Advertisements
Feeds:
Posts
Comments

Posts Tagged ‘bone turnover’


Reporter Aviral Vatsa, PhD MBBS

Annual treatment costs for musculoskeletal diseases in the US are roughly 7.7% (~ $849 billion) of total gross domestic product. Such disorders are the main cause of physical disability in US. Almost half of all chronic conditions in people can be attributed to bone and joint disorders. In addition there is increasing ageing population and associated increases in osteoporosis and other diseases, rising incidences of degenerative intervertebral disk diseases and numbers of revision orthopedic arthroplasty surgeries, and increases in spinal fusions. All these factors contribute towards the increasing requirement of bone regeneration and reconstruction methods and products. Delivery of therapeutic grade products to bone has various challenges. Parenteral administration limits the efficient delivery of drugs to the required site of injury and local delivery methods are often expensive and invasive. The theme issue of Advance Drug Delivery reviews focuses on the current status of drug delivery to bone and the issues facing this field. Here is the first part of these reviews and research articles.

1. Demineralized bone matrix in bone repair: History and use

Abstract

Demineralized bone matrix (DBM) is an osteoconductive and osteoinductive commercial biomaterial and approved medical device used in bone defects with a long track record of clinical use in diverse forms. True to its name and as an acid-extracted organic matrix from human bone sources, DBM retains much of the proteinaceous components native to bone, with small amounts of calcium-based solids, inorganic phosphates and some trace cell debris. Many of DBM’s proteinaceous components (e.g., growth factors) are known to be potent osteogenic agents. Commercially sourced as putty, paste, sheets and flexible pieces, DBM provides a degradable matrix facilitating endogenous release of these compounds to the bone wound sites where it is surgically placed to fill bone defects, inducing new bone formation and accelerating healing. Given DBM’s long clinical track record and commercial accessibility in standard forms and sources, opportunities to further develop and validate DBM as a versatile bone biomaterial in orthopedic repair and regenerative medicine contexts are attractive.

2. Biomimetic hydrogels for controlled biomolecule delivery to augment bone regeneration

Abstract

The regeneration of large bone defects caused by trauma or disease remains a significant clinical problem. Although osteoinductive growth factors such as bone morphogenetic proteins have entered clinics, transplantation of autologous bone remains the gold standard to treat bone defects. The effective treatment of bone defects by protein therapeutics in humans requires quantities that exceed the physiological doses by several orders of magnitude. This not only results in very high treatment costs but also bears considerable risks for adverse side effects. These issues have motivated the development of biomaterials technologies allowing to better control biomolecule delivery from the solid phase. Here we review recent approaches to immobilize biomolecules by affinity binding or by covalent grafting to biomaterial matrices. We focus on biomaterials concepts that are inspired by extracellular matrix (ECM) biology and in particular the dynamic interaction of growth factors with the ECM. We highlight the value of synthetic, ECM-mimicking matrices for future technologies to study bone biology and develop the next generation of ‘smart’ implants.

 

3. Calcium phosphate cements as drug delivery materials

Abstract

Calcium phosphate cements are used as synthetic bone grafts, with several advantages, such as their osteoconductivity and injectability. Moreover, their low-temperature setting reaction and intrinsic porosity allow for the incorporation of drugs and active principles in the material. It is the aim of the present work to: a) provide an overview of the different approaches taken in the application of calcium phosphate cements for drug delivery in the skeletal system, and b) identify the most significant achievements. The drugs or active principles associated to calcium phosphate cements are classified in three groups, i) low molecular weight drugs; ii) high molecular weight biomolecules; and iii) ions.

4. Silk constructs for delivery of musculoskeletal therapeutics

Abstract

Silk fibroin (SF) is a biopolymer with distinguishing features from many other bio- as well as synthetic polymers. From a biomechanical and drug delivery perspective, SF combines remarkable versatility for scaffolding (solid implants, hydrogels, threads, solutions), with advanced mechanical properties and good stabilization and controlled delivery of entrapped protein and small molecule drugs, respectively. It is this combination of mechanical and pharmaceutical features which renders SF so exciting for biomedical applications. This pattern along with the versatility of this biopolymer has been translated into progress for musculoskeletal applications. We review the use and potential of silk fibroin for systemic and localized delivery of therapeutics in diseases affecting the musculoskeletal system. We also present future directions for this biopolymer as well as the necessary research and development steps for their achievement.

5. Demineralized bone matrix as a vehicle for delivering endogenous and exogenous therapeutics in bone repair

Abstract

As a unique human bone extract approved for implant use, demineralized bone matrix (DBM) retains substantial amounts of endogenous osteoconductive and osteoinductive proteins. Commercial preparations of DBM represent a clinically accessible, familiar, widely used and degradable bone-filling device, available in composite solid, strip/piece, and semi-solid paste forms. Surgically placed and/or injected, DBM releases its constituent compounds to bone sites with some evidence for inducing new bone formation and accelerating healing. Significantly, DBM also has preclinical history as a drug carrier by direct loading and delivery of several important classes of therapeutics. Exogenous bioactive agents, including small molecule drugs, protein and peptide drugs, nucleic acid drugs and transgenes and therapeutic cells have been formulated within DBM and released to bone sites to enhance DBM’s intrinsic biological activity. Local release of these agents from DBM directly to surgical sites in bone provides improved control of dosing and targeting of both endogenous and exogenous bioactivity in the context of bone healing using a clinically familiar product. Given DBM’s long clinical track record and commercial accessibility in standard forms and sources, opportunities to formulate DBM as a versatile matrix to deliver therapeutic agents locally to bone sites in orthopedic repair and regenerative medicine contexts are attractive.

6. Nanofiber-based delivery of bioactive agents and stem cells to bone sites

Abstract

Biodegradable nanofibers are important scaffolding materials for bone regeneration. In this paper, the basic concepts and recent advances of self-assembly, electrospinning and thermally induced phase separation techniques that are widely used to generate nanofibrous scaffolds are reviewed. In addition, surface functionalization and bioactive factor delivery within these nanofibrous scaffolds to enhance bone regeneration are also discussed. Moreover, recent progresses in applying these nanofiber-based scaffolds to deliver stem cells for bone regeneration are presented. Along with the significant advances, challenges and obstacles in the field as well as the future perspective are discussed.

 
7. Intra-operatively customized implant coating strategies for local and controlled drug delivery to bone

Abstract

Bone is one of the few tissues in the human body with high endogenous healing capacity. However, failure of the healing process presents a significant clinical challenge; it is a tremendous burden for the individual and has related health and economic consequences. To overcome such healing deficits, various concepts for a local drug delivery to bone have been developed during the last decades. However, in many cases these concepts do not meet the specific requirements of either surgeons who must use these strategies or individual patients who might benefit from them. We describe currently available methods for local drug delivery and their limitations in therapy. Various solutions for drug delivery to bone focusing on clinical applications and intra-operative constraints are discussed and drug delivery by implant coating is highlighted. Finally, a new set of design and performance requirements for intra-operatively customized implant coatings for controlled drug delivery is proposed. In the future, these requirements may improve approaches for local and intra-operative treatment of patients.


8. Local delivery of small and large biomolecules in craniomaxillofacial bone

Abstract

Current state of the art reconstruction of bony defects in the craniomaxillofacial (CMF) area involves transplantation of autogenous or allogenous bone grafts. However, the inherent drawbacks of this approach strongly urge clinicians and researchers to explore alternative treatment options. Currently, a wide interest exists in local delivery of biomolecules from synthetic biomaterials for CMF bone regeneration, in which small biomolecules are rapidly emerging in recent years as an interesting adjunct for upgrading the clinical treatment of CMF bone regeneration under compromised healing conditions. This review highlights recent advances in the local delivery small and large biomolecules for the clinical treatment of CMF bone defects. Further, it provides a perspective on the efficacy of biomolecule delivery in CMF bone regeneration by reviewing presently available reports of pre-clinical studies using various animal models.

9. Immobilized antibiotics to prevent orthopaedic implant infections

Abstract

Many surgical procedures require the placement of an inert or tissue-derived implant deep within the body cavity. While the majority of these implants do not become colonized by bacteria, a small percentage develops a biofilm layer that harbors invasive microorganisms. In orthopaedic surgery, unresolved periprosthetic infections can lead to implant loosening, arthrodeses, amputations and sometimes death. The focus of this review is to describe development of an implant in which an antibiotic tethered to the metal surface is used to prevent bacterial colonization and biofilm formation. Building on well-established chemical syntheses, studies show that antibiotics can be linked to titanium through a self-assembled monolayer of siloxy amines. The stable metal–antibiotic construct resists bacterial colonization and biofilm formation while remaining amenable to osteoblastic cell adhesion and maturation. In an animal model, the antibiotic modified implant resists challenges by bacteria that are commonly present in periprosthetic infections. While the long-term efficacy and stability is still to be established, ongoing studies support the view that this novel type of bioactive surface has a real potential to mitigate or prevent the devastating consequences of orthopaedic infection.

10. Local delivery of nitric oxide: Targeted delivery of therapeutics to bone and connective tissues

Abstract

Non-invasive treatment of injuries and disorders affecting bone and connective tissue remains a significant challenge facing the medical community. A treatment route that has recently been proposed is nitric oxide (NO) therapy. Nitric oxide plays several important roles in physiology with many conditions lacking adequate levels of NO. As NO is a radical, localized delivery via NO donors is essential to promoting biological activity. Herein, we review current literature related to therapeutic NO delivery in the treatment of bone, skin and tendon repair.

Bibliography

  1. Demineralized bone matrix in bone repair: History and use
  2. Biomimetic hydrogels for controlled biomolecule delivery to augment bone regeneration
  3. Calcium phosphate cements as drug delivery materials
  4. Silk constructs for delivery of musculoskeletal therapeutics
  5. Demineralized bone matrix as a vehicle for delivering endogenous and exogenous therapeutics in bone repair
  6. Nanofiber-based delivery of bioactive agents and stem cells to bone sites
  7. Intra-operatively customized implant coating strategies for local and controlled drug delivery to bone
  8. Immobilized antibiotics to prevent orthopaedic implant infections
  9. Local delivery of nitric oxide: Targeted delivery of therapeutics to bone and connective tissues
Advertisements

Read Full Post »


Targeting bone turnover by nature-derived agents for deriving effective treatment of PCa metastases

Reporter: Ritu Saxena, Ph.D.

Introduction and basis of research: Prostate Cancer (PCa) is a leading cause of cancer-related deaths in the men of United States. Metastasis development results in high mortality rate in prostate cancer patients and PCa frequently metastasizes to the bone.

Using nature-derived agents, scientists at the Wayne State University School of medicine, Detroit, Michigan targeted bone remodeling – both bone formation and bone resorption, and proposed it as an effective strategy for the treatment of PCa bone metastasis. The treatment strategy was based on the recent observations pointing towards an increase in both osteoclastic activity and osteoblastic activity in PCa bone metastases which is contrary to the earlier belief that metastases is osteoblastic. Thus, authors designed a study targeting that both osteoclasts (bone forming cells) and osteoclasts (bone resorbing cells) activity for the treatment of PCa bone metastases

Study design: Li et al utilized formulated isoflavone and 3,39-diindolylmethane (BR-DIM) for the suppression of bone remodeling in PCa bone metastases. 3,39-diindolylmethane (DIM) is a natural agent mainly found in the members of the family Cruciferae such as broccoli, and Isoflavone is mainly found in soyabean. Isoflavone genistein has been reported to have the ability to inhibit cancer cell growth both in vitro and in vivo without toxicity. BR-DIM (manufactured by BioResponse, LLC.), as stated by the authors “could downregulate the expression of AR, Akt and NF-kB, leading to the inhibition of PCa growth and the induction of apoptosis in vitro”.  Authors thus, set out to test the hypothesis that “ a mixture of isoflavone and BR-DIM could inhibit the differentiation of osteoclasts and osteoblasts mediated through regulation of cellular signaling pathways that are involved in bone remodeling and PCa bone in vivo”.

A co-culture system involving pre-osteoclastic cell line-RAW264.7 cells, pre-osteoblastic cell line hFOB1.19, and several PCa cell lines, was established to determine how the PCa cells affect differentiation of bone cells. The effect of isoflavone and BR-DIM was then tested on both osteoclast and osteoblast differentiation and PCa cells in the co-culture system.

Results: Isoflavone and BR-DIM inhibited bone remodeling through the inhibition of cell signal transduction associated with osteoclast differentiation (RANKL-mediated signaling), osteoblast differentiation (RUNX2, periostin gene), and PCa growth and signaling. Isoflavone and BR-DIM, infact, were shown to affect multiple signaling pathways that could possibly be useful in the prevention of PCa progression especially in the context of bone metastases.

The study highlights an important message that natural agents could be a source for deriving agents that could be useful in the treatment of diseases such as cancer without toxicity issues.

Sources: Research Article – Li Y, Kong D, Ahmad A, Bao B, Sarkar FH. Targeting bone remodeling by isoflavone and 3,3′-diindolylmethane in the context of prostate cancer bone metastasis. PLoS One. 2012;7(3):e33011. http://www.ncbi.nlm.nih.gov/pubmed?term=22412975

UroToday report: http://www.urotoday.com/UroToday/Prostate-Cancer/targeting-bone-remodeling-by-isoflavone-and-3-3-diindolylmethane-in-the-context-of-prostate-cancer-bone-metastasis-beyond-the-abstract-by-fazlul-h-sarkar-phd-et-al.html

Read Full Post »


Curator: Ritu Saxena, Ph.D.

Reporters: Ritu Saxena, Ph.D. and Dr. Venkat S. Karra, Ph.D.

Merck & Co. declared yesterday, July 12 2012, that it is ending a last-stage clinical trial of the osteoporosis drug Odanacatib based on the results demonstrating the effectively in reducing the post-menopausal fracture risk.

Safety and effectiveness of the drug were being evaluated in the trial enrolling more than 16,000 post-menopausal women and there was clear evidence that the drug was working. Hence, an independent committee decided to end the trial before completion. It was expected to continue until hip fractures had been reported in 237 patients. Merck said the interim analysis was conducted when around 70 percent of the targeted number of hip fractures had been reported. Merck said that it expects to target regulatory approval in the U.S., European Union and Japan in the first half of next year.

Odanacatib is designed to block cathepsin K, the major enzyme in osteoclasts that is responsible for breakdown of existing bone tissue. Osteoclasts, bone “eroding” cells along with bone forming cells, osteoblasts, are involved in bone turnover. In post menopausal osteoporosis, there is a decrease in bone turnover. Blocking the activity of osteoclasts would shift the equilibrium towards bone formation by relative increase in osteoblasts.

Earlier studies have performed 2-3 year long clinical trials showing its effectiveness in treating post-menopausal osteoporosis with a progressive increase in the bone mineral density, increase in bone formation markers expression in molecular studies and that it was generally well tolerated.. The oral drug, taken weekly, is considered more convenient than an older class of osteoporosis drugs known as bisphosphonates. Bisphosphonates, target osteoclasts and have shown to increase the risk of a severe bone disease, osteonecrosis of the jaw. Other safety concerns have also lead to the decline in the use of bisphosphonates.

Sales of Merck’s bisphosphonate drug Fosamax reached $3 billion in 2007, but that revenue has plunged since emergence of generic competition in early 2008. Wall Street analysts, on average, have forecast annual sales of odanacatib at $402 million by 2016, according to Thomson Pharma.

Source: http://www.dddmag.com/news/2012/07/merck-ends-odanacatib-study-early?et_cid=2744025&et_rid=45527476&linkid=http%3a%2f%2fwww.dddmag.com%2fnews%2f2012%2f07%2fmerck-ends-odanacatib-study-early

http://www.huffingtonpost.com/2012/07/12/odanacatib-osteoporosis-drug-fracture-bone_n_1666631.html

http://www.ncbi.nlm.nih.gov/pubmed/20740685

http://www.ncbi.nlm.nih.gov/pubmed/19874198

Read Full Post »


Curator: Ritu Saxena, Ph.D.

News Brief:

Bone-protecting protein discovered

ABC Science, April 19, 2012.

A protein produced by bone cells could help in the development of better treatments for osteoporosis. Professor Hiroshi Takayanagi, of Tokyo Medical and Dental University, and colleagues, report their findings today in the journal Nature.

“I hope our discovery will lead to better treatment developments for osteoporosis, arthritis, or bone fractures,” says Takayanagi. The strength of our bones is controlled by hormones and by the balance between bone formation and breakdown (resorption).

If too much bone is broken down and not enough is made, bone density falls and the chance of fractures increases. Takayanagi and colleagues have found that bone forming cells, or osteoblasts, produce a protein called semaphorin 3A (Sema3A), which has previously been known to regulate nerve and immune cells. They found not only does Sema3A decrease bone breakdown but, unlike current osteoporosis medications that do the same, it also boosts bone formation at the same time.

Mouse studies

When they began their study, Takayanagi and colleagues already knew another protein produced by osteoblasts, called osteoprotegerin, decreases bone breakdown. But, the team suspected there would be other proteins that did the same.

The team checked the activity of proteins produced by osteoblasts from mice genetically engineered to have no osteoprotegerin, and found they were still inhibiting bone breakdown. They isolated the molecule responsible for this inhibition and using mass spectrometry identified it as Sema3A. The researchers then tested mice genetically engineered to have no functional Sema3A and found an increase in bone breakdown and a decrease in bone density.

Surprisingly, however, they also found that bone formation was also lower in these Sema3A knockout mice. In their final experiment they injected Sema3A into diseased mice and found it prevented further bone loss in osteoporosis and accelerated bone regeneration in the case of fractures.

“Many molecules regulate either resorption or formation but this is the first molecule that regulates both at the same time,” says Takayanagi.

http://www.abc.net.au/science/articles/2012/04/19/3480418.htm

‘Exciting discovery’

Dr Gethin Thomas of the Muscoskeletal Genetics Group at The University of Queensland Diamantina Institute welcomes the research. He says more 2 million Australians are currently affected by osteoporosis and half of women over the age of 50 are expected to suffer at least one osteoporotic fracture.

“The gold standard is to find therapies that can build bone as well as stop bone degradation, as osteoporosis is frequently only diagnosed after the bones have already become very weak,” says Thomas.

“This is a very exciting discovery identifying a completely new bone regulating pathway and one that is potentially very ‘druggable’.”

Sema3A is known to play important roles in the development of heart and nervous system, but researchers are yet understand exactly how the protein acts to boost bone formation and inhibit bone resorption. “It’s possible there might be side-effects on the heart or nerve generation but they haven’t explored that at all in this paper,” says bone cell biologist, Associate Professor Natalie Sims from the St Vincent’s Institute.

“It’s important that they’ve found this new factor and what it can do. What’s not clear is how specific it might be and that’s the obviously the next step they need to explore.”

http://www.abc.net.au/science/articles/2012/04/19/3480418.htm

Research:

Takanayagi et al published the research on Sema3a molecule’s bone formation and bone resorption activity in a recent issue of the journal Nature (2012). The research was summarized as:

The bony skeleton is maintained by local factors that regulate bone-forming osteoblasts and bone-resorbing osteoclasts, in addition to hormonal activity. Osteoprotegerin protects bone by inhibiting osteoclastic bone resorption, but no factor has yet been identified as a local determinant of bone mass that regulates both osteoclasts and osteoblasts. Here we show that semaphorin 3A (Sema3A) exerts an osteoprotective effect by both suppressing osteoclastic bone resorption and increasing osteoblastic bone formation. The binding of Sema3A to neuropilin-1 (Nrp1) inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation by inhibiting the immunoreceptor tyrosine-based activation motif (ITAM) and RhoA signalling pathways. In addition, Sema3A and Nrp1 binding stimulated osteoblast and inhibited adipocyte differentiation through the canonical Wnt/β-catenin signalling pathway. The osteopenic phenotype in Sema3a−/− mice was recapitulated by mice in which the Sema3A-binding site of Nrp1 had been genetically disrupted. Intravenous Sema3A administration in mice increased bone volume and expedited bone regeneration. Thus, Sema3A is a promising new therapeutic agent in bone and joint diseases.

http://www.nature.com/nature/journal/v485/n7396/full/nature11000.html

Semaphorins have been known as one family of inhibitory axon guidance molecules. The semaphorins include secreted, transmembrane, and GPI anchored extracellular molecules that are involved in regulating axon guidance by inhibiting axons from growing toward incorrect targets. Semaphorin 3A (Sema3A) may play a particularly interesting role in limiting axon regeneration since it is expressed in meningeal fibroblasts that invade the injured spinal cord and surround the glial scar. In addition, the Sema3A co receptors, Neuropilin 1 and Plexin A1, are expressed on axons that regenerate up to the injured region, but do not cross this Sema3A containing region. Thus, Sema3A and its co receptors may have important roles in regulating axon guidance during neuronal development and after neuronal injury.

http://www.abcam.com/Semaphorin-3A-antibody-ab25999.html

Conclusion and Future perspective:

Takayanagi et al stated in the discussion of the article “Sema3A represents the long sought soluble molecule with the capacity to bring both osteoblasts and osteoclasts into a condition that favours bone mineral increase.”

Mone Zaidi and Jameel Iqbal, bone biology researchers from the Mount Sinai School of Medicine commented on the research stating “The protein Sema3A both restrains bone degradation and stimulates bone building in mice, suggesting a potential therapy for conditions such as osteoporosis”, referring to it as probable “double protection for weakened bones”.

http://www.nature.com/nature/journal/v485/n7396/full/485047a.html

Uncoupling of bone turnover (with a decrease in bone formation and an increase in bone resorption) has been observed in postmenopausal osteoporosis and microgravity-induced bone loss. Most of the available drugs are either anti-resorptive (For eg., bisphonsphonates), or anabolic (For eg., Parathyroid hormone) on bone. However, Sema3a might act as an effective therapeutic agent by targeting both bone formation and bone resorption.

Read Full Post »