BACKGROUND:Botulinum neurotoxins are used to treat masseter muscle prominence (MMP), benign bilateral masseter muscle enlargement which can be aesthetically undesirable. Limited data report botulinum neurotoxin injections in the muscles of mastication, with subsequent reduction in biomechanical loading, may impact mandibular bone density. OBJECTIVES:This study evaluates whether changes in mandibular bone density occur after bilateral masseter treatment with a botulinum neurotoxin, onabotulinumtoxinA, in individuals with MMP. METHODS:Analyses were performed on a prespecified subpopulation (n = 123) from a 12-month, double-blind, placebo-controlled, dose-escalation, Phase 2 study (N = 187). Participants received 1 or 2 bilateral masseter treatments of onabotulinumtoxinA (48, 72, or 96 U) or placebo and had multi-detector computed tomography scans at baseline and Days 90 and 360 post-treatment. Cortical and trabecular bone densities, estimated in Hounsfield units, were calculated for the bilateral condyle, premolar dentoalveolus, and ramus. RESULTS:No clinically significant changes in mandibular bone density were observed in condyle, premolar area, or ramus of onabotulinumtoxinA-treated participants, when compared with placebo or baseline, after 1 or 2 treatments. CONCLUSIONS:In healthy adults with MMP, 1 or 2 bilateral masseter treatments with onabotulinumtoxinA at doses of 48, 72, or 96 U over 1 year did not negatively impact mandibular bone density. LEVEL OF EVIDENCE: 1 (THERAPEUTIC):

OBJECTIVE:This post hoc analysis evaluated the efficacy of abaloparatide treatment in a subgroup of postmenopausal women from the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE; NCT01343004) study who met high fracture risk criteria (defined in several professional society guidelines). METHODS:Women from ACTIVE meeting ≥1 of the following fracture risk criteria were included: fracture within the past 12 months or prevalent vertebral fracture, baseline T score of <-3.0 at any site, very high fracture risk probability by FRAX (ie, 10-yr major osteoporotic fracture >30% or hip fracture >4.5%), or multiple prior fractures at baseline since age ≥45 years. RESULTS:A total of 2,026 participants met ≥1 fracture risk criteria defined in clinical guidelines (abaloparatide, n = 664; placebo, n = 677; teriparatide, n = 685). New vertebral fracture risk was reduced in participants receiving abaloparatide (4 [0.72%]) and teriparatide (6 [0.99%]) versus placebo (28 [4.77%]; both P < 0.0001). Estimated Kaplan-Meier cumulative incidence of nonvertebral fracture was 3.0%, 5.3%, and 3.0% in the abaloparatide, placebo, and teriparatide groups, respectively; 4.0%, 9.0%, 4.3% for clinical fracture; 1.6%, 6.8%, 3.0% for major osteoporotic fractures; and 1.1%, 2.1%, 2.1% for wrist fracture. Abaloparatide was associated with bone mineral density gains from baseline at the lumbar spine, total hip, and femoral neck at all time points (6, 12, and 18 mo; P < 0.0001 for all). Common adverse events reported in participants treated with abaloparatide were hypercalciuria (11.5%), dizziness (11.0%), and arthralgia (8.9%). CONCLUSIONS:Abaloparatide reduced fracture incidence and increased bone mineral density in participants at highest fracture risk, consistent with the overall ACTIVE study.

ABSTRACTObjectiveAbaloparatide (ABL) is a synthetic parathyroid hormone‐related protein analog developed as an anabolic drug to treat osteoporosis. ABL increases bone mineral density (BMD) of the long bones and spine; however, the influence of ABL on alveolar bone regeneration remains unknown. This study assessed the effects of systemic ABL administration on tooth extraction socket healing and dental implant osseointegration in a preclinical rodent model.MethodsSprague‐Dawley rats received daily subcutaneous injection of ABL (25 μg/kg) or vehicle (VEH) at the time of maxillary first molar (M1) extraction surgery; animals underwent either: (1) unilateral M1 extraction followed by sacrifice at 10 or 42d or (2) bilateral M1 extraction followed by staged implant placement in osteotomies with standardized defects and sacrifice at 21 or 28d.ResultsMicro‐computed tomography (micro‐CT) analysis demonstrated that ABL increased bone volume fraction (p = 0.004) and bone mineral density (BMD) (p = 0.006) of regenerated extraction sockets at 42d. Micro‐CT of the femur validated systemic effects of ABL, showing greater trabecular BMD after 6 (p < 0.01), 9 (p < 0.001), and 14 (p < 0.001) weeks of treatment. Histomorphometry confirmed a higher mineralized bone area with ABL treatment in extraction sockets at 42d (p = 0.03) and in the regenerated peri‐implant bone at 21d post‐implant placement (p = 0.01) compared to control.ConclusionSystemic ABL administration enhances osteogenesis in extraction sockets prior to implant placement and accelerates peri‐implant bone formation in the early phase of healing in the present rodent model.

At present, a lack of consensus exists regarding the clinical impact of osteoporosis on alveolar bone metabolism during implant osseointegration. While limited preclinical and clinical evidence demonstrates a negative influence of osteoporosis on dental extraction socket healing, no preclinical studies offer data on the results of implant placement in 6-mo-old, ovariectomized (OVX) Sprague-Dawley rats. This study aimed to investigate the outcomes of dental tooth extraction socket healing and implant placement in a rodent model of osteoporosis following daily vehicle (VEH) or abaloparatide (ABL) administration. Micro-CT and histologic analysis demonstrated signs of delayed wound healing, consistent with alveolar osteitis in extraction sockets following 42 d of healing in both the VEH and ABL groups. In a semiquantitative histological analysis, the OVX-ABL group demonstrated a tendency for improved socket regeneration with a 3-fold greater rate for moderate socket healing when compared to the OVX-VEH group (43% vs 14%), however, this finding was not statistically significant (p=.11). No significant differences were observed between vehicle and test groups in terms of implant outcomes (BMD and bone volume/total volume) at 14- and 21-d post-implant placement. Abaloparatide (ABL) significantly increased BMD of the femoral shaft and intact maxillary alveolar bone sites in OVX animals, demonstrating the therapeutic potential for oral hard tissue regeneration. The present model involving estrogen-deficiency-induced bone loss demonstrated an impaired healing response to dental extraction and implant installation. Osteoporosis is a systemic disease that may negatively impact bone healing in the jaws. This study assesses extraction socket healing and dental implant placement in estrogen-deficient animals treated with a bone building drug, abaloparatide, compared to control. Graphical Abstract

This review aims to consolidate recent observations regarding extra-osseous roles of the RANK-RANKL-OPG axis, primarily within skeletal muscle. Preclinical efforts to decipher a common signalling pathway that links the synchronous decline in bone and muscle health in ageing and disease disclosed a potential role of the RANK-RANKL-OPG axis in skeletal muscle. Evidence suggests RANKL inhibition benefits skeletal muscle function, mass, fibre-type switching, calcium homeostasis and reduces fall incidence. However, there still exists ambiguity regarding the exact mechanistic actions and subsequent functional improvements. Other potential RANK-RANKL-OPG extra-osseous roles include regulation of neural-inflammation and glucose metabolism. Growing evidence suggests the RANK-RANKL-OPG axis may play a regulatory role in extra-osseous tissues, especially in skeletal muscle. Targeting RANKL may be a novel therapy in ameliorating loss of muscle mass and function. More research is warranted to determine the causality of the RANK-RANKL-OPG axis in extra-osseous tissues, especially those affected by aging.

Osteocytes express parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptors and respond to the PTHrP analog abaloparatide (ABL) and to the PTH 1-34 fragment teriparatide (TPTD), which are used to treat osteoporosis. Several studies indicate overlapping but distinct skeletal responses to ABL or TPTD, but their effects on cortical bone may differ. Little is known about their differential effects on osteocytes. We compared cortical osteocyte and skeletal responses to ABL and TPTD in sham-operated and ovariectomized mice. Administered 7 weeks after ovariectomy for 4 weeks at a dose of 40 μg/kg/d, TPTD and ABL had similar effects on trabecular bone, but ABL showed stronger effects in cortical bone. In cortical osteocytes, both treatments decreased lacunar area, reflecting altered peri-lacunar remodeling favoring matrix accumulation. Osteocyte RNA-Seq revealed that several genes and pathways were altered by ovariectomy and affected similarly by TPTD and ABL. Notwithstanding, several signaling pathways were uniquely regulated by ABL. Thus, in mice, TPTD and ABL induced a positive osteocyte peri-lacunar remodeling balance, but ABL induced stronger cortical responses and affected the osteocyte transcriptome differently. We concluded that ABL affected the cortical osteocyte transcriptome in a manner subtly different from TPTD, resulting in more beneficial remodeling/modeling changes and homeostasis of the cortex.

We hypothesized that local improvements in bone mineral density (BMD) would be observed following 6 and 18 mo of abaloparatide versus placebo in hip regions corresponding to femoral Gruen zones that influence the fixation and stability of femoral stems in hip arthroplasty. Low BMD at the time of total hip arthroplasty (THA) increases the risk of compromised implant stability and delayed osseointegration (1). Abaloparatide, a synthetic analog to PTHrP(1-34), is FDA approved for the treatment of men and postmenopausal women with osteoporosis. Abaloparatide increases spine and hip BMD and reduces the risk of vertebral and nonvertebral fractures (2). A subset of 500 postmenopausal women with osteoporosis from the ACTIVE trial (2) who received abaloparatide or placebo (n=250/group) were randomly selected. Hip DXA scans obtained after 6 and 18 mo of treatment underwent 3D modeling via 3D-Shaper software (3), and a virtual Stryker (Mahwah, NJ) Accolade II hip stem was optimally sized and positioned within each 3D-DXA scan. Periprosthetic regions corresponding to Gruen zones 1, 2, 6, and 7 were assessed for volumetric BMD (vBMD) (integral, cortical, trabecular) and cortical thickness (zones 3, 4, and 5 were beyond the DXA region of interest). Treatment comparisons were made with P values derived from a mixed-effect model for repeated measures. Abaloparatide significantly increased integral vBMD compared with placebo in Gruen zones 1, 2, 6, and 7 at 6 and 18 mo (P< 0.01 for all) (Table 1). The largest percent increases were in zones 1 and 7. Abaloparatide increased cortical vBMD at 18 mo in all 4 analyzed zones (P< 0.01), increased trabecular vBMD at 6 and 18 mo in zones 1 and 7 (P< 0.0001), and increased cortical thickness at 6 months in zones 1, 6, and 7 (P< 0.01) and in all zones at 18 months (P< 0.001). Color maps of cross-sectional group mean change in vBMD demonstrates more robust BMD accrual with abaloparatide (Figure 1). Abaloparatide significantly increased vBMD and cortical thickness in virtual Gruen zones 1, 2, 6, and 7 compared with placebo. Abaloparatide may represent an effective agent for bone health optimization prior to THA by inducing orthopedically important localized gains in BMD. Additional research into preoperative augmentation and postoperative treatment is warranted. References: 1. Aro HT et al. Acta Orthop 2012;83;107-14; 2. Miller PD et al. JAMA 2017;317:442; 3. Winzenrieth R et al. Osteoporos Int 2021;32:575–83.

Background: Fracture repair involves the reactivation of developmental signaling cascades, including Wnt signaling that stimulates bone formation and bone regeneration. Rodent data indicate that dual inhibition of the Wnt signaling antagonists sclerostin and Dickkopf-1 (DKK1) increases callus bone volume and strength while increasing bone mass systemically. Methods: We evaluated the effects of 16 weeks of subcutaneously administered carrier solution (vehicle, VEH), anti-sclerostin antibody (Scl-Ab), anti-DKK1 antibody (DKK1-Ab), or Scl-Ab plus DKK1-Ab combination therapy (COMBO) on ulnar osteotomy healing in nonhuman primates (cynomolgus monkeys; 20 to 22 per group). Results: Scl-Ab and COMBO therapy increased systemic markers of bone formation versus VEH, with COMBO leading to synergistic increases versus Scl-Ab or DKK1-Ab monotherapies. The COMBO and Scl-Ab groups showed reduced serum markers of bone resorption versus VEH. The COMBO and DKK1-Ab groups exhibited greater callus bone mineral density (BMD), torsional stiffness, and torsional rigidity versus VEH. Lumbar vertebrae from the Scl-Ab and COMBO groups showed greater BMD and bone formation rate versus VEH, and the femoral mid-diaphysis of the Scl-Ab and COMBO groups showed greater periosteal and endocortical bone formation rates versus VEH. Conclusions: DKK1-Ab increased BMD and strength at the ulnar osteotomy site, Scl-Ab increased bone formation and BMD at uninjured skeletal sites, and Scl-Ab plus DKK1-Ab combination therapy induced all of these effects, in some cases to a greater degree versus 1 or both monotherapies. These results in nonhuman primates suggest that DKK1 preferentially regulates bone healing while sclerostin preferentially regulates systemic bone mass. Clinical Relevance: Combination therapy with antibodies against sclerostin and DKK1 may offer a promising therapeutic strategy for both fracture treatment and fracture prevention.

ABSTRACT Prolonged use of antiresorptives such as the bisphosphonate alendronate (ALN) and the RANKL inhibitor denosumab (DMAb) are associated with rare cases of atypical femoral fracture (AFF). The etiology of AFF is unclear, but it has been hypothesized that potent osteoclast inhibitors may reduce bone fatigue resistance. The purpose of this study was to quantify the relationship between antiresorptive treatment and fatigue life (cycles to failure) in bone from ovariectomized cynomolgus monkeys. We analyzed humeral bone from 30 animals across five treatment groups. Animals were treated for 12 months with subcutaneous (sc) vehicle (VEH), sc DMAb (25 mg/kg/month), or intravenous (iv) ALN (50 μg/kg/month). Another group received 6 months VEH followed by 6 months DMAb (VEH‐DMAb), and the final group received 6 months ALN followed by 6 months DMAb (ALN‐DMAb). A total of 240 cortical beam samples were cyclically tested in four‐point bending at 80, 100, 120, or 140 MPa peak stress. High‐resolution imaging and density measurements were performed to evaluate bone microstructure and composition. Samples from the ALN ( p = 0.014), ALN‐DMAb ( p = 0.008), and DMAb ( p < 0.001) groups illustrated higher fatigue‐life measurements than VEH. For example, at 140 MPa the VEH group demonstrated a median ± interquartile range (IQR) fatigue life of 1987 ± 10593 cycles, while animals in the ALN, ALN‐DMAb, and DMAb groups survived 9850 ± 13648 (+395% versus VEH), 10493 ± 16796 (+428%), and 14495 ± 49299 (+629%) cycles, respectively. All antiresorptive treatment groups demonstrated lower porosity, smaller pore size, greater pore spacing, and lower number of canals versus VEH ( p < 0.001). Antiresorptive treatment was also associated with greater apparent density, dry density, and ash density ( p ≤ 0.03). We did not detect detrimental changes following antiresorptive treatments that would explain their association with AFF. In contrast, 12 months of treatment may have a protective effect against fatigue fractures. © 2022 American Society for Bone and Mineral Research (ASBMR).

Platelet-rich plasma (PRP) is a popular autologous therapy in the tissue regenerative technology space based on its enriched milieu of platelet-released growth factors (GFs), including platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). PRP is frequently used for hair restoration, wound healing, tendon and ligament repairs, and other soft-tissue settings, but PRP did not fulfill its original promise for enhancing bone grafts and bone augmentation in dentistry or orthopedics because it does not consistently promote osteogenesis. The effects of PRP on bone regeneration are often described as controversial, contradictory, and confusing, including evidence that greater platelet enrichment often leads to lesser osteogenic responses. The latter paradox suggests that limited PRP efficacy in bone regeneration may relate to platelet-derived factors that inhibit osteoblasts rather than inadequate GF concentrations. One candidate platelet-derived anti-osteogenic factor is Dickkopf-1 (DKK1), a potent soluble inhibitor of Wnt signaling that limits bone regeneration after bone damage. Recognizing that platelets store DKK1 in their alpha granules and rapidly release it upon platelet activation, we evaluated levels of DKK1, PDGF, and VEGF in human serum, plasma, platelet-poor plasma (PPP), and PRP. Sclerostin, another inhibitor of Wnt signaling that limits bone formation in undamaged bone, was also evaluated because platelets are not known to secrete sclerostin. We show that DKK1, PDGF, and VEGF concentrations are much higher in serum versus plasma, probably due to platelet activation during serum preparation. DKK1, PDGF, and VEGF concentrations were also higher in PRP versus plasma, and in plasma versus PPP. Activation of plasma or PRP with thrombin resulted in marked increases in DKK1, PDGF, and VEGF concentrations, with DKK1 levels in activated PRP being over 40-fold higher than the minimum concentration reported to inhibit osteogenesis in cell culture models. Conversely, sclerostin levels in plasma and PRP were unaffected by platelet activation and were significantly lower in serum versus standard plasma, providing new evidence that platelets do not secrete sclerostin. These results suggest that the beneficial effects of high GF levels in PRP may be limited by the presence of high levels of DKK1 released from the same platelet alpha granules.

This review summarizes recently published data and other developments around osteoanabolic osteoporosis therapies in patients with very high fracture risk, including those undergoing bone-related surgery. Two osteoanabolic agents, abaloparatide and romosozumab, were recently approved for treatment of patients with osteoporosis at high fracture risk. These agents, along with teriparatide, are valuable for primary and secondary fracture prevention. Orthopedic surgeons are well positioned to facilitate secondary fracture prevention via referrals to fracture liaison services or other bone health specialist colleagues. This review aims to help surgeons understand how to identify patients with sufficiently high fracture risk to warrant consideration of osteoanabolic therapy. Recent evidence around the perioperative use and potential benefits of osteoanabolic agents in fracture healing and other orthopedic settings (e.g., spinal fusion and arthroplasty) in individuals with osteoporosis is also discussed. Osteoanabolic agents should be considered for patients with osteoporosis at very high fracture risk, including those with prior osteoporotic fractures and those with poor bone health who are undergoing bone-related surgery.

ABSTRACT Previous subgroup analyses from the ACTIVE trial in women with postmenopausal osteoporosis (NCT01343004) using three‐dimensional (3D)‐processing of dual X‐ray absorptiometry (DXA) scans indicated greater increases in total hip cortical volumetric bone mineral density (Ct.vBMD) and estimated indices of hip strength following 18 months of abaloparatide (ABL) versus placebo or teriparatide. The current post hoc analyses describe hip 3D‐DXA data for ACTIVExtend (NCT01657162), in which 18 months of ABL followed by 24 months of alendronate (ABL/ALN) increased hip and spine areal BMD (aBMD) and reduced fracture risk versus placebo (PBO) followed by ALN (PBO/ALN). In an ACTIVExtend subgroup (ABL/ALN, n = 204; PBO/ALN, n = 202), hip DXA scans retrospectively underwent 3D modeling via 3D‐Shaper software. Changes from baseline in cortical and trabecular compartments were calculated for total hip and hip subregions (femoral neck, trochanter, and shaft). Estimated strength indices comprising cross‐sectional moment of inertia, section modulus, and buckling ratio were calculated for each hip subregion. Correlations between bone turnover marker levels at the time of alendronate initiation and subsequent BMD gains with alendronate were also investigated within each group. Total hip trabecular and cortical 3D‐DXA parameters increased from baseline in both groups (all p < 0.001), with greater average increases for ABL/ALN versus PBO/ALN (trabecular vBMD: 10.87% versus 4.3%; cortical thickness: 2.32% versus 1.14%; Ct.vBMD: 3.41% versus 1.86%; cortical surface BMD: 5.82% versus 3.0%; all p < 0.001). Strength indices in the ABL/ALN group improved in all subregions versus baseline (all p < 0.0001) and versus PBO/ALN (all p < 0.02). In the ABL/ALN group, collagen type I N‐terminal propeptide (P1NP) levels at the time of alendronate initiation correlated with subsequent percent changes in all 3D‐DXA parameters with 24 months of alendronate therapy. In conclusion, sequential ABL/ALN or PBO/ALN treatment improves trabecular and cortical 3D‐DXA parameters at the hip, as well as strength indices of hip subregions, with greater increases with ABL/ALN versus PBO/ALN. © 2022 Radius Health, Inc. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

In ACTIVE, abaloparatide increased areal BMD (aBMD) of the hip and femoral neck vs teriparatide and placebo in women with osteoporosis. Previously, 3D-processing of dual X-ray absorptiometry (DXA) scans of a subgroup of ACTIVE subjects showed similar increases in trabecular volumetric BMD (Tb.vBMD) and greater increases in cortical vBMD (Ct.vBMD) of the total hip with abaloparatide vs teriparatide. The current analyses from this subgroup describe 2D- and 3D-DXA data for hip subregions. Randomly selected subjects from ACTIVE (n = 250/treatment group) who received 18 mo of placebo, abaloparatide 80 µg, or open-label teriparatide 20 µg by daily subcutaneous injection underwent hip DXA at baseline, and mo 6 and 18 of treatment. Areal BMD of the femoral neck, trochanter, and femoral shaft was determined using standard 2D-DXA and 3D-SHAPER software to retrospectively evaluate changes from baseline in volumetric parameters of these 3 hip subregions, including trabecular and cortical segmentation. Changes in biomechanical parameters cross-sectional moment of inertia (CSMI), section modulus (Z), and buckling ratio were also evaluated. Femoral neck, trochanter, and shaft aBMD increased in the abaloparatide and teriparatide groups at mo 6 and 18 vs placebo, with greater increases for abaloparatide vs teriparatide at the femoral neck at mo 6 and the shaft at mo 6 and 18. All 3 subregions showed similar significant increases in Tb.vBMD with abaloparatide and teriparatide vs placebo, whereas Ct.vBMD of all 3 subregions showed greater increases after 18 mo of abaloparatide vs teriparatide. Biomechanical parameters improved in all subregions with abaloparatide and teriparatide vs placebo, with greater improvements in CSMI and Z of the femoral neck and lower shaft after 6 and 18 mo of abaloparatide vs teriparatide. Differential femoral neck and shaft Ct.vBMD responses may explain the greater increases in CSMI and Z of those subregions with abaloparatide vs teriparatide.

Upper extremity fractures, including those at the humerus, are common among women with postmenopausal osteoporosis. Denosumab was shown to reduce humeral fractures in this population; however, no clinical or preclinical studies have quantified the effects of denosumab on humerus bone mineral density or bone microarchitecture changes. This study used micro-computed tomography (μCT) and computed tomography (CT), alongside image-based finite element (FE) models derived from both modalities, to quantify the effects of denosomab (DMAb) and alendronate (ALN) on humeral bone from acutely ovariectomized (OVX) cynomolgus monkeys. Animals were treated with 12 monthly injections of s.c. vehicle (VEH; n = 10), s.c. denosumab (DMAb; 25 mg/kg, n = 9), or i.v. alendronate (ALN; 50 μg/kg, n = 10). Two more groups received 6 months of VEH followed by 6 months of DMAb (VEH-DMAb; n = 7) or 6 months of ALN followed by 6 months of DMAb (ALN-DMAb; n = 9). After treatment, humeri were harvested and μCT was used to quantify tissue mineral density, trabecular morphology, and cortical porosity at the humeral head. Clinical CT imaging was also used to quantify trabecular and cortical bone mineral density (BMD) at the ultra-proximal, proximal, 1/5 proximal and midshaft of the bone. Finally, μCT-based FE models in compression, and CT-based FE models in compression, torsion, and bending, were developed to estimate differences in strength. Compared to VEH, groups that received DMAb at any time demonstrated lower cortical porosity and/or higher tissue mineral density via μCT; no effects on trabecular morphology were observed. FE estimated strength based on μCT was higher after 12-months DMAb (p = 0.020) and ALN-DMAb (p = 0.024) vs. VEH; respectively, FE predicted mean (SD) strength was 4649.88 (710.58) N, and 4621.10 (1050.16) N vs. 3309.4 (876.09) N. All antiresorptive treatments were associated with higher cortical BMD via CT at the 1/5 proximal and midshaft of the humerus; however, no differences in CT-based FE predicted strength were observed. Overall, these results help to explain the observed reductions in humeral fracture rate following DMAb treatment in women with postmenopausal osteoporosis.

Osteoclast differentiation and activity are primarily promoted and regulated via a receptor on osteoclast lineage cells called receptor activator of nuclear factor–kappa B (RANK), which is activated through binding to its only known ligand, RANK ligand (RANKL). Several common diseases presenting with excessive bone loss, such as osteoporosis, osteolytic bone metastases, and rheumatoid arthritis, are characterized by increased RANKL activity. The development and approval of denosumab, a fully human monoclonal antibody against RANKL that inhibits bone resorption in a potent, targeted, and reversible manner, represents a major advance in the treatment of bone diseases. This chapter summarizes the molecular and cellular biology of the RANKL/RANK pathway and reviews preclinical and clinical studies that highlight the efficacy and safety of denosumab and other RANKL inhibitors for the treatment of metabolic and malignant bone diseases.

Destruction of the alveolar bone in the jaws can occur due to periodontitis, trauma or following tumor resection. Common reconstructive therapy can include the use of bone grafts with limited predictability and efficacy. Romosozumab, approved by the FDA in 2019, is a humanized sclerostin-neutralizing antibody (Scl-Ab) indicated in postmenopausal women with osteoporosis at high risk for fracture. Preclinical models show that Scl-Ab administration preserves bone volume during periodontal disease, repairs bone defects surrounding dental implants, and reverses alveolar bone loss following extraction socket remodeling. To date, there are no studies evaluating Scl-Ab to repair osseous defects around teeth or to identify the efficacy of locally-delivered Scl-Ab for targeted drug delivery. In this investigation, the use of systemically-delivered versus low dose locally-delivered Scl-Ab via poly(lactic-co-glycolic) acid (PLGA) microspheres (MSs) was compared at experimentally-created alveolar bone defects in rats. Systemic Scl-Ab administration improved bone regeneration and tended to increase cementogenesis measured by histology and microcomputed tomography, while Scl-Ab delivered by MSs did not result in enhancements in bone or cemental repair compared to MSs alone or control. In conclusion, systemic administration of Scl-Ab promotes bone and cemental regeneration while local, low dose delivery did not heal periodontal osseous defects in this study.

Background: Although the importance of mast cells in asthma has been studied, mast cells-induced global changes in lungs are largely unknown. Data-driven identification contributes to discovering significant biomarkers or therapeutic targets, which are the basis of effective clinical medications. Objective: This study aims to explore the effects of mast cells on gene expression in asthmatic lungs, and to assess the curative effects of inhaled budesonide (BUD). Methods: Pulmonary gene expression in KitWsh mice with or without mast cell engraftment was analyzed with R software. Functional enrichment of Gene Ontology and KEGG was carried out through the DAVID online tool. Hub genes were identified with String and Cytoscape software. Results: The array analyses showed that the mast cell engraftment enhanced inflammation/immune response, cytokine/chemokine signal, and monocyte/neutrophil/lymphocyte chemotaxis. Interleukin (IL)-6 was identified to be a significant hub gene with the highest interaction degree. Based on this, the effects of BUD were investigated on the aspects of anti-inflammation. BUD's treatment was found to reduce serum IL-6 content and pulmonary inflammation in ovalbumin-induced asthma rats. The treatment also downregulated beta-tryptase expression both in lung tissues and serum. Morphologically, the accumulation and degranulation of mast cells were significantly suppressed. Notably, the effects of BUD on inflammation and degranulation were comparable with Tranilast (a classic mast cell inhibitor), while a remarkable synergy was not observed. Conclusion: This study presented a unique pulmonary gene profile induced by mast cell engraftment, which could be reversed through blockage of mast cells or inhaled BUD.