Changes in Skeletal Microstructure Through Four Continuous Years of rhPTH(1–84) Therapy in Hypoparathyroidism

Bone remodeling is reduced in hypoparathyroidism, resulting in increased areal bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) and abnormal skeletal indices by transiliac bone biopsy. We have now studied skeletal microstructure by high-resolution peripheral quantitative computed tomography (HR-pQCT) through 4 years of treatment with recombinant human PTH(1–84) (rhPTH[1–84]) in 33 patients with hypoparathyroidism (19 with postsurgical disease, 14 idiopathic). We calculated Z-scores for our cohort compared with previously published normative values. We report results at baseline and 1, 2, and 4 years of continuous therapy with rhPTH(1–84). The majority of patients (62%) took rhPTH(1–84) 100 μg every other day for the majority of the 4 years. At 48 months, areal bone density increased at the lumbar spine (+4.9% ± 0.9%) and femoral neck (+2.4% ± 0.9%), with declines at the total hip (−2.3% ± 0.8%) and ultradistal radius (−2.1% ± 0.7%) (p < .05 for all). By HR-pQCT, at the radius site, very similar to the ultradistal DXA site, total volumetric BMD declined from baseline but remained above normative values at 48 months (Z-score + 0.56). Cortical volumetric BMD was lower than normative controls at baseline at the radius and tibia (Z-scores −1.28 and − 1.69, respectively) and further declined at 48 months (−2.13 and − 2.56, respectively). Cortical porosity was higher than normative controls at baseline at the tibia (Z-score + 0.72) and increased through 48 months of therapy at both sites (Z-scores +1.80 and + 1.40, respectively). Failure load declined from baseline at both the radius and tibia, although remained higher than normative controls at 48 months (Z-scores +1.71 and + 1.17, respectively). This is the first report of noninvasive high-resolution imaging in a cohort of hypoparathyroid patients treated with any PTH therapy for this length of time. The results give insights into the effects of long-term rhPTH(1–84) in hypoparathyroidism. © 2020 American Society for Bone and Mineral Research.     

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

Bone remodeling is dynamic and is tightly regulated through bone resorption dominated by osteoclasts and bone formation dominated by osteoblasts. Imbalances in this process can cause various pathological conditions, such as osteoporosis. Bone morphogenetic protein 9 (BMP9), a biomolecule produced and secreted by the liver, has many pharmacological effects, including anti-liver fibrosis, antitumor, anti-heart failure, and antidiabetic activities. However, the effects of BMP9 on the regulation of osteoblast and osteoclast functions and the underlying molecular mechanism(s) have not yet been investigated. In this study, BMP9 increased the expression of osteoblastogenic gene markers, such as ALP, Cola1, OCN, RUNX2, and OSX, and ALP activity in MC3T3-E1 cells by upregulating LGR6 and activating the Wnt/β-catenin pathway. BMP9 also suppressed receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation of bone marrow macrophages (BMMs) by inhibiting the Akt-NF-κB-NFATc1 pathway. More importantly, in an ovariectomy (OVX) mouse model, BMP9 attenuated bone loss and improved bone biomechanical properties in vivo by increasing bone-forming activity and suppressing bone resorption activity. Accordingly, our current work highlights the dual regulatory effects that BMP9 exerts on bone remodeling by promoting bone anabolic activity and inhibiting osteoclast differentiation in OVX mice. © 2020 American Society for Bone and Mineral Research.     

Effects of Odanacatib on Bone Structure and Quality in Postmenopausal Women With Osteoporosis: 5-Year Data From the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT) and its Extension

Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double-blind, placebo-controlled, event-driven, Phase 3, Long-term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double-blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), month 24 (ODN n = 112, placebo n = 104), month 36 (ODN n = 42, placebo n = 41), and month 60 (ODN n = 27, placebo n = 20) were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN-treated versus placebo-treated patients after 2 years of treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN-treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. © 2020 American Society for Bone and Mineral Research.     

Effects of Estrogen Replacement on Bone Geometry and Microarchitecture in Adolescent and Young Adult Oligoamenorrheic Athletes: A Randomized Trial

Oligoamenorrheic athletes (OAs) have lower bone mineral density (BMD) and greater impairment of bone microarchitecture, and therefore higher fracture rates compared to eumenorrheic athletes. Although improvements in areal BMD (aBMD; measured by dual-energy X-ray absorptiometry) in OAs have been demonstrated with transdermal estrogen treatment, effects of such treatment on bone microarchitecture are unknown. Here we explore effects of transdermal versus oral estrogen versus no estrogen on bone microarchitecture in OA. Seventy-five OAs (ages 14 to 25 years) were randomized to (i) a 100-μg 17β-estradiol transdermal patch (PATCH) administered continuously with 200 mg cyclic oral micronized progesterone; (ii) a combined 30 μg ethinyl estradiol and 0.15 mg desogestrel pill (PILL); or (iii) no estrogen/progesterone (NONE) and were followed for 12 months. Calcium (≥1200 mg) and vitamin D (800 IU) supplements were provided to all. Bone microarchitecture was assessed using high-resolution peripheral quantitative CT at the distal tibia and radius at baseline and 1 year. At baseline, randomization groups did not differ by age, body mass index, percent body fat, duration of amenorrhea, vitamin D levels, BMD, or bone microarchitecture measurements. After 1 year of treatment, at the distal tibia there were significantly greater increases in total and trabecular volumetric BMD (vBMD), cortical area and thickness, and trabecular number in the PATCH versus PILL groups. Trabecular area decreased significantly in the PATCH group versus the PILL and NONE groups. Less robust differences between groups were seen at the distal radius, where percent change in cortical area and thickness was significantly greater in the PATCH versus PILL and NONE groups, and changes in cortical vBMD were significantly greater in the PATCH versus PILL groups. In conclusion, in young OAs, bone structural parameters show greater improvement after 1 year of treatment with transdermal 17β-estradiol versus ethinyl estradiol–containing pills, particularly at the tibia. © 2019 American Society for Bone and Mineral Research.     

Articular Cartilage Degradation and Aberrant Subchondral Bone Remodeling in Patients with Osteoarthritis and Osteoporosis

Osteoarthritis (OA) and osteoporosis (OP) are two skeletal disorders associated with joint structures. Occasionally, OA and OP occur in the same patient. However, the effect of OP changes on OA progression in patients with osteoporotic OA (OP-OA) has not been reported, especially the potential association between subchondral bone and articular cartilage. Thus we investigated the alterations in the microstructure, biomechanical properties, and remodeling of subchondral bone as well as their association with cartilage damage in the hip joint of patients with OP-OA. Thirty-nine femoral head specimens were obtained from patients who underwent total hip arthroplasty (OA group, n = 19; OP-OA group, n = 20), and healthy specimens from cadaver donors were used (control group, n = 10). The microstructure and biomechanical properties of subchondral bone were evaluated by micro–computed tomography and micro–finite-element analysis. Histology, histomorphometric measurements, and immunohistochemistry were used to assess subchondral bone remodeling and cartilage damage. Linear regression analysis was performed to elucidate the relationship between subchondral bone and articular cartilage. In the subchondral bone of the OP-OA group, compared with that of the OA group, aberrant bone remodeling leads to an inferior microstructure and worsening biomechanical properties, potentially affecting transmission of loading stress from the cartilage to the subchondral bone, and then resulting in accelerated OA progression in patients with OP-OA. The results indicate that changes in subchondral bone could affect OA development and the improvement in subchondral bone with bone-metabolism agents may help mitigate OA progression when OP and OA coexist in the same patients. © 2019 American Society for Bone and Mineral Research.     

Effects of High-Intensity Resistance Training on Osteopenia and Sarcopenia Parameters in Older Men with Osteosarcopenia—One-Year Results of the Randomized Controlled Franconian Osteopenia and Sarcopenia Trial (FrOST)

Dynamic resistance exercise (DRT) might be the most promising agent for fighting sarcopenia in older people. However, the positive effect of DRT on osteopenia/osteoporosis in men has still to be confirmed. To evaluate the effect of low-volume/high-intensity (HIT)-DRT on bone mineral density (BMD) and skeletal muscle mass index (SMI) in men with osteosarcopenia, we initiated the Franconian Osteopenia and Sarcopenia Trial (FrOST). Forty-three sedentary community-dwelling older men (aged 73 to 91 years) with osteopenia/osteoporosis and SMI-based sarcopenia were randomly assigned to a HIT-RT exercise group (EG; n = 21) or a control group (CG; n = 22). HIT-RT provided a progressive, periodized single-set DRT on machines with high intensity, effort, and velocity twice a week, while CG maintained their lifestyle. Both groups were adequately supplemented with whey protein, vitamin D, and calcium. Primary study endpoint was integral lumbar spine (LS) BMD as determined by quantitative computed tomography. Core secondary study endpoint was SMI as determined by dual-energy X-ray absorptiometry. Additional study endpoints were BMD at the total hip and maximum isokinetic hip−/leg-extensor strength (leg press). After 12 months of exercise, LS-BMD was maintained in the EG and decreased significantly in the CG, resulting in significant between-group differences (p < 0.001; standardized mean difference [SMD] = 0.90). In parallel, SMI increased significantly in the EG and decreased significantly in the CG (p < 0.001; SMD = 1.95). Total hip BMD changes did not differ significantly between the groups (p = 0.064; SMD = 0.65), whereas changes in maximum hip−/leg-extensor strength were much more prominent (p < 0.001; SMD = 1.92) in the EG. Considering dropout (n = 2), attendance rate (95%), and unintended side effects/injuries (n = 0), we believe our HIT-RT protocol to be feasible, attractive, and safe. In summary, we conclude that our combined low-threshold HIT-RT/protein/vitamin D/calcium intervention was feasible, safe, and effective for tackling sarcopenia and osteopenia/osteoporosis in older men with osteosarcopenia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Thrombomodulin Functional Domains Support Osteoblast Differentiation and Bone Healing in Diabetes in Mice

Thrombomodulin (TM) is a transmembrane glycoprotein that contains five functional domains. Soluble TM (sTM), comprising extracellular domains TMD1 (lectin-like), TMD2 (epidermal growth factor [EGF]-like repeat containing), and TMD3 (serine-threonine rich), can be shed from cells by the intramembrane protease rhomboid-like-2 (RHBDL2). TM is expressed by osteoblasts, yet its role there has not been determined. Herein we aimed to investigate the properties of TM and its domains in osteoblast function and bone repair following injury in diabetes. In response to a scratch injury of cultured osteoblast-like MG63 cells, expression of TM and RHBDL2 was enhanced, with increased release of sTM. Conditioned media from the injured cells promoted osteoblast migration, an effect that was lacking with conditioned media from MG63 cells in which TM was silenced by shRNA. Exogenous recombinant TMD1 had no effect on osteoblast activities or on bone repair in vivo. However, TM domains 2 and 3 (TMD2/3), induced MG63 cell migration, proliferation and mineralization in vitro, and when locally administered in mice, improved in vivo healing of injured calvarium. This beneficial effect of TMD2/3, mediated via fibroblast growth factor receptor (FGFR)/ERK signaling pathways, was also observed in vitro under high glucose conditions where endogenous TM expression was reduced, and in vivo in diabetic mice following tibia fracture or calvarium injury, where the osteoblastic response and healing were otherwise dampened. Taken together, osteoblast TM participates in bone healing, and recombinant TMD2/3 holds promise as a novel therapy for diabetic bone defect healing. © 2020 American Society for Bone and Mineral Research.     

PDGF Receptor Signaling in Osteoblast Lineage Cells Controls Bone Resorption Through Upregulation of Csf1 Expression

The physiological functions of platelet-derived growth factor receptors (PDGFRs) α and β in osteoblast biology and bone metabolism remain to be established. Here, we show that PDGFRA and PDGFRB genes are expressed by osteoblast-lineage canopy and reversal cells in close proximity to PDGFB-expressing osteoclasts within human trabecular bone remodeling units. We also report that, although removal of only one of the two PDGFRs in Osterix-positive cells does not affect bone phenotype, suppression of both PDGFRs in those osteoblast lineage cells increases trabecular bone volume in male mice as well as in female gonad-intact and ovariectomized mice. Furthermore, osteoblast lineage-specific suppression of PDGFRs reduces Csf1 expression, bone marrow level of macrophage colony-stimulating factor (M-CSF), number of osteoclasts, and, therefore, bone resorption, but does not change bone formation. Finally, abrogation of PDGFR signaling in osteoblasts blocks PDGF-induced ERK1/2-mediated Csf1 expression and M-CSF secretion in osteoblast cultures and calcitriol-mediated osteoclastogenesis in co-cultures. In conclusion, our results indicate that PDGFR signaling in osteoblast lineage cells controls bone resorption through ERK1/2-mediated Csf1 expression. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Targeting the LRP5 Pathway Improves Bone Properties in a Mouse Model of Osteogenesis Imperfecta

The cell surface receptor low‐density lipoprotein receptor‐related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5^p.A214V) that is orthologous to a human HBM‐causing mutation have increased bone mass and strength. Osteogenesis imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5^+/p.A214V mice to Col1a2^+/p.G610C mice, which model human type IV OI. We found that Col1a2^+/p.G610C;Lrp5^+/p.A214V offspring had significantly increased bone mass and strength compared to Col1a2^+/p.G610C;Lrp5^+/+ littermates. The improved bone properties were not a result of altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2^+/p.G610C mice with a monoclonal antibody that inhibits sclerostin activity (Scl‐Ab). We found that antibody‐treated mice had significantly increased bone mass and strength compared to vehicle‐treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI. © 2014 American Society for Bone and Mineral Research.