Effect of implanted bisphosphonate-enriched cement on the trabecular microarchitecture of bone in a rat model using micro-computed tomography

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.     

Osseointegration of porous titanium implants with and without electrochemically deposited DCPD coating in an ovine model

Background

Alendronate (ALN) is the most common form of bisphosphonates used for the treatment of osteoporosis. Osteoprotegerin (OPG) has also been shown to reduce osteoporotic changes in both humans and experimental animals after systemic administration. The aim of this current study was to test if the anti-resorption effects of ALN may be enhanced when used in combination with OPG.

Objectives

To investigate the effects of ALN, OPG or combined on bone mass and bone mechanical properties in ovariectomized (OVX) rats.

Methods

OVX rats were treated with ALN, OPG-Fc, or OPG-Fc and ALN. Biochemical markers, trabecular bone mass, biomechanics, histomorphometry and RANKL expression in the bone tissues were examined following the treatments.

Results

The treatment of ALN, OPG-Fc and ALN+OPG-Fc all prevented bone loss in the OVX-rats, there was no statistical difference among the three treatment groups in terms of vertebrae BMD, mineralizing surfaces, mineral apposition rate, BFR/BS. The ALN+OPG-Fc treatment group had significantly increased the mechanical strength of lumber vertebral bodies and femoral shafts when compared to the ALN and OPG-Fc treatment groups. The RANKL protein expression in the vertebral bones was significantly decreased in the ALN and ALN+OPG-Fc treatment groups, suggesting the combined use of OPG-Fc and ALN might have amplified inhibition of bone resorption through inhibiting RANKL-dependent osteoclastogenesis.

Conclusion

The combined use of OPG-Fc and ALN may be a new treatment strategy for reversing bone loss and restoring bone quality in osteoprotic disorders.     

Bone loss in relation to serum levels of osteoprotegerin and nuclear factor-κB ligand: the Tromsø Study

Summary

In this longitudinal study of 4,137 persons, bone mineral density was negatively associated with osteoprotegerin at baseline in both genders. In postmenopausal women not using hormone replacement therapy (HRT), bone-loss increased with increasing osteoprotegerin levels, whereas no relationship was found in men, premenopausal women, or postmenopausal women taking HRT.

Introduction

In a population-based study of 2,003 men and 2,134 women, the relationship between the osteoprotegerin (OPG)/factor-κB ligand (RANKL) system and bone mineral density (BMD) and changes in BMD was examined.

Methods

Baseline measurements included height, weight, BMD of the forearm, OPG, RANKL, vitamin D, and serum parathyroid hormone (PTH) and information about lifestyle, prevalent diseases, and use of medication. BMD was remeasured at follow-up 6 years later.

Results

BMD was negatively associated with OPG at baseline in both men and women (p trend over OPG levels?=?0.01 and 0.007, respectively, after adjustments for age, and other confounders). In postmenopausal women not on hormone replacement therapy, bone loss increased with increasing OPG (p?=?0.005), whereas no relationship was found in men, premenopausal women, or postmenopausal women on HRT (p?≥?0.28). BMD at baseline and BMD changes were not related to RANKL levels in any of the groups (p?≥?0.14).

Conclusions

In postmenopausal women not using HRT, bone loss associated positively with OPG. The results indicate that in women deficient in sex steroids, the OPG/RANKL system may play an important counter regulatory role in order to avoid bone loss and maintain BMD. In men and women replete in sex steroids, the OPG/RANKL system was not associated with BMD.     

Bone and bone marrow pro-osteoclastogenic cytokines are up-regulated in osteoporosis fragility fractures

Summary

This study evaluates cytokines production in bone and bone marrow of patients with an osteoporotic fracture or with osteoarthritis by real time PCR, Western blot and immunohistochemistry. We demonstrate that the cytokine pattern is shifted towards osteoclast activation and osteoblast inhibition in patients with osteoporotic fractures.

Introduction

Fragility fractures are the resultant of low bone mass and poor bone architecture typical of osteoporosis. Cytokines involved in the control of bone cell maturation and function are produced by both bone itself and bone marrow cells, but the roles of these two sources in its control and the amounts they produce are not clear. This study compares their production in patients with an osteoporotic fracture and those with osteoarthritis.

Methods

We evaluated 52 femoral heads from women subjected to hip-joint replacement surgery for femoral neck fractures due to low-energy trauma (37), or for osteoarthritis (15). Total RNA was extracted from both bone and bone marrow, and quantitative PCR was used to identify the receptor activator of nuclear factor kB Ligand (RANKL), osteoprotegerin (OPG), macrophage colony stimulating factor (M-CSF), transforming growth factor ?? (TGF??), Dickoppf-1 (DKK-1) and sclerostin (SOST) expression. Immunohistochemistry and Western blot were performed in order to quantify and localize in bone and bone marrow the cytokines.

Results

We found an increase of RANKL/OPG ratio, M-CSF, SOST and DKK-1 in fractured patients, whereas TGF?? was increased in osteoarthritic bone. Bone marrow produced greater amounts of RANKL, M-CSF and TGF?? compared to bone, whereas the production of DKK-1 and SOST was higher in bone.

Conclusions

We show that bone marrow cells produced the greater amount of pro-osteoclastogenic cytokines, whereas bone cells produced higher amount of osteoblast inhibitors in patients with fragility fracture, thus the cytokine pattern is shifted towards osteoclast activation and osteoblast inhibition in these patients.     

Suppression of bone turnover by B-cell depletion in patients with rheumatoid arthritis

Summary

The role of B cells in inflammatory bone formation and resorption is controversial. We investigated this in patients with rheumatoid arthritis (RA) treated with rituximab, a B-cell depleting antibody. We found a significant suppression in bone turnover, possibly a direct effect or as a consequence of a reduction in inflammation and disease activity.

Introduction

RA is the most prevalent inflammatory joint disease, in which B cells play an important role. However, the role of B cells in bone turnover is controversial and RA subjects treated with rituximab, a B-cell depleting monoclonal antibody, provide an ideal model for determining the role of B cells in inflammatory bone resorption.

Methods

Serum from 46 RA patients, collected pre- and post-rituximab therapy, was analysed for biomarkers of bone turnover (procollagen type I amino-terminal propeptide [P1NP], osteocalcin, ??-isomerised carboxy-terminal telopeptide of type 1 collagen [??CTX] and osteoprotegerin [OPG]).

Results

A significant decrease in bone resorption was observed 6?months after rituximab (median change ??CTX ?50?ng/L, 95%CI ?136, ?8 p?<?0.001, this equates to ?37%; 95%CI ?6, ?49), mirrored by a reduction in disease activity. Similarly, there was a significant increase in P1NP, a marker of bone formation (median change P1NP 5.0???g/L, 95%CI ?1.0, 11.2, p?=?0.02; 13%; 95%CI ?3, 39), but no significant change in osteocalcin or OPG levels. The percentage change from baseline of ??CTX in a subgroup of patients (not on prednisolone or bisphosphonate) was significantly correlated with the percentage reduction in DAS28 score (r _s?=?0.570, p?=?0.014).

Conclusions

In conclusion, we have found that B-cell depletion increases bone formation and decreases bone resorption in RA patients; this may be a direct effect on osteoblasts and osteoclasts, respectively, and be at least partially explained by the decreased inflammation and disease activity.     

A significant association exists between receptor tyrosine kinase-like orphan receptor 2 gene variants and the OPG/RANKL ratio in human plasma

Summary

There is a paucity of studies investigating association between ROR2 gene variants and osteoporosis and osteoarthritis-related phenotypes. The published literature suggests that osteoprotegerin (OPG) and receptor activator of nuclear factor-kB ligand (RANKL) are essential for bone metabolism and correlate with osteoarthritis manifestation and progression. The present study provides evidence of the significant association between ROR2 variants and the OPG/RANKL ratio in human plasma. The present results also suggest significant association between ROR2 polymorphisms and severity of radiographic hand osteoarthritis.

Introduction

Despite the importance of the ROR-2 in skeletal physiology, there is a paucity of studies investigating the potential association of ROR2 gene variants with phenotypes relevant to osteoporosis and osteoarthritis. On the other hand, there is a considerable body of literature suggesting that OPG and RANKL and their ratio (OPG/RANKL) are essential for regulating bone resorption. This is also correlated with osteoarthritis manifestation and progression. The present study therefore examines whether ROR2 polymorphisms may be associated with the OPG/RANKL ratio and hand osteoarthritis (HOA).

Methods

The study was conducted in a family-based sample of 1,515 Caucasian individuals, assessed for radiographic hand osteoarthritis, using the Kellgren/Lawrence score. Of these, 865 individuals were genotyped for 19 SNPs, relatively equally covering the ROR2 locus, and their plasma levels of OPG and RANKL were assayed. The association between the selected SNPs and OPG, along with the OPG/RANKL ratio and HOA, was explored using the pedigree disequilibrium test.

Results

Of the total of 57 tests, 16 nominally significant results (p?p?p?=?0.006).

Conclusions

The present study provides evidence of the significant association between ROR2 variants and the OPG/RANKL ratio in human plasma and also suggests ROR2 association with HOA.     

Interleukin-35 upregulates OPG and inhibits RANKL in mice with collagen-induced arthritis and fibroblast-like synoviocytes

Summary

IL-35 is a novel anti-inflammatory cytokine, but the exact role of IL-35 in the progression of RA remains unclear, especially associated with osteoporosis and bone erosion. The present research has not been reported. Our purpose is to study how IL-35 affects RA bone destruction.

Introduction

This study investigated the effect of interleukin-35 (IL-35) on OPG and RANKL expression in collagen-induced arthritis (CIA) in rats and in cultured fibroblast-like synoviocytes (FLS).

Methods

Thirty DBA/1J mice were randomly assigned to three groups (n?=?10 per group): the control group, the CIA group, and the CIA?+?IL-35 group. Collagen-induced arthritis was induced by immunization with collagen. IL-35 was intraperitoneally injected daily for 10 days, starting from the 24^th day after immunization. FLS cells were isolated and cultured from CIA. The expression of IL-17, RANKL, and OPG was determined by RT-PCR and Western blot. Each experiment was repeated three times.

Results

CIA mice exhibited arthritis symptoms on day 24, followed by a rapid progression of arthritis. The expression of IL-17 and RANKL was increased and the expression of OPG was decreased in CIA mice compared with control mice. IL-35 treatment inhibited the development of arthritis in CIA mice, accompanied by a decrease in the expression of IL-17 and RANKL and an increase in the expression of OPG. Furthermore, IL-35 dose-dependently inhibited the expression of RANKL and increased the expression of OPG in cultured FLS cells.

Conclusion

IL-35 inhibits RANKL expression and increases OPG expression in CIA mice. IL-35 may be used for treating rheumatoid arthritis.

     

Denosumab significantly increases bone mineral density and reduces bone turnover compared with monthly oral ibandronate and risedronate in postmenopausal women who remained at higher risk for fracture despite previous suboptimal treatment with an oral bisphosphonate

Summary

Managing osteoporotic patients suboptimally adherent to bisphosphonates (BPs) is difficult. Such patients who remained at higher risk for fracture (≥1 risk factor) were transitioned to denosumab or a monthly oral BP. Denosumab-treated subjects had significantly greater increases in bone mineral density and decreases in bone turnover in this 12-month study.

Introduction

A clinical need exists to manage patients who are suboptimally adherent to oral BPs and remain at higher risk for fracture. Here, we compare the effects on bone mineral density (BMD) and bone turnover of transitioning such patients to denosumab or monthly oral BP (ibandronate or risedronate).

Methods

In two previous multicenter, open-label studies, postmenopausal women ≥55 years previously treated with, though suboptimally adherent to, a daily or weekly BP were randomized to denosumab 60 mg subcutaneously every 6 months (N?=?852) or oral BP 150 mg monthly (N?=?851) for 12 months. In this combined post-hoc analysis, a subset of higher risk subjects was identified, and the percentage changes from baseline in BMD and serum C-telopeptide of type I collagen (sCTX-1) were assessed.

Results

In the overall population, denosumab was associated with greater gains in BMD at 12 months than monthly oral BP at the total hip, femoral neck, and lumbar spine (p?<?0.0001 for all). In higher risk subjects, denosumab led to greater gains in BMD than oral BPs at the total hip (2.2 vs 0.8 %), femoral neck (1.8 vs 0.3 %), and lumbar spine (3.7 vs 1.4 %) (p?<?0.0001 for all). Denosumab also led to greater decreases in sCTX-1 in the overall population and higher risk subjects at months 1 and 6 (p?<?0.0001 for both). Adverse events and serious adverse events were generally similar between treatment groups.

Conclusions

Transitioning to denosumab was well tolerated and more effective in increasing BMD and reducing bone turnover than cycling to a monthly oral BP treatment in subjects who remained at higher fracture risk despite suboptimal BP treatment.     

Inflammatory factors in the circulation of patients with active rheumatoid arthritis stimulate osteoclastogenesis via endogenous cytokine production by osteoblasts

Summary

The combination of cytokines present in the circulation of patients with active rheumatoid arthritis might contribute to the generalized bone loss that commonly occurs in these patients, by directly inhibiting osteoblast proliferation and differentiation, but especially by enhancing endogenous cytokine (i.e., receptor activator of nuclear factor-kappa B ligand (RANKL) and interleukin-6 (IL)-6) production by osteoblasts, thereby stimulating osteoclastogenesis.

Introduction

Generalized bone loss, as occurs in patients with rheumatoid arthritis (RA), is related to elevated levels of circulating cytokines. Individual cytokines have deleterious effects on proliferation and differentiation of osteoblast cell lines, but little is known about the effect of the interaction between inflammatory factors in the circulation of patients with active RA on human osteoblast function, including their communication towards other bone cells. We investigated whether serum from patients with active RA enhances cytokine production by osteoblasts, thereby effectively altering osteoblast-stimulated osteoclastogenesis.

Methods

Serum was obtained from 20 patients with active RA (active RA sera) and from the same patients in clinical remission (remission RA sera). To determine osteoclastogenesis, RA serum-pretreated primary human osteoblast cultures were established in direct contact with human osteoclast precursors in the presence or absence of osteoprotegerin (OPG) or IL-6 inhibitor.

Results

Compared to remission RA sera, active RA sera inhibited osteoblast proliferation and differentiation in vitro as demonstrated by a reduced DNA content and gene expression of KI-67, collagen type 1, osteopontin, and osteocalcin. Active RA sera inhibited OPG expression and enhanced RANKL and IL-6 expression but did not alter IL-8 expression in osteoblasts. IL-1β, IL-17, and tumor necrosis factor-α (TNF-α) expression were undetectable. In coculture, active RA sera treatment of osteoblasts stimulated while addition of OPG or IL-6 inhibitory antibodies significantly reduced the number of osteoclasts.

Conclusion

Active RA sera contain circulating factors, likely cytokines and chemokines, that might contribute to bone loss by directly inhibiting osteoblast proliferation and differentiation, but especially, these factors modulate endogenous cytokine production by osteoblasts, thereby affecting osteoclastogenesis.     

A meta-analysis of bisphosphonates for periprosthetic bone loss after total joint arthroplasty

Background

Periprosthetic bone loss, which is common after joint arthroplasty, may cause bone loosening and lead to failed prosthetic fixation. Two previous meta-analyses have confirmed the mid-term effect of bisphosphonates (BPs) in preventing bone loss after arthroplasty. To determine long-term efficacy and gender bias of BPs after joint arthroplasty, we conducted a meta-analysis based on 17 RCTs involving 781 patients to evaluate the effect of BPs.

Methods

Meta-analysis was conducted after a systematic search of Medline, Embase, the Cochrane Collaboration Central Register of Controlled Clinical Trials, CINAHL, and ISI Web of Science, and manual examination of references in selected articles and conference abstracts of key orthopedic journals. Methodological quality and abstracted relevant data were evaluated. In addition to analysis of bone mineral density (BMD), we also conducted systematic analysis of clinically relevant outcomes and bone biochemical markers.

Results

Seventeen trials involving a total of 781 patients were assessed. Significantly less periprosthetic bone loss occurred in the BP-treated group than in the control group at 6 and 12 months (p < 0.0001). This protective effect was not noted at 3 months (p = 0.11) nor from 24–72 months (p = 0.14). The efficacy of BPs in the gender balance, shorter duration, and the non-nitrogenous BPs groups was no different from that for controls. Biochemical bone markers were suppressed in the BPs group. However, clinically relevant outcomes in the BPs group and controls were similar at all times.

Conclusions

The overall moderate-quality evidence from the RCTs confirmed the significant mid-term efficacy of BPs on periprosthetic bone loss after joint arthroplasty. Long-term efficacy of BPs was not observed, and the therapy was of more benefit to women, especially postmenopausal women. To achieve better efficacy, nitrogenous BPs and long duration of treatment may be recommended.     

Bisphosphonates for periprosthetic bone loss after joint arthroplasty: a meta-analysis of 14 randomized controlled trials

Summary

The present meta-analysis aimed to evaluate the middle-term efficacy of bisphosphonates on maintaining periprosthetic bone mass after joint arthroplasty and the potential influential factors. It was found that the protective effect of bisphosphonates, probably modified by its generation and the prosthesis location, could persist in a middle-term follow-up after surgery and after drug discontinuation.

Introduction

A previous meta-analysis of 6 RCTs with follow-up of 12?months suggested that bisphosphonates (BPs) could prevent bone loss after arthroplasty up to 6?months. Our meta-analysis based on 14 RCTs involving 671 patients with follow-up up to 72?months aimed to evaluate the middle-term efficacy of BPs, understand the sources of heterogeneity, and comprehensively identify the potential influential factors.

Methods

Electronic databases searching and hand searching of conference proceedings were conducted. We evaluated the methodological quality and abstracted relevant data. With fixed effect model we calculated the weighted mean differences to evaluate bone mineral density at different time points. We also conducted a systematic review for BP-related adverse effects.

Results

The significantly less periprosthetic bone loss occurred in the BP-treated group than in the control group at 3, 6, and 12?months, and between 24 and 72?months after the index surgery. The protective effect persisted during 18 to 70?months after discontinuation of BPs. The heterogeneity was minimized with the separation of hip and knee trials during the analysis. The efficacy was more potent for the second and the third generation of BPs than the first generation. None of the trials noted serious or fatal adverse effects related to BPs.

Conclusions

The overall moderate evidence from the RCTs confirmed the significantly short-term and middle-term efficacy of BPs on periprosthetic bone loss after joint arthroplasty. To obtain a better efficacy, the second and the third generation of BPs may be the choice.     

Daidzein administration positively affects thyroid C cells and bone structure in orchidectomized middle-aged rats

Summary

Thyroid C cells hormone, calcitonine, inhibits bone resorption. We have demonstrated that daidzein treatment of orchidectomized rats (model for osteoporosis) stimulated C cells and increased trabecular bone mass. These results suggest that, besides direct action, daidzein may also affect bone structure indirectly through enhancement of thyroid C cell activity.

Introduction

Thyroid C cells produce calcitonin (CT) which acts as an inhibitor of bone resorption. In this study, the influence of daidzein treatment on thyroid C cells, bone structure, and bone function in orchidectomized (Orx) middle-aged rats was investigated.

Methods

Sixteen-month-old Wistar rats were divided into Orx and sham-operated (SO) groups. Half the Orx rats were given subcutaneous injections of daidzein (30 mg/kg b.w./day) for 3 weeks. CT-immunopositive thyroid C cells were morphometrically analyzed. The metaphyseal region of the proximal tibia was measured histomorphometrically, and cancellous bone area (B.Ar), trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular separation (Tb.Sp) were calculated. Serum samples were analyzed for CT and osteocalcin (OC), calcium (Ca) and phosphorus concentrations, and urine samples for Ca levels.

Results

Treatment of Orx animals with daidzein significantly increased volume of C cells compared to the Orx rats. Daidzein also enhanced B.Ar, Tb.Th, and Tb.N and reduced Tb.Sp. The serum OC and urinary Ca concentrations decreased significantly in comparison with the Orx group.

Conclusions

These findings indicate that daidzein treatment stimulates thyroid C cells, increase trabecular bone mass, and decrease bone turnover in Orx middle-aged rats, which is the model of male osteoporosis.     

The use of bone cement in difficult distal radius fractures

Background

The lack of structural support remains a challenge in the treatment of comminuted distal radius fractures. Calcium phosphate and calcium sulfate bone cement has been used in other fracture locations in addition to fixation and has been shown to allow for retention of reduction in difficult cases.

Methods

A case-control retrospective review of 34 consecutive distal radius fractures treated with surgery was performed with the patients classified by Arbeitsgemeinschaft für Osteosynthesefragen (AO) classification. Complications and postoperative radiographs were evaluated.

Results

Cement was used in the most difficult cases. Radial height was retained in both groups. Volar tilt was significantly better in the cement group. There were no significant differences between the case and control groups for any complication. No complications related to the use of the cement were found.

Conclusions

The use of bone cement as an adjunct to fixation of distal radius fractures seems to include minimal risks and may afford a technical advantage in maintaining reduction during surgery for difficult fractures. Since there is an aspect of fracture difficulty that we cannot control for by using radiographic assessment alone, cement may provide an advantage over fixation without cement, despite similar outcomes. Bone cement can be part of the "tool box" for difficult distal radius fractures. Further study is necessary to define the technical advantages and limitations of each particular cement product.     

Serum OPG and RANKL levels before and after intravenous bisphosphonate treatment in Paget's disease of bone

Paget's disease of bone (PDB) is a focal disorder of bone remodeling characterized by increased osteoclast-mediated bone resorption. Even though increasing evidence indicates enhanced nuclear factor-kB (NF-kB) signaling as a common mechanism involved in PDB and other related disorders, few studies investigated circulating osteoprotegerin (OPG) and receptor of activator of NF-kB-ligand (RANKL) levels in PDB patients. In this study we explored the relationships between OPG or RANKL levels and bone turnover markers in a group of patients with PDB, before and after intravenous bisphosphonate treatment (pamidronate 60 mg). Both OPG and RANKL were markedly elevated in PDB patients with respect to control groups (healthy or osteoporotic postmenopausal women and elderly men) and were positively associated with bone turnover markers. Higher levels of these cytokines were observed in polyostotic than monostotic PDB cases. The ratio between RANKL and OPG was more than 3-fold higher in PDB patients than in controls. Interestingly, in the group of patients treated with pamidronate, we found an increase in OPG levels that become statistically significant after 3 and 6 months from treatment. A trend toward a decrease in RANKL levels after treatment was also observed. The RANKL/OPG ratio was significantly reduced after 3 and 6 months of therapy. In contrast, in patients classified as non-responders, OPG and RANKL levels after pamidronate infusion did not significantly differ with respect to pre-treatment values. Thus, the positive effect of amino bisphosphonates in the treatment of PDB may be due to either direct or indirect suppression of RANKL-induced bone resorption through decreased RANKL and increased OPG production.     

Clinical efficacy and treatment persistence of monthly minodronate for osteoporotic patients unsatisfied with,and shifted from,daily or weekly bisphosphonates: the BP-MUSASHI study

Summary

This multi-center, prospective, open-label, observational study evaluated the effects of once-monthly minodronate (50 mg) on treatment persistence, bone turnover markers, bone mineral density, low back pain, and upper gastrointestinal symptoms in outpatients with osteoporosis previously treated with daily or weekly bisphosphonate products.

Introduction

The purposes of this study were to investigate the effects of once-monthly oral minodronate (MIN 50 mg) on bone turnover markers and bone mineral density, low back pain, and upper gastrointestinal symptoms, as well as preference for and treatment persistence of MIN 50 mg among Japanese osteoporosis patients currently treated with daily or weekly bisphosphonates.

Methods

Study patients were allocated based on their preference to either the Switch group (patients willing to switch over to MIN 50 mg) or the Continue group (patients wanting to continue their current therapies). Patients’ treatment persistence and satisfaction levels with the therapies were assessed using a self-administered questionnaire. The study endpoints were serum TRACP-5b, serum P1NP, bone mineral density, upper gastrointestinal symptoms, and low back pain.

Results

In total, 264 and 133 patients were allocated into the Switch and Continue groups, respectively. Approximately, 65 % of patients were willing to switch to MIN 50 mg, with the predominant reason being “less frequent dosing more convenient.” Treatment persistence was significantly higher in the Switch group (MIN 50 mg) than the Continue group. Almost all patients with abnormal bone metabolism markers demonstrated normalization after switchover. MIN 50 mg alleviated low back pain and upper gastrointestinal symptoms induced by prior bisphosphonate use.

Conclusions

MIN 50 mg alleviates low back pain, reduces bone turnover markers and increases bone density, and induces fewer upper gastrointestinal symptoms after switchover from prior bisphosphonate products, and therefore, it may provide patients with a more convenient treatment option and enhance long-term treatment persistence.     

Effect of vertebroplasty with bone filler device and comparison with balloon kyphoplasty

Purpose

To evaluate the effect of vertebroplasty with a bone filler device compared with balloon kyphoplasty.

Methods

A total of 222 patients underwent operations from January 2008 to October 2012. One-level fractures numbered 169 (86.7 %) cases and two-level fractures numbered 26 (13.3 %). A total of 221 vertebral levels were analyzed consequently. Vertebral height, compression ratio, and segmental Cobb’s angle were measured in preoperative and postoperative lateral X-rays.

Results

The compression ratio was the most influential parameter among three variables. Adjusted postoperative compression ratio was not significantly different between two operation groups. Bone cement leakage rates did not differ (p < 0.05). Bone cement distribution was spongy type in the majority of the vertebroplasty with bone filler device (94.5 %), but only in 42.0 % of the kyphoplasty. High bone densitometry readings and long period from diagnosis to operation were significant risk factors for bone cement leakage.

Conclusions

Vertebroplasty with a bone filler device could achieve equivalent compression reduction and bone cement leakage rate, as well as greater sponge-type bone cement distribution, which were advantages over balloon kyphoplasty.     

Role of Wnt/β-catenin and RANKL/OPG in bone healing of diabetic Charcot arthropathy patients: A prospective study in 24 patients followed for 2 years

Background and purpose

Charcot neuropathy is characterized by bone destruction in a foot leading to deformity, instability, and risk of amputation. Little is known about the pathogenic mechanisms. We hypothesized that the bone-regulating Wnt/β-catenin and RANKL/OPG pathways have a role in Charcot arthropathy.

Patients and methods

24 consecutive Charcot patients were treated by off-loading, and monitored for 2 years by repeated foot radiography, MRI, and circulating levels of sclerostin, dickkopf-1, Wnt inhibitory factor-1, Wnt ligand-1, OPG, and RANKL. 20 neuropathic diabetic controls and 20 healthy controls served as the reference.

Results

Levels of sclerostin, Dkk-1 and Wnt-1, but not of Wif-1, were significantly lower in Charcot patients than in the diabetic controls at inclusion. Dkk-1 and Wnt-1 levels responded to off-loading by increasing. Sclerostin levels were significantly higher in the diabetic controls than in the other groups whereas Wif-1 levels were significantly higher in the healthy controls than in the other groups. OPG and RANKL levels were significantly higher in the Charcot patients than in the other groups at inclusion, but decreased to the levels in healthy controls at 2 years. OPG/RANKL ratio was balanced in all groups at inclusion, and it remained balanced in Charcot patients on repeated measurement throughout the study.

Interpretation

High plasma RANKL and OPG levels at diagnosis of Charcot suggest that there is high bone remodeling activity before gradually normalizing after off-loading treatment. The consistently balanced OPG/RANKL ratio in Charcot patients suggests that there is low-key net bone building activity by this pathway following diagnosis and treatment. Inter-group differences at diagnosis and changes in Wnt signaling following off-loading treatment were sufficiently large to be reflected by systemic levels, indicating that this pathway has a role in bone remodeling and bone repair activity in Charcot patients. This is of particular clinical relevance considering the recent emergence of promising drugs that target this system.Charcot neuropathy mainly affects diabetic patients with bilateral peripheral neuropathy and is characterized by degenerative changes of the bone, joints, and soft tissues of the foot and ankle. However, the pathophysiological processes that lead to acute Charcot foot remain obscure. The identification of a cytokine system belonging to the tumor necrosis factor family—consisting of RANKL (receptor activator of nuclear factor-κB ligand), its receptor RANK (receptor activator of nuclear factor-κB), and its soluble decoy receptor, osteoprotegerin (OPG)—has substantially increased our understanding of bone regulatory mechanisms responsible for osteolytic activity by osteoclasts. The RANKL/OPG pathway has therefore been implicated in an increasing number of diseases affecting the bone, and several review articles have hypothesized about the possible role of this pathway in Charcot arthropathy (Jeffcoate 2008, Mascarenhas and Jude 2013), although only a few studies have been published. Although there has been much interest in RANKL/OPG signaling, recent research has significantly increased our understanding of the pivotal role played by other pathways in bone regulation. One such pathway is that of Wnt, which has been shown to be a key regulator of embryonic bone development, mechanical loading and unloading of the skeleton, bone growth, bone remodeling, and fracture repair by increasing osteoblast commitment from progenitor cells and by stimulating their proliferation and activation (Agholme and Aspenberg 2011, Kim et al. 2013). In addition, there is crosstalk between the bone anabolic Wnt pathway and the bone-catabolic RANKL/OPG pathway (Diarra et al. 2007), with recent studies suggesting that the Wnt pathway is in control of osteoclast differentiation and activation through its actions on the osteoblasts, and by participating in osteoclast recruitment and the initiation of bone remodeling (Bellido 2014). We are not aware of any study investigating the role of the Wnt system in the pathology of Charcot arthropathy.In this 2-year longitudinal, observational study in Charcot patients, we repeatedly measured plasma levels of endogenous mediators forming part of the RANKL/OPG and Wnt/ß-catenin pathways with the aim of elucidating their role in the pathophysiology of Charcot arthropathy from the acute phase until reaching a cold/chronic state.     

Tibial bone versican content decreases with zoledronate treatment in adult mice

Summary

In bone remodeling, the expression and turnover of the proteoglycans versican and aggrecan are poorly understood. We report changes in adult mouse bone contents of versican and aggrecan associated with both age and treatment with the drug zoledronate. The data may have implications for experimental animal models of osteoporosis and related conditions.

Introduction

Versican and aggrecan are large, aggregating proteoglycans involved in skeletal development, but little is known about their roles in bone remodeling. The purpose of this study was to investigate versican and aggrecan contents in adult mouse bones, and changes in their contents in response to the bisphosphonate zoledronate (ZOL).

Methods

Mice (9 weeks old) were treated with 125 μg/kg ZOL or vehicle for 3 or 15 weeks. Versican and aggrecan were isolated from tibial bones for Western blotting, automated integrated densitometry, and analysis (two-way ANOVA, α?=?0.05).

Results

In ZOL-treated mouse bones, compared to vehicle, 340 and 60 kDa versican content decreased significantly, and 100 and 60 kDa aggrecan content decreased significantly (drug effect). In 24-week-old mouse bones, compared to 12 weeks, statistically significant decreases were observed in 340, 80, 60, and 11 kDa versican, and in 100, 70, and 40 kDa aggrecan (age effect). There was a statistically significant ZOL-age interaction for 330 kDa aggrecan.

Conclusion

This is the first study to assess physiological versican and aggrecan adaptations in adult mammalian bone tissue, in the presence and absence of ZOL. We observed large decreases in some versican and aggrecan species from 12 to 24 weeks. We also observed decreases in several versican and aggrecan species in the presence of ZOL. This indicates that bone proteoglycan expression and turnover may be important in bone remodeling.     

RANKL/RANK/OPG cytokine receptor system: mRNA expression pattern in BPH,primary and metastatic prostate cancer disease

Background

The cytokine system RANKL (receptor activator of NF-κB ligand), its receptor RANK and the antagonist OPG (osteoprotegerin) play a critical role in bone turnover. Our investigation was conducted to describe the gene expression at primary tumour site in prostate cancer patients and correlate the results with Gleason Score and PSA level.

Methods

Seventy-one samples were obtained from prostate cancer patients at the time of radical prostatectomy and palliative prostate resection (n = 71). Patients with benign prostate hyperplasia served as controls (n = 60). We performed real-time RT-PCR after microdissection of the samples.

Results

The mRNA expression of RANK was highest in tumour tissue from patients with bone metastases (p < 0.001) as compared to BPH or locally confined tumours, also shown in clinical subgroups distinguished by Gleason Score (< 7 or ≥ 7, p = 0.028) or PSA level (< 10 or ≥ 10 µg/l, p = 0.004). RANKL and OPG mRNA expression was higher in tumour tissue from patients with metastatic compared to local disease. The RANKL/OPG ratio was low in normal prostate tissue and high tumours with bone metastases (p < 0.05). Expression of all three cytokines was high in BPH tissue but did not exceed as much as in the tumour tissue.

Conclusion

We demonstrated that RANK, RANKL and OPG are directly expressed by prostate cancer cells at the primary tumour site and showed a clear correlation with Gleason Score, serum PSA level and advanced disease. In BPH, mRNA expression is also detectable, but RANK expression does not exceed as much as compared to tumour tissue.