Association of Antibiotic Alterations in Gut Microbiota With Decreased Osseointegration of an Intramedullary Nail in Mice With and Without Osteomyelitis

Treatment of osteomyelitis requires prolonged antibiotic therapy which significantly alters the gut microbiota. While the influences on bone mass and microstructure have been extensively studied, it is poorly understood what impact the changes in gut microbiota may have on the host response to osseointegration around an intramedullary nail implanted. Here, we explored the influence of gut microbiota on the bone osseointegration process around an implant under two conditions: implantation of an intramedullary nail in the bone marrow cavity and chronic osteomyelitis (CO) induced by Staphylococcus aureus infection. Body weight, hepatorenal functions, serum levels of proinflammatory cytokines were monitored. The composition of gut microbiota was assessed via 16S rRNA sequencing, and the bone condition was analyzed via micro-computed tomography, hematoxylin and eosin staining, Safranin O-fast green and Goldner’s trichrome staining. Osteoblastogenesis and osteoclastogenesis were assessed by detecting tartrate-resistant acid phosphatase and osterix expression. We found that perturbation of gut microbiota (increase in Proteobacteria and decrease in Bacteroidetes) associated with delayed osseointegration and increased levels of proinflammatory cytokines in the serum (p<0.05), lower bone mass (p<0.05), deficient endochondral ossification and bone formation, reduced osteoblastogenesis (p<0.05) and enhanced osteoclastogenesis (p<0.001). Survival rates (p=0.002) and bacterial loads (p=0.0363) in bone differed significantly between the CO and antibiotic-treated CO mice, but cytokines levels, bone mineral density, and bone formation did not differ, likely because of the severely damaged bone structure. In summary, antibiotic treatment perturbed the gut microbiota and significantly interfered with the bone osseointegration around the nail by increasing proinflammatory cytokine levels in circulation, inhibiting osteoblastogenesis, enhancing osteoclastogenesis, and thus leading to higher pathogen colonization as well as higher mortality postinfection. This report of ours is the first to demonstrate antibiotic-induced alterations in the gut microbiota affect bone osseointegration, helping us understand the role of gut microbiota disorders in osteoblastogenesis and osteoclastogenesis following implant insertion with or without infection.

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Topical co‐administration of zoledronate with recombinant human bone morphogenetic protein-2 can induce and maintain bone formation in the bone marrow environment

BMC Musculoskeletal Disorders ◽

10.1186/s12891-021-03971-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Hideki Ueyama ◽

Yoichi Ohta ◽

Yuuki Imai ◽

Akinobu Suzuki ◽

Ryo Sugama ◽

...

Keyword(s):

Bone Marrow ◽

Bone Formation ◽

Bone Structure ◽

Precursor Cells ◽

The Other ◽

Bone Morphogenetic Protein 2 ◽

New Bone Formation ◽

Micro Computed Tomography ◽

Mineral Density ◽

Left Femur

Abstract Background Bone morphogenetic proteins (BMPs) induce osteogenesis in various environments. However, when BMPs are used alone in the bone marrow environment, the maintenance of new bone formation is difficult owing to vigorous bone resorption. This is because BMPs stimulate the differentiation of not only osteoblast precursor cells but also osteoclast precursor cells. The present study aimed to induce and maintain new bone formation using the topical co-administration of recombinant human BMP-2 (rh-BMP-2) and zoledronate (ZOL) on beta-tricalcium phosphate (β-TCP) composite. Methods β-TCP columns were impregnated with both rh-BMP-2 (30 µg) and ZOL (5 µg), rh-BMP-2 alone, or ZOL alone, and implanted into the left femur canal of New Zealand white rabbits (n = 56). The implanted β-TCP columns were harvested and evaluated at 3 and 6 weeks after implantation. These harvested β-TCP columns were evaluated radiologically using plane radiograph, and histologically using haematoxylin/eosin (H&E) and Masson’s trichrome (MT) staining. In addition, micro-computed tomography (CT) was performed for qualitative analysis of bone formation in each group (n = 7). Results Tissue sections stained with H&E and MT dyes revealed that new bone formation inside the β-TCP composite was significantly greater in those impregnated with both rh-BMP-2 and ZOL than in those from the other experimental groups at 3 and 6 weeks after implantations (p < 0.05). Micro-CT data also demonstrated that the bone volume and the bone mineral density inside the β-TCP columns were significantly greater in those impregnated with both rh-BMP-2 and ZOL than in those from the other experimental groups at 3 and 6 weeks after implantations (p < 0.05). Conclusions The topical co-administration of both rh-BMP-2 and ZOL on β-TCP composite promoted and maintained newly formed bone structure in the bone marrow environment.

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Increased Marrow Adiposity in Premenopausal Women with Idiopathic Osteoporosis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-1477 ◽

2012 ◽

Vol 97 (8) ◽

pp. 2782-2791 ◽

Cited By ~ 61

Author(s):

Adi Cohen ◽

David W. Dempster ◽

Emily M. Stein ◽

Thomas L. Nickolas ◽

Hua Zhou ◽

...

Keyword(s):

Bone Formation ◽

Bone Mass ◽

Formation Rate ◽

Premenopausal Women ◽

Micro Computed Tomography ◽

Mineral Density ◽

Marrow Fat ◽

Bone Formation Rate ◽

Idiopathic Osteoporosis ◽

Marrow Adiposity

Abstract Context: We have previously reported that premenopausal women with idiopathic osteoporosis based on fractures (IOP) or idiopathic low bone mineral density (ILBMD) exhibit markedly reduced bone mass, profoundly abnormal trabecular microstructure, and significant deficits in trabecular bone stiffness. Bone remodeling was heterogeneous. Those with low bone turnover had evidence of osteoblast dysfunction and the most marked deficits in microstructure and stiffness. Objective: Because osteoblasts and marrow adipocytes derive from a common mesenchymal precursor and excess marrow fat has been implicated in the pathogenesis of bone fragility in anorexia nervosa, glucocorticoid excess, and thiazolidinedione exposure, we hypothesized that marrow adiposity would be higher in affected women and inversely related to bone mass, microarchitecture, bone formation rate, and osteoblast number. Design: We analyzed tetracycline-labeled transiliac biopsy specimens in 64 premenopausal women with IOP or ILBMD and 40 controls by three-dimensional micro-computed tomography and two-dimensional quantitative histomorphometry to assess marrow adipocyte number, perimeter, and area. Results: IOP and ILBMD subjects did not differ with regard to any adipocyte parameter, and thus results were combined. Subjects had substantially higher adipocyte number (by 22%), size (by 24%), and volume (by 26%) than controls (P < 0.0001 for all). Results remained significant after adjusting for age, body mass index, and bone volume. Controls demonstrated expected direct associations between marrow adiposity and age and inverse relationships between marrow adiposity and bone formation, volume, and microstructure measures. No such relationships were observed in the subjects. Conclusions: Higher marrow adiposity and the absence of expected relationships between marrow adiposity and bone microstructure and remodeling in women with IOP or ILBMD suggest that the relationships between fat and bone are abnormal; excess marrow fat may not arise from a switch from the osteoblast to the adipocyte lineage in this disorder. Whether excess marrow fat contributes to the pathogenesis of this disorder remains unclear.

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Osteopontin Deficiency Induces Parathyroid Hormone Enhancement of Cortical Bone Formation

Endocrinology ◽

10.1210/en.2002-220996 ◽

2003 ◽

Vol 144 (5) ◽

pp. 2132-2140 ◽

Cited By ~ 36

Author(s):

Keiichiro Kitahara ◽

Muneaki Ishijima ◽

Susan R. Rittling ◽

Kunikazu Tsuji ◽

Hisashi Kurosawa ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Formation ◽

Bone Mass ◽

Cortical Bone ◽

Cancellous Bone ◽

Wild Type ◽

Mineral Density ◽

Cortical Bone Mass ◽

Intermittent Pth

Intermittent PTH treatment increases cancellous bone mass in osteoporosis patients; however, it reveals diverse effects on cortical bone mass. Underlying molecular mechanisms for anabolic PTH actions are largely unknown. Because PTH regulates expression of osteopontin (OPN) in osteoblasts, OPN could be one of the targets of PTH in bone. Therefore, we examined the role of OPN in the PTH actions in bone. Intermittent PTH treatment neither altered whole long-bone bone mineral density nor changed cortical bone mass in wild-type 129 mice, although it enhanced cancellous bone volume as reported previously. In contrast, OPN deficiency induced PTH enhancement of whole-bone bone mineral density as well as cortical bone mass. Strikingly, although PTH suppressed periosteal bone formation rate (BFR) and mineral apposition rate (MAR) in cortical bone in wild type, OPN deficiency induced PTH activation of periosteal BFR and MAR. In cancellous bone, OPN deficiency further enhanced PTH increase in BFR and MAR. Analysis on the cellular bases for these phenomena indicated that OPN deficiency augmented PTH enhancement in the increase in mineralized nodule formation in vitro. OPN deficiency did not alter the levels of PTH enhancement of the excretion of deoxypyridinoline in urine, the osteoclast number in vivo, and tartrate-resistant acid phosphatase-positive cell development in vitro. These observations indicated that OPN deficiency specifically induces PTH activation of periosteal bone formation in the cortical bone envelope.

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Evaluation of bone mineral density (BMD) and indicators of bone turnover in patients with hemophilia

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2018.2335 ◽

2018 ◽

Vol 18 (2) ◽

pp. 206-210 ◽

Cited By ~ 3

Author(s):

Mehmet Dagli ◽

Ali Kutlucan ◽

Sedat Abusoglu ◽

Abdulkadir Basturk ◽

Mehmet Sozen ◽

...

Keyword(s):

Bone Mineral Density ◽

Vitamin D ◽

Bone Formation ◽

Bone Mass ◽

Bone Mineral ◽

Type I ◽

Healthy Controls ◽

Mineral Density ◽

Lymphocyte Ratio ◽

Significant Difference

A decrease in bone mass is observed in hemophilic patients. The aim of this study was to evaluate bone mineral density (BMD), parathyroid hormone (PTH), 25-hydroxy vitamin D (vitamin D), and a bone formation and resorption marker, procollagen type I N-terminal propeptide (PINP) and urinary N-terminal telopeptide (uNTX) respectively, in hemophilic patients and healthy controls. Laboratory parameters related to the pathogenesis of bone loss such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were also evaluated. Thirty-five men over 18 years of age, with severe hemophilia (A and B) and receiving secondary prophylaxis, were included in the study. The same number of age-, sex-, and ethnicity-matched healthy controls were evaluated. Anthropometric, biochemical, and hormonal parameters were determined in both groups. No significant difference in anthropometric parameters was found between the two groups. The BMD was low in 34% of hemophilic patients. Vitamin D, calcium, and free testosterone levels were significantly lower (p < 0.001, p = 0.011, p < 0.001, respectively), while PTH, PINP, and activated partial thromboplastin time (aPTT) levels were significantly higher (p < 0.014, p = 0.043, p < 0.001, respectively), in hemophilic patients compared to controls. There was no significant difference between the two groups in NLR, PLR, phosphorus, thyroid-stimulating hormone, and uNTX level. The reduction of bone mass in hemophilic patients may be evaluated using the markers of bone formation and resorption, enabling early detection and timely treatment.

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Increasing Dietary Fish Oil Reduces Adiposity and Mitigates Bone Deterioration in Growing C57BL/6 Mice Fed a High-Fat Diet

Journal of Nutrition ◽

10.1093/jn/nxz215 ◽

2019 ◽

Vol 150 (1) ◽

pp. 99-107 ◽

Cited By ~ 4

Author(s):

Jay J Cao ◽

Brian R Gregoire ◽

Kim G Michelsen ◽

Matthew J Picklo

Keyword(s):

Adipose Tissue ◽

Bone Mass ◽

Fish Oil ◽

High Fat Diet ◽

Bone Structure ◽

Tartrate Resistant Acid Phosphatase ◽

Serum Concentrations ◽

Obese Mice ◽

High Fat ◽

Long Chain

ABSTRACT Background Intake of total fat is linked to obesity and inversely associated with bone density in humans. Epidemiologic and animal studies show that long-chain n–3 (ω-3) PUFAs supplied as fish oil (FO) are beneficial to skeletal health. Objective This study tested the hypothesis that increasing dietary FO would decrease adiposity and improve bone-related outcomes in growing obese mice. Methods Male C57BL/6 mice at 6 wk old were assigned to 6 treatment groups and fed either a normal-fat diet (3.85 kcal/g and 10% energy as fat) or a high-fat diet (HF; 4.73 kcal/g and 45% energy as fat) containing either 0%, 3%, or 9% energy as FO (0FO, 3FO, and 9FO, respectively) ad libitum for 6 mo. Bone structure, body composition, and serum bone-related cytokines were measured. Results The HF diet increased the expression of the adipose tissue tumor necrosis factor α (Tnfa) and serum concentrations of leptin and tartrate-resistant acid phosphatase (TRAP), and decreased serum concentrations of osteocalcin and bone-specific alkaline phosphatase (P < 0.05). FO decreased fat mass (P < 0.05), serum TRAP (P < 0.05), and adipose tissue Tnfa expression (P < 0.01). Bone content of long-chain n–3 PUFAs was increased and n–6 PUFAs were decreased with the elevation in dietary FO content (P < 0.01). Compared with mice fed 9FO, animals fed 3FO had higher femoral bone volume/total volume (25%), trabecular number (23%), connectivity density (82%), and bone mass of second lumbar vertebrae (12%) and lower femoral trabecular separation (−19%). Mice fed the 3FO HF diet had 42% higher bone mass than those fed the 0FO HF diet. Conclusions These data indicate increasing dietary FO ≤3% energy can decrease adiposity and mitigate HF diet–induced bone deterioration in growing C57BL/6 mice possibly by reducing inflammation and bone resorption. FO at 9% diet energy had no further beneficial effects on bone of obese mice.

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Decreasing the Ratio of Dietary Linoleic to α-Linolenic Acid from 10 to 4 by Changing Only the Former Does Not Prevent Adiposity or Bone Deterioration in Obese Mice

Journal of Nutrition ◽

10.1093/jn/nxaa044 ◽

2020 ◽

Vol 150 (6) ◽

pp. 1370-1378 ◽

Cited By ~ 1

Author(s):

Jay J Cao ◽

Brian R Gregoire ◽

Kim G Michelsen ◽

Matthew J Picklo Sr

Keyword(s):

Bone Mass ◽

Linolenic Acid ◽

Fat Mass ◽

Bone Structure ◽

Structural Parameters ◽

Tartrate Resistant Acid Phosphatase ◽

Low Grade ◽

Obese Mice ◽

Treatment Groups ◽

Serum Trap

ABSTRACT Background Linoleic acid (LA; 18:2n–6) has been considered to promote low-grade chronic inflammation and adiposity. Studies show adiposity and inflammation are inversely associated with bone mass. Objectives This study tested the hypothesis that decreasing the dietary ratio of LA to α-linolenic acid (ALA, 18:3n–3), while keeping ALA constant, mitigates high-fat diet (HF)-induced adiposity and bone loss. Methods Male C57BL/6 mice at 6 wk old were assigned to 4 treatment groups and fed 1 of the following diets ad libitum for 6 mo: a normal-fat diet (NF; 3.85 kcal/g and 10% energy as fat) with the ratio of the PUFAs LA to ALA at 6; or HFs (4.73 kcal/g and 45% energy as fat) with the ratio of LA to ALA at 10:1, 7:1, or 4:1, respectively. ALA content in the diets was kept the same for all groups at 1% energy. Bone structure, body composition, bone-related cytokines in serum, and gene expression in bone were measured. Data were analyzed using 1-factor ANOVA. Results Compared with those fed the NF, mice fed the HFs had 19.6% higher fat mass (P < 0.01) and 13.5% higher concentration of serum tartrate-resistant acid phosphatase (TRAP) (P < 0.05), a bone resorption cytokine. Mice fed the HFs had 19.5% and 12.2% lower tibial and second lumbar vertebral bone mass, respectively (P < 0.01). Decreasing the dietary ratio of LA to ALA from 10 to 4 did not affect body mass, fat mass, serum TRAP and TNF-α, or any bone structural parameters. Conclusions These data indicate that decreasing the dietary ratio of LA to ALA from 10 to 4 by simply reducing LA intake does not prevent adiposity or improve bone structure in obese mice.

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Cortical bone dynamics, strength, and densitometry after induction of emphysema in hamsters

Journal of Applied Physiology ◽

10.1152/japplphysiol.01049.2002 ◽

2003 ◽

Vol 95 (2) ◽

pp. 631-634 ◽

Cited By ~ 7

Author(s):

Jill E. Shea ◽

Scott C. Miller ◽

David C. Poole ◽

John P. Mattson

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Bone Formation ◽

Cortical Bone ◽

Pulmonary Disease ◽

Bone Mineral ◽

Bone Structure ◽

Chronic Obstructive ◽

Pathophysiological Mechanism ◽

Mineral Density ◽

Obstructive Pulmonary Disease

Recent evidence suggests that patients suffering from chronic obstructive pulmonary disease are also at an increased risk of developing osteoporosis. The pathophysiological mechanism(s) linking these progressive diseases is unknown. The goal of this investigation was to determine whether there were alterations in bone mineral density and content, cortical bone structure and strength, and indexes of bone formation and resorption in the elastase-induced emphysematous hamster. At 3 wk after induction of emphysema, the femoral bone mineral content was 8% less ( P = 0.026) and the femoral fracture strength was 6% less ( P = 0.032) in the emphysematous hamster than in controls. The cortical area was 8.4% less ( P = 0.013) and the periosteal mineral appositional rate was 27% less ( P = 0.05) than in controls. Additionally, the endocortical eroded surface in the emphysematous group was about twice that in the control group ( P = 0.003). Differences in some indexes of bone formation and resorption, paralleled by differences in bone structure and strength, were observed 3 wk after induction of emphysema. These differences in skeletal metabolism and strength may help explain some of the skeletal changes associated with chronic obstructive pulmonary disease in humans.

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Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

Cellular Physiology and Biochemistry ◽

10.1159/000492549 ◽

2018 ◽

Vol 48 (5) ◽

pp. 2091-2102 ◽

Cited By ~ 3

Author(s):

Xin Sui ◽

Shijian Deng ◽

Mengmeng Liu ◽

Linlin Fan ◽

Yunfei Wang ◽

...

Keyword(s):

Bone Loss ◽

Bone Mass ◽

Bone Growth ◽

Osteoclast Differentiation ◽

Marker Genes ◽

Tartrate Resistant Acid Phosphatase ◽

Bone Homeostasis ◽

Micro Computed Tomography ◽

Constitutive Activation

Background/Aims: Activation of the Wnt/β-catenin signalling pathway has been widely investigated in bone biology and shown to promote bone formation. However, its specific effects on osteoclast differentiation have not been fully elucidated. Our study aimed to identify the role of β-catenin in osteoclastogenesis and bone homeostasis. Methods: In the present study, exon 3 in the β-catenin gene (Ctnnb1) allele encoding phosphorylation target serine/threonine residues was flanked by floxP sequences. We generated mice exhibiting conditional β-catenin activation (Ctsk-Cre;Ctnnb1flox(exon3)/+, designated CA-β-catenin) by crossing Ctnnb1flox(exon3)/flox(exon3) mice with osteoclast-specific Ctsk-Cre mice. Bone growth and bone mass were analysed by micro-computed tomography (micro-CT) and histomorphometry. To further examine osteoclast activity, osteoclasts were induced from bone marrow monocytes (BMMs) isolated from CA-β-catenin and Control mice in vitro. Osteoclast differentiation was detected by tartrate-resistant acid phosphatase (TRAP) staining, immunofluorescence staining and reverse transcription-quantitative PCR (RT–qPCR) analysis. Results: Growth retardation and low bone mass were observed in CA-β-catenin mice. Compared to controls, CA-β-catenin mice had significantly reduced trabecular bone numbers under growth plates as well as thinner cortical bones. Moreover, increased TRAP-positive osteoclasts were observed on the surfaces of trabecular bones and cortical bones in the CA-β-catenin mice; consistent results were observed in vitro. In the CA-β-catenin group, excessive numbers of osteoclasts were induced from BMMs, accompanied by the increased expression of osteoclast-associated marker genes. Conclusion: These results indicated that the constitutive activation of β-catenin in osteoclasts promotes osteoclast formation, resulting in bone loss.

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Gut microbiota induce IGF-1 and promote bone formation and growth

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1607235113 ◽

2016 ◽

Vol 113 (47) ◽

pp. E7554-E7563 ◽

Cited By ~ 174

Author(s):

Jing Yan ◽

Jeremy W. Herzog ◽

Kelly Tsang ◽

Caitlin A. Brennan ◽

Maureen A. Bower ◽

...

Keyword(s):

Bone Formation ◽

Gut Microbiota ◽

Bone Mass ◽

Bone Growth ◽

Serum Levels ◽

Short Chain Fatty Acids ◽

Skeletal Growth ◽

Microbial Colonization ◽

Adult Mice ◽

Specific Pathogen

Appreciation of the role of the gut microbiome in regulating vertebrate metabolism has exploded recently. However, the effects of gut microbiota on skeletal growth and homeostasis have only recently begun to be explored. Here, we report that colonization of sexually mature germ-free (GF) mice with conventional specific pathogen-free (SPF) gut microbiota increases both bone formation and resorption, with the net effect of colonization varying with the duration of colonization. Although colonization of adult mice acutely reduces bone mass, in long-term colonized mice, an increase in bone formation and growth plate activity predominates, resulting in equalization of bone mass and increased longitudinal and radial bone growth. Serum levels of insulin-like growth factor 1 (IGF-1), a hormone with known actions on skeletal growth, are substantially increased in response to microbial colonization, with significant increases in liver and adipose tissue IGF-1 production. Antibiotic treatment of conventional mice, in contrast, decreases serum IGF-1 and inhibits bone formation. Supplementation of antibiotic-treated mice with short-chain fatty acids (SCFAs), products of microbial metabolism, restores IGF-1 and bone mass to levels seen in nonantibiotic-treated mice. Thus, SCFA production may be one mechanism by which microbiota increase serum IGF-1. Our study demonstrates that gut microbiota provide a net anabolic stimulus to the skeleton, which is likely mediated by IGF-1. Manipulation of the microbiome or its metabolites may afford opportunities to optimize bone health and growth.

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Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice

Journal of Endocrinology ◽

10.1530/joe-18-0153 ◽

2018 ◽

Vol 238 (1) ◽

pp. 13-23 ◽

Cited By ~ 12

Author(s):

Thomas Funck-Brentano ◽

Karin H Nilsson ◽

Robert Brommage ◽

Petra Henning ◽

Ulf H Lerner ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Bone Mass ◽

Trabecular Bone ◽

Cortical Bone ◽

Bone Strength ◽

Bending Test ◽

Bone Homeostasis ◽

Mineral Density

WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

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