Development of a First-in-Class Unimolecular Dual GIP/GLP-2 Analogue, GL-0001, for the Treatment of Bone Fragility.

Due to aging of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone extracellular matrix (ECM) material properties, i.e., the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-2 (GIP/GLP-2) analogue, GL-0001, that activates simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cyclic adenosine monophosphate-lysyl oxidase pathway to enhance collagen maturity. Furthermore, bilateral ovariectomy was performed in 32 BALB/c mice at 12 weeks of age prior to random allocation to either saline, dual GIP/GLP-2 analogues (GL-0001 or GL-0007) or zoledronic acid groups (n = 8/group). Treatment with dual GIP/GLP-2 analogues was initiated 4 weeks later for 8 weeks. At the organ level, GL-0001 modified biomechanical parameters by increasing ultimate load, postyield displacement, and energy-to-fracture of cortical bone. GL-0001 also prevented excess trabecular bone degradation at the appendicular skeleton and enhanced bone ECM material properties in cortical bone through a reduction of the mineral-to-matrix ratio and augmentation in enzymatic collagen cross-linking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering from bone fragility. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

[Gly²]-GLP-2, But Not Glucagon or [D-Ala²]-GLP-1, Controls Collagen Crosslinking in Murine Osteoblast Cultures.

Bone tissue is organized at the molecular level to resist fracture with the minimum of bone material. This implies that several modifications of the extracellular matrix, including enzymatic collagen crosslinking, take place. We previously highlighted the role of several gut hormones in enhancing collagen maturity and bone strength. The present study investigated the effect of proglucagon-derived peptides on osteoblast-mediated collagen post-processing. Briefly, MC3T3-E1 murine osteoblasts were cultured in the presence of glucagon (GCG), [D-Ala²]-glucagon-like peptide-1 ([D-Ala²]-GLP-1), and [Gly²]-glucagon-like peptide-2 ([Gly²]-GLP-2). Gut hormone receptor expression at the mRNA and protein levels were investigated by qPCR and Western blot. Extent of collagen postprocessing was examined by Fourier transform infrared microspectroscopy. GCG and GLP-1 receptors were not evidenced in osteoblast cells at the mRNA and protein levels. However, it is not clear whether the known GLP-2 receptor is expressed. Nevertheless, administration of [Gly²]-GLP-2, but not GCG or [D-Ala²]-GLP-1, led to a dose-dependent increase in collagen maturity and an acceleration of collagen post-processing. This mechanism was dependent on adenylyl cyclase activation. In conclusion, the present study highlighted a direct effect of [Gly²]-GLP-2 to enhance collagen post-processing and crosslinking maturation in murine osteoblast cultures. Whether this effect is translatable to human osteoblasts remains to be elucidated.

Osteoporosis in older adults.

The incidence of fragility fractures increases progressively with advance in age after 50 years, and the phenomenon of population ageing will lead to an increased proportion of the world population having osteoporosis and fractures. The consequences of fractures are more serious in older adults: all low-trauma fractures were associated with increased mortality risk and the risk of a second major osteoporotic fracture after a first one also increased with advance in age. Along with the decrease in bone mineral density, falls play an essential role in the occurrence of fragility fractures in older adults, and the assessment of the risk of falling is part of the fracture risk assessment. Despite advances in the diagnosis of osteoporosis, the assessment of fracture risk, and a wide range of effective anti-osteoporosis medications, with parenteral route which can improve observance, many data indicate that the therapeutic care gap is particularly wide in the elderly in whom the importance and impact of a treatment are high and even more in those living in institutions.

Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study.

BACKGROUND: The objective of this quasi-experimental study was to determine whether bolus vitamin D supplementation taken either regularly over the preceding year or after the diagnosis of COVID-19 was effective in improving survival among hospitalized frail elderly COVID-19 patients. METHODS: Seventy-seven patients consecutively hospitalized for COVID-19 in a geriatric unit were included. Intervention groups were participants regularly supplemented with vitamin D over the preceding year (Group 1), and those supplemented with vitamin D after COVID-19 diagnosis (Group 2). The comparator group involved participants having received no vitamin D supplements (Group 3). Outcomes were 14-day mortality and highest (worst) score on the ordinal scale for clinical improvement (OSCI) measured during COVID-19 acute phase. Potential confounders were age, gender, functional abilities, undernutrition, cancer, hypertension, cardiomyopathy, glycated hemoglobin, number of acute health issues at admission, hospital use of antibiotics, corticosteroids, and pharmacological treatments of respiratory disorders. RESULTS: The three groups (n = 77; mean ± SD, 88 ± 5years; 49% women) were similar at baseline (except for woman proportion, p = 0.02), as were the treatments used for COVID-19. In Group 1 (n = 29), 93.1% of COVID-19 participants survived at day 14, compared to 81.2% survivors in Group 2 (n = 16) (p = 0.33) and 68.7% survivors in Group 3 (n = 32) (p = 0.02). While considering Group 3 as reference (hazard ratio (HR) = 1), the fully-adjusted HR for 14-day mortality was HR = 0.07 (p = 0.017) for Group 1 and HR = 0.37 (p = 0.28) for Group 2. Group 1 had longer survival time than Group 3 (log-rank p = 0.015), although there was no difference between Groups 2 and 3 (log-rank p = 0.32). Group 1, but not Group 2 (p = 0.40), was associated with lower risk of OSCI score ≥5 compared to Group 3 (odds ratio = 0.08, p= 0.03). CONCLUSIONS: Regular bolus vitamin D supplementation was associated with less severe COVID-19 and better survival in frail elderly.

High Incidence of Amoxicillin-Induced Crystal Nephropathy in Patients Receiving High Dose of Intravenous Amoxicillin.

BACKGROUND: Amoxicillin (AMX)-induced crystal nephropathy (AICN) is considered as a rare complication of high dose intravenous (IV) AMX administration. However, recently, its incidence seems to be increasing based on French pharmacovigilance centers. Occurrence of AICN has been observed mainly with IV administration of AMX and mostly under doses over 8 g/day. Given that pharmacovigilance data are based on declaration, the real incidence of AICN may be underestimated. Thus, the primary objective of the present study was to determine the incidence of AICN in the current practice. MATERIALS AND METHODS: We conducted a retrospective study between 1 January 2015 and 31 December 2017 in Angers University Hospital. Inclusion criteria were age over 18 years-old and IV AMX administration of at least 8 g/day for more than 24 h. Patients admitted directly into the intensive care units were excluded. Medical records of patients that developed Kidney Disease:Improving Global Outcome (KDIGO) stage 2-3 acute kidney injury (AKI) were reviewed by a nephrologist and a specialist in pharmacovigilance. AICN was retained if temporality analysis was conclusive, after exclusion of other causes of AKI, in absence of other nephrotoxic drug administration. RESULTS: A total of 1303 patients received IV AMX for at least 24 h. Among them, 358 (27.5%) were exposed to AMX doses of at least 8 g/day and were included. Patients were predominantly males (68.2%) with a mean age of 69.1 years-old. AMX was administered for a medical reason in 78.5% of cases. Patients received a median dose of AMX of 12 g/day (152.0 mg/kg/day). Seventy-three patients (20.4%) developed AKI, 42 (56.8%) of which were KDIGO stage 2 or 3. Among the latter, AICN diagnosis was retained in 16 (38.1%) patients, representing an incidence of 4.47% of total patients exposed to high IV AMX doses. Only female gender was associated with an increased risk of AICN. AMX dose was not significantly associated with AICN development. CONCLUSION: This study suggests a high incidence of AICN in patients receiving high IV AMX doses, representing one third of AKI causes in our study. Female gender appeared as the sole risk factor for AICN in this study.

Enteroendocrine K Cells Exert Complementary Effects to Control Bone Quality and Mass in Mice.

The involvement of a gut-bone axis in controlling bone physiology has been long suspected, although the exact mechanisms are unclear. We explored whether glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine K cells were involved in this process. The bone phenotype of transgenic mouse models lacking GIP secretion (GIP-GFP-KI) or enteroendocrine K cells (GIP-DT) was investigated. Mice deficient in GIP secretion exhibited lower bone strength, trabecular bone mass, trabecular number, and cortical thickness, notably due to higher bone resorption. Alterations of microstructure, modifications of bone compositional parameters, represented by lower collagen cross-linking, were also apparent. None of these alterations were observed in GIP-DT mice lacking enteroendocrine K cells, suggesting that another K-cell secretory product acts to counteract GIP action. To assess this, stable analogues of the known K-cell peptide hormones, xenin and GIP, were administered to mature NIH Swiss male mice. Both were capable of modulating bone strength mostly by altering bone microstructure, bone gene expression, and bone compositional parameters. However, the two molecules exhibited opposite actions on bone physiology, with evidence that xenin effects are mediated indirectly, possibly via neural networks. Our data highlight a previously unknown interaction between GIP and xenin, which both moderate gut-bone connectivity. © 2020 American Society for Bone and Mineral Research.

Vitamin D Supplementation in France in patients with or at risk for osteoporosis: Recent data and new practices.

With intermittent vitamin D supplementation, serum 25-hydroxyvitamin D (25OHD) levels may remain stable only if the dosing interval is shorter than 3 months, the ideal perhaps being about 1 month. Recent data support moderate daily vitamin D doses instead of high intermittent doses, notably in elderly patients prone to falls. The level of evidence is low, however, with no head-to-head comparisons of clinical outcomes such as fractures and falls in groups given identical dosages daily versus intermittently. A challenge to daily vitamin D supplementation in France is the absence of a suitable pharmaceutical formulation. In addition, daily dosing carries a high risk of poor adherence. Until suitable vitamin D3 formulations such as tablets or soft capsules each containing 1000 or 1500 IU become available, we suggest intermittent supplementation according to 2011 GRIO guidelines. Among the available dosages, the lowest should be preferred, with the shortest possible interval, e.g., 50,000 IU monthly rather than 100,000 every two months.

The prognosis of streptococcal prosthetic bone and joint infections depends on surgical management-A multicenter retrospective study.

BACKGROUND: The optimal treatment of streptococcal prosthetic joint infections (PJIs) is unclear. METHODS: A cohort of streptococcal PJIs was reviewed retrospectively in seven reference centers for the management of complex bone and joint infections, covering the period January 1, 2010 to December 31, 2012. RESULTS: Seventy patients with monomicrobial infections were included: 47 had infections of total hip arthroplasty and 23 had infections of total knee arthroplasty. The median age was 77 years (interquartile range (IQR) 69-83 years), the median Charlson comorbidity score was 4 (IQR 3-6), and 15.6% (n=11) had diabetes. The most commonly identified streptococcal species were Streptococcus agalactiae and Streptococcus dysgalactiae (38.6% (n=27) and 17.1% (n=12), respectively). Debridement, antibiotics and implant retention (DAIR) was performed after a median time of 7 days (IQR 3-8 days), with polyethylene exchange (PE) in 21% of cases. After a minimum follow-up of 2 years, 27% of patients had relapsed, corresponding to 51.4% of DAIR treatment cases and 0% of one-stage (n=15) or two-stage (n=17) exchange strategy cases. Rifampicin or levofloxacin in combination therapy was not associated with a better outcome (adjusted p= 0.99). S. agalactiae species and DAIR treatment were associated with a higher risk of failure. On multivariate analysis, only DAIR treatment and S. agalactiae were independent factors of relapse. Compared to DAIR without PE, DAIR with PE was only associated with a trend towards a benefit (odds ratio 0.33, 95% confidence interval 0.06-1.96; adjusted p= 0.44). CONCLUSIONS: Streptococcal PJIs managed with DAIR have a poor prognosis and S. agalactiae seems to be an independent factor of treatment failure.

Vitamin D in adults: update on testing and supplementation.

Hypovitaminosis D, a frequent condition in adults, is accompanied by adverse skeletal and non-skeletal events. The objective of the present article was to propose an update on the indications and use of vitamin D testing and supplementation in adults. Among healthy middle-aged adults, the serum 25-hydroxyvitamin D (25(OH)D) target concentration is 50 nmol/L. Natural intakes (sun exposure and diet) are sufficient, and there is no indication for systematic blood test or supplementation. In middle-aged adults who are either sick or dependent or frail, natural intakes are generally insufficient but should be encouraged. In this population, the loading phase of the supplementation targets a 25(OH)D concentration of 75 nmol/L, and the pattern of supplementation (200,000 to 400,000 IU orally over 2 months) depends on the measure of circulating 25(OH)D (which is not reimbursed outside the scope defined by the French national authority for health). In adults over 65 years of age, the loading phase of the supplementation should be systematic and targets a concentration of 75 nmol/L (pattern of 300,000 IU orally over 3 months). Regardless of age, the loading phase should be followed by a long-term maintenance phase of supplementation to maintain the 25(OH)D concentration above the target. A measure of serum 25(OH)D is useful after 9 months of supplementation to adjust the frequency or dosage of supplements if necessary.

Trabecular Bone Score: Where are we now?

The Trabecular Bone Score is a rather new index obtained at the lumbar spine at the same time as a real bone mineral density. It was developed to reflect bone microarchitecture. It was proposed to be easily used in everyday practice as a surrogate of bone strength. Our aim was to review 1. technical points such as correlations between Trabecular Bone Score and bone microarchitectural parameters, Trabecular Bone Score and bone strength, the effects of dual-energy X-ray absorptiometry image spatial resolution, age, macroarchitecture, body mass index, and osteoarthritis, on Trabecular Bone Score, and 2. evidences to use Trabecular Bone Score for separating individuals with fragility fractures from controls, predicting fragility fractures, and for longitudinally monitoring changes related to treatments. Correlations between Trabecular Bone Score and bone microarchitectural parameters vary widely across bone sites, microarchitectural parameters, and study designs. In vivo, the Trabecular Bone Score explains little of the variance in trabecular microarchitectural parameters. We emphasize that it is a texture parameter. The Trabecular Bone Score is reduced in patients with fragility fracture. Several retrospective and prospective studies have shown its discriminative ability regarding the fracture risk. When combining the areal Bone mineral Density and Trabecular Bone Score, the Trabecular Bone Score remains a predictor of fracture but not the areal Bone Mineral Density. However in prospective studies, the best predictor of fracture remains hip areal bone mineral density. Due to the lack of evidence, we recommend not to use Trabecular Bone Score for following patients treated by anti-osteoporotic drugs.

Difficulties in the diagnosis of vertebral fracture in men: agreement between doctors.

UNLABELLED: The agreement for vertebral fracture (VF) diagnosis in men, between doctors is poor. OBJECTIVES: To assess the agreement for VF diagnosis, in men, on standard radiographs, between experts, before and after consensual workshop and establishing an algorithm. METHODS: The agreement between thirteen experimented rheumatologists has been calculated in thirty osteoporotic men. Then, the group discussed in a workshop and 28 other radiograph sets of osteoporotic men with follow-up radiographs and incident confirmed VF, have been reviewed. The experts identified and hierarchised 18 pathological features of vertebral deformation and established an algorithm of VF diagnosis. Eleven experts have realized a second reading of the first set of radiographs. We compared the agreement between the 2 readings without and with the algorithm. RESULTS: After consensus and the use of the algorithm the results are: number of fractured patients (with at least 1 VF) according to the experts varies from 13 to 26 patients out of 30 (13 to 28 during the first reading). The agreement between the experts at the patient level is 75% (70% at the first reading). Among the 390 vertebrae analyzed by the experts, the number of VF detected varies from 18 to 59 (18 to 98 at the first reading). The agreement between the experts at the vertebral level is 92% (89% at the first reading). The algorithm allows a good improvement of the agreement, especially for 8 of the 11 experts. Discrepancies for the VF diagnosis between experts exist. The algorithm improves the agreement.

Is androgen therapy indicated in men with osteoporosis?

Male osteoporosis is not rare, and its management is a public health issue. The clinical evaluation must include investigations for one or more etiological factors such as hypogonadism, which is found in 5% to 15% of men with osteoporosis. Gradual development of moderate hypogonadism is the most common situation, and the prevalence of hypogonadism increases with advancing age. The wealth of scientific data establishing a major role for sex hormones in growth, bone turnover, and the osteoporotic fracture risk is in striking contrast to the paucity of therapeutic trials. Androgen therapy did not consistently produce bone mass gains, and no data on potential anti-fracture effects are available. Androgen therapy was not associated with significant increases in mortality, prostate disorders, or cardiovascular events, but few data were obtained in patients older than 75 years. In practice, in a male patient with osteoporosis, a diagnosis of marked and persistent hypogonadism requires investigations for treatable causes. In patients younger than 75 years of age, androgen replacement therapy should be started, in collaboration with an endocrinologist. A history of fractures indicates a need for additional osteoporosis pharmacotherapy. The risk/benefit ratio of androgen therapy is unclear in men older than 75 years, in whom a reasonable option consists in combining fall-prevention measures, vitamin D supplementation, and a medication proven to decrease the risk of proximal femoral fractures.

High parathyroid hormone, but not low vitamin D concentrations, expose elderly inpatients to hypertension.

AIM: Serum parathyroid hormone (PTH) and 25-hydroxyvitamin D (25OHD) concentrations might contribute to blood pressure (BP) levels. Mixed results in previous literature could be due to the failure to consider both these hormones concurrently, despite their long-known relationship. Our objective was to examine the association of serum intact PTH and 25OHD concentrations with BP levels amongst older inpatients, while accounting for each other. METHODS: The participants were 284 Caucasian older inpatients with no suspicion of primary hyperparathyroidism (mean age 85.87 ± 5.90 years; 65.8% female) admitted to the geriatric acute care unit of Angers University Hospital, France. They were divided into two groups according to the existence of hypertension (i.e. systolic blood pressure [SBP] >140 mmHg, or diastolic blood pressure [DBP] >90 mmHg). Age, sex, numbers of chronic diseases and of drugs taken daily, use of antihypertensive or corticosteroid drugs and of calcium supplements/vitamin D, thyroid-stimulating hormone and albumin concentrations, creatinine clearance, and season tested were used as covariables. RESULTS: Hypertensive participants (n=106) had higher intact PTH concentrations than normotensive patients (P=0.044). There was a positive linear association of BP with intact PTH concentrations (adjusted ß=0.08, P=0.015 for SBP; adjusted ß=0.05, P=0.044 for DBP), but not with vitamin D. Serum intact PTH concentration, unlike 25OHD, was associated with hypertension (adjusted OR 1.01, P=0.038). CONCLUSIONS: Irrespective of 25OHD, PTH was associated with hypertension by increasing both SBP and DBP.

Glucocorticoids reduce alveolar and trabecular bone in mice.

UNLABELLED: Glucocorticoid (GC) treatment is the main cause of secondary osteoporosis. There are some controversies about the relationships between alveolar bone loss and bone loss at the appendicular and axial skeleton. OBJECTIVE: To assess, in parallel, the effects of GCs on alveolar bone and on the tibia in a mice model. METHODS: Five-month-old male Swiss-Webster mice were randomized into two groups. Pellets releasing 5 mg/kg/day of prednisolone or control pellets were subcutaneously implanted for 28 days. After euthanasia, the right tibia and the right hemimandible of each mouse were analyzed by histomorphometry and microcomputed tomography. Alveolar bone consists of a thin slab between the incisor and the molar roots connected with the alveolar processes. A 2D-frontal section was done through the pulp chamber of the first molar and was used to measure the thickness of the alveolar bone slab. A 2D-sagittal section was done through the pulp chamber of the three molars and was used to measure bone volume in the alveolar processes. RESULTS: At day 28, thickness and bone volume of alveolar bone were significantly decreased in the GC group (P<0.05). At the tibia, GCs decreased bone formation with a reduced mineral apposition rate and bone formation rate and a significant decrease in BV/TV and Tb.Th (P<0.05). CONCLUSION: Although the amount of alveolar bone is very low in the mouse, this study shows that GCs can induce an alveolar bone loss in long-term treated animals.

[Osteoporosis in men]. / Ostéoporose chez l'homme.

Epidemiologic studies have shown that 25% of osteoporotic fractures occur in men. Their prognosis is poor with one third of deaths in the year following the proximal femur fracture. Screening is based on the analysis of risk factors (prolonged corticosteroid therapy, anti androgen, smoking or alcohol abuse, liver disease or chronic inflammatory diseases), taking into account fracture history and bone density measurement. The prescription of bisphosphonates or teriparatide must be preceded by an etiologic investigation, a withdrawal of bone loss-induced drugs (tobacco, alcohol, steroids), a recovery of walking and a specific action on fall risk, especially after 70 years.

Is transiliac bone biopsy a painful procedure?

Despite an increased availability of non-invasive procedures to assess bone mass, histological examination of undecalcified transiliac bone biopsies remains a very valuable tool in the diagnosis of metabolic or malignant bone disorders. Nonetheless, clinicians are sometimes reluctant to perform this "invasive" examination, arguing that it might be a painful procedure. The aim of our study was to evaluate pain and anxiety described by patients in the months following the biopsy and to characterize potential early or late side effects. A single interviewer conducted a phone survey (19 items questionnaire) in 117 patients in whom a bone biopsy had been performed by two experienced physicians, with the same material and similar anesthetic and technical procedure. The topics covered pain during or after the biopsy, anxiety, comparison of other potentially painful procedures, early or late side effects as well as global evaluation by the patients. Bone biopsy was judged as non-painful by almost 70% of patients; some discomfort was present in 25% in the following days. The procedure was described as similar as or less painful than bone marrow aspiration, venipuncture or tooth extraction. About 90% of the patients estimated that it was a quite bearable diagnostic procedure. Side effects were not serious. About 7% remembered a vasovagal episode, 47% of local bruising in the following days. There was no report of hematoma or infection. In experienced hands and adapted trephine, transiliac bone biopsy is a safe procedure that brings invaluable information in bone disorders.