Bone Mineral Density Enhancement Research Articles

Clinical Studies On Romosozumab: An Alternative For Individuals With A High Risk Of Osteoporotic Fractures: A Current Concepts Review (Part II)

Romosumab (ROMO) should be used to treat postmenopausal women with osteoporosis at high fracture risk after carefully considering the cardiovascular status and the risk/benefit balance. Clinicians should avoid ROMO for patients with a history of myocardial infarction or stroke in the past 12 months. Although ROMO offers an alternative for patients with a high risk of osteoporotic fractures, it is affected by previous osteoporosis treatment: using denosumab (DENO) and oral bisphosphonates for over one year attenuates its effect. An additional 12 months of DENO appears to be more effective than ibandronate for the enhancement of bone mineral density (BMD) as a sequential agent after 12 months of ROMO, with few severe adverse events. However, it is important to emphasize that ROMO is not a first-choice medication. It is only indicated when bisphosphonates cannot help, and its clinical use has demonstrated cardiovascular risks. The cost and availability could also make its use problematic in clinical practice. Therefore, although ROMO represents an important advance in the treatment of osteoporosis, it is by no means a solution for osteoporosis.

Effect of photobiomodulation therapy with different wavelengths on bone mineral density in osteoporotic rats.

Osteoporosis is associated with severe pain, bone deformity, fracture, and bone loss. It is important to find strategies to prevent bone resorption and treat osteoporosis. This study sought to assess the effect of photobiomodulation therapy (PBMT) with different wavelengths on bone mineral density (BMD) in osteoporotic rats. This animal study evaluated 63 adult female rats. The rats underwent ovariectomy to induce osteoporosis. Ovariectomized rats were randomly divided into 9 groups of control (OC), treatment with zoledronic acid alone (0.02mg/kg), and treatment with 660nm, 810nm, and 940nm PBMT alone (3 times a week for 6weeks, energy density of 4J/cm2), and combined with zoledronic acid. The healthy control group (HC) only underwent sham surgery. The rats underwent cone-beam computed tomography (CBCT) 52days after the first treatment session to measure their BMD according to the gray value (GV) of images. To assess the biomechanical properties of bone, the resected bones were subjected to 3-point bending test (3-PBT). The experimental groups had significant differences with the OC group regarding radiographic and biomechanical properties of bone (P < 0.05), indicating a healing course. No significant difference was noted between the experimental groups treated with different laser wavelengths and those treated with zoledronic acid (P > 0.05). In the condition of this study, it was found that PBMT at a constant energy density of 4J/cm2 with 660-, 810-, and 940-nm wavelengths is effective for enhancement of bone mineral density and biomechanical properties. No significant difference was noted between different wavelengths of diode laser regarding radiographic and biomechanical properties of bone.

Carfilzomib alleviated osteoporosis by targeting PSME1/2 to activate Wnt/β-catenin signaling

Osteoporosis (OP) is characterized by decreased bone mineral density and impaired bone strength. Carfilzomib (CFZ) is a new-generation proteasome inhibitor and has been found to affect bone metabolism. However, the effect and mechanism of CFZ on OP has not been investigated systematically. In this study, we found that protein levels of proteasome activator subunit 1/2 (PSME1/2) increased in OP, and accumulated mostly in osteoblasts and osteoclasts. Treatment with PSME1/2 recombinant protein inhibited osteogenesis and promoted osteoclast formation in vitro. Also, PSME1/2 inhibited the expression of β-catenin protein, resulting in limitation of Wnt/β-catenin signaling. CFZ inhibited PSME1 and PSME2 proteasome activities and increased β-catenin protein level, resulting in the translocation of β-catenin to the nucleus and activation of canonical Wnt/β-catenin signaling, further promoting osteogenesis and inhibiting osteoclastic differentiation. In vivo, we conducted ovariectomy (OVX) to create a model of OVX-induced postmenopausal OP in mice. When analyzed by micro-CT scanning, enhancement of bone mineral density, bone volume, trabecular number, and thickness was seen in the CFZ-treated mice. Also, we noticed increased osteogenesis and decreased osteoclastogenesis, diminished expression of PSME1 and PSME2 and activated Wnt/β-catenin signaling in bone sections from OP mice treated with CFZ. Overall, our data indicated that PSME1/2 may serve as new targets for the treatment of OP, and targeting PSME1/2 with CFZ provides a candidate therapeutic molecule for postmenopausal OP.

Gene transfection achieved by utilizing antibacterial calcium phosphate nanoparticles for enhanced regenerative therapy

Protamine-coated multi-shell calcium phosphate (CaP) was developed as a non-viral vector for tissue regeneration therapy. CaP nanoparticles loaded with different amounts of plasmid DNA encoding bone morphogenetic protein 2 (BMP-2) and insulin-like growth factor 1 (IGF-1) were used to treat MC3T3E1 cells, and the yield of the released BMP-2 or IGF-1 was measured using ELISA 3 days later. Collagen scaffolds containing CaP nanoparticles were implanted into rat cranial bone defects, and BMP-2 and IGF-1 yields, bone formation, and bone mineral density enhancement were evaluated 28 days after gene transfer. The antibacterial effects of CaP nanoparticles against Streptococcus mutans and Aggregatibacter actinomycetemcomitans increased with an increase in the protamine dose, while they were lower for Staphylococcus aureus and Porphyromonas gingivalis. In the combination treatment with BMP-2 and IGF-1, the concentration ratio of BMP-2 and IGF-1 is an important factor affecting bone formation activity. The calcification activity and OCN mRNA of MC3T3E1 cells subjected to a BMP-2:IGF-1 concentration ratio of 1:4 was higher at 14 days. During gene transfection treatment, BMP-2 and IGF-1 were released simultaneously after gene transfer; the loaded dose of the plasmid DNA encoding IGF-1 did not impact the BMP-2 or IGF-1 yield or new bone formation ratio in vitro and in vivo. In conclusion, two growth factor-releasing systems were developed using an antibacterial gene transfer vector, and the relationship between the loaded plasmid DNA dose and resultant growth factor yield was determined in vitro and in vivo.

Enhancement of bone mineral density and body mass in newborn chickens by in ovo injection of ionic-hydroxyapatite nanoparticles of bacterial origin

Using non-drug, non-surgical treatments for improving bone mineral diseases in newborn babies is an important topic for neonatologists. The present study introduces bacterial synthesized ionic nano-hydroxyapatite (Bio-HA) for the development of bone mineral density in the chicken embryo model. In vitro cytotoxicity analyses were demonstrated the optimal concentrations of Bio-HA compared to a chemically-synthesized hydroxyapatite (Ch-HA). Toxicity of Bio-HA on MCF-7 human cell lines was negligible at the concentrations less than 500 μg/mL whereas Ch-HA showed similar results at the concentrations less than 100 μg/mL. Therefore, concentrations at 50 μg/mL and 100 μg/mL were selected for in ovo injection of both materials into the fertilized eggs. The newly hatched chickens were sacrificed in order to monitor their serological factors, total body mass, bone mineral contents and bone mineral density. The results confirmed that Bio-HA increased the average body weight and bone mineral indices of chickens in comparison to the Ch-HA and negative controls (normal saline and intact groups). In view of the intact group, no liver or kidney damage occurred in the groups receiving Bio-HA which promises the effectiveness of these nanoparticles for the treatment of afterbirth bone mineral deficiency.

Committee Opinion No.702: Female Athlete Triad.

The female athlete triad is a medical condition observed in physically active females involving three components: 1) low energy availability with or without disordered eating, 2) menstrual dysfunction, and 3) low bone density. An individual does not need to show clinical manifestations of all three components of the female athlete triad simultaneously to be affected by the condition. Consequences of these clinical conditions may not be completely reversible, so prevention, early diagnosis, and intervention are critical. All athletes are at risk of the female athlete triad, regardless of body build or sport. All active females should be assessed for components of the triad and further evaluation should be performed if one or more components are identified. The obstetrician-gynecologist has the opportunity to screen athletes for components of the female athlete triad at comprehensive visits for preventive care. Using the menstrual cycle as a vital sign is a useful tool for identifying athletes at risk of female athlete triad and should be an integral part of the preparticipatory sports physical. The goal of treatment for those diagnosed with female athlete triad is restoration of regular menses as a clinical marker of reestablishment of energy balance and enhancement of bone mineral density. The female athlete triad is a result of energy imbalance; thus, adjusting the energy expenditure and energy availability is the main intervention. Pharmacologic treat-ment may be considered when nonpharmacologic treatment has failed. A team approach involving the patient, obstetrician-gynecologist, sports nutritionist, coaches, parents, and mental health care provider, if indicated, is optimal.

Committee Opinion No. 702 Summary: Female Athlete Triad.

The female athlete triad is a medical condition observed in physically active females involving three components: 1) low energy availability with or without disordered eating, 2) menstrual dysfunction, and 3) low bone density. An individual does not need to show clinical manifestations of all three components of the female athlete triad simultaneously to be affected by the condition. Consequences of these clinical conditions may not be completely reversible, so prevention, early diagnosis, and intervention are critical. All athletes are at risk of the female athlete triad, regardless of body build or sport. All active females should be assessed for components of the triad and further evaluation should be performed if one or more components are identified. The obstetrician-gynecologist has the opportunity to screen athletes for components of the female athlete triad at comprehensive visits for preventive care. Using the menstrual cycle as a vital sign is a useful tool for identifying athletes at risk of female athlete triad and should be an integral part of the preparticipatory sports physical. The goal of treatment for those diagnosed with female athlete triad is restoration of regular menses as a clinical marker of reestablishment of energy balance and enhancement of bone mineral density. The female athlete triad is a result of energy imbalance; thus, adjusting the energy expenditure and energy availability is the main intervention. Pharmacologic treat-ment may be considered when nonpharmacologic treatment has failed. A team approach involving the patient, obstetrician-gynecologist, sports nutritionist, coaches, parents, and mental health care provider, if indicated, is optimal.

The Impact of Glucagon-Like Peptide-1 on Bone Metabolism and Its Possible Mechanisms

The impact of antidiabetic drugs on bone metabolism is drawing increasing attention due to the discovery of a correlation between type 2 diabetes mellitus (T2DM) and osteoporosis. Glucagon-like peptide-1 (GLP-1) receptor agonists are a novel and promising class of drugs for T2DM, which may also have clinical applications in bone tissue disorders. This review examines the impact of GLP-1 on bone metabolism, including enhancement of bone mineral density and improvement of bone quality. However, the precise effect of GLP-1 on fracture risk has not been unambiguously defined. This review also summarizes our current understanding of the mechanisms by which GLP-1 affects bone metabolism. GLP-1 may act on bone by promoting bone formation, inhibiting bone resorption, and affecting the coordination of the two processes. We describe molecular pathways and proteins, such as Wnt and calcitonin, that are associated with GLP-1 and bone tissue. The specific processes and related molecular mechanisms of the effects of GLP-1 on bone metabolism need to be further explored and clarified.

The Female Athlete Triad

Context:The female athlete triad (the triad) is an interrelationship of menstrual dysfunction, low energy availability (with or without an eating disorder), and decreased bone mineral density; it is relatively common among young women participating in sports. Diagnosis and treatment of this potentially serious condition is complicated and often requires an interdisciplinary team.Evidence Acquisition:Articles from 1981 to present found on PubMed were selected for review of major components of the female athlete triad as well as strategies for diagnosis and treatment of the conditions.Results:The main goal in treatment of young female athletes with the triad is a natural return of menses as well as enhancement of bone mineral density. While no specific drug intervention has been shown to consistently improve bone mineral density in this patient population, maximizing energy availability and optimizing vitamin D and calcium intake are recommended.Conclusions:Treatment requires a multidisciplinary approach involving health care professionals as well as coaches and family members. Prevention of this condition is important to minimize complications of the female athlete triad.

Bioactive silica-based nanoparticles stimulate bone-forming osteoblasts, suppress bone-resorbing osteoclasts, and enhance bone mineral density in vivo

Bone is a dynamic tissue that undergoes renewal throughout life in a process whereby osteoclasts resorb worn bone and osteoblasts synthesize new bone. Imbalances in bone turnover lead to bone loss and development of osteoporosis and ultimately fracture, a debilitating condition with high morbidity and mortality. Silica is a ubiquitous biocontaminant that is considered to have high biocompatibility. The authors report that silica nanoparticles (NPs) mediate potent inhibitory effects on osteoclasts and stimulatory effects on osteoblasts in vitro. The mechanism of bioactivity is a consequence of an intrinsic capacity to antagonize activation of NF-κB, a signal transduction pathway required for osteoclastic bone resorption but inhibitory to osteoblastic bone formation. We further demonstrate that silica NPs promote a significant enhancement of bone mineral density (BMD) in mice in vivo, providing a proof of principle for the potential application of silica NPs as a pharmacological agent to enhance BMD and protect against bone fracture. From the Clinical EditorIn this paper, silicate nanoparticles are utilized in an animal model to stimulate bone growth by inhibiting osteoclasts while enhancing the activity of osteoblasts. This result may have important ramification in future applications to a variety of bone diseases, including but not limited to osteoporosis, pathological fractures, metastatic bone lesions, different types of bone cancer, etc.

Wnt Isoform-Specific Interactions with Coreceptor Specify Inhibition or Potentiation of Signaling by LRP6 Antibodies

β-catenin-dependent Wnt signaling is initiated as Wnt binds to both the receptor FZD and coreceptor LRP5/6, which then assembles a multimeric complex at the cytoplasmic membrane face to recruit and inactivate the kinase GSK3. The large number and sequence diversity of Wnt isoforms suggest the possibility of domain-specific ligand-coreceptor interactions, and distinct binding sites on LRP6 for Wnt3a and Wnt9b have recently been identified in vitro. Whether mechanistically different interactions between Wnts and coreceptors might mediate signaling remains to be determined. It is also not clear whether coreceptor homodimerization induced extracellularly can activate Wnt signaling, as is the case for receptor tyrosine kinases. We generated monoclonal antibodies against LRP6 with the unexpected ability to inhibit signaling by some Wnt isoforms and potentiate signaling by other isoforms. In cell culture, two antibodies characterized further show reciprocal activities on most Wnts, with one antibody antagonizing and the other potentiating. We demonstrate that these antibodies bind to different regions of LRP6 protein, and inhibition of signaling results from blocking Wnt binding. Antibody-mediated dimerization of LRP6 can potentiate signaling only when a Wnt isoform is also able to bind the complex, presumably recruiting FZD. Endogenous autocrine Wnt signaling in different tumor cell lines can be either antagonized or enhanced by the LRP6 antibodies, indicating expression of different Wnt isoforms. As anticipated from the roles of Wnt signaling in cancer and bone development, antibody activities can also be observed in mice for inhibition of tumor growth and in organ culture for enhancement of bone mineral density. Collectively, our results indicate that separate binding sites for different subsets of Wnt isoforms determine the inhibition or potentiation of signaling conferred by LRP6 antibodies. This complexity of coreceptor-ligand interactions may allow for differential regulation of signaling by Wnt isoforms during development, and can be exploited with antibodies to differentially manipulate Wnt signaling in specific tissues or disease states.

Skull Bone Regeneration in Nonhuman Primates by Controlled Release of Bone Morphogenetic Protein-2 from a Biodegradable Hydrogel

The objective of this study was to investigate the feasibility of biodegradable gelatin hydrogels as the controlled-release carrier of bone morphogenetic protein-2 (BMP-2) to enhance bone regeneration at a skull defect of nonhuman primates. Hydrogels with 3 different water contents were prepared through glutaraldehyde crosslinking of gelatin with an isoelectric point of 9.0 under varied reaction conditions. A critical-sized defect (6 mm in diameter) was prepared at the skull bone of skeletally mature cynomolgus monkeys, and gelatin hydrogels incorporating various doses of BMP-2 were applied to the defects. When the bone regeneration was evaluated by soft radiography and bone mineral density (BMD) examinations, the gelatin hydrogel incorporating BMP-2 exhibited significantly higher osteoinduction activity than did an insoluble bone matrix that incorporated BMP-2 (one of the best osteoinduction systems), although the activity depended on the water content of hydrogels. BMD enhancement was highest for the gelatin hydrogel that had a water content of 97.8 wt% among all types of hydrogels. Moreover, the gelatin hydrogel enabled BMP-2 to induce the bone regeneration in nonhuman primates even at low doses. We conclude that the controlled release of BMP-2 for a certain time period was essential to inducing the osteoinductive potential of BMP-2.

Skull bone regeneration in primates in response to basic fibroblast growth factor.

The feasibility of using a biodegradable hydrogel incorporating basic fibroblast growth factor (bFGF) to induce bone regeneration at the site of a skull defect in monkeys was investigated. Basic fibroblast growth factor was incorporated into a bioabsorbable hydrogel, which was prepared through glutaraldehyde crosslinking of gelatin. Following treatment of monkey skull defects measuring 6 mm in diameter (six defects/experimental group) with gelatin hydrogel incorporating bFGF, skull bone regeneration was evaluated using soft x-ray studies, dual x-ray absorptometry, and histological examinations. The water content of the hydrogels varied according to the glutaraldehyde concentration in the hydrogel preparation. Gelatin hydrogels incorporating 100 microg of bFGF significantly promoted bone regeneration and the skull defect was completely closed 21 weeks after implantation. This is in marked contrast with the effect of the same dose of bFGF in solution form. Bone mineral density (BMD) measured at the sites of skull defect was enhanced by the bFGF-incorporating hydrogels. The BMD enhancement was more prominent at lower water contents of hydrogel. Empty gelatin hydrogels neither induced nor interfered with skull bone regeneration. The findings of this study indicate that bFGF coupled with bioabsorbable hydrogel is a very promising tool to assist in the regrowth of bone at the site of a skull defect, which clinically has been recognized as almost impossible.