PURPOSE: Here, we evaluate a PET displacement model with a Single-step and Numerical solution in healthy individuals using the synaptic vesicle glycoprotein (SV2A) PET-tracer [11C]UCB-J and the anti-seizure medication levetiracetam (LEV). We aimed to (1) validate the displacement model by comparing the brain LEV-SV2A occupancy from a single PET scan with the occupancy derived from two PET scans and the Lassen plot and (2) determine the plasma LEV concentration-SV2A occupancy curve in healthy individuals. METHODS: Eleven healthy individuals (five females, mean age 35.5 [range: 25-47] years) underwent two 120-min [11C]UCB-J PET scans where an LEV dose (5-30 mg/kg) was administered intravenously halfway through the first PET scan to partially displace radioligand binding to SV2A. Five individuals were scanned twice on the same day; the remaining six were scanned once on two separate days, receiving two identical LEV doses. Arterial blood samples were acquired to determine the arterial input function and plasma LEV concentrations. Using the displacement model, the SV2A-LEV target engagement was calculated and compared with the Lassen plot method. The resulting data were fitted with a single-site binding model. RESULTS: SV2A occupancies and VND estimates derived from the displacement model were not significantly different from the Lassen plot (p = 0.55 and 0.13, respectively). The coefficient of variation was 14.6% vs. 17.3% for the Numerical and the Single-step solution in Bland-Altman comparisons with the Lassen plot. The average half maximal inhibitory concentration (IC50), as estimated from the area under the curve of the plasma LEV concentration, was 12.5 µg/mL (95% CI: 5-25) for the Single-Step solution, 11.8 µg/mL (95% CI: 4-25) for the Numerical solution, and 6.3 µg/mL (95% CI: 0.08-21) for the Lassen plot. Constraining Emax to 100% did not significantly improve model fits. CONCLUSION: Plasma LEV concentration vs. SV2A occupancy can be determined in humans using a single PET scan displacement model. The average concentration of the three computed IC50 values ranges between 6.3 and 12.5 µg/mL. The next step is to use the displacement model to evaluate LEV occupancy and corresponding plasma concentrations in relation to treatment efficacy. CLINICAL TRIAL REGISTRATION: NCT05450822. Retrospectively registered 5 July 2022 https://clinicaltrials.gov/ct2/results? term=NCT05450822&Search=Search.
PURPOSE: The purpose of the study was to assess the changes in flexibility during night-time bracing in skeletally immature adolescent idiopathic scoliosis (AIS) with curves in the surgical range. MATERIALS AND METHODS: We included a consecutive cohort of 89 AIS patients with curves ≥ 45° and an estimated growth potential. All patients were eventually treated with fusion surgery, and all patients had side-bending radiographs prior to both bracing and surgery. Curves were classified as structural or non-structural curves according to Lenke at both timepoints. RESULTS: The main curve progressed by a mean of 12 ± 10° and the secondary curve by 8 ± 8°. Flexibility of the main curve decreased from 50 ± 19% to 44 ± 19% (p = 0.001) and the underlying curve from 85 ± 21% to 77 ± 22% (p = 0.005). In 69 patients (79%), the Lenke category did not progress during bracing. In 14 patients (15%), the progression in Lenke type occurred in the thoracic region (i.e., Lenke type 1 to type 2), while six patients (7%) progressed in the lumbar region (i.e., type 1 to type 3). In the 69 patients that did not progress, we found that the last touched vertebra moved distally by one or two levels in 26 patients. CONCLUSIONS: This is the first study to describe that curve flexibility decreases during bracing in severe AIS. However, this had only a modest impact on the surgical strategy. Bracing as a holding strategy can be applied, but the risk of losing flexibility in the lumbar spine should be outweighed against the risks of premature fusion surgery.
Raman spectroscopy provides non-destructive, label-free quantitative studies of chemical compositions at the microscale as used on NASA's Perseverance rover on Mars. Such capabilities come at the cost of high requirements for instrumentation. Here we present a centimeter-scale miniaturization of a Raman spectrometer using cheap non-stabilized laser diodes, densely packed optics, and non-cooled small sensors. The performance is comparable with expensive bulky research-grade Raman systems. It has excellent sensitivity, low power consumption, perfect wavenumber, intensity calibration, and 7 cm-1 resolution within the 400-4000 cm-1 range using a built-in reference. High performance and versatility are demonstrated in use cases including quantification of methanol in beverages, in-vivo Raman measurements of human skin, fermentation monitoring, chemical Raman mapping at sub-micrometer resolution, quantitative SERS mapping of the anti-cancer drug methotrexate and in-vitro bacteria identification. We foresee that the miniaturization will allow realization of super-compact Raman spectrometers for integration in smartphones and medical devices, democratizing Raman technology.
Background: Reliable animal models are critical for preclinical research and should closely mimic the disease. With respect to route of infection, pathogenic agent, disease progression, clinical signs, and histopathological changes. Sheep have similar bone micro- and macrostructure as well as comparable biomechanical characteristics to humans. Their use in bone research is established, however their use in bone infection research is limited. This systematic review will summarise the key features of the available bone infection models using sheep, providing a reference for further development, validation, and application. Method: This systematic review was designed according to the PRISMA guidelines and registered with PROSPERO. Quality was assessed using SYRICLE's risk of bias tool adapted for animal studies. PubMed, MEDLINE, Web of Science and EMBASE were searched until March 2022.1921 articles were screened by two independent reviewers, and 25 were included for analysis. Results: Models have been developed in nine different breeds. Staphylococcus aureus was used in the majority of models, typically inoculating 108 colony forming units in tibial or femoral cortical defects. Infection was established with either planktonic or biofilm adherent bacteria, with or without foreign material implanted. Most studies used both radiological and microbiological analyses to confirm osteomyelitis. Conclusions: There is convincing evidence supporting the use of sheep in bone infection models of clinical disease. The majority of sheep studied demonstrated convincing osteomyelitis and tolerated the infection with minimal complications. Furthermore, the advantages of comparable biology and biomechanics may increase the success for translating in vivo results to successful therapies. The Translational potential of this article: In the realm of preclinical research, the translation to viable clinical therapies is often perilous, and the quest for reliable and representative animal models remains paramount. This systematic review accentuates the largely untapped potential of sheep as large animal models, especially in bone infection research. The anatomical and biomechanical parallels between sheep and human bone structures position sheep as an invaluable asset for studying osteomyelitis and periprosthetic joint infection. This comprehensive exploration of the literature demonstrates the robustness and translational promise of these models. Furthermore, this article underscores the potential applicability for sheep in developing effective therapeutic strategies for human bone infections.
Optimal sampling, preservation, and culturing of SARS-CoV-2 from COVID-19 patients are critical for successful recovery of virus isolates and to accurately estimate contagiousness of the patient. In this study, we investigated the influence of the type of sampling media, storage time, freezing conditions, sterile filtration, and combinations of these to determine the optimal pre-analytic conditions for virus recovery and estimation of infectious viral load in COVID-19 patients. Further, we investigated the viral shedding kinetics and mucosal antibody response in 38 COVID-19 hospitalized patients. We found Universal Transport Medium (Copan) to be the most optimal medium for preservation of SARS-CoV-2 infectivity. Our data showed that the probability of a positive viral culture was strongly correlated to Ct values, however some samples did not follow the general trend. We found a significant correlation between plaque forming units and levels of mucosal antibodies and found that high levels of mucosal antibodies correlated with reduced chance of isolating the virus. Our data reveals essential parameters to consider from specimen collection over storage to culturing technique for optimal chance of isolating SARS-CoV-2 and accurately estimating patient contagiousness.
COVID-19 , SARS-CoV-2 , Humans , COVID-19/diagnosis , Viral Load , COVID-19 Testing , Specimen Handling/methods , RNA, Viral
PURPOSE: Adolescent idiopathic scoliosis (AIS) is characterized by coronal scoliosis and often a sagittal hypokyphosis. The effect of bracing on the sagittal profile is not well understood. The aim of this study is to assess the effect of night-time bracing on the sagittal profile in patients with AIS. METHODS: We retrospectively included AIS patients with a main curve of 25-45° treated with a night-time brace in our institution between 2005 and 2018. Patients with estimated growth potential based on either Risser stage, hand X-rays, or menarchal status were included. Coronal and sagittal radiographic parameters were recorded at both brace- initiation and -termination. Patients were followed until surgery or one year after brace termination. Results were compared to a published cohort of full-time braced patients. RESULTS: One hundred forty-six patients were included. Maximum thoracic kyphosis (TK) increased 2.5° (± 9.7) (p = 0.003), corresponding to a 3.5-fold relative risk increase post bracing in TK compared to a full-time brace cohort. Twenty-seven percent (n = 36) of the patients were hypokyphotic (T4/T12 < 20°) at brace initiation compared with 19% (n = 26) at brace termination (p = 0.134). All other sagittal parameters remained the same at follow-up. We found no association between progression in the coronal plane and change in sagittal parameters. CONCLUSION: This is the first study to indicate that night-time bracing of AIS does not induce hypokyphosis. We found a small increase in TK, with a substantially lower risk of developing flat back deformity compared to full-time bracing. The coronal curve progression was not coupled to a change in TK.
Kyphosis , Scoliosis , Humans , Adolescent , Scoliosis/therapy , Scoliosis/surgery , Retrospective Studies , Kyphosis/diagnostic imaging , Braces , Radiography , Treatment Outcome
In this forensic case report, we present autopsy findings from a young male in his thirties who had been self-injecting paraffin oil into his upper extremities 8 years prior to death. The injections induced an inflammatory response, leading to granuloma formation. This, in turn, resulted in severe hypercalcemia. The external autopsy examination revealed gross macroscopic ulcerations and enlargement of upper extremities, while calcifications of ligaments, heart, kidneys and dura mater was revealed on postmortem CT-scans. Histopathological examination showed extensive multiorgan metastatic calcifications in several tissues including the lungs, heart and kidney. Cause of death was estimated to be the extensive calcific deposits in the heart likely resulting in cardiac arrest. To our knowledge this is the first case reporting findings from an autopsy in which the cause of death was linked to cosmetic oil injections.
Background: Arteriovenous (AV) grafts often develop severe complications of stenosis due to neointimal proliferation that occurs either at the venous anastomosis site or at the outflow receiving vein. This study compares primary patency during 12 months of follow up for a new experimental Biomodics© interpenetrating polymer network (IPN) drug-eluting graft prototype with state-of-the-art GORE® ACUSEAL (ACUSEAL) in an AV graft model in sheep. Methods and results: An end-to-end bypass from the common carotid artery to the jugularis vein was performed bilaterally in 12 sheep. The usage of ACUSEAL or the IPN, both 6.0â mm in diameter, was determined via randomization. The sheep were followed up every 4 weeks with ultrasonic duplex scanning to determine patency; the experienced observer was blinded to the randomization. One sheep died after 11 days, and the final sample accordingly consisted of 11 animals. When comparing neointimal hyperplasia after 12 months in the two grafts, Fisher's exact test showed a significant difference with none out of 11 in the IPN grafts and 9 out of 11 in the ACUSEAL graft (p < 0.001). However, the Biomodics© IPN exhibited severe deterioration over time. Conclusions: Almost all of the grafts occluded during the 12 months of follow up. Although the zwitterion-bounded interpenetrating drug eluting polymer network showed signs to impair neointimal hyperplasia and thrombosis, age-related degeneration hindered demonstrating a potential improvement in patency.
Objective: The objective of this study is to characterize bladder mucosal trauma associated with intermittent catheterization with conventional eyelet catheters (CECs) and to assess if a microhole zone catheter (MHZC) design concept reduces this adverse effect. Materials and Methods: A porcine model was developed to reflect human catheterization and bladder drainage. Nine pigs were randomized for catheterization with CEC (n = 6) or MHZC (n = 3). The bladder was drained repeatedly 20 times through the catheter. Cystoscopy was performed before and after the procedure, and bladders were analysed by histopathology. Two additional pigs were used for cystoscopy visualization of suction events in vivo. Cystoscopy, gross pathology, histopathological score, leucocyte infiltration, and intracatheter pressure at flow stops during voiding were compared for each group. Results: A significant higher pressure gradient was measured inside the CECs compared with MHZCs during flow stop. Consequently, CECs resulted in suction events inflicting bladder trauma characterized by loss of epithelium, oedema, haemorrhage, and neutrophil tissue infiltration. No significant trauma was identified when using MHZC. Conclusions: Considerable mucosal bladder trauma is inflicted by CECs which may be an overlooked risk factor for urinary tract infection. Catheters can be designed to minimize mucosal suction and reduce associated trauma. This may be a solution to reduce infection frequency and increase user comfort. Furthermore, the study demonstrates the potential of pigs as an attractive animal model for investigating urinary catheter performances.
BACKGROUND AND PURPOSE: The efficacy of bracing larger curves in adolescent idiopathic scoliosis (AIS) patients is uncertain. We aimed to assess the influence of night-time bracing in AIS patients with main curves exceeding 40° Cobb angle at brace initiation. METHODS: We reviewed AIS patients treated with nighttime braces between 2005 and 2018. Patients with curves ≥ 25° and estimated growth potential were included. Patients were monitored with radiographs from brace initiation until brace weaning at skeletal maturity. Patients were grouped based on curve magnitude at initial evaluation: a control group (25-39°) and a large-curves group (≥ 40°). Progression was defined as > 5° increase. RESULTS: We included 299 patients (control group, n = 125; large-curves group, n = 174). In the control group, 65 (52%) patients progressed compared with 101 (58%) in the large-curves group (P = 0.3). The lower-end vertebra (LEV) shifted distally post-bracing in 41 (23%) patients in the largecurves group. Patients with progressive large curves were younger (age 13.2 [SD 1.5] vs. 13.9 [SD 1.1], P = 0.009) and more premenarchal (n = 36 [42%] vs. n = 6 [9%], P < 0.001) compared with non-progressive large curves. CONCLUSION: Progression risk in patients with curves exceeding 40° treated with night-time bracing is similar to smaller curves. The LEV moved distally in almost one-fourth of the larger curves, possibly affecting fusion levels in cases of surgery.
Kyphosis , Scoliosis , Humans , Adolescent , Scoliosis/diagnostic imaging , Scoliosis/therapy , Spine , Radiography , Braces , Disease Progression , Retrospective Studies , Treatment Outcome
Catheterisation of the urinary bladder is needed in many types of human disease models in pigs. Based on our extensive experience with the pig as an infection model, we here demonstrate an approach of catheterising domestic pigs (40 attempts) and Göttingen minipigs (10 attempts) using a blinded method, that is, without speculums or videoscopes to visualise the urethral opening. The procedure was tested on control animals and pigs with experimental Escherichia coli urinary tract infection (UTI) to assess the potential influence of this condition on procedural outcome. Lastly, we performed cystoscopy in three animals to visualise the route to the urethra and to localise potential anatomical obstacles. All domestic pigs were catheterised successfully in an average of 2 minutes and 23 seconds, and this was not influenced by UTI (p = 0.06) or bladder urine content at the time of catheterisation (p = 0.32). All Göttingen minipigs were successfully catheterised in an average of 4 minutes and 27 seconds. We conclude that blinded catheterisation is a fast and reliable approach that can be performed in pigs with or without UTI with minimal risk of trauma or contamination.
Herein, we report the hit-to-lead identification of a drug-like pleuromutilin conjugate 16, based on a triaromatic hit reported in 2020. The lead arose as the clear candidate from a hit-optimization campaign in which Gram-positive antibacterial activity, solubility, and P-gp affinity were optimized. Conjugate 16 was extensively evaluated for its in vitro ADMET performance which, apart from solubility, was overall on par with lefamulin. This evaluation included Caco-2 cell permeability, plasma protein binding, hERG inhibition, cytotoxicity, metabolism in microsomes and CYP3A4, resistance induction, and time-kill kinetics. Intravenous pharmacokinetics of 16 proved satisfactory in both mice and pigs; however, oral bioavailability was limited likely due to insufficient solubility. The in vivo efficacy was evaluated in mice, systemically infected with Staphylococcus aureus, where 16 showed rapid reduction in blood bacteriaemia. Through our comprehensive studies, lead 16 has emerged as a highly promising and safe antibiotic candidate for the treatment of Gram-positive bacterial infections.
Diterpenes , Polycyclic Compounds , Staphylococcal Infections , Humans , Animals , Mice , Swine , Pleuromutilins , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacokinetics , Caco-2 Cells , Diterpenes/pharmacology , Diterpenes/therapeutic use , Staphylococcal Infections/drug therapy , Biological Availability , Polycyclic Compounds/pharmacology , Microbial Sensitivity Tests
Osteon morphology provides valuable information about the interplay between different processes involved in bone remodelling. The correct quantitative interpretation of these morphological features is challenging due to the complexity of interactions between osteoblast behaviour, and the evolving geometry of cortical pores during pore closing. We present a combined experimental and mathematical modelling study to provide insights into bone formation mechanisms during cortical bone remodelling based on histological cross-sections of quiescent human osteons and hypothesis-testing analyses. We introduce wall thickness asymmetry as a measure of the local asymmetry of bone formation within an osteon and examine the frequency distribution of wall thickness asymmetry in cortical osteons from human iliac crest bone samples from women 16-78 years old. Our measurements show that most osteons possess some degree of asymmetry, and that the average degree of osteon asymmetry in cortical bone evolves with age. We then propose a comprehensive mathematical model of cortical pore filling that includes osteoblast secretory activity, osteoblast elimination, osteoblast embedment as osteocytes, and osteoblast crowding and redistribution along the bone surface. The mathematical model is first calibrated to symmetric osteon data, and then used to test three mechanisms of asymmetric wall formation against osteon data: (i) delays in the onset of infilling around the cement line; (ii) heterogeneous osteoblastogenesis around the bone perimeter; and (iii) heterogeneous osteoblast secretory rate around the bone perimeter. Our results suggest that wall thickness asymmetry due to off-centred Haversian pores within osteons, and that nonuniform lamellar thicknesses within osteons are important morphological features that can indicate the prevalence of specific asymmetry-generating mechanisms. This has significant implications for the study of disruptions of bone formation as it could indicate what biological bone formation processes may become disrupted with age or disease.
Haversian System , Osteoblasts , Humans , Female , Adolescent , Young Adult , Adult , Middle Aged , Aged , Haversian System/anatomy & histology , Bone and Bones , Osteocytes , Cortical Bone
Multiple Myeloma (MM) is the second most common hematological malignancy and is characterized by clonal expansion of malignant plasma cells in the bone marrow. In spite of recent advances in the field of MM, the disease has remained incurable. MM is preceded by a premalignant state known as monoclonal gammopathy of undetermined significance (MGUS), with a risk of progression to MM of 1% per year. Establishing a scalable approach that refines the identification of MGUS patients at high risk of progression to MM can transform the clinical management of the disease, improve the patient's quality of life, and will have significant socioeconomic implications. Here, we provide evidence that changes in the bone marrow adipose tissue (BMAT) provide an early sign for progression from MGUS to MM. We employed AI-assisted histological analysis of unstained bone marrow biopsies from MGUS subjects with or without progression to MM within 10 years (n = 24, n = 17 respectively). Although the BMAT fraction was not different between the two groups, bone marrow adipocyte (BMAd) density was decreased in MGUS patients who developed MM, compared to non-progressing MGUS patients. Importantly, the distribution profile for BMAd size and roundness was significantly different between the two groups, indicating a shift toward increased BMAd size and roundness in MGUS patients who developed MM. These early changes in the BMAT could serve as valuable early indicators for the transition from MGUS to MM, potentially enabling timely interventions and personalized treatment strategies. Finally, the AI-based approach for histological characterization of unstained bone marrow biopsies is cost-effective and fast, rendering its clinical implementation feasible.
Monoclonal Gammopathy of Undetermined Significance , Multiple Myeloma , Humans , Multiple Myeloma/diagnosis , Multiple Myeloma/pathology , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Monoclonal Gammopathy of Undetermined Significance/pathology , Bone Marrow/pathology , Quality of Life , Adipocytes/pathology , Disease Progression
Urinary tract infections (UTIs) are the main complication associated with clean intermittent catheterization (CIC) and are facilitated by post-void residual urine and trauma to the mucosa during voiding. The risk of UTI may be diminished by reducing the residual volumes and preventing microtrauma caused by mucosal suction through the eyelets of conventional eyelet catheters (CEC). A new micro-hole zone catheter (MHZC) was developed and tested in an ex vivo porcine lower urinary tract model and in vivo, in pigs, against a CEC. It was shown that, irrespective of the micro-hole diameter, the new catheter ensured increased flowrates and significantly lower residual volumes at the first flow-stop. Furthermore, with a micro-hole diameter of 0.4 mm, mucosal suction was virtually eliminated, regardless of the insertion depth or simulated intra-abdominal pressure mimicking sitting or standing humans. Pressure profile experiments and endoscopy studies indicated that the bladder gradually folds against the drainage tip of the new catheter, without blocking the flow, and, unlike with the CEC, sharp pressure variations and flow-stops did not occur during voiding. The MHZC outperformed the CEC in all tested scenarios and decreased residual volumes, thus potentially decreasing the risk of UTIs.
Intermittent Urethral Catheterization , Urinary Retention , Urinary Tract Infections , Humans , Animals , Swine , Urinary Bladder , Urinary Tract Infections/prevention & control , Urinary Tract Infections/etiology , Intermittent Urethral Catheterization/adverse effects , Catheters/adverse effects
PURPOSE: New total-body PET scanners with a long axial field of view (LAFOV) allow for higher temporal resolution due to higher sensitivity, which facilitates perfusion estimation by model-free deconvolution. Fundamental tracer kinetic theory predicts that perfusion can be estimated for all tracers despite their different fates given sufficiently high temporal resolution of 1 s or better, bypassing the need for compartment modelling. The aim of this study was to investigate whether brain perfusion could be estimated using model-free Tikhonov generalized deconvolution for five different PET tracers, [15O]H2O, [11C]PIB, [18F]FE-PE2I, [18F]FDG and [18F]FET. To our knowledge, this is the first example of a general model-free approach to estimate cerebral blood flow (CBF) from PET data. METHODS: Twenty-five patients underwent dynamic LAFOV PET scanning (Siemens, Quadra). PET images were reconstructed with an isotropic voxel resolution of 1.65 mm3. Time framing was 40 × 1 s during bolus passage followed by increasing framing up to 60 min. AIF was obtained from the descending aorta. Both voxel- and region-based calculations of perfusion in the thalamus were performed using the Tikhonov method. The residue impulse response function was used to estimate the extraction fraction of tracer leakage across the blood-brain barrier. RESULTS: CBF ranged from 37 to 69 mL blood min-1 100 mL of tissue-1 in the thalamus. Voxelwise calculation of CBF resulted in CBF maps in the physiologically normal range. The extraction fractions of [15O]H2O, [18F]FE-PE2I, [11C]PIB, [18F]FDG and [18F]FET in the thalamus were 0.95, 0.78, 0.62, 0.19 and 0.03, respectively. CONCLUSION: The high temporal resolution and sensitivity associated with LAFOV PET scanners allow for noninvasive perfusion estimation of multiple tracers. The method provides an estimation of the residue impulse response function, from which the fate of the tracer can be studied, including the extraction fraction, influx constant, volume of distribution and transit time distribution, providing detailed physiological insight into normal and pathologic tissue.
Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Humans , Positron-Emission Tomography/methods , Fluorodeoxyglucose F18 , Brain/diagnostic imaging , Perfusion
Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a multi-faceted treatment approach with medication, surgery, and radiation. The established treatments with intravenous or subcutaneous antiresorptives can cause debilitating adverse events for patients, mainly osteonecrosis of the jaw, which, traditionally, has been difficult to manage. Now, oral surgery is recommended and proven successful in 60-85% of patients. Patients with spinal involvement may benefit from surgery in the form of vertebroplasty and kyphoplasty for pain relief, improved mobility, and reestablished sagittal balance, as well as the restoration of vertebral height. These procedures are considered safe, but the full therapeutic impact needs to be investigated further. Ixazomib, the first oral proteasome inhibitor, increases osteoblast differentiation, and recently published preliminary results in patients treated with Ixazomib maintenance have promisingly shown increased trabecular volume caused by prolonged bone formation activity. Other novel potential treatment strategies are discussed as well.
In hypoparathyroidism, lack of parathyroid hormone (PTH) leads to low calcium levels and decreased bone remodeling. Treatment with recombinant human PTH (rhPTH) may normalize bone turnover. This study aimed to investigate whether rhPTH(1-84) continued to activate intracortical bone remodeling after 30 months and promoted the transition from erosion to formation and whether this effect was transitory when rhPTH(1-84) was discontinued. Cortical histomorphometry was performed on 60 bone biopsies from patients (aged 31 to 78 years) with chronic hypoparathyroidism randomized to either 100 µg rhPTH(1-84) a day (n = 21) (PTH) or similar placebo (n = 21) (PLB) for 6 months as add-on to conventional therapy. This was followed by an open-label extension, where patients extended their rhPTH(1-84) (PTH) (n = 5), continued conventional treatment (CON) (n = 5), or withdrew from rhPTH(1-84) and resumed conventional therapy (PTHw) for an additional 24 months (n = 8). Bone biopsies were collected at months 6 (n = 42) and 30 (n = 18). After 6 and 30 months, the overall cortical microarchitecture (cortical porosity, thickness, pore density, and mean pore diameter) in the PTH group did not differ from that of the PLB/CON and PTHw groups. Still, the PTH group had a significantly and persistently higher percentage of pores undergoing remodeling than the PLB/CON groups. A significantly higher percentage of these pores was undergoing bone formation in the PTH compared with the PLB/CON groups, whereas the percentage of pores with erosion only was not different. This resulted in a shift in the ratio between formative and eroded pores, reflecting a faster transition from erosion to formation in the PTH-treated patients. In the rhPTH(1-84) withdrawal group PTHw, the latter effects of PTH were completely reversed in comparison to those of the PLB/CON groups. In conclusion, rhPTH(1-84) replacement therapy in hypoparathyroidism patients promotes intracortical remodeling and its transition from erosion to formation without affecting the overall cortical microstructure. The effect persists for at least 30 months and is reversible when treatment is withdrawn. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
