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Local Strategies to Prevent and Treat Osteoporosis
Abstract
Despite advances in systemic osteoporosis therapeutic outcomes, management of fragility fractures and implant fixation in osteoporotic bone remain difficult clinical challenges. Low initial bone density and a prolonged healing response can lead to fracture nonunion and aseptic implant loosening. Local treatment strategies could be used to prevent fracture, accelerate healing, and increase implant fixation by locally stimulating anabolic pathways or inhibiting catabolic pathways. Local strategies under investigation include direct drug release from injectable materials or implant surface coatings. Common locally delivered drugs include bisphosphonates, parathyroid hormone, and bone morphogenetic proteins, yet additional compounds targeting novel pathways in bone biology are also being actively explored. Mechanical stimulation via low intensity pulsed ultrasound, alone or in combination with drug therapy, may also prove effective to promote local bone healing and implant fixation within osteoporotic bone.
... Moreover, these antiresorptive drugs also suffer from a slow onset of efficacy, which usually start to take effects in more than half a year. Such drawbacks of these drugs can often fail to provide structural support for implant fixation during the osteoporotic fracture treatment [3]. Thus, it is of great significance to increase the local bone density which enhance the holding force of internal implants in osteoporotic fractures management. ...
... Notably, the bone defect was found to be healed completely in the MAM/SRT group, filled with regenerated bone tissue and integrated with surrounding bone seamlessly (Fig. 8B). Moreover, according to previous studies [1][2][3], the pathological parameters reflecting bone formation [BV/TV, Osteoblast number (N. Ob/B. ...
The imbalance of bone homeostasis is the root cause of osteoporosis. However current therapeutic approaches mainly focus on either anabolic or catabolic pathways, which often fail to turn the imbalanced bone metabolism around. Herein we reported that a SIRT-1 agonist mediated molecular therapeutic strategy to reverse the imbalance in bone homeostasis by simultaneously regulating osteogenesis and osteoclastogenesis via locally sustained release of SRT2104 from mineral coated acellular matrix microparticles. Immobilization of SRT2104 on mineral coating (MAM/SRT) harnessing their electrostatic interactions resulted in sustained release of SIRT-1 agonist for over 30 days. MAM/SRT not only enhanced osteogenic differentiation and mineralization, but also attenuated the formation and function of excessive osteoclasts via integrating multiple vital upstream signals (β-catenin, FoxOs, Runx2, NFATc1, etc.) in vitro. Osteoporosis animal model also validated that it accelerated osteoporotic bone healing and improved osseointegration of the surrounding bone. Overall, our work proposes a promising strategy to treat osteoporotic bone defects by reversing the imbalance in bone homeostasis using designated small molecule drug delivery systems.
... BP related osteonecrosis of jaw (BRONJ) is a rare condition that has been associated with high-dose or long-term BP therapy (Fig. 1). The incidence rate of BRONJ among BPs has been estimated at between 0.03% to 4.3% [11,12]. Despite achievements in systemic prevention and treatment of osteoporosis, the fragility fractures, their healing and implant osseointegration, long time stability in osteoporotic bone remain difficult clinical problem. ...
... Experimental biological models are considered as required part in introduction of new drugs and medical technologies. US Food and Drug Administration regulation asks at least two animal species for preclinical assessment of new experimental drugs in treatment of osteoporosis [11]. A new treatment strategy as the "local treatment of osteoporosis" is to target specific areas of the skeletal system that are prone to clinically significant osteoporotic fractures. ...
Osteoporosis is a chronic, metabolic and systemic skeletal disease characterized by low bone mineral density (BMD) and micro-architectural deterioration, resulting in increased bone fragility and fracture risk. Changes in the mineral structure occur due to aging or because of progressive pathologic processes such as osteoporosis, as well as in both aging and effects of bone diseases.
... A prolonged healing response can lead to fracture nonunion (Takeuchi, 2009). Local treatment strategies could be used to prevent fracture, accelerate healing, and increase implant fixation by locally stimulating anabolic pathways or inhibiting catabolic pathways (Torstrick and Guldberg, 2014). In this context, we considered LLLT and LIPUS as local strategies (Torstrick and Guldberg, 2014). ...
... Local treatment strategies could be used to prevent fracture, accelerate healing, and increase implant fixation by locally stimulating anabolic pathways or inhibiting catabolic pathways (Torstrick and Guldberg, 2014). In this context, we considered LLLT and LIPUS as local strategies (Torstrick and Guldberg, 2014). The consistent action of biophysical agents such as LLLT and LIPUS on bones has been often studied; study results show that they are able to encourage osteogenesis, accelerate fracture consolidation, and augment bone mass (Lirani and Lazaretti-Castro, 2005). ...
To compare the in vitro effectiveness of Low-Level Laser Therapy (LLLT) and Low Intensity Pulsed Ultrasound (LIPUS) on bony cells and related stem cells. In this study, we aim to systematically review the published scientific literature which explores the use of LLLT and LIPUS to biostimulate the activity or the proliferation of bony cells or stem cells in vitro. We searched the database PubMed for LLLT or LIPUS, with/without bone, osteoblast, osteocyte, stem cells, the human osteosarcoma cell line (MG63), bone-forming cells, and cell culture (or in vitro). These studies were subdivided into categories exploring the effect of LLLT or LIPUS on bony cells, stem cells, and other related cells. 75 articles were found between 1987 and 2016; these included: 50 full paper articles on LLLT and 25 full papers on LIPUS. These articles met the eligibility criteria and were included in our review. A detailed and concise description of the LLLT and the LIPUS protocols and their individual effects on bony cells or stem cells and their results are presented in five tables. Based on the main results and the conclusions of the reviewed articles in the current work, both, LLLT and LIPUS, apply a biostimulatory effect on osteoblasts, osteocytes, and enhance osteoblast proliferation and differentiation on different bony cell lines used in in vitro studies, and therefore, these may be useful tools for bone regeneration therapy. Moreover, in consideration of future cell therapy protocols, both, LLLT and LIPUS (especially LLLT), enhnce a significant increase in the initial number of SCs before differentiation, thus increasing the number of differentiated cells for tissue engineering, regenerative medicine, and healing. Further studies are necessary to determine the LLLT or the LIPUS parameters, which are optimal for biostimsulating bony cells and SCs for bone healing and regenerative medicine.
... Aonuma et al. concluded that alendronate plus LIPUS caused an extra increase in BMD at the affected metaphysis. Torstrick and Guldberg suggested local treatment strategies such as external mechanical stimulation via LIPUS to provide for the local treatment of osteoporotic fracture, either alone or combined with other therapies [57]. However, the effect of LIPUS on intact osteoporotic bone is inconclusive [57]. ...
... Torstrick and Guldberg suggested local treatment strategies such as external mechanical stimulation via LIPUS to provide for the local treatment of osteoporotic fracture, either alone or combined with other therapies [57]. However, the effect of LIPUS on intact osteoporotic bone is inconclusive [57]. ...
Material and methods:
18 female rats were distributed into the following groups: 1) control healthy, 2) LASER-healthy (890nm, 80Hz, 1.5J/cm(2), three days weekly, 60days), 3) control OVX, 4) LASER-OVX, 5) Alendronate (Alen.)-OVX [0.5mg/kg, 5days per week, 60days], and 6) Alen.+LASER-OVX. Ovariectomy was done on rats of groups 3, 4, 5 and 6. After that all rats were euthanized and their MSC harvested and cultured in complete osteogenic medium. In all groups, BMMSC viability, and calcium colorimetric assay were performed.
Results:
We observed a significant increase in optical density (OD) of BMMSCs viability in LASER healthy group compared to control-OVX, Alen.-OVX, LASER-OVX, LASER+Alen.-OVX, groups. LASER+Alen.-OVX group displayed a significant escalation in OD of BMMSCs viability compared to LASER-OVX, Alen.-OVX, and control-OVX groups. There were a significant increase in calcium ion release of LASER-healthy group compared to control healthy, control-OVX, Alen.-OVX, LASER-OVX, and LASER+Alen.-OVX groups. LASER+Alen.-OVX group displayed a significant escalation in calcium ion release compared to LASER-OVX, Alen.-OVX, and control-OVX groups.
Conclusion:
Pulse wave (PW) PBM significantly stimulated viability and cell proliferation of healthy BMMSCs compared to those of control-OVX, OVX-alendronate, OVX-LASER, and LASER+alendronate-OVX. In addition stimulatory effect of LASER+alendronate on viability and cell proliferation of OVX-BMMSCs compared to those of control-OVX, alendronate-OVX, and LASER-OVX groups were found.
... The occurrence of osteoporotic fracture becomes more frequent with an aging global population [2] and often leads to the loss of patient's mobility and autonomy [3]. Though various orthopedic surgical implants have been designed to resolve this issue, repair/fixation of osteoporotic bone fracture remains a major clinical challenge [4]. Magnesium (Mg) alloys are promising biodegradable implant materials to repair osteoporotic bone fracture due to their mechanical compatibility and biological safety which can avoid or reduce the stress-shielding effect as a result of a low modulus [5,6]. ...
... Immobilization of BP onto HA-coated titanium implants has proven to increase implants fixation in osteoporotic conditions [33][34][35][36]. However, the conventional calcium phosphate (CaP) coatings deposited by high-temperature processing such as plasma spraying usually have limited drug loading capacity [4,37]. Moreover, immobilization of BP by immersing HA-coated implants in a BP solution usually leads to burst release of BP during the initial stage of implantation. ...
Osteoporosis is a significant public health problem associated with increased fracture risk. Magnesium (Mg) alloys are promising biodegradable implant materials for osteoporotic bone fracture repair due to their mechanical compatibility and biological safety. However, the degradation rate of Mg alloy does not match the healing rate of the fracture and the growth rate of new bone tissues. In order to treat and prevent osteoporosis, enhance peri-implant bone formation, inhibit bone resorption and slow down the degradation of Mg alloy, herein, we developed a novel bio-inspired therapeutic coating strategy by co-immobilizing strontium (Sr) substituted hydroxyapatite (Sr-HA) nanocrystals and bisphosphonate (BP) alendronate on the surface of AZ31 Mg alloy with the aid of polydopamine and carboxymethyl chitosan (CMCS). Such novel functionalized coating can not only improve the corrosion resistance of Mg alloy but also stimulate the proliferation and differentiation of osteoblast cells due to the sustained release of ALN and Sr ions from Sr-HA nanocrystals. The present coating strategy provides deep insights into clinical repair of osteoporosis-associated fractures and can potentially be extended to design of many other orthopedic devices.
... implants have been designed to increase load-sharing, fixation in osteoporotic bone remains a major challenge 5 . Bone cements such as polymethylmethacrylate (PMMA) improve fixation physically but not physiologically 6,7 . ...
... PMMA can only physically enhance the strength of osteoporotic bone 6,7 , and exothermic polymerization reaction, potential leakage, and the presence of a permanent foreign body in the vertebra with PMMA may cause osseous or neural tissue injury 6,[36][37][38] . Local applications of bone anabolic agents, such as BMPs 9-11 , promote bone formation at a specific site and have numerous advantages compared with systemic treatments in terms of therapeutic efficiency and tolerance 5,39 . This topical treatment approach could strengthen implant fixation in osteoporotic bone. ...
Background:
Osteoporosis leads to poor osseointegration and reduces implant stability. Statins have been found to stimulate bone formation, but the bioavailability from oral administration is low. Local application may be more effective at augmenting bone formation and enhancing implant stability. This study was performed to evaluate the efficacy of an intraosseous injection of simvastatin in thermosensitive poloxamer 407 hydrogel to enhance pedicle-screw fixation in calcium-restricted ovariectomized minipigs.
Methods:
Nine mature female Guangxi Bama minipigs underwent bilateral ovariectomy and were fed a calcium-restricted diet for 18 months. Simvastatin (0, 0.5, or 1 mg) in thermosensitive poloxamer 407 hydrogel was injected into the lumbar vertebrae (L4-L6), and titanium alloy pedicle screws were implanted. Bone mineral density (BMD) measurements of the lumbar vertebrae were determined by dual x-ray absorptiometry (DXA) before and 3 months after treatment. The lumbar vertebrae were harvested and analyzed with use of microcomputed tomography, biomechanical pull-out testing, histological analysis, and Western blot analysis for bone morphogenetic protein (BMP)-2 and vascular endothelial growth factor (VEGF) expression.
Results:
Evaluation over a 3-month study period demonstrated that the BMD of the vertebrae injected with 0.5 and 1.0 mg of simvastatin had increased by 31.25% and 31.09%, respectively, compared with vehicle-only injection (p ≤ 0.00014 for both) and increased by 32.12% and 28.16%, respectively, compared with the pre-treatment levels (p < 0.0001 for both). A single injection of simvastatin in poloxamer 407 increased trabecular volume fraction, thickness, and number and decreased trabecular separation (p ≤ 0.002). The bone formation and mineral apposition rates significantly increased (p ≤ 0.023). The percentage of osseointegration in the simvastatin 0.5 and 1-mg groups was 46.54% and 42.63% greater, respectively, than that in the vehicle-only group (p ≤ 0.006), and the maximum pull-out strength was 45.75% and 51.53% greater, respectively, than in the vehicle-only group (p ≤ 0.0005). BMP-2 and VEGF expressions were higher than for the vehicle-only injection.
Conclusions:
A single intraosseous injection of simvastatin in thermosensitive poloxamer 407 hydrogel stimulated bone formation, increased BMD, improved bone microstructure, promoted osseointegration, and significantly enhanced the stability of pedicle screws in calcium-restricted ovariectomized minipigs.
Clinical relevance:
These results provide rationale for evaluating intraosseous injection of simvastatin in poloxamer 407 to enhance implant fixation in patients with osteoporosis.
... Therefore, regulating the response of osteoblasts and osteoclasts at the fracture site to maintain a dynamic balance between bone formation and resorption is crucial for successful healing. Although various methods are available to address osteoporotic fractures, including surgical implants and medication, their efficacy is still unsatisfactory and typical examples are fixation/reconstruction devices [5] . ...
Zn and its alloys are increasingly under consideration for biodegradable bone fracture fixation implants owing to their attractive biodegradability and mechanical properties. However, their clinical application is a challenge for osteoporotic bone fracture healing, due to their uneven degradation mode, burst release of zinc ions, and insufficient osteo-promotion and osteo-resorption regulating properties. In this study, a type of Zn2+ coordinated zoledronic acid (ZA) and 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP) metal-organic hybrid nanostick was synthesized, which was further mixed into zinc phosphate (ZnP) solution to mediate the deposition and growth of ZnP to form a well-integrated micro-patterned metal-organic/inorganic hybrid coating on Zn. The coating protected noticeably the Zn substrate from corrosion, in particular reducing its localized occurrence as well as suppressing its Zn2+ release. Moreover, the modified Zn was osteo-compatible and osteo-promotive and, more important, performed osteogenesis in vitro and in vivo of well-balanced pro-osteoblast and anti-osteoclast responses. Such favorable functionalities are related to the nature of its bioactive components, especially the bio-functional ZA and the Zn ions it contains, as well as its unique micro- and nano-scale structure. This strategy provides not only a new avenue for surface modification of biodegradable metals but also sheds light on advanced biomaterials for osteoporotic fracture and other applications. STATEMENT OF SIGNIFICANCE: Developing appropriate biodegradable metallic materials is of clinical relevance for osteoporosis fracture healing, whereas current strategies are short of good balance between the bone formation and resorption. Here, we designed a micropatterned metal-organic nanostickmediated zinc phosphate hybrid coating modified Zn biodegradable metal to fulfill such a balanced osteogenicity. The in vitro assays verified the coated Zn demonstrated outstanding pro-osteoblasts and anti-osteoclasts properties and the coated intramedullary nail promoted fracture healing well in an osteoporotic femur fracture rat model. Our strategy may offer not only a new avenue for surface modification of biodegradable metals but also shed light on better understanding of new advanced biomaterials for orthopedic application among others.
... The cost of osteoporosis including pharmacological intervention in the EU in 2021 was estimated at €56.9 billion. 1 The healing of bone fractures in osteoporotic patients is complicated by poor bone quality, which can complicate fracture fixation and stability. 2 The treatment of osteoporosis has necessitated medical care for several decades. In the last century, osteoporosis was treated mainly with estrogen, 3 calcitonin, 4 or calcium and vitamin D supplementation. ...
Purpose:
Osteoporosis is a severe health problem with social and economic impacts on society. The standard treatment consists of the systemic administration of drugs such as bisphosphonates, with alendronate (ALN) being one of the most common. Nevertheless, complications of systemic administration occur with this drug. Therefore, it is necessary to develop new strategies, such as local administration.
Methods:
In this study, emulsion/dispersion scaffolds based on W/O emulsion of PCL and PF68 with ALN, containing hydroxyapatite (HA) nanoparticles as the dispersion phase were prepared using electrospinning. Scaffolds with different release kinetics were tested in vitro on the co-cultures of osteoblasts and osteoclast-like cells, isolated from adult osteoporotic and control rats. Cell viability, proliferation, ALP, TRAP and CA II activity were examined. A scaffold with a gradual release of ALN was tested in vivo in the bone defects of osteoporotic and control rats.
Results:
The release kinetics were dependent on the scaffold composition and the used system of the poloxamers. The ALN was released from the scaffolds for more than 22 days. The behavior of cells cultured in vitro on scaffolds with different release kinetics was comparable. The difference was evident between cell co-cultures isolated from osteoporotic and control animals. The PCL/HA scaffold show slow degradation in vivo and residual scaffold limited new bone formation inside the defects. Nevertheless, the released ALN supported bone formation in the areas surrounding the residual scaffold. Interestingly, a positive effect of systemic administration of ALN was not proved.
Conclusion:
The prepared scaffolds enabled tunable control release of ALN. The effect of ALN was proved in vitro and in in vivo study supported peri-implant bone formation.
... Additionally, these treatments can be local, systemic, or a combination This article is part of the Topical Collection on Regenerative Biology and Medicine in Osteoporosis thereof. For example, osteoporosis may require systemic treatment [8] but would likely benefit from concurrent local treatments for areas of greatest concern [9]. ...
Purpose of Review
Tissue regenerative solutions for musculoskeletal disorders have become increasingly important with a growing aged population. Current growth factor treatments often require high dosages with the potential for off-target effects. Growth factor immobilization strategies offer approaches towards alleviating these concerns. This review summarizes current growth factor immobilization techniques (encapsulation, affinity interactions, and covalent binding) and the effects of immobilization on growth factor loading, release, and bioactivity.
Recent Findings
The breadth of immobilization techniques based on encapsulation, affinity, and covalent binding offer multiple methods to improve the therapeutic efficacy of growth factors by controlling bioactivity and release. Growth factor immobilization strategies have evolved to more complex systems with the capacity to load and release multiple growth factors with spatiotemporal control.
Summary
The advancements in immobilization strategies allow for development of new, complex musculoskeletal tissue treatment strategies with improved spatiotemporal control of loading, release, and bioactivity.
... Em busca de terapias capazes de manter a ação benéfica dos BPOs, enquanto se tentam evitar os efeitos colaterais e melhorar a sua biodisponibilidade, diferentes grupos de investigação têm procurado vias de administração alternativas e formulações inovadoras. Este processo passa, por vezes, pelo desenvolvimento de formulações de BPOs que possam ser aplicadas diretamente no tecido ósseo, no decurso de uma intervenção cirúrgica [63]. Tal é o caso de, por exemplo, cimentos ósseos contendo na sua composição BPOs como o alendronato ou pamidronato [64,65]. ...
... Em busca de terapias capazes de manter a ação benéfica dos BPOs, enquanto se tentam evitar os efeitos colaterais e melhorar a sua biodisponibilidade, diferentes grupos de investigação têm procurado vias de administração alternativas e formulações inovadoras. Este processo passa, por vezes, pelo desenvolvimento de formulações de BPOs que possam ser aplicadas diretamente no tecido ósseo, no decurso de uma intervenção cirúrgica [63]. Tal é o caso de, por exemplo, cimentos ósseos contendo na sua composição BPOs como o alendronato ou pamidronato [64,65]. ...
... However, its effect is still controversial. 3 A large, multicentre, blind, randomised controlled clinical trial showed that LIPUS did not accelerate the radiographic fracture healing and the functional recovery. 4 Another adjuvant therapy option is the administration of bone morphogenetic protein (BMP)-2, which has osteogenic effects and has a therapeutic effect on open tibiofibular fractures. ...
Introduction
Both animal studies and clinical trials have shown that daily parathyroid hormone administration promotes bone fracture healing. We previously found that weekly injections of the recombinant human parathyroid hormone teriparatide at a dosage of 20 μg/kg promoted tibial fracture healing to the same extent as daily injections of teriparatide at a dosage of 10 μg/kg in a rodent model. However, the effect of weekly teriparatide administration on human fracture healing is unreported. This protocol describes a randomised controlled clinical trial designed to evaluate whether weekly administration of teriparatide accelerates fracture repair in humans.
Methods and analysis
This single-centre, double-blind, randomised controlled trial will be conducted in Peking University Third Hospital. Eligible patients with Colles’ fracture incurred within 48 hours will be randomly divided into two groups (n=40 per group) that will receive 14 weekly subcutaneous injections of either saline or teriparatide (40 μg/week). The primary outcome will be the time taken to achieve radiographic healing, as assessed using the modified radiographic union scale for tibial fractures. The secondary outcomes will be functional assessments, including the self-administered Patient-Rated Wrist Evaluation questionnaire, grip strength and rate of fracture non-union.
Ethics and dissemination
Ethical approval has been obtained from the Peking University Third Hospital Medical Science Research Ethics Committee (M2020207). The findings will be disseminated in peer-reviewed publications.
Trial registration number
NCT04473989 : protocol version: 1.
... Some of these are alternative oral dosage forms that aim at improving bioavailability and reducing the side effects of enteric absorption, while others are directed to nonenteric administration. In particular, researchers have been seeking ways to achieve direct delivery of BPs to the bone, 116 avoiding not only the discomfort of the oral intake but the systemic dispersion of these compounds. It is important to notice, however, that, while these methodologies offer valuable administration approaches that may be of use sometime in the near future, the studies described in the following sections comprise, essentially, in vivo evaluation on an animal model. ...
Bisphosphonates, used for a long time in osteoporosis management, are currently the target of intensive research, from pre-formulation studies to more advanced stages of clinical practice. This review presents an overview of the contributions of this family of compounds to human health, starting with the chemistry and clinical uses of bisphosphonates. Following this, their pharmacology is described, highlighting administration-borne handicaps and undesirable effects. The last three sections of the review describe the research efforts that seek to curb delivery-related issues and expand bisphosphonate use. Innovative routes and strategies of administration, such as nano-encapsulation for oral intake or injectable cements for local or in-bone delivery are presented, as well as the latest results of case studies or preclinical studies proposing new therapeutic indications for the clinically approved bisphosphonates. Finally, a selection of anti-infectious bisphosphonate new drug candidates is shown, with focus on the molecules reported in the last two decades.
... On the other hand, the beneficial effect of LLLT on bone is attributed to its biostimulatory action, where it is capable of increasing mitochondrial activity, bone formation, osteocalcin and osteopontin gene expression, as well as alkaline phosphate activity [46]. This is supported by Torstrick et al., [47] who pointed out that LLLT could be utilized to prevent fracture, improve healing, and accelerate implant fixation. Accordingly, the results of the present study propose the possibility of using LLLT as local treatment strategy that could act as a good alternative with minimal side effects and superior outcome. ...
Our aim in this study was to evaluate the effect of low-level laser therapy (LLLT) by means of diode laser bio-stimulation compared to Teriparatide in induced osteoporosis in rats. A total of 45 adult female Egyptian albino rats were used. Rats were divided into five groups: normal control, osteoporotic control, Teriparatide (TPTD) group (T), laser group (L), and laser and teriparatide (T+L) combination group. Osteoporosis was induced by performing double ovariectomy in rats. Lower jaws and left femurs were dissected. The specimens were tested using a Computed tomography unit, scanning EM (SEM) equipped with Energy Dispersive X-Ray Analyzer, and Rat PINP ELISA Kit. The histopathologic examination of experimental rat jaws and femurs revealed changes in bone architecture among the various groups throughout the experiment. CT examination showed a noticeable difference in radiodensity between jaw and femur bones. By SEM, bones of the Normal Control (NC) group showed normal bone porosity. However, bones of the Osteoporotic Control (OC) group showed a great difference as bone pores were large and numerous with irregular outlines. The ELISA test for PINP concentration showed a steady rise in the PINP concentrations in OC, T, L and T+L groups. We concluded that TPTD has osteogenic potential and is capable to enhance bone architecture by inducing the formation of new well-organized bone with narrower bone pore diameter. LLLT can be used as a good alternative local treatment strategy with minimal side effects and superior outcomes.
... However, without long-term bioactivity of inhibiting the function of osteoclast, regenerated bone tissue would still at the risks of microfracture and malunion under the microenvironment of osteoporosis (Giannoudis & Schneider, 2006). Hence, anti-osteoporosis drugloaded biomaterials which could both regulate the microenvironment and occupy the defect areas are promising (Torstrick & Guldberg, 2014). ...
Researches of biomaterials for osteoporotic bone defects focus on the improvement of its anti‐osteoporosis ability, due to osteoporosis is a kind of systemic and long‐range bone metabolism disorder. Nevertheless, how to steadily deliver anti‐osteoporosis drugs in osteoporotic bone defects is rarely studied. Reported evidences have shown that alendronate (Aln) is known to not only restrain osteoclasts from mediating bone resorption but also stimulate osteoblasts to regenerate bone tissue. Here, we developed an engineered implantable scaffold that could sustainably release Aln for osteoporotic bone defects. Briefly, Aln was added into 2% collagen (Col) solution to form a 5mg/mL mixture. Then the mixture was filled into pre‐designed round models (diameter:5 mm, height:2 mm) and crosslinked to obtain engineered Col‐Aln scaffolds. The release kinetics showed that Aln was released at an average rate of 2.99 μg/d in the initial 8 days and could sustainably release for one month. To detect the repair effects of the Col‐Aln scaffolds for osteoporotic defects, the Col and Col‐Aln scaffolds were implanted into 5 mm cranial defects in ovariectomized rats. After 3 months, the cranial defects implanted with Col‐Aln scaffolds achieved more bone regeneration in defect area (11.74±3.82%) than Col scaffold (5.12±1.15%) (p<0.05). Moreover, ovariectomized rats in Col‐Aln scaffold group possessed more trabecular bone in femur metaphysis than Col scaffold group as analyzed by Micro‐CT. This study demonstrated the engineered Col‐Aln scaffold has the potential to repair osteoporotic bone defects and resist bone loss in osteoporosis.
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... Drugs for the treatment of osteoporosis could be divided into anabolic and antiresorptive categories. Bisphosphonates (including alendronate and ibandronate, target osteoclast), estrogen, selective estrogen receptor modulators, and denosumab (an antibody to RANKL) are antiresorptive drugs, whereas PTH and its analogs are anabolic agents [43][44][45] . However, long-term trials showed that these drugs had no effects on the prevention of hip fractures. ...
Background:
Radiation induces rapid bone loss and enhances bone resorption and adipogenesis, leading to an increased risk of bone fracture. There is still a lack of effective preventive or therapeutic method for irradiation-induced bone injury. Receptor activator of nuclear factor κB ligand (RANKL) provides the crucial signal to induce osteoclast differentiation and plays an important role in bone resorption. However, the mechanisms of radiation-induced osteoporosis are not fully understood.
Aim:
To investigate the role of CR6-interacting factor-1 (Crif1) in osteoclastogenesis after radiation and its possible mechanism.
Methods:
C57BL/6 mice were exposed to Co-60 gamma rays and received 5 Gy of whole-body sublethal irradiation at a rate of 0.69 Gy/min. For in vitro study, mouse bone marrow mesenchymal stem/stromal cells (BM-MSCs) were irradiated with Co-60 at a single dose of 9 Gy. For osteoclast induction, monocyte-macrophage RAW264.7 cells were cocultured with mouse BM-MSCs for 7 d. ClusPro and InterProSurf were used to investigate the interaction interface in Crif1 and protein kinase cyclic adenosine monophosphate (cAMP)-activited catalytic subunit alpha complex. Virtual screening using 462608 compounds from the Life Chemicals database around His120 of Crif1 was carried out using the program Autodock_vina. A tetrazolium salt (WST-8) assay was carried out to study the toxicity of compounds to different cells, including human BM-MSCs, mouse BM-MSCs, and Vero cells.
Results:
Crif1 expression increased in bone marrow cells after radiation in mice. Overexpression of Crif1 in mouse BM-MSCs and radiation exposure could increase RANKL secretion and promote osteoclastogenesis in vitro. Deletion of Crif1 in BM-MSCs could reduce both adipogenesis and RANKL expression, resulting in the inhibition of osteoclastogenesis. Deletion of Crif1 in RAW264.7 cells did not affect the receptor activator of nuclear factor κB expression or osteoclast differentiation. Following treatment with protein kinase A (PKA) agonist (forskolin) and inhibitor (H-89) in mouse BM-MSCs, Crif1 induced RANKL secretion via the cAMP/PKA pathway. Moreover, we identified the Crif1-protein kinase cyclic adenosine monophosphate-activited catalytic subunit alpha interaction interface by in silico studies and shortlisted interface inhibitors through virtual screening on Crif1. Five compounds dramatically suppressed RANKL secretion and adipogenesis by inhibiting the cAMP/PKA pathway.
Conclusion:
Crif1 promotes RANKL expression via the cAMP/PKA pathway, which induces osteoclastogenesis by binding to receptor activator of nuclear factor κB on monocytes-macrophages in the mouse model. These results suggest a role for Crif1 in modulating osteoclastogenesis and provide insights into potential therapeutic strategies targeting the balance between osteogenesis and adipogenesis for radiation-induced bone injury.
... При рассмотрении работ, посвященных хирургическому ведению пациентов с переломами бедренной кости, было выявлено, что остеопороз является самым частым лимитирующим фактором в достижении стабильности имплантата [14,21,23,28]. Некоторые очевидные успехи в достижении стабильности конструкции были получены с началом использования метода аугментации кости в сочетании с остеосинтезом. ...
He research provides an overview of studies on osteosynthesis of proximal femoral nail antirotation (PFNA) with augmentation in patients with fractures of the femur on the background of osteoporosis. Descriptive and analytical methods were used in the work. The search for publications was made in the databases: Google Scholar, e-Library and Medline, as well as in Cochrane Consort library with the use of MeSh terminology. At the present time in order to obtain full evidence base on the benefits of using PFNA with augmentation in osteosynthesis of hip fractures on the background of osteoporosis it is necessary to conduct randomized controlled trials, despite the obvious advantages of this technology.
... Furthermore, as the U.S. Food and Drug Administration (FDA) has already approved LIPUS treatment for fresh fractures and established non-unions, parallel approval for osteoporosis can therefore be expected. It is also worth mentioning that LIPUS has the potential to provide local treatment (Ferreri et al. 2011;Torstrick and Guldberg 2014) at skeletal sites at risk, which represents a unique advantage over current systemic agents, as bone loss may be more prominent in the hip, spine and wrist for people 50 y old (Trajanoska et al. 2018) and in the load-bearing bones for astronauts (Thomsen et al. 2012). With the advantages of being non-invasive, radiation-free, relatively inexpensive, portable and convenient, LIPUS stimulation is an attractive candidate for osteoporosis and deserves considerably more research attention. ...
This study investigated the effects of low-intensity pulsed ultrasound (LIPUS) of different spatial-average-temporal-average intensity (ISATA) ranging from 15-150 mW/cm2 on the treatment of osteoporosis in ovariectomized rats. Healthy 3-mo-old female Sprague-Dawley rats were randomly divided into nine groups (n = 12 per group): sham-ovariectomy (OVX) control group, OVX control group and OVX groups treated with LIPUS at seven different intensities (ISATA: 15, 30, 50, 75, 100, 125 and 150 mW/cm2, respectively). LIPUS was applied to bilateral femurs 12 wk post-OVX for 20 min/d for 6 wk. Micro-computed tomography, biomechanical tests, serum biochemical analysis and grip strength tests were performed to evaluate the therapeutic effects of LIPUS at different intensities. Results revealed that LIPUS intensity yielded strong correlations with bone mineral density and bone microstructure (R2 = 0.57-0.83) and bone mechanical strength (R2 = 0.80-0.97), and that the intensity of 150 mW/cm2, instead of the 30 mW/cm2 widely used in bone fracture healing, was most effective in maintaining bone mass among all the LIPUS signals between 15 and 150 mW/cm2. This suggests that higher ultrasound intensity (i.e., 150 mW/cm2) may be more effective than lower intensity in mitigation of osteopenia and osteoporosis.
... • the similarity of phosphonate groups with the phosphates, so the noted affinity for hydroxyapatite surfaces in bone and tooth [1,2]; • the P-C-P bridge is non-hydrolysable by means of pyrophosphatase [2,3]; • if one of the C 1 substituent groups is hydroxyl (OH), the capacity of binding on the mineral part of bone is improved [4,5]; • the organic substituent of C 1 is able to interact with different biochemical processes, especially with the osteoclast-osteoblast equilibrium [6][7][8][9]. ...
Sodium risedronate (Rise) is a third generation of bisphosphonates, compounds active in suppressing the bone resorption and therefore used in orthopedy, dentistry and bone cancer treatment. The stability of Rise as bioactive compound was studied by thermoanalysis (TA) and kinetic analysis under non-isothermal conditions, as well as by FTIR spectroscopy of samples treated at different temperatures. The data were compared with these obtained for similar compounds (sodium alendronate and zoledronic acid) and reveal a low stability: The decomposition begins under 100 °C, and the activation energy is relatively small. The possibilities of increasing the thermal stability were studied using binary mixture (1:1) in mass parts of Rise with talc, silica, mannitol, starch, microcrystalline cellulose and magnesium stearate. By both methods, TA and FTIR interaction between Rise and mannitol was detected. Regarding the kinetic analysis, the nonparametric kinetic methods reveal its advantages by an objective and complete kinetic description of Rise thermal decomposition.
... При анализе результатов хирургического ведения пациентов было выявлено, что ОП является самым частым лимитирующим фактором в достижении стабильности имплантата [13][14][15][16]. Определенные успехи в достижении стабильности конструкции были получены с началом использования метода аугментации кости в сочетании с остеосинтезом. ...
We analyzed the results of one-stage correction of the asymmetry of mammary glands in 51 patients with a diagnosis of hypomastia. On the basis of obtained results the algorithm of one-stage restoration of symmetry at the given category of patients, based on the type and severity of the asymmetry was developed, which contributes to the achievement of good aesthetic results in 94.1% of cases.
... Low initial bone density and an extended healing response can not only result in fracture nonunion but also lead to aseptic implant loosening. Local treatment strategies could be utilized to prevent fracture, improve healing, and accelerate implant fixation by locally provoking anabolic pathways or by inhibiting catabolic pathways (Torstrick and Guldberg, 2014). ...
Postmenopausal osteoporosis (OP) is a major concern for public health. Low-level laser therapy (LLLT) has a positive effect on the health of bone marrow mesenchymal stem cells (BMMSCs). The purpose of this study is to evaluate the influence of LLLT and oxytocin (OT) incubation-individually and in combination-on osteoporotic BMMSCs in ovariectomized rats. Twelve female rats were randomized into two groups to undergo either a sham surgery (sham group) or ovariectomy-induced osteoporosis OP (OVX group). MSCs harvested from the BM of healthy and OVX rats underwent culture expansion. There were five groups. In Groups one (sham-BMMSC) and two (OVX-BMMSC) the cells were held in osteogenic condition medium without any intervention. In the group three (OT), OT incubation with optimum dose was performed for 48 hours (two times, 10(-12) molar). In Group four, laser-treated-OVX-BMMSCs were treated with optimum protocol of LLLT (one time, 1.2 J/cm(2) ). In Group five (laser + OT group), the OT incubation plus the laser irradiation was performed. The biostimulatory effect of LLLT is demonstrated by a significant increase in the viability of OVX-BMMSCs, cell cycle, and extracellular levels of Transforming growth factor beta (TGF-β), insulin-like growth factor-I (IGF-I), and Alkaline phosphatase (ALP) compared to control OVX-BMMSCs and/or the sham group. OT incubation and laser + OT incubation have a positive effect on OVX-BMMSCs. However, LLLT is more effective statistically. We conclude that LLLT significantly improved cell viability, enhanced the osteogenic potential of the OVX-BMMSCs, and increased the extracellular levels of the TGF-β, IGF-I, and ALP. This article is protected by copyright. All rights reserved.
... A number of new approaches is being explored for the prevention of fractures in osteoporotic bones [2]. Local strategies under investigation include direct drug release from injectable materials, biomaterials or surface coated implants [3]. A new treatment strategy is to target specific areas of the skeletal system that are prone to clinically significant osteoporotic fractures. ...
To target areas of the skeletal system which are clinically significant sites is a new strategy as the"local treatment of osteoporosis". Synthetic bioceramics implanted into critical sized bone defect of rats with experimental osteoporosis demonstrateds better effect to bone tissue repair in osteoporosis and/or osteoporosis status. Stem cell transplantation may improve bone mineral density in animal models of osteoporosis. An adequate blood supply of mesenchymal cells (MSCs and osteoprogenitors) is important for efficient bone regeneration. The concentration and quality of MSCs may vary significantly, depending on the individual (especially in older people), the cell obtaining sites and techniques used. Combination of BCP and stem cells are not studied on old experimental animals with double induced osteoporosis.
... Анализ результатов хирургического ведения пациентов выявил, что ОП является самым частым лимитирующим фактором в достижении стабильности имплантата [13][14][15][16].Определенные успехи в достижении стабильности конструкции были получены с началом использования метода аугментации кости в сочетании с остеосинтезом. Понятие аугментации костной ткани включает в себя разные способы наращивания кости и восстановление потерянного объема костной ткани. ...
This article provides an analysis of the literature data devoted to research on the use of the proximal femoral nail antirotation (PFNA) with and without augmentation in patients in fractures of the osteoporotic femur. The authors used the descriptive and analytical methods. The search for relevant publications carried out in the databases: Google Scholar, e-Library Medline, and the Cochrane Consort library. To date, the evidence base for the benefits of using PFNA with augmentation in osteosynthesis of hip fractures accompanied by osteoporosis need to provide the randomized controlled trials, despite the obvious theoretical and experimental advantages of the method.
Objective: To examine the integrated dose-effect relationship of near-infrared (NIR) light-emitting diode (LED) light therapy in promoting bone defect repair in the rat model for osteoporosis (OP). Background: Low-intensity laser therapy has been shown to promote bone regeneration in OP rats. However, its integrated dose-effect relationship is not clear. Methods: Twenty-week-old male Sprague-Dawley rats were randomly assigned to 11 groups: (1) no-treatment control group (C group), (2) tail suspension (TS)-induced disuse OP experimental group (TS-OP group), and (3) OP rats with LED light treatment at nine dosages (L1-L9 groups). The tail of the rat was tied and suspended on the beam of the cage to suspend their hind limbs to induce bone loss for 4 or 7 weeks. The rats were then released and returned to their regular positions. An NIR LED at 810 nm was used on the bilateral hind limbs daily for 4 weeks. The C group rats were not given any treatment. The TS-OP group rats were subjected to identical procedures with L groups, with the exception that the light power was not turned on. After the experiment, the dual-energy X-rays or the microcomputed tomography scan analysis was performed to evaluate bone tissue status. Data analysis was done using SPSS and the health scale. Results: The trabecular thickness, trabecular number, bone volume/total volume, and connectivity density of cancellous bone and the biomechanical properties of femur in light groups were significantly increased compared with the TS-OP group, while the trabecular separation and structure model index were significantly decreased. Conclusions: NIR LED light therapy may promote trabecular bone repair of TS-OP rats. Light intensity influences photobiomodulation. In our dose levels, the greater the light intensity, usually the more effective.
Background
With the increasing utilization of total knee arthroplasty (TKA) in a continually aging United States population, the number of patients who have low bone mineral density who undergo TKA may concomitantly increase. This study aimed to assess the rates of short-term complications following TKA in patients who did and did not have a recent history of a prior fragility fracture.
Methods
A matched retrospective cohort study analyzing 48,796 patients was performed using a national database to determine the impact of a preceding fragility fracture on rates of short-term complications following TKA. The rates of complications at 1 and 2 years post-TKA were analyzed using multivariate logistic regressions.
Results
Prior fragility fracture was associated with increased rates of 1-year hospital readmissions (Hazard Ratio = 1.30, 95% Confidence Interval (CI), 1.22 – 1.38), periprosthetic fractures (Odds Ratio (OR) = 2.72, 95% CI, 1.89-3.99), non-infection related revisions (OR = 1.32, 95% CI, 1.09-1.60), secondary fragility fractures (OR = 4.62, 95% CI, 4.19-5.12), prosthesis dislocations (OR = 1.76, 95% CI, 1.22-2.56), prosthesis instabilities (OR = 1.64, 95% CI, 1.25-2.15), and periprosthetic infections (OR = 1.49, 95% CI, 1.29-1.71), with similar trends in implant-related complications also seen at the 2-year mark. Patients who filled a prescription for osteoporosis pharmacotherapy had clinically similar rates of these complications compared to those who did not.
Conclusion
Sustaining a fragility fracture prior to TKA is associated with an increased risk of hospital readmission and significant implant-related postoperative complications, potentially increasing the morbidity and mortality of TKA in these patients.
In concordance with the principle of regenerative medicine which is to develop the science and tools that can help repair or replace damaged or diseased human cells or tissues, in dentistry this is matching with the concept of restoring function of damaged teeth or their supporting tissues. Dentistry has not only been the lead of restorative medicine but truly practice it. The restorative landscape of dentistry ranges from restoring decayed, fractured, or pulpal affected teeth and progress to dental implant and high-technology bone scaffold fabrication and end with a stem cell-based soft tissue engineering as well as bone bio-stimulation. In fact, the oral tissues, besides their ease accessibility, are a rich source of stem cells. Additionally, oral stem cells are likely to be perfect source for genetically reprogrammed cells, for instance, induced pluripotent stem (iPS) cells. This role of regenerative medicine in dentistry has kept it at the forefront of regenerative medicine developments. This chapter will shed light on the most recent advances of the contemporary dental regenerative medicine with regard to clinical availability and applications in dentistry.KeywordsRegenerative medicineDentistryDental stem cellBio-stimulationScaffoldTissue engineeringTooth banking
Wrist and hand disorders are commonplace in musculoskeletal medicine, and for their prompt management, integration of clinical and ultrasonographic findings is paramount. In this chapter, we briefly describe the sonoanatomy of the wrist/hand, focusing on the spatial planning of the ultrasound-guided procedures. Taking into consideration several high-cost medications (e.g., orthobiologic agents) and/or possibility of various interventional procedures (e.g., hydrodissection) as regards regenerative medicine, ultrasonographic imaging and guidance would be of extra importance in comparison to blind injections. In this sense, patient and probe positionings along with particular technical tips for handling the needle are rendered for wrist/hand pathologies.KeywordsUltrasonographyExaminationWristHandIntervention
Background and aims:
Osteoporosis, which is a disease characterized by weakening of the bone, affects a large portion of the senior population. The current therapeutic options for osteoporosis have side effects, and there is no effective treatment for severe osteoporosis. Thus, we urgently need new treatment strategies, such as topical therapies and/or safe and effective stem cell therapies.
Methods:
We investigated the therapeutic potential of directly injecting human tonsil-derived mesenchymal stem cells (TMSC) into the right proximal tibias of ovariectomized postmenopausal osteoporosis model mice. Injections were given once (1×) or twice (2×) during the 3-month experimental period. At the end of the experiment, micro-computed tomographic images revealed some improvement in the proximal tibias and more significant improvement in the femoral heads of treated mice.
Results:
Osteogenic effect was qualitatively and quantitatively more pronounced in TMSC/2× -treated mice. Furthermore, TMSC/2× mice exhibited significant recovery of the serum osteocalcin level, which is pathologically elevated in osteoporosis, and increased serum alkaline phosphatase, which indicates bone formation. TMSC therapy was generally well tolerated and caused no apparent toxicity in the experimental mice. Moreover, TMSC therapy reduced visceral fat.
Conclusion:
Our results demonstrate that double injection of TMSC directly into the proximal tibia triggers recovery of osteoporosis, and thus could be a potential therapeutic approach for severe bone loss.
The aim of this paper is to study the in vivo potency of low-level laser therapy (LLLT) and low intensity pulsed ultrasound (LIPUS) alone, accompanied by bone grafts, or accompanied by other factors on fracture healing in animal models and patients. In this paper, we aim to systematically review the published scientific literature regarding the use of LLLT and LIPUS to accelerate fracture healing in animal models and patients. We searched the PubMed database for the terms LLLT or LIPUS and/or bone, and fracture. Our analysis also suggests that both LIPUS and LLLT may be beneficial to fracture healing in patients, and that LIPUS is more effective. These finding are of considerable importance in those treatments with a LIPUS, as a laser device may reduce healing time. The most clinically relevant impact of the LIPUS treatment could be a significant reduction in the proportion of patients who go on to develop a nonunion. If it is confirmed that the therapeutic influence is true and reliable, patients will obtain benefits from LIPUS and LLLT. Further clinical trials of high methodological quality are needed in order to determine the optimal role of LIPUS and LLLT in fracture healing in patients.
Background:
Pulsed wave (PW) lasers exhibit biostimulatory effects on fractures in healthy and diabetic animals.
Objective:
This study aims to assess the effects of photobiomodulation on bone strength and Hounsfield unit (HU) for repair of a bone defect in an experimental rat model of type I diabetes mellitus (TIDM) and osteoporosis (OP).
Methods:
We divided 30 female rats into six groups of n = 5 per group: (1) ovariectomy (OVX) control, (2) OVX + PW laser and no TIDM, (3) OVX control + TIDM, (4) OVX + TIDM + PW laser, (5) OVX + TIDM + alendronate, and (6) OVX + TIDM + PW laser + alendronate. TIDM was induced in rats by streptozotocin (STZ). A partial osteotomy was made in the right tibia of each rat. We used an infrared laser (890 nm, 80 Hz, 1.5 J/cm(2)) 3 times per week. At 30 days after surgery, the callus areas within the rats' tibias were submitted to computed tomography scanning followed by the three-point bending test.
Results:
The PW laser + alendronate group had significantly increased HU and biomechanical properties of repairing bone defect in STZ + OVX rats compared with the control groups.
Conclusions:
Combined treatment of PW laser and alendronate significantly enhanced bone repair in an experimental model rat of TIDM and OP.
In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.
Purpose
Bisphosphonates (BPs) are antiresorptive drugs typically used to inhibit bone resorption. The latest reports show that BPs play an important role in not only achieving better bone mineral density but also in improving bone microarchitecture. The mechanism of action of the BPs is complex and multifactorial. We tried to determine whether there are any changes in the microarchitectural bone structure during local use of BP (Pamifos 60). The aim of this study was to see if BP-enriched cement used in rat models had positive effects on bone formation.
Methods
Research was performed on 40 adult male Wistar rats that were divided into four groups: two control groups and two experimental groups. Rats in the experimental groups were implanted with BP-enriched cement into the bone, while the control group rats were implanted with clean bone cement (without BP). Micro-computed tomography was applied for the investigation of trabecular microarchitecture of the proximal physis of the tibial bone in all animals three and six weeks after surgery. In all microCT images variables such as bone volume density (BV/TV), trabecular thickness (TbTh), trabecular separation (TbSp) and trabecular number (TbN) were used to describe trabecular bone morphometry.
Results
The major finding of this study is that using BP-enriched cement results in distinct changes in bone microarchitecture. We showed that local use of pamidronate (Pamifos 60) in orthopaedic cement had a positive effect on bone formation. It significantly changed three variables. We noticed increasing bone volume fraction and trabecular thickness together with decreasing trabecular separation.
Conclusion
In this paper we demonstrate the efficacy of using BP-enriched cement in vitro in the tibiae of rats. Our most significant finding based on micro-CT picture analysis allows us to start further work on more suitable applications of BP-enriched cement in humans. We believe that future successful experiments will facilitate potential use of BP-enriched cement in clinical applications.
The skeleton is a high-renewal organ that undergoes ongoing cycles of remodeling. The regenerative bone formation arm ultimately declines in the aging, postmenopausal skeleton, but current therapies do not adequately address this deficit. Bone marrow is the primary source of the skeletal anabolic response and the mesenchymal stem cells (MSCs), which give rise to bone matrix-producing osteoblasts. The identity of these stem cells is emerging, but it now appears that the term 'MSC' has often been misapplied to the bone marrow stromal cell (BMSC), a progeny of the MSC. Nevertheless, the changes in BMSC phenotype associated with age and estrogen depletion likely contribute to the attenuated regenerative competence of the marrow and may reflect alterations in MSC phenotype. Here we summarize current concepts in bone marrow MSC identity, and within this context, review recent observations on changes in bone marrow population dynamics associated with aging and menopause.
Osteoclasts, the multinucleated cells that resorb bone, develop from hematopoietic cells of monocyte/macrophage lineage. Osteoclast-like
cells (OCLs) are formed by coculturing spleen cells with osteoblasts or bone marrow stromal cells in the presence of bone-resorbing
factors. The cell-to-cell interaction between osteoblasts/stromal cells and osteoclast progenitors is essential for OCL formation.
Recently, we purified and molecularly cloned osteoclastogenesis-inhibitory factor (OCIF), which was identical to osteoprotegerin
(OPG). OPG/OCIF is a secreted member of the tumor necrosis factor receptor family and inhibits osteoclastogenesis by interrupting
the cell-to-cell interaction. Here we report the expression cloning of a ligand for OPG/OCIF from a complementary DNA library
of mouse stromal cells. The protein was found to be a member of the membrane-associated tumor necrosis factor ligand family
and induced OCL formation from osteoclast progenitors. A genetically engineered soluble form containing the extracellular
domain of the protein induced OCL formation from spleen cells in the absence of osteoblasts/stromal cells. OPG/OCIF abolished
the OCL formation induced by the protein. Expression of its gene in osteoblasts/stromal cells was up-regulated by bone-resorbing
factors. We conclude that the membrane-bound protein is osteoclast differentiation factor (ODF), a long-sought ligand mediating
an essential signal to osteoclast progenitors for their differentiation into osteoclasts. ODF was found to be identical to
TRANCE/RANKL, which enhances T-cell growth and dendritic-cell function. ODF seems to be an important regulator in not only
osteoclastogenesis but also immune system.
Introduction:
During fracture healing, alendronate encourages callus volume by inhibiting bone resorption, whereas low-intensity pulsed ultrasound (LIPUS) enhances bone regeneration by promoting an anabolic response.
Methods:
In the present study, 9-month-old Sprague-Dawley rats, with a unilateral proximal tibial osteotomy, were treated with alendronate (daily, 1 µg/kg) plus sham-LIPUS (n = 14), saline plus LIPUS (20 min/day) (n = 18), alendronate plus LIPUS (n = 16), or saline plus sham-LIPUS as a control (n = 13) for 4 weeks. The rats were then examined for changes in bone mineral density (BMD) during metaphyseal bone repair.
Results:
The combined therapy significantly increased BMD at the osteotomy site at 4 weeks (p < 0.001) compared with the control, without affecting the contralateral, non-osteotomized tibia. Both alendronate and LIPUS alone also exerted a positive, albeit less, effect on BMD in the affected limb (p < 0.001 and p = 0.006, respectively).
Conclusion:
Alendronate and LIPUS cooperate to enhance BMD during metaphyseal bone healing.
Vertebral compression fractures (VCFs) are the most prevalent fractures in osteoporotic patients. The classical conservative
management of these fractures is through rest, pain medication, bracing and muscle relaxants. The aim of this paper is to
review prospective controlled studies comparing the efficacy and safety of minimally invasive techniques for vertebral augmentation,
vertebroplasty (VP) and balloon kyphoplasty (BKP), versus non-surgical management (NSM). The Fracture Working Group of the
International Osteoporosis Foundation conducted a literature search and developed a review paper on VP and BKP. The results
presented for the direct management of osteoporotic VCFs focused on clinical outcomes of these three different procedures,
including reduction in pain, improvement of function and mobility, vertebral height restoration and decrease in spinal curvature
(kyphosis). Overall, VP and BKP are generally safe procedures that provide quicker pain relief, mobility recovery and in some
cases vertebral height restoration than conventional conservative medical treatment, at least in the short term. However,
the long-term benefits and safety in terms of risk of subsequent vertebral fractures have not been clearly demonstrated and
further prospective randomized studies are needed with standards for reporting. Referral physicians should be aware of VP/BKP
and their potential to reduce the health impairment of patients with VCFs. However, VP and BKP are not substitutes for appropriate
evaluation and treatment of osteoporosis to reduce the risk of future fractures.
KeywordsIOF–Kyphoplasty–Osteoporosis–Pain management–Vertebral fractures–Vertebroplasty
Context:
The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years.
Objective:
The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure.
Design, setting, and participants:
This was a multicenter, international, open-label study of 4550 women.
Intervention:
Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover).
Main outcome measures:
Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported.
Results:
Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture.
Conclusion:
Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.
The major Food and Drug Association-approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst-like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 μg/mL, total dose 0.375 and 0.75 μg in 75 μg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 μg/mL, total dose 2.25 μg in 75 μg total volume), and a high BMP2 concentration range (150, 300, and 600 μg/mL, total dose 11.25, 22.5, and 45 μg in 75 μg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 μg/mL.
Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management.
Percutaneous vertebroplasty is increasingly used for treatment of pain in patients with osteoporotic vertebral compression fractures, but the efficacy, cost-effectiveness, and safety of the procedure remain uncertain. We aimed to clarify whether vertebroplasty has additional value compared with optimum pain treatment in patients with acute vertebral fractures.
Patients were recruited to this open-label prospective randomised trial from the radiology departments of six hospitals in the Netherlands and Belgium. Patients were aged 50 years or older, had vertebral compression fractures on spine radiograph (minimum 15% height loss; level of fracture at Th5 or lower; bone oedema on MRI), with back pain for 6 weeks or less, and a visual analogue scale (VAS) score of 5 or more. Patients were randomly allocated to percutaneous vertebroplasty or conservative treatment by computer-generated randomisation codes with a block size of six. Masking was not possible for participants, physicians, and outcome assessors. The primary outcome was pain relief at 1 month and 1 year as measured by VAS score. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00232466.
Between Oct 1, 2005, and June 30, 2008, we identified 431 patients who were eligible for randomisation. 229 (53%) patients had spontaneous pain relief during assessment, and 202 patients with persistent pain were randomly allocated to treatment (101 vertebroplasty, 101 conservative treatment). Vertebroplasty resulted in greater pain relief than did conservative treatment; difference in mean VAS score between baseline and 1 month was -5·2 (95% CI -5·88 to -4·72) after vertebroplasty and -2·7 (-3·22 to -1·98) after conservative treatment, and between baseline and 1 year was -5·7 (-6·22 to -4·98) after vertebroplasty and -3·7 (-4·35 to -3·05) after conservative treatment. The difference between groups in reduction of mean VAS score from baseline was 2·6 (95% CI 1·74-3·37, p<0·0001) at 1 month and 2·0 (1·13-2·80, p<0·0001) at 1 year. No serious complications or adverse events were reported.
In a subgroup of patients with acute osteoporotic vertebral compression fractures and persistent pain, percutaneous vertebroplasty is effective and safe. Pain relief after vertebroplasty is immediate, is sustained for at least a year, and is significantly greater than that achieved with conservative treatment, at an acceptable cost.
ZonMw; COOK Medical.
To investigate whether calcium supplements increase the risk of cardiovascular events.
Patient level and trial level meta-analyses.
Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), reference lists of meta-analyses of calcium supplements, and two clinical trial registries. Initial searches were carried out in November 2007, with electronic database searches repeated in March 2010.
Eligible studies were randomised, placebo controlled trials of calcium supplements (>or=500 mg/day), with 100 or more participants of mean age more than 40 years and study duration more than one year. The lead authors of eligible trials supplied data. Cardiovascular outcomes were obtained from self reports, hospital admissions, and death certificates.
15 trials were eligible for inclusion, five with patient level data (8151 participants, median follow-up 3.6 years, interquartile range 2.7-4.3 years) and 11 with trial level data (11 921 participants, mean duration 4.0 years). In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P=0.035). Non-significant increases occurred in the incidence of stroke (1.20, 0.96 to 1.50, P=0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, P=0.057), and death (1.09, 0.96 to 1.23, P=0.18). The meta-analysis of trial level data showed similar results: 296 people had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, P=0.038).
Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.
A number of recent case reports and series have identified a subgroup of atypical fractures of the femoral shaft associated with bisphosphonate use. A population-based study did not support this association. Such a relationship has not been examined in randomized trials.
We performed secondary analyses using the results of three large, randomized bisphosphonate trials: the Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial (PFT). We reviewed fracture records and radiographs (when available) from all hip and femur fractures to identify those below the lesser trochanter and above the distal metaphyseal flare (subtrochanteric and diaphyseal femur fractures) and to assess atypical features. We calculated the relative hazards for subtrochanteric and diaphyseal fractures for each study.
We reviewed 284 records for hip or femur fractures among 14,195 women in these trials. A total of 12 fractures in 10 patients were classified as occurring in the subtrochanteric or diaphyseal femur, a combined rate of 2.3 per 10,000 patient-years. As compared with placebo, the relative hazard was 1.03 (95% confidence interval [CI], 0.06 to 16.46) for alendronate use in the FIT trial, 1.50 (95% CI, 0.25 to 9.00) for zoledronic acid use in the HORIZON-PFT trial, and 1.33 (95% CI, 0.12 to 14.67) for continued alendronate use in the FLEX trial. Although increases in risk were not significant, confidence intervals were wide.
The occurrence of fracture of the subtrochanteric or diaphyseal femur was very rare, even among women who had been treated with bisphosphonates for as long as 10 years. There was no significant increase in risk associated with bisphosphonate use, but the study was underpowered for definitive conclusions.
The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain.
In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke.
Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group.
In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)
Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis.
We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures.
As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab.
Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)
Balloon kyphoplasty is a minimally invasive procedure for the treatment of painful vertebral fractures, which is intended to reduce pain and improve quality of life. We assessed the efficacy and safety of the procedure.
Adults with one to three acute vertebral fractures were eligible for enrolment in this randomised controlled trial at 21 sites in eight countries. We randomly assigned 300 patients by a computer-generated sequence to receive kyphoplasty treatment (n=149) or non-surgical care (n=151). The primary outcome was the difference in change from baseline to 1 month in the short-form (SF)-36 physical component summary (PCS) score (scale 0-100) between the kyphoplasty and control groups. Quality of life and other efficacy measurements and safety were assessed up to 12 months. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00211211.
138 participants in the kyphoplasty group and 128 controls completed follow-up at 1 month. By use of repeated measures mixed effects modelling, all 300 randomised participants were included in the analysis. Mean SF-36 PCS score improved by 7.2 points (95% CI 5.7-8.8), from 26.0 at baseline to 33.4 at 1 month, in the kyphoplasty group, and by 2.0 points (0.4-3.6), from 25.5 to 27.4, in the non-surgical group (difference between groups 5.2 points, 2.9-7.4; p<0.0001). The frequency of adverse events did not differ between groups. There were two serious adverse events related to kyphoplasty (haematoma and urinary tract infection); other serious adverse events (such as myocardial infarction and pulmonary embolism) did not occur perioperatively and were not related to procedure.
Our findings suggest that balloon kyphoplasty is an effective and safe procedure for patients with acute vertebral fractures and will help to inform decisions regarding its use as an early treatment option.
It is a clinical challenge to obtain a sufficient orthopaedic implant fixation in weak osteoporotic bone. When the primary implant fixation is poor, micromotions occur at the bone-implant interface, activating osteoclasts, which leads to implant loosening. Bisphosphonate can be used to prevent the osteoclastic response, but when administered systemically its bioavailability is low and the time it takes for the drug to reach the periprosthetic bone may be a limiting factor. Recent data has shown that delivering bisphosphonate locally from the implant surface could be an interesting solution. Local bisphosphonate delivery increased periprosthetic bone density, which leads to a stronger implant fixation, as demonstrated in rats by the increased implant pullout force. The aim of the present study was to verify the positive effect on periprosthetic bone remodelling of local bisphosphonate delivery in an osteoporotic sheep model. Four implants coated with zoledronate and two control implants were inserted in the femoral condyle of ovariectomized sheep for 4 weeks. The bone at the implant surface was 50% higher in the zoledronate-group compared to control group. This effect was significant up to a distance of 400mum from the implant surface. The presented results are similar to what was observed in the osteoporotic rat model, which suggest that the concept of releasing zoledronate locally from the implant to increase the implant fixation is not species specific. The results of this trial study support the claim that local zoledronate could increase the fixation of an implant in weak bone.
Previous studies have demonstrated that lasofoxifene, a nonsteroidal selective estrogen-receptor modulator, decreases bone resorption, bone loss, and low-density lipoprotein cholesterol in postmenopausal women. Its effects of the risk of fractures, breast cancer, and cardiovascular disease are unclear. The postmenopausal evaluation and risk-reduction with lasofoxifene trial was an international, randomized, placebo-controlled trial that investigated the effects of lasofoxifene on the risk of fractures, estrogen receptor (ER)-positive breast cancer, and cardiovascular disease in a population of postmenopausal women with osteoporosis. The study subjects were a population of women between the ages of 59 and 80 years who had a bone mineral density T score of -2.5 or less at the femoral neck or spine. Participants were randomized to receive once-daily lasofoxifene at a dose of either 0.25 mg (low-dose, n = 2852) or 0.5 mg (high-dose, n = 2852) or placebo (n = 2852, control group) for 5 years. The trial was conducted at 113 sites in 32 countries. Vertebral and nonvertebral fractures and ER-positive breast cancer were the primary study end points. Major coronary heart disease events and stroke were the secondary endpoints. Compared with placebo, treatment with the high-dose lasofoxifene was associated with a reduction in the risk of vertebral fractures (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.47-0.70), nonvertebral fractures (18.7 vs. 24.5 cases per 1000 person-years; HR, 0.76; 95% CI, 0.64-0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; HR, 0.19; 95% CI, 0.07-0.56), major coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; HR, 0.68; 95% CI, 0.50―0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; HR, 0.64; 95% CI, 0.41-0.99). At 5 years compared to the placebo group, postmenopausal women receiving low-dose lasofoxifene showed reduced rates of vertebral fractures (16.0 vs. 22.4 per 1000 person-years; HR, 0.69; 95% CI, 0.57-0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; HR, 0.61; 95% CI, 0.39-0.96). Both drug doses were associated with increased risk of a venous thromboembolic event: Compared to the placebo which had 1.4 venous thromboembolic events per 1000 person-years, the low-dose group had 3.8 events per 1000 person-years (HR, 2.67; 95% CI, 1.55-4.58) and the high-dose group had 2.9 events per 1000 person-years (HR, 2.06; 95% CI, 1.17- 3.61). No increased risk of endometrial hyperplasia or endometrial cancer was observed at 5 years with either dose. Deaths per 1000 person-years were 7.0 and 5.7 for low dose and high dose, respectively, compared to 5.1 for the placebo (P = ns for both comparisons). These findings show that treatment of postmenopausal women with osteoporosis using a daily dose of lasofoxifene of 0.5 mg is associated with reduced risks of vertebral and nonvertebral fractures, ER-positive breast cancer, major coronary heart disease, and stroke, and an increased risk of thromboembolic events.
The effects of postmenopausal osteoporosis for bone defect healing processes have already been reported, but not for senile osteoporosis caused by low-turnover metabolism. Low-Intensity-Pulsed Ultrasound (LIPUS) is known to promote bone defect healing in high-turnover osteoporosis an animal model. The aim of this study was to investigate the effect of LIPUS on the bone-healing process in a low-turnover osteoporosis model using the Senescence-Accelerated Mouse Prone 6 (SAMP6) strain of mice. Twenty-week-old SAMP6 and Senescence-Accelerated Mouse Resistant (SAMR1) mice were used as senile osteoporosis and normal aging models, respectively. Bone defects (diameter, 0.9 mm) were created in the both SAMP6 and SAMR1 femurs. At 7days after surgery, the LIPUS irradiation groups of SAMR1 (R1LG) and SAMP6 (P6LG) were exposed to LIPUS (1.0 MHz, 320 mW, 15 min/day) for 6 days. The non-irradiation groups of SAMR1 (R1CG) and SAMP6 (P6CG) were used as controls. All groups were sacrificed at 14 days after creation of bone defects. Radiological analysis, histological evaluation and immunohistochemical staining for osteocalcin (OC) were performed. From the radiological evaluation, the new bone of defected area in SAMR1 group showed cortical bone-like structure, but that in the SAMP6 group showed trabecular bone-like structures. The increase in bone area in P6LG was greater than that in P6CG according to chronological change analysis using X-ray micro-CT (p < 0.01). Histological analysis revealed outward new bone formation originating in the periosteum in P6LG. Positive reaction for OC was localized on the surface of new bone in P6CG, whereas that in P6LG was observed over the whole region of new bone, from the outer to the bone marrow side. These results showed that LIPUS accelerates healing on low-turnover osteoporosis by promoting bone formation from periosteum and supplementing reduced bone formation from bone marrow.
OBJECTIVE: Bone morphogenetic protein type 2 (BMP-2) is an osteoinductive growth factor with strong effects on bone and cartilage growth. In March 2007, INFUSE Bone Graft ( rhBMP2 Product) was approved as an alternative to autogenous bone grafts for localized alveolar ridge augmentations for defects associated with extraction sockets. Although BMP-2 is widely used, the lack of specificity to bone cells brings significant drawbacks to its application in the clinic, including formation of cyst-like bone and significant soft tissue swelling. METHODS: In this study, we evaluated dose-dependent effects of BMP-2 in two models: a femoral segmental defect model, and a minimally traumatic femoral onlay model. The distinct adipogenesis induced by high doses of BMP-2 was found and further investigated in vivo and in vitro. RESULTS: In the femoral segmental defect model, a previously established BMP-2 dose of 30 g/ml was able to fuse the defect without adverse effects. However, a higher BMP-2 dose range (150, 300, or 600 g/ml) was able to fuse the defect, but also induced formation of cyst-like bony shells containing adipose tissue. Peroxisome proliferator-activated receptorγ, the key transcriptional factor in adipocyte differentiation, was significantly activated by high doses of BMP-2. Similar dose-dependent effects of BMP-2 were recapitulated in vitro using the M2-10B4 mouse stromal cell line. In the femoral onlay model, addition of 4 mg/ml BMP2 induced significant tissue inflammatory infiltrates and exudates compared to control, accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. CONCLUSION: We consistently reproduced the adverse effects of cyst-like bone and soft tissue swelling using high BMP-2 doses and elucidated potential mechanisms by which they occur. Avoiding using BMP-2 in excessive doses means ensuring that bone growth is of high quality and lower the possible adverse effects on patients. (Funding: DE 016107-01 )
Non-persistence (never starting or stopping medication prematurely) and non-compliance (taking medication inappropriately) with fracture prevention medication among those at high risk of fracture remain significant barriers to optimal reduction of osteoporotic fractures. Current research suggest that for patients to persist and comply with prescriptions for fracture prevention medication, they need to believe that they are at significant risk of fracture, that the prescribed medication can safely reduce their risk of fracture without exposing them to long-term harm, that equally effective non-medicinal therapies are not available, and that they can successfully execute medication use in the context of their daily task demands. Further research is needed to understand; a) the mental models of osteoporosis, fractures, and medications used to treat osteoporosis that patients employ when making decisions as to whether or not to take fracture prevention medication; and b) how patients arbitrage information from various sources (health care providers, family, friends, and other sources) to formulate their beliefs about osteoporosis and medications used to treat it.
The aim of the study was to gain experience about the short-term effects of zoledronic acid (ZOL) on bone-implant contact (BIC), bone regeneration and bone area (BA).
In this in-vivo study, ZOL was released locally from a drug-loaded pre-shaped calcium phosphate bone cement plug which was implanted into a bone defect in the proximal tibia of rats. At 1 and 3 weeks post implantation, tissue reactions as well as bone regeneration capabilities at the implant site were investigated. Furthermore, tissue samples, harvested at placebo and verum plug sites were used to analyse the gene expression of selected bone-specific markers by using quantitative polymerase chain reaction. Data were normalized against ribosomal RNA (Rn18s) subunits.
In the placebo interface a higher amount of cells could be detected as indicated by higher expression of small subunit Rn18s. Nevertheless, comparing the normalized data of the selected gene expression levels, no significant differences were detected. The histomorphometric results showed a significant higher BIC and BA for ZOL-loaded plugs at 3 weeks after implantation.
In this model, ZOL was demonstrated to be effective in impacting the bone regeneration process towards reduction of early bone resorption and enhanced bone formation.
The Spemann organizer in amphibian embryos is a tissue with potent head-inducing activity, the molecular nature of which is unresolved. Here we describe dickkopf-1 (dkk-1), which encodes Dkk-1, a secreted inducer of Spemann's organizer in Xenopus and a member of a new protein family. Injections of mRNA and antibody indicate that dkk-1 is sufficient and necessary to cause head induction. dkk-1 is a potent antagonist of Wnt signalling, suggesting that dkk genes encode a family of secreted Wnt inhibitors.
Background:
Fracture is the major complication of osteoporosis, and it allows the identification of individuals needing medical intervention for osteoporosis. After nonvertebral fracture, patients often do not receive osteoporosis medical treatment despite evidence that this treatment reduces the risk of subsequent fracture. In this pre planned analysis of the results of the three-year, placebo-controlled FREEDOM trial, we evaluated the effect of denosumab administration on fracture-healing to address theoretical concerns related to initiating or continuing denosumab therapy in patients presenting with a nonvertebral fracture.
Methods:
Postmenopausal women aged sixty to ninety years with osteoporosis were randomized to receive 60 mg of denosumab (n = 3902) or a placebo (n = 3906) subcutaneously every six months for three years. Investigators reported complications associated with a fracture or its management and with fracture-healing for all nonvertebral fractures that occurred during the study. Delayed healing was defined as incomplete fracture-healing six months after the fracture.
Results:
Six hundred and sixty-seven subjects (303 treated with denosumab and 364 who received a placebo) had a total of 851 nonvertebral fractures (386 in the denosumab group and 465 in the placebo group), including 199 fractures (seventy-nine in the denosumab group and 120 in the placebo group) that were treated surgically. Delayed healing was reported in seven subjects (two in the denosumab group and five in the placebo group), including one with subsequent nonunion (in the placebo group). Neither delayed healing nor nonunion was observed in any subject who had received denosumab within six weeks preceding or following the fracture. A complication associated with the fracture or intervention occurred in five subjects (2%) and twenty subjects (5%) in the denosumab and placebo groups,respectively (p = 0.009).
Conclusions:
Denosumab in a dose of 60 mg every six months does not seem to delay fracture-healing or contribute to other complications, even when it is administered at or near the time of the fracture.
Fracture healing and fracture fixation in the context of osteoporosis is extremely difficult. To inhibit osteoclast-induced bone resorption and associated implant loosening in this pathology, we describe a local delivery strategy to delivery RNA interfering technology to bone sites to target and down-regulate osteoclast formation and function. Resorbable polymer, poly(lactic-co-glycolic acid) (PLGA) microparticles were exploited as a passive phagocyte-targeting carrier to deliver RANK siRNA to both osteoclast precursors and osteoclasts - the professional phagocytes in bone. These natural phagocytes internalize micron-sized particles while most other non-targeted cells in bone cannot. PLGA-siRNA microparticles were dispersed within biomedical grade calcium-based injectable bone cement clinically used in osteoporosis as a bone augmentation biomaterial for fragility fracture prevention and fixation. siRNA released from this formulation in vitro retains bioactivity against the cell target, RANK, in cultured osteoclast precursor cells, inhibiting their progression toward the osteoclastic phenotype. These data support the proof-of-concept to utilize a clinically relevant approach to locally deliver siRNA to phagocytes in bone and improve fragility fracture healing in the context of osteoporosis. This local delivery system delivers siRNA therapeutics directly to osteoporosis sites from clinically familiar injected bone augmentation materials but could be extended to other injectable biomaterials for local siRNA delivery.
Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management. © 2010 American Society for Bone and Mineral Research.
Parathyroid hormone (PTH) is a well-known therapeutic agent for osteoporosis treatment, however, the inconvenience of daily administration and side effect from systematic administration severely limits its application in clinic. PTH has been incorporated into a biomimetic calcium phosphate (CaP) coating via a co-precipitation method in a modified simulated body fluid. The aim of the current study is to evaluate the osseointegration response of PTH incorporated CaP coating on titanium implants. Implants with different doses of PTH were inserted into tibiae of mice and evaluated by X-ray, micro-CT, histology and back-scattered scanning electron microscopy. Improved osseointegration of the implants loaded with PTH was observed compared to CaP coating only after 28 days of implantation in mouse tibiae. Micro-CT analysis showed better bone integration around the implant incorporated with PTH. Bone area and bone contact evaluations have demonstrated that peri-implant bone regeneration is highly dependent on the dosage of PTH incorporated. The higher the PTH content, the more bone formed surrounding the implant. Therefore, our results suggest that biomimetic CaP coating could be a useful a carrier for PTH local delivery, which results in improved bone-to-implant integration.
Gene delivery to bone is useful both as an experimental tool and as a potential therapeutic strategy. Among its advantages over protein delivery are the potential for directed, sustained and regulated expression of authentically processed, nascent proteins. Although no clinical trials have been initiated, there is a substantial pre-clinical literature documenting the successful transfer of genes to bone, and their intraosseous expression. Recombinant vectors derived from adenovirus, retrovirus and lentivirus, as well as non-viral vectors, have been used for this purpose. Both ex vivo and in vivo strategies, including gene-activated matrices, have been explored. Ex vivo delivery has often employed mesenchymal stem cells (MSCs), partly because of their ability to differentiate into osteoblasts. MSCs also have the potential to home to bone after systemic administration, which could serve as a useful way to deliver transgenes in a disseminated fashion for the treatment of diseases affecting the whole skeleton, such as osteoporosis or osteogenesis imperfecta. Local delivery of osteogenic transgenes, particularly those encoding bone morphogenetic proteins, has shown great promise in a number of applications where it is necessary to regenerate bone. These include healing large segmental defects in long bones and the cranium, as well as spinal fusion and treating avascular necrosis.
We investigated the effect of local low-intensity pulsed ultrasound (LIPUS) on polyethylene debris induced periprosthetic osteolysis. The periprosthetic osteolysis model was made by injecting endotoxin-free pure polyethylene particles into the distal part of the femur canal and inserting a stainless steel plug into this femur. The effects of polyethylene and LIPUS were assessed histologically and by the shear strength test and periprosthetic bone mineral density (BMD) test. Sixteen rabbits received a stainless steel plug on one side and both polyethylene and a stainless steel plug on the other side. Three months later, the side that received polyethylene showed periprosthetic osteolysis. Subsequently, another 16 rabbits received polyethylene plus local LIPUS (200 mW/cm(2) for 20 min daily) on one side and polyethylene alone on the other side. Three months later, LIPUS effectively prevented the periprosthetic osteolysis caused by polyethylene in this rabbit model.
Bi-functional coatings of carbonated calcium deficient hydroxyapatite (CDHA) on Ti alloys were developed by using a biomimetic coating process. The bi-functionality was achieved by loading alendonate sodium (AS), an approved bisphosphonate drug used for the treatment of osteoporosis, into the inner layers of CDHA coatings. Three possible methods of loading AS into CDHA coatings were systematically studied and compared. The results indicated that the co-precipitation method had greater benefits and can modify the release profile of AS by incorporating AS in the inner layers of the coatings. As a preliminary study, the influences of applied AS dosage to CDHA coatings were evaluated using XRD and SEM. In vitro tests indicated that the AS content on CDHA coatings played a significant role, and optimum AS content in local area is beneficial for osteoblast cells proliferation. It is expected that the CDHA-AS coatings via the co-precipitation approach have potential for bone tissue engineering applications.
Studies show conflicting results regarding the possible excess risk of atypical fractures of the femoral shaft associated with bisphosphonate use.
In Sweden, 12,777 women 55 years of age or older sustained a fracture of the femur in 2008. We reviewed radiographs of 1234 of the 1271 women who had a subtrochanteric or shaft fracture and identified 59 patients with atypical fractures. Data on medications and coexisting conditions were obtained from national registries. The relative and absolute risk of atypical fractures associated with bisphosphonate use was estimated by means of a nationwide cohort analysis. The 59 case patients were also compared with 263 control patients who had ordinary subtrochanteric or shaft fractures.
The age-adjusted relative risk of atypical fracture was 47.3 (95% confidence interval [CI], 25.6 to 87.3) in the cohort analysis. The increase in absolute risk was 5 cases per 10,000 patient-years (95% CI, 4 to 7). A total of 78% of the case patients and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33.3 (95% CI, 14.3 to 77.8). The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. The duration of use influenced the risk (odds ratio per 100 daily doses, 1.3; 95% CI, 1.1 to 1.6). After drug withdrawal, the risk diminished by 70% per year since the last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38).
These population-based nationwide analyses may be reassuring for patients who receive bisphosphonates. Although there was a high prevalence of current bisphosphonate use among patients with atypical fractures, the absolute risk was small. (Funded by the Swedish Research Council.).
Parathyroid hormone (PTH) is a potent bone growth stimulator used for osteoporosis treatment. However, the inconvenience of daily administration and side effect of systemic exposure severely limit its use in clinical applications. Local, controlled delivery is a promising approach which can maintain therapeutic concentration locally for a long period. In this study, PTH was incorporated into a biomimetic calcium phosphate (CaP) coating via a coprecipitation process in a modified simulated body fluid (m-SBF). It was found that PTH was successfully incorporated into biomimetic CaP coating on titanium surface with a high incorporation efficiency. The incorporation of PTH into coatings had significantly changed the coating morphology, but the composition of the coating remained unchanged. Localized release of PTH had occurred in vitro, and was accompanied with partial dissolution of CaP coatings. Cell culture study demonstrated that the PTH released from CaP coatings fully retained its bioactivity. It had improved substantially MC3T3-E1 cell proliferation but slightly delayed the expression of alkaline phosphatase (ALP) of the cells. In summary, our results have shown that CaP coatings incorporated with PTH may be a promising approach for osteoporosis and other bone-related disease treatment in the future.
The purpose of this study was to analyze the local treatment effects of rhBMP-2 combined with fibrin sealant (FS) on bone mineral density, microarchitectural and mechanical properties in osteoporotic ovine spine.
Postmenopausal osteoporosis was induced in eight sheep through ovariectomy (OVX) and a low-calcium diet for a period of 12 months. According to the Latin square design, L3-L6 vertebrae were randomly assigned to four treatment groups: A (rhBMP-2/FS), B (rhBMP-2), C (FS) and D (blank control). All materials were injected into the assigned vertebra transpedicularly. All animals were euthanized 3 months after treatment. Bone mineral density (BMD), microarchitectural and mechanical properties were assessed. ANOVA analysis of variance was used to determine effects of rhBMP-2/FS (α = 0.05).
The BMD in group A (rhBMP-2/FS) was 18.8, 30.4 and 27.9% higher than that in group B, C and D, respectively. Analysis of bone structure by micro-CT revealed higher trabecular bone volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N) in the rhBMP-2/FS group (P < 0.01). In addition, vertebrae treated with rhBMP-2/FS exhibited higher yield stress, ultimate stress, energy absorption and bone modulus compared to the control groups.
Local administration of rhBMP-2/FS showed a positive trend in improving BMD, microarchitectural parameters and mechanical strength of osteoporotic vertebra. Slow release of rhBMP-2 using FS appeared to be an effective method of protein delivery. The local treatment of osteoporosis in the spine can increase bone strength and reduce fracture risk quickly.
Osteoporotic fracture is a critical medico-social challenge leading to burdens in health care costs and hospital bed stays. Low-intensity pulsed ultrasound (LIPUS) was reported to accelerate normal fracture; however, its effect on osteoporotic fracture has not been previously addressed. We hypothesize that LIPUS can accelerate osteoporotic fracture healing and up-regulate the expression in the osteogenesis-, remodeling- and angiogenesis-related genes. Ovariectomy-induced osteoporotic fracture rat model was used to investigate the effects of LIPUS. Fractured rats were assigned to LIPUS or control group and healing was assessed by gene expression quantification, radiographic callus morphometry and histomorphometry. In the LIPUS group, Col-1 and bone morphogenetic protein-2 were up-regulated at earlier time points of week 2 to week 4 post-fracture; vascular endothelial growth factor was found to be up-regulated at week 4 to week 8; osteoprotegerin was up-regulated at week 2 post-fracture, followed by the surge of RANKL expression. Callus width and area measurements showed higher callus formation at weeks 2-4 in the LIPUS group and more rapid drop at weeks 6-8. Histomorphometry showed enhanced endochondral ossification in the callus at weeks 2-4, and lower at week 8. We conclude that LIPUS can accelerate osteoporotic fracture healing by enhancing callus formation, angiogenesis and callus remodeling.
Osteoporosis is a disease characterized by low bone mass, increased bone fragility, and a greater risk for bone fracture. Currently, pharmacological intervention can generally aid in the prevention and treatment of osteoporosis, but these therapies are often accompanied by undesirable side effects. Therefore, alternative therapies that minimize side effects are necessary. Biophysical stimuli, especially low-intensity ultrasound stimulation (LIUS), may be potential alternatives to drug-based therapies for osteoporosis. Hence, we sought to address whether LIUS therapy can effectively prevent or treat osteoporotic bone loss induced by estrogen deficiency. LIUS (1.5 MHz frequency, 1.0 kHz pulse repetition on frequency, 30 mW/cm(2) intensity, 200 µs pulse length) was applied to right tibiae of eight 14-week-old ovariectomized virgin ICR female mice for 20 min per day, 5 days per week, over a 6-week period. Changes in 3D structural bone characteristics were detected using in vivo micro-computed tomography. Left tibiae served as controls. Structural characteristics including bone volume/tissue volume, trabecular number, trabecular bone pattern factor, and mean polar moment inertia were significantly enhanced 6 weeks after LIUS compared to the control, nonstimulated group (p < 0.05). In particular, the bone volume/tissue volume in the region exposed directly to LIUS was significantly higher in the treated group (p < 0.05). These findings indicate that new bone formation may be activated or that bone structure may be maintained by LIUS, and that LIUS may be effective for preventing estrogen deficiency-induced bone loss.
Sclerostin, an osteocyte-secreted protein, negatively regulates osteoblasts and inhibits bone formation. In this first-in-human study, a sclerostin monoclonal antibody (AMG 785) was administered to healthy men and postmenopausal women. In this phase I, randomized, double-blind, placebo-controlled, ascending, single-dose study, 72 healthy subjects received AMG 785 or placebo (3:1) subcutaneously (0.1, 0.3, 1, 3, 5, or 10 mg/kg) or intravenously (1 or 5 mg/kg). Depending on dose, subjects were followed for up to 85 days. The effects of AMG 785 on safety and tolerability (primary objectives) and pharmacokinetics, bone turnover markers, and bone mineral density (secondary objectives) were evaluated. AMG 785 generally was well tolerated. One treatment-related serious adverse event of nonspecific hepatitis was reported and was resolved. No deaths or study discontinuations occurred. AMG 785 pharmacokinetics were nonlinear with dose. Dose-related increases in the bone-formation markers procollagen type 1 N-propeptide (P1NP), bone-specific alkaline phosphatase (BAP), and osteocalcin were observed, along with a dose-related decrease in the bone-resorption marker serum C-telopeptide (sCTx), resulting in a large anabolic window. In addition, statistically significant increases in bone mineral density of up to 5.3% at the lumbar spine and 2.8% at the total hip compared with placebo were observed on day 85. Six subjects in the higher-dose groups developed anti-AMG 785 antibodies, 2 of which were neutralizing, with no discernible effect on the pharmacokinetics or pharmacodynamics. In summary, single doses of AMG 785 generally were well tolerated, and the data support further clinical investigation of sclerostin inhibition as a potential therapeutic strategy for conditions that could benefit from increased bone formation.
Sclerostin is the product of the SOST gene. Loss-of-function mutations in the SOST gene result in a high-bone-mass phenotype, demonstrating that sclerostin is a negative regulator of bone mass. Primarily expressed by osteocytes in bone, sclerostin is reported to bind the LRP5/6 receptor, thereby antagonizing canonical Wnt signaling and negatively regulating bone formation. We therefore investigated whether systemic administration of a sclerostin-neutralizing antibody would increase the regeneration of traumatized metaphyseal bone in rats. Young male rats had a screw inserted in the proximal tibia and were divided into six groups given 25 mg/kg of sclerostin antibody or control twice a week subcutaneously for 2 or 4 weeks. In four groups, the screws were tested for pull-out strength. At the time of euthanasia, a similar screw also was inserted in the contralateral tibia and pull-out tested immediately. Sclerostin antibody significantly increased the pull-out force by almost 50% compared with controls after 2 and 4 weeks. Also, the screws inserted at the time of euthanasia showed increased pull-out force. Micro-computed tomography (µCT) of the remaining two groups showed that the antibody led to a 30% increase in bone volume fraction in a region surrounding the screw. There also was a general increase in trabecular thickness in cancellous bone. Thus, as measured by the amount of bone and its mechanical resistance, the sclerostin antibody increased bone formation during metaphyseal repair but also in untraumatized bone.
Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1-year dose-finding trial with a 1-year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50 mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T-scores of -2.0 or less but not less than -3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty-four months of treatment produced progressive dose-related increases in BMD. With the 50-mg dose of odanacatib, lumbar spine and total-hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (-0.2% and -0.9%). Biochemical markers of bone turnover exhibited dose-related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose-related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well-tolerated and increased lumbar spine and total-hip BMD in a dose-related manner in postmenopausal women with low BMD.
Pharmaceutical agents are often used to stimulate new bone formation for the treatment of bone injuries or diseases (such as osteoporosis). However, there are several problems associated with current orthopedic drug delivery methods. First, conventional systemic administration of pharmaceutical agents may not effectively reach targeted sites and, thus, they can cause nonspecific bone formation in areas not affected by injury or disease. Second, even if intentionally delivered or implanted locally to the damaged bone tissue, these agents tend to rapidly diffuse into adjacent tissues due to weak physical bonding to their drug carriers, which limits their potential to promote prolonged bone formation in targeted areas of bone disease. Therefore, in this study, biodegradable ceramic/polymer nanocomposites were explored as novel drug carriers for orthopedic applications to prolong local drug release and, thus, improve drug effectiveness at bone disease sites. Specifically, a bone morphogenetic protein (BMP-7) derived peptide (DIF-7c) was used as a model drug in this study and was first loaded onto nanocrystalline hydroxyapatite (nano-HA) by either covalent chemical attachment or physical adsorption. These drug-carrying nano-HA particles were then dispersed into a degradable polymer (poly-lactide-co-glycolide or PLGA) matrix to create an implantable system capable of long-term drug release. The aminophase silane covalent chemical immobilization process was utilized in this study. These nanocomposite-based drug delivery systems were then characterized for drug loading efficiency and in vitro drug release. Results demonstrated that DIF-7c was successfully immobilized onto nano-HA placed in PLGA. Moreover, a greater prolonged two-phase release profile (of more than 3 months) was achieved when using aminophase silane chemical immobilization to nano-HA particles. Since previous studies have demonstrated greater in vivo bone growth on nano- compared with micron-HA particles placed in rat calvaria, this study continued to demonstrate that ceramic/polymer nanocomposites are promising candidates as novel orthopedic materials to promote bone regeneration.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) has generated great interest in the medical and research communities yet remains an enigma, given its unknown pathogenesis. The goal of this review is to summarize the various proposed hypotheses underlying BRONJ. Although a role of the oral mucosa has been proposed, the bone is likely the primary tissue of interest for BRONJ. The most popular BRONJ hypothesis-manifestation of necrotic bone resulting from bisphosphonate--induced remodeling suppression--is supported mostly by indirect evidence, although recent data have shown that bisphosphonates significantly reduce remodeling in the jaw. Remodeling suppression would be expected, and has been shown, to allow accumulation of nonviable osteocytes, whereas a more direct cytotoxic effect of bisphosphonates on osteocytes has also been proposed. Bisphosphonates have antiangiogenic effects, leading to speculation that this could contribute to the BRONJ pathogenesis. Compromised angiogenesis would most likely be involved in post-intervention healing, although other aspects of the vasculature (eg, blood flow) could contribute to BRONJ. Despite infection being present in many BRONJ patients, there is no clear evidence as to whether infection is a primary or secondary event in the pathophysiology. In addition to these main factors proposed in the pathogenesis, numerous cofactors associated with BRONJ (eg, diabetes, smoking, dental extraction, concurrent medications) could interact with bisphosphonates and affect remodeling, angiogenesis/blood flow, and/or infection. Because our lack of knowledge concerning BRONJ pathogenesis results from a lack of data, it is only through the initiation of hypothesis-driven studies that significant progress will be made to understand this serious and debilitating condition.
Osteoporosis is a skeletal disorder characterized by low bone mass and deterioration of bone microarchitecture resulting in bone fragility, which impairs fixation of the implants. Zoledronic acid (ZOL) is a potential inhibitor of osteoclast-mediated bone resorption and basic fibroblast growth factor (bFGF) is a growth factor that stimulates osteoblast-mediated bone formation, and these drugs could enhance fixation of implants under osteoporotic conditions. In this study, 40 ovariectomized (OVX) rats were randomly divided into 4 groups (n=10 for each group) and underwent bilateral tibiae implantation using hydroxyapatite (HA)-coated titanium implant: Control group (distilled water immersing before implantation), ZOL group (1 mg/ml of ZOL immersing), bFGF group (20 microg/ml of bFGF immersing), and ZOL+bFGF group (1 mg/ml of ZOL and 20 microg/ml of bFGF immersing). At 3 months after implantation, all animal were sacrificed and the tibiae were harvested for histology, micro-CT examinations and biomechanical testing. Bone area and contact, determined by histomorphometric analysis, were 2.7-fold and 1.8-fold in the ZOL-treated implants, 1.9-fold and 1.8-fold in the bFGF-treated implants, 3.6-fold and 2.3-fold in the both-treated implants compared with controls (p<0.01). Such significant effects were further confirmed by microstructure parameters, the bone volume ratio and the percentage osteointegration were significantly increased by ZOL treatment (3.0-fold and 1.8-fold), bFGF treatment (1.2-fold and 1.9-fold) and ZOL+bFGF treatment (3.3-fold and 2.7-fold) (p<0.001). In addition, push-out test showed that the maximum force and the corresponding interfacial shear strength of the implants treated by ZOL, bFGF and ZOL+bFGF was 8.4-fold and 8.6-fold, 3.8-fold and 3.7-fold, 10.8-fold and 10.7-fold of the control levels, respectively (p<0.05). The combined treatment was better than either treatment alone for force, but was not different from ZOL alone for interfacial strength. The significant correlation between biomechanical and micro-CT parameters demonstrates the role of microstructure assessments in predicting mechanical fixation of implants (p<0.01). Our study suggests that locally applied ZOL or bFGF may improve implant fixation in the ovariectomized rats, and that combined treatment has more beneficial effects on osseointegration, peri-implant bone formation and maximum force than either intervention alone.
We have investigated the effect of Alendronate and Pamidronate, two bisphosphonates widely employed for the treatment of pathologies related to bone loss, on the setting properties and in vitro bioactivity of a calcium phosphate bone cement. The cement composition includes alpha-tricalcium phosphate (alpha-TCP) (90 wt%), nanocrystalline hydroxyapatite (5 wt%) and CaHPO(4) x 2H(2)O (5 wt%). Disodium Alendronate and disodium Pamidronate were added to the liquid phase (bidistilled water) at two different concentrations: 0.4 and 1mM (AL0.4, AL1.0, PAM0.4, PAM1.0). Both the initial and the final setting times of the bisphosphonate-containing cements increase with respect to the control cement. X-ray diffraction analysis, mechanical tests, and SEM investigations were carried out on the cements after different times of soaking in physiological solution. The rate of transformation of alpha-TCP into calcium deficient hydroxyapatite, as well as the microstructure of the cements, is not affected by the presence of Alendronate and Pamidronate. At variance, the bisphosphonates provoke a modest worsening of the mechanical properties. MG63 osteoblasts grown on the cements show a normal morphology and biological tests demonstrate very good rate of proliferation and viability in every experimental time. In particular, both Alendronate and Pamidronate promote osteoblast proliferation and differentiation, whereas they inhibit osteoclastogenesis and osteoclast function.
Glass-ceramic A-W, containing crystalline apatite and wollastonite in a MgO-CaO-SiO2 glassy matrix shows high bioactivity as well as high mechanical strength, but other ceramics containing the same kinds of crystalline phases in different glassy matrices do not show the same bioactivity. In order to investigate the bone-bonding mechanism of this type of glass-ceramic, surface structural changes of the glass-ceramics after exposure to simulated body fluid were analyzed with various techniques. A solution with ion concentrations which are almost equal to those of the human blood plasma was used as the simulated body fluid, instead of Tris-buffer solution hitherto used. For analyzing the surface structural changes, thin-film x-ray diffraction was used in addition to conventional techniques. It was found that a bioactive glass-ceramic forms a Ca, P-rich layer on its surface in the fluid but nonbioactive ones do not, and that the Ca, P-rich layer consists of carbonate-containing hydroxyapatite of small crystallites and/or defective structure. These findings were common to those of Bioglass-type glasses. So, we conclude that the essential condition for glass and glass-ceramic to bond to bone is the formation of the surface apatite layer in the body environment but it is not essential to contain apatite within the material. Bioactivity of glass and glass-ceramic can be evaluated in vitro by examining the formation of the surface apatite layer in the simulated body fluid described above.
Sixty-seven closed or grade-I open fractures of the tibial shaft were examined in a prospective, randomized, double-blind evaluation of use of a new ultrasound stimulating device as an adjunct to conventional treatment with a cast. Thirty-three fractures were treated with the active device and thirty-four, with a placebo control device. At the end of the treatment, there was a statistically significant decrease in the time to clinical healing (86 +/- 5.8 days in the active-treatment group compared with 114 +/- 10.4 days in the control group) (p = 0.01) and also a significant decrease in the time to over-all (clinical and radiographic) healing (96 +/- 4.9 days in the active-treatment group compared with 154 +/- 13.7 days in the control group) (p = 0.0001). The patients' compliance with the use of the device was excellent, and there were no serious complications related to its use. This study confirms earlier animal and clinical studies that demonstrated the efficacy of low-intensity ultrasound stimulation in the acceleration of the normal fracture-repair process.
Degradable matrices containing expression plasmid DNA [gene-activated matrices (GAMs)] were implanted into segmental gaps created in the adult rat femur. Implantation of GAMs containing beta-galactosidase or luciferase plasmids led to DNA uptake and functional enzyme expression by repair cells (granulation tissue) growing into the gap. Implantation of a GAM containing either a bone morphogenetic protein-4 plasmid or a plasmid coding for a fragment of parathyroid hormone (amino acids 1-34) resulted in a biological response of new bone filling the gap. Finally, implantation of a two-plasmid GAM encoding bone morphogenetic protein-4 and the parathyroid hormone fragment, which act synergistically in vitro, caused new bone to form faster than with either factor alone. These studies demonstrate for the first time that repair cells (fibroblasts) in bone can be genetically manipulated in vivo. While serving as a useful tool to study the biology of repair fibroblasts and the wound healing response, the GAM technology may also have wide therapeutic utility.
Pycnodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature, maps to chromosome 1q21. Cathepsin K, a cysteine protease gene that is highly expressed in osteoclasts, localized to the pycnodysostosis region. Nonsense, missense, and stop codon mutations in the gene encoding cathepsin K were identified in patients. Transient expression of complementary DNA containing the stop codon mutation resulted in messenger RNA but no immunologically detectable protein. Thus, pycnodysostosis results from gene defects in a lysosomal protease with highest expression in osteoclasts. These findings suggest that cathepsin K is a major protease in bone resorption, providing a possible rationale for the treatment of disorders such as osteoporosis and certain forms of arthritis.