A practical approach for anabolic treatment of bone fragility with romosozumab.

BACKGROUND: Romosozumab, a fully humanized anti-sclerostin-antibody, is a bone-builder stimulating osteoblasts and inhibiting osteoclast by activation of the canonical Wnt-beta catenin signaling. This unique mechanism of action has the potential to address unmet needs in osteoporosis management. METHODS: The multifaceted practical clinical issues related to romosozumab are discussed, especially focusing on the rationale of employing a sclerostin inhibitor to target bone fragility as first line or second line treatment in post-menopausal osteoporosis and in males at increased risk of fractures. RESULTS: Four randomized clinical trials with several post-hoc analyses and more than ten observational studies have consistently demonstrated that romosozumab is effective in rapidly increasing bone mineral density (BMD) and decreasing risk of vertebral, non-vertebral and hip fractures in post-menopausal women at very-high risk of fractures. In male osteoporosis, only data on BMD are available. Noteworthy, romosozumab was shown to be more effective and rapid than teriparatide in improving BMD, bone structure and strength at the hip, especially in women already treated with anti-resorptive drugs. Interestingly, even if romosozumab displays best results in treatment-naïve patients, its favourable effects on BMD were observed even in women previously treated with teriparatide or denosumab, although to a lesser extent. CONCLUSIONS: Based on the available evidence, romosozumab could be proposed as ideal drug in several clinical settings, such as non-fractured post-menopausal women at very-high risk of fractures, patients with recent hip fracture, patients non responder to bisphosphonates and short-term denosumab therapy.

[Male infertility, environment and lifestyle]. / Infertilité masculine, environnement et mode de vie.

BACKGROUND: Since the 1970s, there has been a quantitative and qualitative decline in sperm parameters. The main hypothesis to explain such a rapid evolution is the involvement of environmental and behavioral phenomena. METHODS: A bibliographic search limited to English and French literature in men published before 7/2023 was carried out on the links between fertility and pollution, xenobiotics, tobacco, narcotics, cannabis, alcohol, weight, sport, sedentary lifestyle, sleep and anabolics. RESULTS: Profound changes in lifestyle have occurred over the past 50 years: reduced sleep time, sedentary lifestyle, dietary changes, tobacco consumption, use of narcotics and anabolics. These changes have a proven impact on spermogram parameters, and should be corrected in an effort to optimize reproductive health. Other environmental parameters: pollution, exposure to heavy metals, exposure to xenobiotics, phthalates and pesticides… will be more difficult to exclude from patients' daily lives, but deserve to be taken more into account. CONCLUSION: This review should help the urologist to assess and counsel patients in order to improve their reproductive health. These factors should be routinely investigated in infertile men.

Comparison of the efficacy between sequential therapy with teriparatide and denosumab and denosumab monotherapy in suppressing fragility fracture risk.

In this retrospective study, the effectiveness of short-term teriparatide with denosumab in reducing fragility fracture risk was determined in comparison with denosumab monotherapy. Administration of sequential teriparatide with denosumab showed excellent outcomes in suppressing the risk for fragility fractures compared with denosumab monotherapy. INTRODUCTION: To determine the effectiveness of short-term teriparatide with denosumab in reducing the risk of fragility fractures in comparison to denosumab monotherapy. METHODS: The data of postmenopausal patients treated with denosumab for > 2 years between August 2015 and October 2020 were retrospectively analyzed. One hundred sixty four postmenopausal women of a total 615 were excluded, since they did not undergo > 2 bone mineral density (BMD) tests, were lost to follow-up, or received long-term teriparatide therapy. Total 320 patients received denosumab monotherapy and 131 patients received teriparatide for ≥ 3 months followed by denosumab. The number of osteoporotic fractures, presence of back pain before and after treatment, and annual BMD during treatment were comparatively assessed using t-test, Chi-square test, and linear mixed model analysis. RESULTS: Before treatment, the denosumab monotherapy group had fewer osteoporotic fractures (mean ± standard deviation; 0.459 ± 0.689) than the sequential therapy group had (1.037 ± 0.871; p < 0.001). After treatment, the sequential therapy group had fewer osteoporotic fractures than the denosumab monotherapy group had (0.119 ± 0.348 versus 0.144 ± 0.385; p < 0.001). At 1 and 2 years after treatment, the increase in lumbar spine BMD was greater in the sequential therapy group than in the denosumab monotherapy group (p = 0.08, group × time). The difference between post and pre-treatment back pain visual analog scale score was significantly lower in the sequential therapy group than in the monotherapy group (3.246 ± 3.426 versus 1.734 ± 3.049; p < 0.001). CONCLUSION: Short-term teriparatide use before denosumab showed excellent outcomes in suppressing the risk of fragility fractures compared with denosumab monotherapy.

Romosozumab efficacy and safety in European patients enrolled in the FRAME trial.

In this post hoc analysis, we assessed romosozumab efficacy and safety in European patients enrolled in FRAME. Romosozumab treatment through 12 months, followed by denosumab for a further 24 months, resulted in early and sustained risk reduction for major fracture categories, associated with large gains in bone mineral density. INTRODUCTION: In the multinational FRAME phase 3 trial of romosozumab in postmenopausal women with osteoporosis, marked differences between clinical and non-vertebral fracture outcomes were observed among patients from Central and Southern America versus rest of world. This post hoc analysis assessed romosozumab efficacy and safety in European patients enrolled in the FRAME trial and extension study. METHODS: In FRAME (NCT01575834), patients were randomised 1:1 to romosozumab 210 mg or placebo monthly (QM) for 12 months, followed by open-label denosumab 60 mg Q6M to month 36, including a 12-month extension study. We report incidence of major fracture outcomes, bone mineral density (BMD) change from baseline and safety for European patients enrolled in FRAME. RESULTS: In FRAME, 3013/7180 (41.96%) patients were European; 1494 received romosozumab and 1519 received placebo. Through 12 months, romosozumab reduced fracture risk versus placebo for non-vertebral fracture (1.4% versus 3.0%; p = 0.004), clinical fracture (1.4% versus 3.6%; p < 0.001), new vertebral fracture (0.4% versus 2.1%; p < 0.001) and major osteoporotic fracture (0.9% versus 2.8%; p < 0.001), with results sustained through 36 months following transition to denosumab. Hip fractures were numerically reduced with romosozumab at month 12 (0.2% versus 0.6%; p = 0.092). Romosozumab increased BMD versus placebo at month 12; all patients in the romosozumab and placebo groups experienced further increases by month 36 after transition to denosumab. Adverse events were balanced between groups. CONCLUSIONS: Among European patients in FRAME, romosozumab resulted in early and sustained risk reduction for all major fracture categories, associated with large BMD gains that continued after transition to denosumab.

Bone Density After Teriparatide Discontinuation With or Without Antiresorptive Therapy in Pregnancy- and Lactation-Associated Osteoporosis.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare and severe disorder that causes low-trauma or spontaneous fractures, most commonly multiple vertebral fractures, in the late pregnancy or lactation period [1]. In severe PLO, teriparatide (TPTD) might aid in bone mineral density (BMD) recovery and subsequent fracture risk reduction. However, it is unclear whether TPTD can be discontinued without sequential antiresorptive therapy (ART) in premenopausal women with PLO. In this retrospective cohort study, we investigated the changes in BMD in premenopausal women with PLO treated with TPTD 20 mcg daily with or without sequential ART. Data for 67 patients diagnosed with PLO from 2007 through 2017 were reviewed. Among 43 women with annual follow-up dual-energy X-ray absorptiometry data for 3 years, 33 were treated with TPTD (median 12 months) with (TPTD-ART, n = 13; median, 18 months) or without (TPTD-no ART, n = 20) sequential ART. The two groups showed no differences in the mean age (31 vs. 31 years), body mass index (BMI, 20.5 vs. 21.0 kg/m2), and baseline lumbar spine (LS) BMD (0.666 vs. 0.707 g/cm2; p > 0.05 for all). LSBMD increased at 1, 2, and 3 years from baseline in both the TPTD-ART (14.1%, 21.8%, and 24.0%, respectively) and TPTD-no ART (17.3%, 24.1%, and 23.4%, respectively) groups, without significant between-group differences. Similar results were observed for the total hip BMD. LSBMD gain at 3 years did not differ by ART use (adjusted ß, 0.40; p = 0.874) in univariable and multivariable models adjusted for age, BMI, and baseline LSBMD. In summary, BMD gain by TPTD administration in premenopausal women with PLO can be well maintained without sequential ART treatment.

Consensus Statement on the Use of Bone Turnover Markers for Short-Term Monitoring of Osteoporosis Treatment in the Asia-Pacific Region.

Osteoporosis is a major health issue. By 2050, a greater than 2-fold increase in patients number with hip fractures will occur in Asia representing 50% of all hip fractures worldwide. For the Asia-Pacific (AP) region, more efforts on controlling osteoporosis and the subsequent fractures are crucial. Bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) is commonly used to diagnose osteoporosis and monitor osteoporosis treatment. However, the inconvenience, cost, limited availability of DXA and the delay in detection of BMD changes after treatment initiation support an important role for bone turnover markers (BTMs), as short-term tools to monitor therapy. With regards to low adherence rates of medical treatment of osteoporosis, the experts reached consensus on the use of BTMs for both raising awareness and short-term monitoring of osteoporosis treatment in the AP region. The experts endorse the use of BTMs, especially serum C-terminal telopeptide of type 1 collagen (CTX) and serum procollagen type 1 N propeptide (P1NP), as short-term monitoring tools to help clinicians assess the responses to osteoporosis therapies and appropriately adjust treatment regimens earlier than BMD. Either the absolute values or the degree of change from baseline in BTMs can be used to monitor the potential efficacy of osteoporosis therapies. The use of BTMs can be incorporated in osteoporosis care programs, such as fracture liaison service (FLS), to improve patient adherence and treatment outcomes. Encouraging sufficient reimbursement from health care systems may facilitate widespread use of BTMs in clinical practice in the AP region.

Effects of muscular strength training and growth hormone (GH) supplementation on femoral bone tissue: analysis by Raman spectroscopy, dual-energy X-ray absorptiometry, and mechanical resistance.

The aim of the present study was to verify the effects of muscular strength training and growth hormone (GH) supplementation on femoral bone tissue by Raman spectroscopy (Raman), dual-energy X-ray absorptiometry (DXA), and mechanical resistance (F-max) analysis. A total of 40 male Wistar animals, 60 days old, were used. The animals were distributed into four groups: control (C), control with GH (GHC), muscular strength training (T), and muscular strength training with GH (GHT). Blood samples were collected for the quantification of creatine kinase (CK-MB) and the femurs were removed for analysis by Raman, DXA, and F-max. A more pronounced increase in the bone mineral components was verified in the T group, for all the variables obtained by the Raman (calcium, phosphate, amide, and collagen). In addition, for animals submitted to GH supplementation, there was a reduction in the variable bone mineral density (BMD) obtained by the DXA (p < 0.05). Finally, the animals that received GH supplementation presented a higher F-max, but without statistical significance (p > 0.05). It was concluded that animals that received GH supplementation demonstrated a decrease in BMD. In addition, T alone was able to promote increased calcium, phosphate, amide, and collagen compounds in bone tissue.

Abaloparatide-SC improves trabecular microarchitecture as assessed by trabecular bone score (TBS): a 24-week randomized clinical trial.

In a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to one of three different doses of abaloparatide-SC, subcutaneous teriparatide, or placebo for 24 weeks, abaloparatide-SC resulted in improvements in skeletal microarchitecture as measured by the trabecular bone score. INTRODUCTION: Subcutaneous abaloparatide (abaloparatide-SC) increases total hip and lumbar spine bone mineral density and reduces vertebral and non-vertebral fractures. In this study, we analyzed the extent to which abaloparatide-SC improves skeletal microarchitecture, assessed indirectly by trabecular bone score (TBS). METHODS: This is a post hoc analysis of a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to abaloparatide-SC (20, 40, or 80 µg), subcutaneous teriparatide (20 µg), or placebo for 24 weeks. TBS was measured from lumbar spine dual X-ray absorptiometry (DXA) images in 138 women for whom the DXA device was TBS software compatible. Assessments were made at baseline, 12 and 24 weeks. Between-group differences were assessed by generalized estimating equations adjusted for relevant baseline characteristics, and a pre-determined least significant change analysis was performed. RESULTS: After 24 weeks, TBS increased significantly by 2.27, 3.14, and 4.21% versus baseline in participants on 20, 40, and 80 µg abaloparatide-SC daily, respectively, and by 2.21% in those on teriparatide (p < 0.05 for each). The TBS in the placebo group declined by 1.08%. The TBS increase in each treatment group was significantly higher than placebo at 24 weeks (p < 0.0001 for each) after adjustment for age, BMI, and baseline TBS. A dose-response was observed at 24 weeks across the three doses of abaloparatide-SC and placebo (p = 0.02). The increase in TBS in the abaloparatide-SC 80 µg group was significantly greater than TPTD (p < 0.03). CONCLUSIONS: These results are consistent with an effect of abaloparatide-SC to improve lumbar spine skeletal microarchitecture, as assessed by TBS.

Effects of bone remodeling agents following teriparatide treatment.

Teriparatide is an anabolic therapy used to treat patients with osteoporosis and is only approved for 2 years of treatment. This is the first study to look at two common osteoporosis drugs in maintaining its beneficial effects: denosumab and zoledronic acid. Denosumab treatment was associated with the greatest increase in bone mineral density (BMD) at the femoral neck and lumbar spine, an amount that was statistically greater than no treatment and zoledronic acid treatment. INTRODUCTION: Teriparatide, a hallmark treatment for osteoporosis, has been shown to increase BMD and bone turnover. This can be measured using BMD scans, N-terminal propeptide of type-1 collagen (P1NP) for bone formation and C-terminal telopeptide (CTX) for bone resorption. This study examines the effects of the two most common antiresorptive drugs prescribed following 2 years of teriparatide treatment: zoledronic acid and denosumab. The purpose of this study is to quantify the beneficial effects of teriparatide and compare the ability of each antiresorptive drug to maintain the effects. METHODS: Ninety-four patients with prior fragility fractures were identified from a bone health clinic associated with a level I trauma center. All of the study participants completed 2 years of treatment with teriparatide between 2008 and 2013 followed by 2 years of treatment with zoledronic acid, denosumab, or no treatment. After excluding patients with insufficient laboratory data, 64 patients remained for analysis in this retrospective cohort study. Bone mineral density was measured in the lumbar spine and femoral neck. RESULTS: Following completion of teriparatide, patients who were started on denosumab showed the largest increase in bone mineral density after 2 years of treatment: lumbar spine 4.94% ± 8.2%, femoral neck 5.68% ± 6.7%. CONCLUSIONS: Patients who elected to discontinue osteoporosis treatment experienced a significant decline in the change in BMD compared to the change on teriparatide putting them at higher risk for recurrence of fragility fractures. Patients on denosumab following teriparatide had the largest increase in BMD.

Bone Loss After Romosozumab/Denosumab: Effects of Bisphosphonates.

Romosozumab and denosumab are monoclonal antibodies for the treatment of osteoporosis. Both have a rapid offset of effect resulting in loss of bone density (BMD) gained on-treatment and, in some cases, multiple vertebral fractures following treatment cessation. We recently reported disappointing results from transitioning patients from denosumab to intravenous zoledronate at the time the next denosumab injection is due. The present report re-assesses the role of bisphosphonates following the use of denosumab. In the FRAME trial, osteoporotic women were randomized to romosozumab or placebo for 1 year, then both groups were provided with open-label denosumab for the subsequent 2 years. In women completing this study at our center, we offered treatment with either oral or intravenous bisphosphonates. In the eleven women opting for intravenous treatment, zoledronate was given after a median delay of 65 days from trial-end, in the hope that this might increase skeletal uptake of the drug and, thereby, its efficacy to maintain bone density. In these women, spine BMD was 17.3% above baseline at trial-end, and still 12.3% above baseline a year later, a 73% (CI: 61%, 85%) retention of the treatment benefit. The comparable BMD figures for the total hip were 10.7 and 9.2% above baseline, a 87% (CI: 77%, 98%) retention of treatment effect. In contrast, those not receiving treatment after the conclusion of the FRAME trial lost 80-90% of the BMD gained on-trial in the following 12 months. Women treated with risedronate showed an intermediate response. In the zoledronate group, mean PINP 6 months post-FRAME was 23 ± 4 µg/L and at 12 months it was 47 ± 8 µg/L, suggesting that repeat zoledronate dosing is needed at 1 year to maintain the BMD gains. In conclusion, delaying administration of intravenous bisphosphonate when transitioning from short-term denosumab appears to increase the extent to which the gains in BMD are maintained.

Antiresorptive Agents are More Effective in Preventing Titanium Particle-Induced Calvarial Osteolysis in Ovariectomized Mice Than Anabolic Agents in Short-Term Administration.

Aseptic loosening due to wear particle-induced osteolysis is the main cause of arthroplasty failure and the influence of postmenopausal osteoporosis and anti-osteoporosis treatment on Titanium (Ti) particle-induced osteolysis remains unclear. 66 C57BL/6J female mice were used in this study. Ovariectomy (OVX) was performed to induce osteopenia mice and confirmed by micro-CT. The Ti particle-induced mouse calvaria osteolysis model was established subsequently and both OVX and Sham-OVX mice were divided into four groups, respectively: Ti (-) group, Ti group, Ti + zoledronic acid (ZOL) group (50ug/kg, local administration, single dose) and Ti + teriparatide (TPTD) group (40ug/kg/d, subcutaneous injection*14d). Mice calvarias were collected for micro-CT and histomorphometric analysis 2 weeks after particle induction. 8 weeks after bilateral OVX, significantly reduced BMD and microstructure parameters in both proximal tibia and calvaria were observed in OVX mice when comparing with Sham-OVX mice. OVX mice in Ti group had not only markly decreased BMD and BV/TV, but also significantly increased total porosity, eroded surface area and osteoclast numbers when comparing with Sham-OVX mice. Shown by Two-way ANOVA analysis, the interaction terms between OVX and Ti implantation on micro-CT and histomorphometry parameters didn't reach significant difference. As illustrated by micro-CT and histological analysis, ZOL treatment markedly inhibited Ti particle-induced osteolysis in OVX mice and Sham-OVX mice, and there were significant differences when comparing to both Ti and Ti+TPTD group. The combination of osteoporosis and Ti particle implantation result in aggravated bone resorption, accompanied with increased osteoclasts and excessive inflammation response. ZOL was more effective in preventing Ti particle-induced osteolysis in both OVX mice and Sham-OVX mice than TPTD in short-term administration. ZOL exert the protective effects on Ti particle-induced bone loss via the suppression of osteoclasts.

Mass spectrometric studies on selective androgen receptor modulators (SARMs) using electron ionization and electrospray ionization/collision-induced dissociation.

Selective androgen receptor modulators (SARMs) have been identified as a promising class of drug candidates potentially applicable to diverse pathological conditions commonly associated with significantly reduced muscle mass. Due to a suspected and meanwhile repeatedly proven misuse of SARMs in elite and amateur sport, sustaining constantly updated doping control analytical methods is critical for sports drug testing laboratories. These test methods predominantly utilize mass spectrometry-based instrumentations and, consequently, studies on the mass spectrometric behavior of new compounds and, where available, their metabolic products are vital for comprehensive doping controls. In this communication, the dissociation patterns of three new SARM drug candidates referred to as GSK2881078, PF-06260414, and TFM-4 AS-1 as observed under electron ionization as well as electrospray ionization/collision-induced dissociation are discussed. By means of high resolution/high accuracy tandem mass spectrometry employing quadrupole-orbitrap mass analyzers, information on precursor-product ion relationships and elemental compositions was obtained and subsequently utilized to suggest dissociation routes of the target compounds. This information can contribute to future studies concerning structure assignments of metabolites and accelerate the identification of related substances if distributed and/or illicitly used in the world of sport.

Theobromine Upregulates Osteogenesis by Human Mesenchymal Stem Cells In Vitro and Accelerates Bone Development in Rats.

Theobromine (THB) is one of the major xanthine-like alkaloids found in cacao plant and a variety of other foodstuffs such as tea leaves, guarana and cola nuts. Historically, THB and its derivatives have been utilized to treat cardiac and circulatory disorders, drug-induced nephrotoxicity, proteinuria and as an immune-modulator. Our previous work demonstrated that THB has the capacity to improve the formation of hydroxyl-apatite during tooth development, suggesting that it may also enhance skeletal development. With its excellent safety profile and resistance to pharmacokinetic elimination, we reasoned that it might be an excellent natural osteoanabolic supplement during pregnancy, lactation and early postnatal growth. To determine whether THB had an effect on human osteoprogenitors, we subjected primary human bone marrow mesenchymal stem cells (hMSCs) to osteogenic assays after exposure to THB in vitro and observed that THB exposure increased the rate of osteogenesis and mineralization by hMSCs. Moreover, THB exposure resulted in a list of upregulated mRNA transcripts that best matched an osteogenic tissue expression signature as compared to other tissue expression signatures archived in several databases. To determine whether oral administration of THB resulted in improved skeletal growth, we provided pregnant rats with chow supplemented with THB during pregnancy and lactation. After weaning, offspring received THB continuously until postnatal day 50 (approximately 10 mg kg-1 day-1). Administration of THB resulted in neonates with larger bones, and 50-day-old offspring accumulated greater body mass, longer and thicker femora and superior tibial trabecular parameters. The accelerated growth did not adversely affect the strength and resilience of the bones. These results indicate that THB increases the osteogenic potential of bone marrow osteoprogenitors, and dietary supplementation of a safe dose of THB to expectant mothers and during the postnatal period could accelerate skeletal development in their offspring.

WNT-mediated Modulation of Bone Metabolism: Implications for WNT Targeting to Treat Extraskeletal Disorders.

The WNT-signaling pathway is involved in cellular and tissue functions that control such diverse processes as body axis patterning, cellular proliferation, differentiation, and life span. The long list of molecules that can participate or modify WNT signaling makes this pathway one of the most complex in cell biology. In bone tissues, WNT signaling is required for proper skeletal development, and human mutations in various components of the cascade revealed insights into pharmacologic targeting that can be harnessed to improve skeletal health. In particular, mutations in genes that code for the WNT-signaling inhibitor sclerostin or the WNT coreceptor lipoprotein receptor-related protein 5 have highlighted the potential therapeutic value of recapitulating those effects in patients with low bone mass. A constant challenge in this area is selectively modifying WNT components in the tissue of interest, as WNT has manifold effects in nearly every tissue.

Abaloparatide.

Abaloparatide is an investigational analog of human PTHrP (1-34) being developed for the treatment of osteoporosis. The amino-acid sequence of abaloparatide is identical to that of PTHrP in the first 20 amino-acids, while over half of the remaining amino-acids are different. Some studies in animals and in humans reported that abaloparatide presented a potent anabolic activity with reduced effects on bone resorption as compared to that observed with teriparatide. This may be due to a more transient signaling response of abaloparatide related to differing affinities of the two drugs to the specific conformations of the PTH1 receptor. In the ACTIVE study, a phase 3 fracture prevention trial, 2460 postmenopausal osteoporotic women at high risk for fracture were randomized to receive 18-months of either daily abaloparatide 80 µg s.c., placebo or teriparatide 20 µg s.c. The reduction in vertebral fracture rate with respect to placebo was 86% in the abaloparatide group and 80% in the teriparatide group. Abaloparatide also produced a significant 43% reduction in the rate of nonvertebral fractures (2.7 vs 4.0% with placebo, p=0.04) whereas teriparatide determined a 28% reduction (2.9 vs 4.0% with placebo, p=NS). Abaloparatide or teriparatide showed similar increases in BMD at lumbar spine, while the patients of the abaloparatide group showed significantly greater increases in BMD at both total hip (4.18 vs 3.26%) and femoral neck (3.60 vs 2.66%). Therefore, if the preliminary data of the ACTIVE study is confirmed, abaloparatide may become an important option for the anabolic treatment of postmenopausal osteoporosis.

Perspectives on osteoporosis therapies.

Osteoporosis is a skeletal disease which predisposes to fragility fractures with high morbidity and economic impact, and, therefore, the goal of any osteoporosis treatment is to reduce the fracture risk. In the various forms of osteoporosis an imbalance between bone resorption and apposition is present, that generally leads to a reduction of bone mineral density and bone quality, and finally to the increased fracture risk. Nowadays, several drugs are available with a demonstrated anti-fracturative effect obtained by inhibiting bone resorption or stimulating bone formation. However, their use is not free from limitations and side effects. Importantly, to date, the available antiresorptive drugs have also an inhibiting, though to a lesser extent, effect on bone apposition and, similarly, the anabolic drugs lead to an increase also of bone resorption. Advances in our knowledge about bone biology, with molecular insights into mechanisms underlying osteoblast, osteoclast, and osteocyte activity, have led to the recognition of new potential targets and consequently to the formulation of new therapeutic agents to treat osteoporosis. New potential developments among the antiresorptive drugs include cathepsin K inhibitors and among the osteoanabolic drugs those activating the Wnt signaling pathway, such as the monoclonal antibodies against sclerostin. The novelty of these compounds is that their mechanism of action gives the exciting possibility to uncouple bone resorption and bone formation, and data available so far appear to be promising. Finally, several new therapeutic targets are under investigation in preclinical studies which could open further approaches to treat osteoporosis in the future.

A supra-cellular model for coupling of bone resorption to formation during remodeling: lessons from two bone resorption inhibitors affecting bone formation differently.

The bone matrix is maintained functional through the combined action of bone resorbing osteoclasts and bone forming osteoblasts, in so-called bone remodeling units. The coupling of these two activities is critical for securing bone replenishment and involves osteogenic factors released by the osteoclasts. However, the osteoclasts are separated from the mature bone forming osteoblasts in time and space. Therefore the target cell of these osteoclastic factors has remained unknown. Recent explorations of the physical microenvironment of osteoclasts revealed a cell layer lining the bone marrow and forming a canopy over the whole remodeling surface, spanning from the osteoclasts to the bone forming osteoblasts. Several observations show that these canopy cells are a source of osteoblast progenitors, and we hypothesized therefore that they are the likely cells targeted by the osteogenic factors of the osteoclasts. Here we provide evidence supporting this hypothesis, by comparing the osteoclast-canopy interface in response to two types of bone resorption inhibitors in rabbit lumbar vertebrae. The bisphosphonate alendronate, an inhibitor leading to low bone formation levels, reduces the extent of canopy coverage above osteoclasts. This effect is in accordance with its toxic action on periosteoclastic cells. In contrast, odanacatib, an inhibitor preserving bone formation, increases the extent of the osteoclast-canopy interface. Interestingly, these distinct effects correlate with how fast bone formation follows resorption during these respective treatments. Furthermore, canopy cells exhibit uPARAP/Endo180, a receptor able to bind the collagen made available by osteoclasts, and reported to mediate osteoblast recruitment. Overall these observations support a mechanism where the recruitment of bone forming osteoblasts from the canopy is induced by osteoclastic factors, thereby favoring initiation of bone formation. They lead to a model where the osteoclast-canopy interface is the physical site where coupling of bone resorption to bone formation occurs.

Orthopaedic surgeons' strategies in pharmacological treatment of fragility fractures.

Fragility fractures are the most severe complications of osteoporosis and the poor mechanical properties of bone can make fixation and healing of these fracture extremely difficult. The role of orthopaedic surgeons does not end in skillful fixation of the fractures, but they have the unique opportunity to prevent complications which can negatively affect the patient's quality of life. The best practice for preventing the risk of further fractures in patients presenting fragility fractures includes fall prevention, investigation of possible causes underlying osteoporosis, attention to exercise, calcium and vitamin D supplementation as well as prescription of drugs. Actually two classes of agents can be used for their effect on fracture prevention: antiresorptive and bone forming agents. Systemic therapy reduces the risk of vertebral (30-70%) and non-vertebral fractures (12-53%), depending on agents and patients' compliance. Preclinical and clinical studies have shown that pharmacological agents involved in osteoporosis can also influence the phases of fracture repair. Preclinical studies and evidences from case reports showed a positive effect of anabolic drugs on bone healing and implant osseointegration. The interventions in the process of fracture healing had evolved from a diamond to a pentagon concept, with interactions between the mechanical environment, the local therapies, the vascularity of the fracture site, the biology of the host and the systemic therapy which has the potential to represent the fifth interaction factor. The orthopaedic surgeon plays a central role in clinical setting to evaluate the efficacy of systemic anti-fracture drugs for improving fracture repair and preventing complications.

Annual banned-substance review 16th edition-Analytical approaches in human sports drug testing 2022/2023.

In this 16th edition of the annual banned-substance review on analytical approaches in human sports drug testing, literature on recent developments in this particular section of global anti-doping efforts that was published between October 2022 and September 2023 is summarized and discussed. Most recent additions to the continuously growing portfolio of doping control analytical approaches and investigations into analytical challenges in the context of adverse analytical findings are presented, taking into account existing as well as emerging challenges in anti-doping, with specific focus on substances and methods of doping recognized in the World Anti-Doping Agency's 2023 Prohibited List. As in previous years, focus is put particularly on new or enhanced analytical options in human doping controls, appreciating the exigence and core mission of anti-doping and, equally, the conflict arising from the opposingly trending extent of the athlete's exposome and the sensitivity of instruments nowadays commonly available in anti-doping laboratories.