Bisphosphonates Research Articles

Efficacy of Xianling Gubao capsule vs. its combination therapy in the treatment of primary osteoporosis: A network meta-analysis of randomized controlled trials

ObjectiveThis study aimed to evaluate the efficacy of the Xianling Gubao (XLGB) capsule alone and its combination therapy in primary osteoporosis (POP). MethodsDatabases including PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang Data, VIP, and SinoMed were searched from their inception to January 16, 2024, for randomized controlled trials (RCTs) investigating the XLGB treatment for POP. A network meta-analysis (NMA) was performed to evaluate the efficacy and safety of multiple interventions in the treatment of POP. The Cochrane risk-of-bias tool was used to assess the quality of RCTs included in the meta-analysis. Software Stata (version 15.0) was used for statistical analysis. The surface under the cumulative ranking curve (SUCRA) method was used to present the findings from this NMA numerically and graphically by ranking multiple interventions. ResultsA total of 107 RCTs were included in the meta-analysis, involving 10,032 participants and 21 interventions. Meta-analysis showed that XLGB + calcium (Ca) + calcitonin (99.9 %) was the most desirable treatment option for improving clinical efficacy. XLGB + Ca + bisphosphonate (BP) was most effective for improving bone mineral density (BMD) at the lumbar spine, femoral neck BMD, and serum bone Gla protein (BGP). SUCRA values for improving these three outcome measures by XLGB + Ca + BP were 87.4 %, 77.2 %, and 84.3 %, respectively. XLGB + calcitonin was the optimal option in terms of safety evaluation and improving visual analogue scale (VAS), with the SUCRA values being 89.6 % and 94.9 %, respectively. ConclusionsThe XLGB combination therapy is a desirable option for treating POP as it can effectively improve the therapeutic effects, BMD, and serum BGP, as well as relieve pain in patients with POP.

Surrogate markers in assessment of bisphosphonate effectiveness in osteoporosis treatment (bone mineral density, bone turnover markers)

A review of the literature which summarizes our knowledge on the use of surrogate markers of the osteoporosis treatment effectiveness when on bisphosphonate (BP) therapy. Bone mineral density (BMD) and markers of bone turnover, which have been shown to be associated with the clinical fracture end point, have been used as surrogate criteria for the effectiveness of treatment of osteoporosis in randomized controlled trials. When prescribing BP for the treatment of osteoporosis, BMD measurement every 12 months by dual-energy x-ray absorptiometry (DXA) is the well-described surrogate marker of BP efficacy. At the same time, stabilization of BMD is also a criterion for the treatment effectiveness since changes in BMD determined only 16% of the anti-fracture effectiveness of BP. Markers of bone remodeling can be used as surrogate markers after 3 (bone resorption) or 6 (bone formation) months from the start of BP therapy. A decrease of 30% or more is considered to be prognostically effective for both antifracture and BMD gain. There is a direct relationship between the degree of bone remodeling markers decrease and the antifracture effectiveness of BP therapy. The decrease in markers persists throughout the entire period of therapy and, accordingly, they can be used as surrogate markers of effectiveness and adherence to BP therapy throughout the entire treatment period. However, the presence of pathological fractures is a key clinical manifestation of osteoporosis and should be considered first in every decision making compared to any surrogate marker.Thus, when prescribing BP treatment, surrogate markers of changes in BMD and/or markers of bone remodeling can be used to monitor the effectiveness of treatment throughout the entire period of treatment and patients’ monitoring.

Dentists’ Perspective on Osteoporosis Therapy: A Pilot Survey Study

Objective: Osteoporotic fractures are a major public health problem worldwide. Effective therapies have been available since 1995, with bisphosphonates (BPs) as the most used first-line drugs. Zoledronic acid and denosumab (Dmab) became available soon thereafter. However, both BPs and Dmab, but not other osteoporosis therapies, are associated with rare occurrences of osteonecrosis of the jaw (ONJ) and atypical femur fracture (AFF), the two most common major barriers either for initiating or maintaining effective anti-fracture therapies. In this pilot study, we aimed to determine dentists’ perceptions and practice patterns to mitigate ONJ. Methods: After approval from the Institutional Review Board, we e-mailed an online 7-point survey questionnaire to licensed dental practitioners, the members of the Michigan Dental Association (MDA), to ascertain the range of approaches dentists would take to treat patients who were using osteoporosis medications. Results: Members of the MDA were surveyed with a series of questions, and 40 responses were received. Respondents were 50% women, and 28 worked in suburban areas, 8 in urban areas, and 4 in rural areas. 48% of the dentists have been practicing for > 20 years, 32% for 5–20 years, and 20% for < 5 years. When asked about the interruption of osteoporosis medications for low-risk dental procedures, such as cavities, 68% never stopped therapy, 17% stopped in certain scenarios, and 15% reported stopping after a discussion with the patient’s provider. When asked about the interruption of osteoporosis medications for high-risk dental procedures, such as tooth extractions, 15% would not interrupt therapy, 23% would interrupt in certain scenarios, 7% would always interrupt therapy, and 55% would interrupt therapy after discussion with the patient’s provider. Conclusion: Despite the extreme rarity of ONJ, no specific guidelines exist from the American Dental Association (ADA), and dentists’ perspectives on mitigating ONJ are quite varied. Our study suggests that many dentists feel that osteoporosis therapy is a major barrier to safe dental practice and indicates an urgent need for education of our dentist colleagues on the rationale and validity of interrupting osteoporosis therapies.

Unveiling Medication-Related Osteonecrosis of the Jaw: A Rapid Review of Etiology, Drug Holidays, and Treatment Strategies

This rapid review critically evaluates recent advancements in the management of medication-related osteonecrosis of the jaw (MRONJ) from 2022 to 2023, employing a specific article selection protocol to focus on the latest literature. Initially screening 262 articles and ultimately selecting 22 based on their relevance and uniqueness, the process involved meticulous screening, methodological evaluation, and data extraction by the authors. The findings, organized into epidemiology, treatment effectiveness, and drug holidays, are synthesized following rapid review guidelines. The review addresses the risk of MRONJ associated with tooth extraction in patients undergoing antiresorptive medication therapy, such as bisphosphonates (BPs) and denosumab (DS), and evaluates the effectiveness of drug holidays in reducing this risk. Recent studies suggest that drug holidays may not effectively mitigate MRONJ risks as previously believed. Furthermore, it highlights that conservative treatment can benefit asymptomatic early-stage MRONJ patients, whereas surgical intervention is more effective for those in advanced stages. Ultimately, this review synthesizes current findings to enhance clinical practice, suggesting that while drug holidays may not significantly reduce MRONJ risks, treatment strategies should be tailored, ranging from conservative approaches in early stages to surgical interventions in advanced stages, thereby guiding evidence-based clinical decisions.

Bisphosphonates activated keratin assembled nanoparticle targeting bone fracture for enhanced immunomodulatory and osteoinductivity

Bone fractures pose significant clinical challenges and require innovative solutions for effective treatment and rapid recovery. Nanoscale protein-based materials are prominent in biotechnology and biomedicine, demonstrating versatility in biological processes and drug delivery. Herein, we designed and fabricated self-assembled keratin nanoparticles via a bisphosphonate (BP)-activated conformation-conservative assembly process. We determined the structural properties of the nanoparticles and explored the immunomodulatory and osteoinductivity functions retained from keratin. In addition, the keratin-BP nanoparticles could repair bone fractures. This study on multifunctional self-assembled protein-drug nanoparticles provides useful baseline data for exploring novel therapeutic options for acute bone fracture and other diseases.

Long-term bisphosphonates use and atypical femoral fracture

Osteoporosis is a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration, increasing the risk of fractures. As the global incidence of osteoporosis rises, it has become a pressing concern for healthcare professionals. Long-term use of bisphosphonates (BPs), commonly prescribed for osteoporosis, has been associated with atypical femur fractures (AFFs). While AFFs are relatively rare, they are a serious concern due to their potential complications.

Treatment of Osteoporosis in Men on Androgen Deprivation Therapy in Japan.

Background and Objectives: Androgen deprivation therapy (ADT) for prostate cancer has greatly improved treatment outcomes. As patient survival rates have increased, reports of decreased bone density and increased bone fractures as side effects of ADT have emerged. The prevalence of osteoporosis in Japanese men was 4.6%. The purpose of this study was to evaluate the effect of osteoporosis treatment in prostate cancer patients who underwent ADT in Japan. Materials and Methods: The subjects were 33 male patients who had undergone ADT for prostate cancer, who were noted to have decreased bone density. Mean age was 76.2 ± 7.7 years (64-87). Medications included vitamin D in one case, bisphosphonates (BP) in 27 cases, and denosumab in five cases. The evaluation method examined the rate of change in bone mineral density (BMD) before osteoporosis treatment and 1 year after. For comparison, a group without osteoporosis treatment intervention (n = 33) was selected, and matched for prostate cancer treatment and age. The rate of change in trabecular bone score (TBS) was also calculated. Results: The percentage changes in BMD before and 1 year after treatment were as follows: lumbar spine, 7.1 ± 5.8% in the treatment group versus -3.9 ± 4.1% in the no treatment group; femoral neck, 5.5 ± 6.2% in the treatment group versus -0.9 ± 3.9% in the no treatment group; total femur, 6.6 ± 6.4% in the treatment group versus the no treatment group which was -1.7 ± 3.2%. In all cases, there was a clear significant difference (p < 0.01). The percent change in TBS was further calculated in the same manner. There was no significant difference between the two groups: +1.7 ± 3.8% in the treated group versus +0.3 ± 4.1% in the untreated group. Conclusions: Osteoporosis treatment in Japanese patients with prostate cancer on ADT therapy was found to significantly increase BMD compared to the untreated group. BP and denosumab were found to be very effective in increasing BMD.

Long-term consequences of osteoporosis therapy with bisphosphonates

Bisphosphonates (BPs) are medications widely used in clinical practice to treat osteoporosis (OP) and reduce fragility fractures. The extended use of antiresorptive therapy has drawn attention to two extremely rare, although severe, adverse events. Аtypical femoral fracture (AFF) and medication-related osteonecrosis of the jaw (MRONJ) are more common in patients with high cumulative doses and longer duration of therapy. The risk of AFF depends on the duration of treatment and is significantly increased among patients receiving BPs for more than 8 years. The risk may decrease and return to the initial level with discontinuation of BPs, it decreases by more than 50% during one year after the discontinuation. The risk of MRONJ is less dependent on the duration of therapy, it occurs more often in patients with cancer who are receiving higher cumulative doses of BPs. The combination of local trauma, microbial contamination and concomitant diseases induces this condition in patients with OP who are receiving BPs. BPs have demonstrated safety and effectiveness throughout the years and evidenced increased BMD and reduced fracture risks, and these benefits overweight the risks of rare adverse events.

Results of bisphosphonate withdrawal: duration of antiresorptive activity, fractures, changes in BMD and bone turnover markers

The review discusses the possibility of discontinuation of bisphosphonates (BPs), based on the mechanism of action of the drugs, the duration of their antiresorptive activity, criteria for discontinuation and return to therapy. BPs have a unique feature – maintaining the clinical effect for a long time after their withdrawal. Since BPs therapy is carried out for a long time, their accumulation in bone tissue, on the one hand, and the risk of developing severe adverse events, on the other hand, gave rise to discussion on the concept of temporary withdrawal of drugs and the organization of «drug holidays». The main criteria that are relied upon in the question of discontinuation of BPs and re-prescription at present are: 1) the risk of developing new fractures, 2) changes in bone mineral density (BMD), 3) dynamics of markers of bone metabolism. The conducted studies suggest that the suspension of treatment after 3-5 years of continuous therapy with BPs is possible in women who do not have low BMD indicators at the end of the course of therapy, while with continuing low levels of BMD, additional benefits from continuing therapy are likely. The loss of bone mass in the proximal femur and its preservation in the spine 2 years after discontinuation of BPs treatment is explained by their different localization and longer-term effect on bone metabolism in the spongy bone, i.e. in the spine. Delivery and absorption of BPs in the spine may be more intense than in other parts of the skeleton. Tracking the level of markers during a break in the treatment of BPs can be useful to determine the time of resumption of therapy: if their concentration approaches the baseline (before treatment), the patient’s condition should be reassessed and the issue of resuming therapy should be discussed. It should be noted that the optimal duration of «drug holidays» has not been established and should be selected individually depending on clinical circumstances, taking into account the presence of fractures, a significant decrease in BMD or an increase in markers of bone metabolism, as well as the presence and/or appearance of new clinically significant risk factors.

Current vision on mechanism of action of bisphosphonates. The effect of long-term administration of bisphosphonates on bone tissue (preclinical studies)

Osteoporosis (OP) is one of the common chronic diseases in the elderly, which requires long–term therapy. Bisphosphonates (BP) belong to the first-line choice medications for the treatment of OP, however, prolonged period of bisphosphonates use has been associated with increased risk of atypical femoral fractures (AFFs), medication-related osteonecrosis of the jaw (MRONJ) and the impact on fracture healing, which attracts increased attention to the current widespread use of them.The article presents the existing classes of BP according to their chemical structure and mechanism of action, differences in their antiresorptive potencies. The data of studies on animal models on the effect of BP on the mechanical properties of bone, fracture repair, as well as the development of MRONJ are presented.

Bisphosphonate-related Osteonecrosis of The Jaw : Is the Medication Duration Related to Advanced Disease Stage?

Abstract Objectives Osteonecrosis of the jaw (ONJ) is a serious adverse effect of therapy with bisphosphonates (BP) and other antiresorptive agents. The aim of the study was to report thirteen bisphosphonates related osteonecrosis of the jaw (BRONJ) patient cases at Kaohsiung Veterans General Hospital (VGHKS), Taiwan and their medical history and disease outcomes. Methods Thirteen symptomatic patients with BRONJ were reviewed between 1985 and 2021 at VGHKS. We included symptomatic patients who were in advanced BRONJ stage two and three. Four multiple myeloma, three bone metastatic breast cancer and six advanced osteoporosis patients. Results Seven patients were AAOMS MRONJ stage three and six were stage two. The average anti-resorptive medication duration was 25.83 ± 31.45 months in BRONJ stage two patients and 53.71 ± 31.25 months in BRONJ stage three patients respectively. No correlation was found between the anti-resorptive agent duration and BRONJ stage (p value = 0.098; Mann-Whitney U test) among cancer (p value = 0.157; Mann-Whitney U test) and osteoporosis patients (p value = 0.184; Mann-Whitney U test). Conclusion Most of them died of terminal stage cancer disease or complications of being bedridden. The correlation between the duration of anti-resorptive agents and BRONJ stage needs larger patient data to confirm the result.

Evaluating calcium channel blockers and bisphosphonates as otoprotective agents in cochlear implantation hearing preservation candidates

Objectives Evaluate potential effects of calcium channel blockers (CCB) and bisphosphonates (BP) on residual hearing following cochlear implantation. Methods Medications of 303 adult hearing preservation (HP) candidates (low frequency pure tone average [LFPTA] of 125, 250, and 500 Hz ≤80 dB HL) were reviewed. Postimplantation LFPTA of patients taking CCBs and BPs were compared to controls matched by age and preimplantation LFPTA. Results Twenty-six HP candidates were taking a CCB (N = 14) or bisphosphonate (N = 12) at implantation. Median follow-up was 1.37 years (range 0.22–4.64y). Among subjects with initial HP, 29% (N = 2 of 7) CCB users compared to 50% (N = 2 of 4) controls subsequently lost residual hearing 3–6 months later (OR = 0.40, 95% CI = 0.04–4.32, p = 0.58). None of the four BP patients with initial HP experienced delayed loss compared to 50% (N = 2 of 4) controls with initial HP (OR = 0.00, 95% CI = 0.00–1.95, P = 0.43). Two CCB and one BP patients improved to a LFPTA <80 dB HL following initial unaided thresholds that suggested loss of residual hearing. Discussion There were no significant differences in the odds of delayed loss of residual hearing with CCBs or BPs. Conclusion Further investigation into potential otoprotective adjuvants for maintaining residual hearing following initial successful hearing preservation is warranted, with larger cohorts and additional CCB/BP agents.

Medication-Related Osteonecrosis of the Jaw – 2024 Update

As the global number of patients with osteoporosis and malignant diseases such as breast cancer, multiple myeloma, and prostate cancer increases every year, there is an associated rise in the use of antiangiogenic medications and antiresorptive medications. With increasing frequencies in the use of antiangiogenic and antiresorptive medications, there is an associated increase in the number of medication-related osteonecrosis of the jaw (MRONJ) cases reported from patients. MRONJ has emerged as a significant comorbidity in cancer patients treated with antiangiogenics or high doses of potent antiresorptive agents, such as bisphosphonates (BPs) or denosumab. MRONJ first emerged from BP-treated cancer patients who presented with a spectrum of dental problems, including delayed wound healing following a dental extraction or oral surgery, exposed bone, soft tissue infection and inflammation, anesthesia, paresthesia, odontalgia, sinus pain, and aching bone pain in the mandible, which continues to be a significant source of problems for dentists, physicians, and patients today. A significant number of MRONJ cases secondary to osteoporosis have also been reported in osteoporotic patients receiving antiresorptive medications. The American Association of Oral and Maxillofacial Surgeons (AAOMS) has established diagnostic standards for MRONJ based on pharmacological history, clinical signs, and radiographic findings. However, as the expertise and knowledge base for MRONJ continues to evolve, revisions and refinements for MRONJ pathogenesis and treatment strategies are necessary to reflect the current research status of the disease correctly. This review highlights current scientific information associated with MRONJ to identify and summarize preventative measures, and treatment interventions for reading the impact of this debiliating disorders.

Hierarchical zeolite coatings featuring a spatial gradient architecture for sequentially-controlled bisphosphonate release in the modulation of osteogenic–osteoclastic balance

Osteogenic–osteoclastic microenvironment imbalance impairs osseointegration between joint prostheses and the marrow cavity, which is a crucial contributor to the high incidence of complications such as implant loosening and periprosthetic fractures in osteoporosis (OPs). Previously, we employed hydrogel-based bisphosphonate (BPs) coatings on 3D-printed porous titanium alloy implants (pTi) to modulate the OPs microenvironment through controlled release. However, challenges persisted, including the limited duration of BPs release and associated organic material degradation-induced toxicity. To address these issues, we modified pTi surfaces by introducing chemically stable zeolites and BPs. In this study, we applied Ca2+-functionalized hierarchical zeolite coating on pTi for the first time. By combining mesoporous adsorption and Ca2+ chelation, we achieved efficient encapsulation of zoledronate (ZOL), creating a bioactive interface characterized by a spatial gradient structure with a “microporous-mesoporous-macroporous” morphology. The coating achieves the release of ZOL through the mesoporous structure and facilitates the gradual release of chelated ZOL via ion exchange, resulting in hierarchical drug delivery. Moreover, the spatial gradient structure of the coatings significantly influenced cell extension. Simultaneously, we constructed a bioactive coating with a drug concentration gradient, achieving graded drug release within the microenvironment, which facilitated the accurate regulation of osteogenesis and bone resorption. This coating has the potential to substantially enhance the management of postoperative complications in OPs patients undergoing prosthetic replacement surgery by achieving a balanced osteogenic-osteoclastic response.

Differences in bone histomorphometry between White postmenopausal women with and without atypical femoral fracture after long-term bisphosphonate therapy.

Bone histomorphometric endpoints in transilial biopsies may be associated with an increased risk of atypical femoral fracture (AFF) in patients with osteoporosis who take antiresorptives, including bisphosphonates (BPs). One way to test this hypothesis is to evaluate bone histomorphometric endpoints in age-, gender-, and treatment time-matched patients who either had AFF or did not have AFF. In this study, we performed transiliac bone biopsies in 52 White postmenopausal women with (n= 20) and without (n= 32) AFFs, all of whom had been treated for osteoporosis continuously with alendronate for 4-17yr. Despite the matched range of treatment duration (4-17yr), AFF patients received alendronate for significantly longer time (10.7yr) than non-AFF patients (8.0yr) (P= .014). Bone histomorphometric endpoints reflecting microstructure and turnover were assessed in cancellous, intracortical, and endocortical envelopes from transilial biopsy specimens obtained from BP-treated patients 3-6mo after AFF and from non-AFF patients with similar age-, gender-, and range of BP treatment duration. However, in both cancellous and intracortical envelopes, AFF patients had significantly lower wall thickness (W.Th) and higher osteoclast surface (Oc.S/BS) than non-AFF patients. In addition, AFF patients had significantly higher eroded surface (ES/BS) only in the intracortical envelope. None of the dynamic variables related to bone formation and turnover differed significantly between the groups. In conclusion, in the ilium of BP-treated patients with osteoporosis, AFF patients have lower thickness of superficial bone (lower W.Th) of the cancellous and cortical envelopes than non-AFF patients. AFF and non-AFF patients have a similar bone turnover rate in the ilium. Furthermore, in this population, as in previous work, AFF is more likely to occur in BP-treated patients with longer treatment duration.

Assessment of Role of Bisphosphonates on Dental Implant Treatment in Post-menopausal Ladies.

To examine the impact of bisphosphonates (BPs) on dental implant treatment and alveolar bone in post-menopausal ladies. Twenty post-menopausal ladies who had at least one dental implant within the previous 5 years participated in the current study. Ten subjects were categorized into two groups: Group A had BP medication for 1.5 years, and group B received parathyroid hormone (PTH). Both groups' bone thickness and bone mineral density (BMD) were measured. Group A had 5%, and group B had 5% of dental implants failures. BMD of cortical bone was 1468 ± 136 mg/mL and 1008 ± 84 mg/mL in groups A and B, correspondingly. The cortical and cancellous bone densities in both the groups were statically significant. Cortical bone thickness was insignificant in comparison. Both cortical and cancellous bones' bone mineral density decreased in both groups. With continued usage of BPs, the cortical bone thickness increased.

Patient preference, efficacy, and compliance with zoledronic acid for glucocorticoid-induced osteoporosis in patients with autoimmune diseases.

We evaluated the preference, patient satisfaction, and efficacy of zoledronic acid compared with oral bisphosphonates (BPs) for glucocorticoid-induced osteoporosis (GIOP) in patients with autoimmune diseases. We enrolled 50 patients with new fractures or osteoporosis detected on follow-up bone densitometry after at least 1year of oral BP use among patients diagnosed with GIOP during treatment for autoimmune diseases. After 1year of zoledronic acid treatment, patients completed a survey for preference and satisfaction assessment. Treatment efficacy was analysed by comparing bone mineral density changes and fractures with those in a control group of patients who continued oral BP use. Age, sex, treatment duration, and medication history did not differ significantly between the two groups. Among the participants, 86.7% preferred and were more satisfied with intravenous zoledronic acid than with oral BPs, primarily because of the convenience of its administration interval. Only two patients (4%) reported infusion-related adverse events with zoledronic acid. Furthermore, no significant differences were observed in the annualized percentage change in the bone mineral density of the lumbar spine, femur neck, and hip between patients receiving zoledronic acid and those receiving oral BPs. The occurrence of new fractures was consistent across both groups, with two cases in each, showing no significant differences. Patients showed a preference for and greater satisfaction with zoledronic acid, and its efficacy in treating osteoporosis was comparable to that of oral BPs. Therefore, zoledronic acid is a suitable treatment option for GIOP in patients with autoimmune diseases.

Unexpected chronic lymphocytic leukemia B cell activation by bisphosphonates

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, often presenting comorbidities like osteoporosis and requiring, in a relevant proportion of cases, treatment with bisphosphonates (BPs). This class of drugs was shown in preclinical investigations to also possess anticancer properties. We started an in vitro study of the effects of BPs on CLL B cells activated by microenvironment-mimicking stimuli and observed that, depending on drug concentration, hormetic effects were induced on the leukemic cells. Higher doses induced cytotoxicity whereas at lower concentrations, more likely occurring in vivo, the drugs generated a protective effect from spontaneous and chemotherapy-induced apoptosis, and augmented CLL B cell activation/proliferation. This CLL-activation effect promoted by the BPs was associated with markers of poor CLL prognosis and required the presence of bystander stromal cells. Functional experiments suggested that this phenomenon involves the release of soluble factors and is increased by cellular contact between stroma and CLL B cells. Since CLL patients often present comorbidities such as osteoporosis and considering the diverse outcomes in both CLL disease progression and CLL response to treatment among patients, illustrating this phenomenon holds potential significance in driving additional investigations.

Bisphosphonates do not affect healing of a critical-size defect in estrogen-deficient mice

Bisphosphonates (BP) are anti-resorptive drugs that are widely used to prevent bone loss in osteoporosis. Since inhibition of bone resorption will cause a decrease in bone formation through a process called coupling, it is hypothesized that extended treatment protocols may impair bone healing. In this study, β-tri‑calcium-phosphate (βTCP) ceramics were inserted into critical-size long bone defects in estrogen-deficient mice under BP therapy. The study assessed the benefits of coating the ceramics with Bone Morphogenetic Protein-2 (BMP2) and an engineered BMP2 analogue (L51P) that inactivates BMP antagonists on the healing process, implant resorption, and bone formation.Female NMRI mice (11–12 weeks of age) were ovariectomized (OVX) or sham operated. Eight weeks later, after the manifestation of ovariectomy-induced osteoporotic bone changes, BP therapy with Alendronate (ALN) was commenced. After another five weeks, a femoral critical-size defect was generated, rigidly fixed, and βTCP-cylinders loaded with 0.25 μg or 2.5 μg BMP2, 2.5 μg L51P, and 0.25 μg BMP2/2.5 μg L51P, respectively, were inserted. Unloaded βTCP-cylinders were used as controls. Femora were collected six and twelve weeks post-implantation.Histological and micro-computer tomography (MicroCT) evaluation revealed that insertion of cylinders coated with 2.5 μg BMP2 accelerated fracture repair and induced significant bone formation compared to controls (unloaded cylinders or coated with 2.5 μg L51P, 0.25 μg BMP2) already six weeks post-implantation, independent of estrogen-deficiency and BP therapy. The simultaneous administration of BMP2 and L51P (0.25 μg BMP2/2.5 μg L51P) did not promote fracture healing six and twelve weeks post-implantation. Moreover, new bone formation within the critical-size defect was directly linked to the removal of the βTCP-implant in all experimental groups. No evidence was found that long-term therapy with ALN impaired the resorption of the implanted graft. However, osteoclast transcriptome signature was elevated in sham and OVX animals upon treatment with BP, with transcript levels being higher at six weeks than at twelve weeks post-surgery. Furthermore, the transcriptome profile of the developing repair tissue confirmed an accelerated repair process in animals treated with 2.5 μg BMP2 implants. L51P did not increase the bioefficacy of BMP2 in the applied defect model.The present study provides evidence that continuous administration of BP does not inhibit implant resorption and does not alter the kinetics of the healing process of critical-size long bone defects. Furthermore, the BMP2 variant L51P did not enhance the bioefficacy of BMP2 when applied simultaneously to the femoral critical-size defect in sham and OVX mice.

Assessing bone formation on hydrophilic and hydrophobic implant surfaces in a murine model treated with bisphosphonates.

To evaluate the osseointegration of implants with hydrophobic (HFB) and hydrophilic (HFL) surfaces in a murine model of high-dose bisphosphonates (BPs). Sixty-four rats were randomly allocated into four groups: control group with HFB implants (CG-HFB), control group with HFL implants (CG-HFL), BP group with HFB implants (BP-HFB), and BP group with HFL implants (BP-HFL). Animals were euthanized after 15 and 45 days (n=8). The dependent variables assessed were the removal torque (biomechanical analysis), the bone volume around the implants (%BV/TV) (microtomographic analysis), the bone-implant contact (%BIC), the bone between the threads (%BBT) (histomorphometric analysis), and the expression of bone metabolism markers (immunohistochemistry analysis). The CG-HFL and BP-HFL groups presented higher removal torque than the CG-HFB and BP-HFB implants. The %BIC of the CG-HFL surfaces was slightly higher than that of the CG-HFB implants. The BP-HFB and BP-HFL groups presented a higher %BIC than that of the CG-HFB and CG-HFL groups (p<0.001). BP therapy also increased the %BBT at both implant surfaces. Higher levels of ALP were observed in the matrix region of bone tissue on the HFL surfaces than on the HFB surfaces. Both surfaces enable osseointegration in rats under BP therapy. The study demonstrates that hydrophobic (HFB) and hydrophilic (HFL) implant surfaces can promote osseointegration in rats undergoing bisphosphonate therapy. The HFL surfaces exhibited improved biomechanical performance, higher bone-implant contact, and increased bone volume, suggesting their potential clinical relevance for implant success in individuals on bisphosphonate treatment.