Osteoanabolic Drug Research Articles

Exercise for optimizing bone health after hormone-induced increases in bone stiffness.

Hormones and mechanical loading co-regulate bone throughout the lifespan. In this review, we posit that times of increased hormonal influence on bone provide opportunities for exercise to optimize bone strength and prevent fragility. Examples include endogenous secretion of growth hormones and sex steroids that modulate adolescent growth and exogenous administration of osteoanabolic drugs like teriparatide, which increase bone stiffness, or its resistance to external forces. We review evidence that after bone stiffness is increased due to hormonal stimuli, mechanoadaptive processes follow. Specifically, exercise provides the mechanical stimulus necessary to offset adaptive bone resorption or promote adaptive bone formation. The collective effects of both decreased bone resorption and increased bone formation optimize bone strength during youth and preserve it later in life. These theoretical constructs provide physiologic foundations for promoting exercise throughout life.

Bridging the Gap: Pregnancy-And Lactation-Associated Osteoporosis.

Early diagnosis of pregnancy- and lactation-associated osteoporosis (PLO) is mandatory for a good outcome. Standard care is not a matter of conventional guidelines, rather it requires an individualized strategy while true overall incidence and pathogeny remain open issues. This is a narrative review based on full-length English articles, published between January 2021 and March 2023 and accessed via PubMed (no traumatic fractures or secondary osteoporosis are included). Our case-sample-based analysis included 836 females with PLO (the largest cohort based on published cases so far) through 12 studies and 24 single case reports. Except for one survey, these involved retrospective cohorts of small size (6-10 females/study) to medium size (23-47 women/study), and large cohorts with >50 subjects per study (a maximum of 379). Age of diagnosis: from 24 to 40 years for case reports (most subjects being over 30 and primigravida), while original studies indicated an average age between 31 and 34.18 years. Type of fractures underlined a most frequent vertebral phenotype (a mean of 2 to 5.8 vertebral fractures per patient) versus a most severe non-vertebral phenotype (hip and femoral neck fractures mostly requiring surgery). Potential contributors varied: smoking (1/3-1/2 of subjects), family history of osteoporosis (1/3), heparin and glucocorticoid use in pregnancy, low body mass index (majority of cases), hypovitaminosis D; and (with a low level of statistical significance) anti-psychotic medication, gestational diabetes, lupus, thrombophilia, anemia, in vitro fertilization (1/3 in one study), twin pregnancy, tocolysis with MgSO4, and postpartum thyroiditis. Most remarkably, up to 50% of PLO patients harbor mutations of LRP5, WNT1, and COL1A1/A2 (more damaged form with potential benefits from osteoanabolic drugs); gene testing might become the new norm in PLO. The low index of clinical suspicion should be supported by performing magnetic resonance imaging (gold standard in pregnancy) with DXA (in lactation). Low bone mineral density is expected (Z-score varying from -2.2 SD to -4 SD, unless normal which does not exclude PLO). Bone turnover markers might be useful in individuals with normal DXA, in pregnancy when DXA cannot be performed, and in following the response to anti-osteoporosis drugs. Alternatively, microarchitecture damage might be reflected by DXA-trabecular bone score and high-resolution peripheral quantitative computed tomography. Specific medical interventions are currently focused on teriparatide (TPT) use (3 studies; n = 99 females treated with TPT and an additional subgroup of 18 patients from the gene-analysis-based study, thus a total of 117 females) which seems to be the therapy of choice as reflected by these new data: 6-24 months, 20 µg/day, no sequential therapy needed; case selection based on high fracture risk is necessary). The first case using romosozumab was reported in 2022. PAO/LAO remains a challenging condition which is a battle for the wellbeing of two individuals, on one hand, considering maternal-fetal outcomes and taking care of the offspring, but it is a battle for a multidisciplinary team, on the other hand, since a standardized approach is lacking.

Mussel-inspired self-assembly platform for staged implant osseointegration: Combining early anti-infection and late osteoinduction

Current implant systems still lack the ability to combat implant-associated infections (IAI) and insufficient osseointegration to reduce the risk of implant failure. There’s an urgent need to develop an effective implant modification method to match the needs of different biological stages post-implantation, which requires anti-infection at the initial stage and osseointegration at the latter long-term stage. Here, we constructed a mussel-inspired layer-by-layer (LbL) self-assembly implant modification platform via tannic acid (TA), sequentially anchoring osteoanabolic drug (Abaloparatide, ABL) and antibacterial (Dimethylaminohexadecyl methacrylate, DMAHDM) to the Titanium (Ti) surface (Ti/ABL/DMAHDM). The Ti/ABL/DMAHDM exhibited outstanding antibacterial properties at the initial stage with an antibacterial rate of 100 % both in vitro (24 h) and in vivo (48 h). Moreover, it showed significant osteogenic induction ability at the latter long-term stage both in vitro (7 days and 14 days) and in vivo (4 weeks), accompanied by good biocompatibility. This TA-mediated self-assembly modification implants platform with staged regulation of anti-infection and osteoinduction offers potential clinical prospects for improving osseointegration after implantation.

Anti-sclerostin antibodies: a new frontier in fragility fractures treatment.

Bone fragility is the determinant of the increased risk of minimal trauma fracture and must be treated with a multimodal approach that includes pharmacological therapy, physical exercise, and adequate nutrition. Pharmacological therapy, to date based on the administration of antiresorptive drugs, such as bisphosphonates and denosumab, or osteoanabolic drugs, such as teriparatide and abaloparatide, has shown to be effective in reducing the risk of fracture in osteoporotic patients. In the context of the cellular and molecular mechanisms that regulate bone metabolism, the discovery of the Wnt signaling pathway and its role in bone tissue homeostasis has allowed the identification of sclerostin as an inhibitor of osteoblastic activity and simultaneously as a stimulator of osteoclastic activity. Therefore, the use of a monoclonal antibody, romosozumab, against this protein has been tested as a potential drug with a dual action, stimulating bone neo-apposition and inhibiting bone resorption. The efficacy of romosozumab has been demonstrated in numerous clinical trials against both placebo and other drugs commonly used in the treatment of patients affected by osteoporosis. The advantages of this drug lie above all in its rapid action which makes it particularly suitable in clinical situations where it is necessary to improve bone strength very quickly due to the imminent risk of fragility fracture. Clinical studies and guidelines suggest romosozumab as an initial drug in an ideal sequential approach from osteoanabolic to antiresorptive drugs. Some aspects of cardiovascular safety remain to be fully investigated, therefore its use in osteoporotic patients at high cardiovascular risk should be avoided until further data become available.

Abaloparatide and teriparatide enhance mandibular growth in adolescent rats with site-specific and mechano-related effects.

Teriparatide (TPTD) and abaloparatide (ABL) are two osteoanabolic drugs targeting parathyroid hormone (PTH)1R signalling. This study aimed to investigate the effects of TPTD and ABL on the adolescent mandibular growth. In total, 70 4-week-old male Sprague-Dawley rats were randomly divided into 14 groups, treated with intermittent TPDT or ABL at various doses, accompanied by mandibular advancement (MA) or not. 3D printing was used to fabricate an innovative splint for MA. After a 4-week treatment, morphological measurement, histological and immunohistochemical analysis were performed. Mandibular condylar chondrocytes (MCCs) were treated with TPTD or ABL, followed by CCK-8 assay, alcian blue staining, real time-PCR and immunofluorescent staining. In vivo, TPTD or ABL alone increased the condylar length and cartilage thickness, with up-regulated SOX9 and COL II, whilst down-regulated COL X; however, when combined with MA, the promotive effects were attenuated. TPTD or ABL alone increased the mandibular body height and mandibular angle width, whilst increased the mandibular body length and alveolar bone width when combined with MA. In vitro, TPTD or ABL enhanced the MCC proliferation, glycosaminoglycan synthesis, COL II and SOX9 expression, whilst down-regulated COL X, Ihh and PTH1R expression. Both ABL and TPTD enhance mandibular growth in adolescent rats with site-specific and mechano-related effects, including propelling chondrogenesis at the condylar cartilage and promoting bone apposition at other mechano-responsive sites. They behave as promising drugs for mandibular growth modification, and in general ABL seems more potent than TPTD in this context.

Romosozumab for the treatment of postmenopausal women at high risk of fracture

ABSTRACT Introduction Romosozumab is a monoclonal antibody that binds to sclerostin (an inhibitor of the Wingless-related integration site (Wnt) signaling pathway). It is a new osteoanabolic drug that simultaneously increases bone formation and decreases bone resorption. It has recently been approved by the US and EU authorities in postmenopausal women with at high risk of fractures. Areas covered The literature on romosozumab in preclinical and in phase II and III clinical studies has been reviewed about the effect on bone, bone markers, and fracture reduction and its safety. Expert opinion Compared to antiresorptive agents, its unique mechanism of action results in a quicker and greater increase in bone mineral density, it repairs and restores trabecular and cortical bone microarchitecture, and reduces fracture risk more rapidly and more effectively than alendronate, with persisting effects for at least two years after transition to antiresorptive agents. This finding has introduced the concept that, in patients at very high risk of fractures, the optimal sequence of treatment is to start with an osteoanabolic agent, followed by a potent AR drug. Recent national and international guidelines recommend the use of romosozumab as an initial treatment in patients at very high fracture risk without a history of stroke or myocardial infarction.

Abaloparatide outperforms teriparatide in protecting against alveolar bone loss in experimental periodontitis.

The aim of this study was to compare the effects of two osteoanabolic drugs, abaloparatide (ABL) and teriparatide (TPTD), on protecting alveolar bone in experimental periodontitis. Twenty-four 9-week-old, male, Sprague-Dawley rats were placed with silk suture around the right maxillary second molar, and then were randomly divided into three groups, that is, the ABL, TPTD, and saline group, receiving intermittent subcutaneous injections of ABL (80μg/kg), TPTD (80μg/kg) or saline respectively every other day for 4weeks. Samples on both sides were assessed through micro-computerized tomography, histological, and immunohistochemical analysis. Mouse pre-osteoblast MC3T3 cell was cultured with lipopolysaccharide (LPS) and treated with ABL or TPTD, before assays of cell proliferation, alkaline phosphatase (ALP) activity and real-time polymerase chain reaction. On the ligature side, both ABL and TPTD significantly reduced alveolar bone loss, and ABL had significantly better effects with higher expression of runt-related transcription factor 2 (RUNX2) and Bglap (formerly called osteocalcin); meanwhile, the ligature induced osteoclastogenesis and down-regulation of osteoprotegerin (OPG) was affected by neither drug. On the non-ligature side, ABL also showed better osteoanabolic effects. In vitro studies revealed that, in the presence of LPS, ABL, and TPTD similarly promoted MC3T3 proliferation, whereas ABL induced higher ALP activity and osteoblastic gene expression compared to TPTD. Both ABL and TPTD protect and regenerate alveolar bone in experimental periodontitis, and ABL behaves even better than TPTD at the same dose, attributed to its stronger osteoanabolic effects in this context.

Protocol for Developing a Femur Osteotomy Model in Wistar Albino Rats.

Fracture healing is a physiological process resulting in the regeneration of bone defects by the coordinated action of osteoblasts and osteoclasts. Osteoanabolic drugs have the potential to augment the repair of fractures but have constraints like high costs or undesirable side effects. The bone healing potential of a drug can initially be determined by in vitro studies, but in vivo studies are needed for the final proof of concept. Our objective was to develop a femur osteotomy rodent model that could help researchers understand the development of callus formation following fracture of the shaft of the femur and that could help establish whether a potential drug has bone healing properties. Adult male Wistar albino rats were used after Institutional Animal Ethics Committee clearance. The rodents were anesthetized, and under aseptic conditions, complete transverse fractures at the middle one-third of the shafts of the femurs were created using open osteotomy. The fractures were reduced and internally fixed using intramedullary K-wires, and secondary fracture healing was allowed to take place. After surgery, intraperitoneal analgesics and antibiotics were given for 5 days. Sequential weekly x-rays assessed callus formation. The rats were sacrificed based on radiologically pre-determined time points, and the development of the fracture callus was analyzed radiologically and using immunohistochemistry.

Interactome of PTH-Regulated miRNAs and Their Predicted Target Genes for Investigating the Epigenetic Effects of PTH (1–34) in Bone Metabolism

Osteoporosis is a metabolic bone disease that mostly affects the elderly. A lot of drugs are available, mostly with an antiresorptive effect but just a few with an osteoanabolic effect, meaning they promote bone building. PTH (1-34) or teriparatide is an osteoanabolic drug, but its efficacy varies between individuals. We performed a literature review and extracted a dataset of 62 microRNAs (miRNAs) from 10 different studies; predicted miRNA target interactions (MTIs) were obtained with the help of four software tools: DIANA, miRWalk, miRDB and TargetScan. With the construction of an interactome of PTH-regulated miRNAs and their predicted target genes, we elucidated miR-146a-5p, miR-551b-5p, miR-205-3p, miR-33a-3p, miR-338-5p as miRNAs with the most interactions and miR-410-3p as the miRNA targeting bone-related pathways with the highest significance. These miRNAs could help in further understanding the mechanism of action of PTH on bone metabolism and osteoporosis. They also have the potential for novel network-based biomarkers for osteoporosis treatment efficacy and safety and as new therapeutic targets.

Prevention and Treatment of Glucocorticoid-Induced Osteoporosis in Adults: Consensus Recommendations From the Belgian Bone Club.

Glucocorticoids are effective immunomodulatory drugs used for many inflammatory disorders as well as in transplant recipients. However, both iatrogenic and endogenous glucocorticoid excess are also associated with several side effects including an increased risk of osteoporosis and fractures. Glucocorticoid-induced osteoporosis (GIOP) is a common secondary cause of osteoporosis in adults. Despite availability of clear evidence and international guidelines for the prevention of GIOP, a large treatment gap remains. In this narrative review, the Belgian Bone Club (BBC) updates its 2006 consensus recommendations for the prevention and treatment of GIOP in adults. The pathophysiology of GIOP is multifactorial. The BBC strongly advises non-pharmacological measures including physical exercise, smoking cessation and avoidance of alcohol abuse in all adults at risk for osteoporosis. Glucocorticoids are associated with impaired intestinal calcium absorption; the BBC therefore strongly recommend sufficient calcium intake and avoidance of vitamin D deficiency. We recommend assessment of fracture risk, taking age, sex, menopausal status, prior fractures, glucocorticoid dose, other clinical risk factors and bone mineral density into account. Placebo-controlled randomized controlled trials have demonstrated the efficacy of alendronate, risedronate, zoledronate, denosumab and teriparatide in GIOP. We suggest monitoring by dual-energy X-ray absorptiometry (DXA) and vertebral fracture identification one year after glucocorticoid initiation. The trabecular bone score might be considered during DXA monitoring. Extended femur scans might be considered at the time of DXA imaging in glucocorticoid users on long-term (≥ 3 years) antiresorptive therapy. Bone turnover markers may be considered for monitoring treatment with anti-resorptive or osteoanabolic drugs in GIOP. Although the pathophysiology of solid organ and hematopoietic stem cell transplantation-induced osteoporosis extends beyond GIOP alone, the BBC recommends similar evaluation, prevention, treatment and follow-up principles in these patients. Efforts to close the treatment gap in GIOP and implement available effective fracture prevention strategies into clinical practice in primary, secondary and tertiary care are urgently needed.

A-769662 stimulates the differentiation of bone marrow-derived mesenchymal stem cells into osteoblasts via AMP-activated protein kinase-dependent mechanism.

AMP-activated protein kinase (AMPK) signaling shows an important role in energy metabolism and has recently been involved in osteogenic and adipogenic differentiation. In this study we aimed to investigate the role of AMPK activator, A-769662, in regulating the differentiation of mesenchymal stem cells derived from bone marrow (BMSCs) into osteoblastic and adipocytic cell lineage. The effect of A-769662 on osteogenesis was assessed by quantitative alkaline phosphatase (ALP) activity, matrix mineralization stained with Alizarin red, and gene expression analysis by quantitative polymerase chain reaction (qPCR). Adipogenesis was determined by Oil Red O staining for fat droplets and qPCR analysis of adipogenic markers. A-769662 activated the phosphorylation of AMPKα1 during the osteogenesis of mBMSCs as revealed by western blot analysis. A-769662 promoted the early stage of the commitment of mouse (m) BMSCs differentiation into osteoblasts, while inhibiting their differentiation into adipocytes in a dose-dependent manner. The effects of A-769662 on stimulating osteogenesis and inhibiting adipogenesis of mBMSCs were significantly eliminated in the presence of either AMPKα1 siRNA or Compound C, an inhibitor of AMPK pathway. In conclusion, we identified A-769662 as a new compound that promotes the commitment of BMSCs into osteoblasts versus adipocytes via AMPK-dependent mechanism. Thus our data show A-769662 as a potential osteo-anabolic drug for treatment of osteoporosis.

Osteoporosis Treatment with Anti-Sclerostin Antibodies-Mechanisms of Action and Clinical Application.

Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures and significant long-term disability. Although both anti-resorptive treatments and osteoanabolic drugs, such as parathyroid hormone analogues, are effective in fracture prevention, limitations exist due to lack of compliance or contraindications to these drugs. Thus, there is a need for novel potent therapies, especially for patients at high fracture risk. Romosozumab is a monoclonal antibody against sclerostin with a dual mode of action. It enhances bone formation and simultaneously suppresses bone resorption, resulting in a large anabolic window. In this opinion-based narrative review, we highlight the role of sclerostin as a critical regulator of bone mass and present human diseases of sclerostin deficiency as well as preclinical models of genetically modified sclerostin expression, which led to the development of anti-sclerostin antibodies. We review clinical studies of romosozumab in terms of bone mass accrual and anti-fracture activity in the setting of postmenopausal and male osteoporosis, present sequential treatment regimens, and discuss its safety profile and possible limitations in its use. Moreover, an outlook comprising future translational applications of anti-sclerostin antibodies in diseases other than osteoporosis is given, highlighting the clinical significance and future scopes of Wnt signaling in these settings.

The difference of muscle fatigue in forearm during propelling a wheelchair with and without a badminton racquet

Parathyroid hormone (PTH) is the only clinically approved osteoanabolic drug for osteoporosis treatment. However, PTH is not established for the treatment of fracture healing, and doses of PTH diverge significantly between different studies. We hypothesized that the effect of PTH on promoting fracture healing and bone formation is dose dependent.In vivo, mice were treated with PTH (10, 40, and 200 μg/kg) in a closed femoral fracture model. Fracture healing was analyzed after 4 weeks. The fourth lumbar vertebra was analyzed to assess systemic effects. In addition, osteoblasts from calvaria of mice were treated in vitro with PTH doses of 10−5-50 nM, and their differentiation was analyzed after 26 days.In vivo, PTH dose-dependently stimulated bone formation in the fracture callus and the vertebral body. However, PTH treatment did not increase biomechanical stiffness of the fractured femora in a dose-dependent manner. The increased bone formation in the 200 μg/kg group was associated with a depletion of osteoclasts, indicating diminished bone remodeling. Of interest, in vitro, we observed diminished mineralization with the highest doses of PTH in osteoblast cultures.PTH dose-dependently stimulates bone formation in vivo. However, during fracture healing, this did not result in a dose-dependent increase of the mechanical stiffness of the fracture callus. Taken together, our in vivo and in vitro data indicate that the dose-dependent effects of PTH during fracture healing are based on the actions on multiple cell types, thereby influencing not only bone formation but also osteoclastic callus remodeling.

Teriparatide for the Treatment of Medication-Related Osteonecrosis of the Jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a painful and intractable disease of the jaw that clinically presents as an area of ulceration with exposed necrotic bone. In severe cases, it can predispose to jaw fracture, skin fistula, or osteolysis extending beyond the region of the alveolar bone. No effective treatment has been established for this condition. Recently, teriparatide, a recombinant parathyroid hormone, and the only FDA-approved osteoanabolic drug for the treatment of glucocorticoid-induced osteoporosis, has been used for the treatment of MRONJ. We review the literature highlighting the effectiveness of teriparatide alone or as an adjunct in the treatment of MRONJ. Twenty publications met our selection criteria, comprising 54 patients with stage 2 or 3 MRONJ secondary to antiresorptive/antiangiogenic drugs. Trauma due to implant placement was the most common triggering factor for the development of MRONJ. Patients were treated with subcutaneous injections of 20-μg teriparatide for 3-12 months (5 1/2 months average). Symptomatic relief was achieved in almost all cases, with lesions healing completely in 49 of 54 patients. Based on our findings, teriparatide can play an important role in the treatment of MRONJ.

Osteoanabolic and dual action drugs.

Teriparatide (TPTD) and abaloparatide (ABL) are the only osteoanabolic drugs available, at this time, for treatment of osteoporosis. TPTD is a 34-amino acid fragment that is identical in its primary sequence to the 34 amino acids of full-length human parathyroid hormone [hPTH(1-84)]. ABL is identical to parathyroid hormone-related peptide (PTHrP) through the first 22 residues with significantly different amino acids inserted thereafter, between residues 22 and 34. The osteoanabolic actions of PTH are due directly to its effects on cells of the osteoblast lineage and indirectly by stimulating IGF-I synthesis and suppressing sclerostin and associated enhancement of Wnt signalling. Both TPTD and ABL are ligands that bind to and activate the PTH receptor type 1 (PTHR1) receptor but they appear to do so differently: ABL favours the transient, more anabolic configuration of the receptor. Both TPTD and ABL reduce the risk of vertebral fractures and non-vertebral fractures. Both drugs are administered for a maximum of 24 months, and should be followed by an antiresorptive agent to maintain gains in bone mineral density (BMD). Romosozumab, a monoclonal antibody that binds to and inhibits sclerostin, appears to have dual actions by stimulating bone formation and reducing bone resorption. In the pivotal clinical trial, romosozumab, administered as a 210mg monthly subcutaneous dose, significantly reduced new vertebral fractures and in a subsequent study reduced both vertebral and non-vertebral fractures.

A Novel H2S-releasing Amino-Bisphosphonate which combines bone anti-catabolic and anabolic functions

Bisphosphonates (BPs) are the first-line treatment of bone loss resulting from various pathological conditions. Due to their high affinity to bone they have been used to develop conjugates with pro-anabolic or anti-catabolic drugs. We recently demontrated that hydrogen sulfide (H2S), promotes osteogenesis and inhibits osteoclast differentiation. Here we developed an innovative molecule, named DM-22, obtained from the combination of alendronate (AL) and the H2S-releasing moiety aryl-isothiocyanate. DM-22 and AL were assayed in vitro in the concentration range 1-33 μM for effects on viability and function of human osteoclasts (h-OCs) and mesenchymal stromal cells (h-MSCs) undergoing osteogenic differentiation. Amperometric measures revealed that DM-22 releases H2S at a slow rate with a thiol-dependent mechanism. DM-22 significantly inhibited h-OCs differentiation and function, maintaining a residual h-OCs viability even at the high dose of 33 μM. Contrary to AL, in h-MSCs DM-22 did not induce cytotoxicity as revealed by LDH assay, significantly stimulated mineralization as measured by Alizarin Red staining and increased mRNA expression of Collagen I as compared to control cultures. In conclusion, DM-22 is a new BP which inhibits h-OCs function and stimulate osteogenic differentiation of h-MSCs, without cytotoxicity. DM-22 is an ideal candidate for a novel family of osteoanabolic drugs.

Dose-dependent effect of parathyroid hormone on fracture healing and bone formation in mice

BackgroundParathyroid hormone (PTH) is the only clinically approved osteoanabolic drug for osteoporosis treatment. However, PTH is not established for the treatment of fracture healing, and doses of PTH diverge significantly between different studies. We hypothesized that the effect of PTH on promoting fracture healing and bone formation is dose dependent. Materials and methodsIn vivo, mice were treated with PTH (10, 40, and 200 μg/kg) in a closed femoral fracture model. Fracture healing was analyzed after 4 weeks. The fourth lumbar vertebra was analyzed to assess systemic effects. In addition, osteoblasts from calvaria of mice were treated in vitro with PTH doses of 10−5-50 nM, and their differentiation was analyzed after 26 days. ResultsIn vivo, PTH dose-dependently stimulated bone formation in the fracture callus and the vertebral body. However, PTH treatment did not increase biomechanical stiffness of the fractured femora in a dose-dependent manner. The increased bone formation in the 200 μg/kg group was associated with a depletion of osteoclasts, indicating diminished bone remodeling. Of interest, in vitro, we observed diminished mineralization with the highest doses of PTH in osteoblast cultures. ConclusionsPTH dose-dependently stimulates bone formation in vivo. However, during fracture healing, this did not result in a dose-dependent increase of the mechanical stiffness of the fracture callus. Taken together, our in vivo and in vitro data indicate that the dose-dependent effects of PTH during fracture healing are based on the actions on multiple cell types, thereby influencing not only bone formation but also osteoclastic callus remodeling.

The anabolic action of intermittent parathyroid hormone on cortical bone depends partly on its ability to induce nitric oxide-mediated vasorelaxation in BALB/c mice.

There is strong evidence that vasodilatory nitric oxide (NO) donors have anabolic effects on bone in humans. Parathyroid hormone (PTH), the only osteoanabolic drug currently approved, is also a vasodilator. We investigated whether the NO synthase inhibitor L‐NAME might alter the effect of PTH on bone by blocking its vasodilatory effect. BALB/c mice received 28 daily injections of PTH[1–34] (80 µg/kg/day) or L‐NAME (30 mg/kg/day), alone or in combination. Hindlimb blood perfusion was measured by laser Doppler imaging. Bone architecture, turnover and mechanical properties in the femur were analysed respectively by micro‐CT, histomorphometry and three‐point bending. PTH increased hindlimb blood flow by >30% within 10 min of injection (P < 0.001). Co‐treatment with L‐NAME blocked the action of PTH on blood flow, whereas L‐NAME alone had no effect. PTH treatment increased femoral cortical bone volume and formation rate by 20% and 110%, respectively (P < 0.001). PTH had no effect on trabecular bone volume in the femoral metaphysis although trabecular thickness and number were increased and decreased by 25%, respectively. Co‐treatment with L‐NAME restricted the PTH‐stimulated increase in cortical bone formation but had no clear‐cut effects in trabecular bone. Co‐treatment with L‐NAME did not affect the mechanical strength in femurs induced by iPTH. These results suggest that NO‐mediated vasorelaxation plays partly a role in the anabolic action of PTH on cortical bone. © 2016 The Authors. Cell Biochemistry and Function published by John Wiley & Sons, Ltd.

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.

Actualización en el tratamiento de la osteoporosis: manejo desde una unidad del dolor (1.ª parte)

Osteoporosis (OP) is defined as a skeletal disorder characterized by decreased bone strength, which predisposes to an increase in fracture risk. In Europe produced 2.7 million fragility fractures in both men and women with a direct cost of 36 billion euros. These fractures are associated with increased morbidity and mortality. The risk of osteoporotic fracture is determined by the presence of one or more risk factors and decreased bone mineral density (BMD) assessed by Dual Energy technique absortiometry X-ray (DEXA) densitometry. The indication for treatment is made based on the absolute risk of fragility fracture. In patients with a low risk of fracture are sufficient hygienic measures, preventing falls and maintaining an adequate intake of calcium and vitamin D. In patients with a moderate risk should be individualized drug treatment need and initiate treatment in those at high risk of fracture. The most commonly used drugs are bisphosphonates, inhibitors of bone resorption, also used as hormone teriparatide, osteoanabolic drug and monoclonal antibodies such as denosumab.