone strength parameters. It is concluded that KY-054 preferentially promotes metaphysis and diaphysis cortical bone osteogenesis with little effect on metaphysis trabecular bone resorption, and is a potential orally active osteogenic anti-osteoporosis drug candidate.

Osteoporosis management in primary care.

Osteoporosis is the most prevalent bone disease in the US. Once diagnosed, osteoporosis requires ongoing management; therefore, primary care providers are vital in managing both primary and secondary fracture prevention. Safe, efficacious, and economical medications are available, but osteoporosis remains underdiagnosed and undertreated. Bisphosphonates, selective estrogen receptor modulators (raloxifene), conjugated estrogens/bazedoxifene, estrogen therapy/hormone therapy, parathyroid hormone analogues, RANK ligand inhibitors (denosumab), sclerostin inhibitors (romosozumab), and calcitonin are all drugs or drug classes commonly used to treat osteoporosis that are discussed in this article.

The Risk of Developing Osteosarcoma After Teriparatide Use: A Systematic Review.

Teriparatide is a recombinant human parathyroid hormone analog with anabolic mechanism of action utilized in the treatment of osteoporosis with well-established clinical efficacy. Its use is significantly hindered due to label warnings resulting from pre-clinical rat studies demonstrating an increased risk of osteosarcoma. However, clinical trials and post-marketing surveillance studies did not demonstrate any increased risk of osteosarcoma, even after prolonged periods of surveillance reaching up to 15 years, with most of the identified cases of osteosarcomas being solitary and predominantly attributed to other factors. This systematic review provides a comprehensive overview of the currently available literature and provides the highest level of clinical evidence towards demonstrating the lack of any substantial evidence towards osteosarcoma development in patients utilizing TPTD.

Human Parathyroid Hormone Analog (3–34/29–34) promotes wound re-epithelialization through inducing keratinocyte migration and epithelial–mesenchymal transition via PTHR1-PI3K/AKT activation

BackgroundRe-epithelialization is important in the process of wound healing. Various methods have been identified to expedite the process, but their clinical application remains limited. While parathyroid hormone (PTH) has shown promising results in wound healing due to its role in promoting collagen deposition and cell migration, application is limited by its potentially inhibitive effects when being continuously and locally administrated. Herein, we developed a novel PTH analog, Human parathyroid hormone (hPTH) (3–34/29–34) (henceforth MY-1), by partially replacing and repeating the amino acid sequences of hPTH (1–34), and evaluated its effect on skin wound re-epithelialization.MethodsCCK-8, colony formation unit assay, and Ki67 immunofluorescent staining were performed to evaluate the effect of MY-1 on HaCaT cell proliferation. Then, wound scratch assay, Transwell assay and lamellipodia staining were carried out to evaluate the effect of MY-1 on cell migration. Moreover, the epithelial–mesenchymal transition (EMT) markers were measured using qPCR and western blot analysis. For in-vivo drug delivery, gelatin methacryloyl (GelMA) hydrogel was employed to load the MY-1, with the physicochemical characteristics evaluated prior to its application in wound models. Then, MY-1’s role in wound healing was determined via acute skin wound models. Finally, the mechanism that MY-1 activated was also detected on HaCaT cells and in-vivo wound models.ResultsIn-vitro, MY-1 accelerated the migration and EMT of HaCaT cells, while having little effect on cell proliferation. GelMA and MY-1-incorporated GelMA hydrogels showed similar physicochemical characteristics and were used in the in-vivo studies, where the results revealed that MY-1 led to a stronger re-epithelialization by inducing basal keratinocyte migration and EMT. Further studies on in-vivo wound models and in-vitro HaCaT cells revealed that MY-1 regulated cell migration and EMT through activating PI3K/AKT signaling. The parathyroid hormone type 1 receptor (PTHR1), the main receptor of PTH, was found to be the upstream of PI3K/AKT signaling, through interfering PTHR1 expression with a small interference RNA following detection of the PI3K/AKT activation.ConclusionCollectively, our study demonstrated that MY-1 accelerates skin wound re-epithelialization by inducing keratinocyte migration and EMT via PTHR1-PI3K/AKT axis activation.8WeJxjiMKQ-SAupiANbiq5Video

Do peri-operative parathyroid hormone (PTH) analogues improve bone density and decrease mechanical complications in spinal deformity correction?—a minimum 2-year radiological study measuring Hounsfield units

ObjectiveTo delineate whether use of a PTH analogue in the 1-year peri-operative period improves lumbar bone density.MethodsA prospectively collected data registry of 254 patients who underwent CMIS correction of ASD (Cobb angle > 20 or SVA > 50 mm or (PI-LL) > 10) from Jan 2011 to Jan 2020 was analysed. Patients who were placed on PTH analogues for one year in conjunction with surgery were included in the study. Ultimately, 41 patients who had pre- and two-year post-operative CT scans for review were included in this study. Hounsfield units were measured off of the L1–L3 levels for all patients before and after surgery on pre-op and post-op CT scans.ResultThe mean age of patients in this study was 70 (52–84, SD 7). Mean follow-up was 66 (24–132, SD 33) months. Twenty-three patients met criteria for severe deformity (Cobb angle > 50 degrees or SVA > 95 mm or PI/LL mismatch > 20 or PT > 30). Based off 2-year post-op CT scan, there were significant improvements in L1 Hounsfield units when comparing pre-op values (96; SD 55) to post-op values (185 SD 102); p. < 0.05. There was no screw loosening or screw pull out. There were 2 patients with PJF (4.8%). Both these patients had not completed their PTH treatment: one only took PTH for 3 months (PJF at 2-year post-op) and the other one took it only for 1 month (PJF at 1-year post-op). No increase in bone density was noted (based off of Hounsfield units) in five patients (12%) despite completion of their PTH therapy. Only one patient experienced nausea from PTH therapy. There were no other PTH related adverse events.ConclusionThe incidence of PTH analogues failing to increase bone density in our series was low at 12%. This study shows that PTH analogues may be a powerful adjunct for increasing bone density and may help to mitigate the risk of mechanical complications in patients undergoing deformity correction with minimally invasive techniques. Future comparative studies are warranted to confirm these latter findings and to potentially protocolize the ideal peri-operative bone health optimization strategy.

Abstract #1377932: An Inherited Metabolic Disorder That Masquerades as Osteoporosis

Hypophosphatasia is a rare genetic disorder caused by loss-of-function mutations in the ALPL gene, which encodes tissue non-specific alkaline phosphatase. The enzyme defect results in the accumulation of substrates like inorganic pyrophosphate, thereby inhibiting mineralization of bones and teeth. Clinical features include premature loss of deciduous teeth, bowed legs, lower extremity stress fractures, bone pain and impaired mobility. Serum alkaline phosphatase (ALP) is a marker of bone turnover. Low ALP, high serum vitamin B6 and high urine phosphoethanolamine are diagnostic hallmarks of hypophosphatasia. A 54-year-old lady was referred to the endocrinology clinic for severe osteoporosis, characterized by an olecranon fracture and low bone mineral density (T score -3.0 at the left femoral neck). Bone disease risk factors included premature menopause at age 38 years and maternal history of hip fracture. There was no personal or family history of recurrent fractures, impaired mobility, or unexplained tooth loss. Despite treatment with ibandronate, zoledronic acid and teriparatide, her bone mineral density declined over the course of a decade. Physical examination revealed low BMI (18.07 kg/m2), normal gait and intact muscle strength. Lab testing disclosed low serum alkaline phosphatase (ALP) 18 units/L [reference 45 to 117 units/L], high serum vitamin B6 131.8 nmol/L [reference 20.0 to 125.0 nmol/L] and high urine phosphoethanolamine 104 nmol/mg Cr [reference < 48]. ALP results prior to bisphosphonate exposure were unavailable. Vitamin D status, thyroid function, parathyroid hormone, corrected serum calcium, ceruloplasmin and zinc levels were normal. Exome sequencing identified a pathogenic heterozygous nonsense ALPL gene mutation, c.1282C >T (p.Arg428X). She was counselled to avoid bisphosphonate therapy indefinitely. ALP measurement was advised for her blood relatives since hypophosphatasia is an autosomal recessive or dominant disorder. With asfotase alfa, the only FDA-approved therapy for juvenile-onset hypophosphatasia, there have been no further fractures to date, and her mobility remains unimpaired. Hypophosphatasia can be mistaken for osteoporosis since both conditions present with low bone mineral density on DEXA scan. Furthermore, bisphosphonate therapy and hypophosphatasia are mutually exclusive entities that can present with low ALP. Thus, bisphosphonate exposure may pose a diagnostic quandary when distinguishing between osteoporosis and hypophosphatasia. This case highlights the importance of assessing ALP when evaluating osteoporosis with atypical features such as age of onset under fifty years, remarkably low bone mineral density, fracture(s), and inadequate response to anti-osteoporosis agents. Moreover, if ALP is low, some index of suspicion for hypophosphatasia ought to be maintained, even if dental or lower extremity bone symptoms are absent. Genetic testing is confirmatory. Bisphosphonate therapy and parathyroid hormone analogs are not established treatment modalities for hypophosphatasia. Instead, enzyme replacement with asfotase alfa is recommended.