Bisphosphonate Treatment Research Articles

Safety of therapy with and withdrawal from denosumab in fibrous dysplasia and McCune-Albright syndrome: an observational study

ABSTRACTDenosumab (Dmab) treatment can benefit patients with fibrous dysplasia/McCune‐Albright syndrome (FD/MAS) by suppressing the receptor activator of nuclear factor κB ligand (RANKL)‐mediated increased bone resorption. However, limited data of two pediatric cases indicate that a rebound phenomenon may occur after withdrawal. Therefore we studied the safety of Dmab discontinuation in FD/MAS. Thirty‐seven patients using Dmab, mostly after unsuccessful bisphosphonate (BP) treatment, were included. Health records were screened for pain scores, side effects, and bone turnover markers (BTMs) (calcium, alkaline phosphatase [ALP], procollagen 1 N‐terminal propeptide [P1NP], and β‐crosslaps [B‐CTX, also termed β–C‐terminal telopeptide]) during treatment, and for BTMs and clinical rebound effects after withdrawal. BTM levels after withdrawal were compared to pretreatment values. Data were calculated as median (interquartile range [IQR]). BTMs normalized in two‐thirds of patients and pain scores decreased significantly during treatment (p = 0.002). One patient (2.7%) developed osteonecrosis of the jaw. Sixteen patients discontinued Dmab treatment after a median of 1.6 years (IQR 1.0 years) because of insufficient effect on pain (n = 10, 63%), side effects (n = 4, 25%), or other reasons (n = 4, 25%). Follow‐up posttreatment was 3.2 (2.8) years, wherein no fractures, pain flares, or lesion progression occurred. Calcium remained normal in all but one patient, who had a mild asymptomatic hypercalcemia (2.73 mmol/L) 5 months after discontinuation. ALP passed pretreatment levels in five of 11 patients (46%), increased most after 6 months by 18 (43) U/L, and returned to baseline levels thereafter. P1NP exceeded pretreatment levels in four of nine patients (44%), CTX in eight of nine patients (89%). P1NP rose most after 3 months and stabilized thereafter. CTX showed the highest relative elevation. Patients with high pretreatment levels responding well to Dmab seemed to have the highest rebound. These results suggest beneficial effects of Dmab on pain and BTMs, and show a biochemical but asymptomatic rebound phenomenon after withdrawal in adults with FD/MAS, mainly in case of high pretreatment levels, good response, and multiple injections. Further studies on the safety of Dmab and withdrawal are needed and ongoing. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Longitudinal Changes of Circulating miRNAs During Bisphosphonate and Teriparatide Treatment in an Animal Model of Postmenopausal Osteoporosis.

ABSTRACTMicroRNAs regulate bone homeostasis, and circulating microRNAs have been proposed as novel bone biomarkers. The effect of anti‐osteoporotic treatment on circulating microRNAs has not been described in detail. Therefore, we performed a comprehensive analysis of microRNA serum levels in ovariectomized (OVX) and sham‐operated (SHAM) rats over 12 weeks of antiresorptive or osteoanabolic treatment. Forty‐two Sprague Dawley rats underwent SHAM surgery (n = 10) or ovariectomy (n = 32). After 8 weeks, OVX rats were randomized to antiresorptive treatment with zoledronate (n = 11), osteoanabolic treatment with teriparatide (n = 11), or vehicle treatment (n = 10). Serum samples were collected at weeks 8, 12, 16, and 20 after surgery. A total of 91 microRNAs were analyzed by RT‐qPCR in serum samples collected at week 20. Based on the results, 29 microRNAs were selected for longitudinal analysis at all four study time points. Changes in bone mineral density and microstructure were followed up by in vivo micro‐CT and ex vivo nano‐CT. Ovariectomy resulted in the loss of trabecular bone, which was reversed by osteoanabolic and antiresorptive treatment. Differential expression analysis identified 11 circulating miRNAs that were significantly regulated after treatment. For example, miR‐107 and miR‐31‐5p increased in vehicle‐treated OVX animals, whereas they decreased during teriparatide treatment. Additional miRNAs were identified that showed significant correlations to bone microstructure or bone miRNA expression, including miR‐203a‐3p, which exhibited a significant negative correlation to vertebral and tibial trabecular bone volume fraction (%). Longitudinal analysis confirmed eight microRNAs with significant changes in serum over time that were prevented by teriparatide and zoledronate treatment (miR‐34a‐5p, miR‐31‐5p, miR‐30d‐3p, miR‐378a‐5p) or teriparatide treatment only (miR‐375‐3p, miR‐183‐5p, miR‐203a‐3p, miR‐203b‐3p). Gene target network analysis identified WNT and Notch signaling as the main signaling pathways controlled by these miRNAs. Thus, ovariectomy results in time‐dependent deregulation of circulating miRNAs compared with SHAM animals. Anti‐osteoporotic treatments can rescue this effect, showing that bone‐related miRNAs might act as novel biomarkers for treatment monitoring. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

PMS12 Cost-Effectiveness of Binosto (BUFFERED SOLUBLE ALENDRONATE 70 MG) Effervescent Tablet for the Treatment of Postmenopausal Women with Osteoporosis in Italy

Binosto® (buffered soluble alendronate 70 mg) effervescent tablet represents an alternative option to traditional oral bisphosphonates for the management of osteoporosis, being associated to a lower frequency of gastro-intestinal adverse reactions and greater medication persistence. This study aimed to assess the cost-effectiveness of Binosto® compared with relevant alternative treatments for postmenopausal osteoporotic women in Italy. A previously validated Markov microsimulation model was adjusted to the Italian healthcare setting to estimate the lifetime costs (expressed in €2019) per quality-adjusted life-years (QALY) of Binosto® compared with generic alendronate, denosumab, zoledronic acid and no treatment. Pooled efficacy data for bisphosphonates derived from the most recent NICE network meta-analysis were used for bisphosphonate treatments and 1-year persistence of Binosto® and alendronate was derived from a prospective observational study. Analyses were conducted for high-risk women 60-80 years of age with a bone mineral density (BMD) T-score ≤-3.0 or with existing vertebral fractures. One-way and probabilistic sensitivity analyses were performed to test the robustness of the model results. In all simulated populations, Binosto® was dominant (more QALYs, less costs) compared to denosumab. The cost per QALY gained of Binosto® compared to generic alendronate and no treatment always fall below €20,000 per QALY gained. Zoledronic acid was associated with more QALY than Binosto® but the cost per QALY gained of zoledronic acid compared with Binosto® was always higher than €70,000 per QALY gained, meaning that zoledronic acid was not cost-effective. Probabilistic sensitivity analyses suggested that Binosto® was the most cost-effective intervention for willingness to pay between €5,000 and €75,000 per QALY gained. This study provides the first economic analysis of an alendronate effervescent tablet, suggesting that Binosto® represents a cost-effective strategy compared with relevant alternative treatments for postmenopausal women with osteoporosis in Italy aged 60 years and over.

Treatment strategy for atypical ulnar fracture due to severely suppressed bone turnover caused by long-term bisphosphonate therapy: a case report and literature review

BackgroundAtypical fractures may occur due to the combined effect of severely suppressed bone turnover (SSBT) caused by long-term bisphosphonate treatment and chronic repetitive bone microdamage. Atypical fracture of the ulna due to SSBT is a rare entity; there is no standardized treatment strategy for this condition. We successfully treated a patient with atypical fracture of the ulna. Herein, we present this patient, review the relevant literature, and discuss the treatment strategy.Case presentationAn 84-year-old woman presented with atypical fracture of the left ulnar shaft due to SSBT. She had a history of bisphosphonate therapy (ibandronate and alendronate) since more than 10 years; her bone turnover was severely suppressed. We performed open reduction and internal fixation (ORIF) using dual plate with some additional treatments. These included drilling and decortication, use of autogenous bone graft, low-intensity pulsed ultrasound (LIPUS) treatment, and administration of teriparatide. Finally, bone union was observed at 11 months after surgery.ConclusionsBased on the literature review and our experience with this case, ORIF alone may not be adequate to achieve bone union; drilling, decortication, and use of cancellus bone graft is important to achieve favorable outcomes. Administration of teriparatide and LIPUS may facilitate early bone union, although further studies are required to provide more definitive evidence. Furthermore, ORIF using dual plate may help avoid implant failure owing to the long time required for bone union.

Duration-Dependent Increase of Human Bone Matrix Mineralization in Long-Term Bisphosphonate Users with Atypical Femur Fracture.

Bisphosphonates (BPs) are the most widely used drugs for the treatment of osteoporosis but prolonged use of BPs might increase the risk of atypical femur fracture (AFF). There are only a few studies that address the bone material quality in patients on long-term BP treatment with or without AFFs. We analyzed 52 trans-iliac bone biopsies from patients on long-term BP therapy with (n=26) and without (n=26) AFF. At the microscopic level, the degree of mineralization of bone (DMB) was assessed on whole bone by X-ray digitized microradiography while microhardness by Vickers microindentation, and bone matrix characteristics by Fourier transform infrared microspectroscopy (FTIRM) (mineral/organic ratio, mineral maturity and crystallinity, and collagen maturity) were measured at random focal areas. The AFF patients were treated longer than non-AFF patients (9.7 ± 3.3 years versus 7.9 ± 2.7 years). As expected, bone remodeling was low in both groups, without difference between them. The AFF group had significantly higher DMB in cortical bone (+2.9%, p=.001), which remained so after adjusting for treatment duration (p=.007), and showed a trend in cancellous bone (+1.6%, p=.05). Consistent with higher DMB, heterogeneity index (HI) was lower in the AFF than in the non-AFF group, illustrating lower heterogeneity of mineralization in the AFF group. A significant positive correlation between the duration of treatment and DMB in cortical bone was found in AFF, and not in the non-AFF group. Microhardness and bone matrix characteristics were similar between groups. We conclude that the AFF group had a duration-dependent increase in DMB leading to a significantly higher DMB than the non-AFF. Because BPs have high affinity to bone mineral and lining the walls of the osteocyte lacunae, the accumulation of matrix-bound BPs in AFF could lead to inhibition of the osteocyte cytoskeleton blunting their response to mechanical strains, a hypothesis to be further investigated. © 2021 American Society for Bone and Mineral Research (ASBMR).

Clinical features, treatments and outcomes of calcinosis in adult patients with dermatomyositis: a single cohort study.

The occurrence of calcinosis cutis as a clinical feature of dermatomyositis in adult patients is not well understood. Cohort studies of adult patients with calcinosis are rare. We systematically describe the clinical features, treatments and outcomes of adult patients with calcinosis. We initially enrolled 627 adult DM patients. Of those enrolled, 35 (5.6%) were found to have calcinosis. We analysed the clinical features associated with calcinosis in this subgroup. The risk factors associated with calcinosis were analysed using the Poisson regression model. Multivariate analysis showed that a younger age at disease onset [odds ratio (OR) = 0.945, 95% CI 0.925, 0.966, P < 0.001], dysphagia (OR = 2.609, 95% CI 1.189, 5.728, P = 0.017), skin ulcer (OR = 5.705, 95% CI 3.041, 10.705, P < 0.001) and the presence of anti-nuclear matrix protein 2 antibody (OR = 5.917, 95% CI 2.754, 12.714, P < 0.001) were independently associated with calcinosis. In both the low- and high-dose prednisone treatment groups, no difference in treatment response was seen between the bisphosphonate treatment group and the group not receiving bisphosphonate treatment (P = 1.000 and P = 0.375, respectively). A follow-up study revealed that the mortality rate of the calcinosis group was 5.7%. Additionally, 60.6% of the cases had a chronic polycyclic disease course and 17.1% had mild complications secondary to calcinosis. Calcinosis is an uncommon, but significant clinical feature in adult patients with DM. Bisphosphonates were not found to effectively treat calcinosis, however, the overall health outcomes of adult DM patients with calcinosis were favourable.

Tooth extraction in mice administered zoledronate increases inflammatory cytokine levels and promotes osteonecrosis of the jaw.

Osteonecrosis of the jaw (ONJ) occurring after invasive dental treatment often adversely affects patients' activities of daily living. Long-term administration of strong anti-bone resorptive agents such as bisphosphonates prior to invasive dental treatment is considered an ONJ risk factor; however, pathological mechanisms underlying ONJ development remain unclear. We developed an ONJ mouse model in which a tooth is extracted during treatment with the bisphosphonate zoledronate. We observed induction of apoptosis in osteocytes, resulting in formation of empty lacunae in jaw bones at sites of tooth extraction but not in other bones of the same mice. We also observed elevated levels of inflammatory cytokines such as TNFα, IL-6 and IL-1 in jaw bone at the extraction site relative to other sites in zoledronate-treated mice. We also report that treatment in vitro with either zoledronate or an extract from Porphyromonas gingivalis, an oral bacteria, promotes expression of inflammatory cytokines in osteoclast progenitor cells. We demonstrate that gene-targeting of either TNFα, IL-6 or IL-1 or treatment with etanercept, a TNFα inhibitor, or a neutralizing antibody against IL-6 can antagonize ONJ development caused by combined tooth extraction and zoledronate treatment. Taken together, the cytokine storm induced by invasive dental treatment under bisphosphonate treatment promotes ONJ development due to elevated levels of inflammatory cytokine-producing cells. Our work identifies novel targets potentially useful to prevent ONJ.

Mandibular involvement in SAPHO syndrome: a retrospective study

BackgroundMandible osteomyelitis can occur in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, a rare chronic inflammatory disease; however, few studies have explored its characteristics and management.MethodsWe reviewed the medical records of consecutive SAPHO patients with mandible involvement diagnosed in Peking Union Medical College Hospital from September 2014 to July 2019. Demographic, clinical, laboratory, and imaging data were collected at baseline. Prescription data and follow-up magnetic resonance imaging (MRI) and cone beam computed tomography (CBCT) images were collected from the hospital information system. An electronic questionnaire was distributed to all patients to obtain their latest symptoms.ResultsA total of 26 SAPHO patients with mandibular involvement were involved, all of whom responded to the questionnaire (38.5% male; median age, 28 years; median follow-up duration, 2.1 years). Ten patients (38.5%) had undergone an oral procedure 1 month before the onset of mandibular symptoms. All 14 of the patients who underwent a surgical intervention relapsed within a median duration of 2 months (range 0.25–4.0 months), and 24 patients (92.3%) achieved improvement with conservative treatment. Following bisphosphonate treatment, remission of bone marrow oedema and osteolysis was observed on MRI and CBCT, and 5 patients receiving bisphosphonates with follow-up CBCT after remission did not relapse in 5.4 months (mean 6.0, range 3.2–9.9 months).ConclusionMandibular involvement of SAPHO syndrome predominantly occurs in young women. Dental procedures are a possible risk factor. Conservative treatment, especially intravenous bisphosphonates, can lead to oral improvement.

Effects of bisphosphonate and calcium carbonate on normal aortic valve and cholecalciferol induced in vivo rabbit aortic stenosis model

Abstract Background Calcific aortic valve disease (CAVD) is the most common valvular heart disease. Bisphosphonates are stable analogs of pyrophosphates and commonly prescribed in the treatment of osteoporosis. The effects of bisphosphonate treatment on CAVD are not clearly known and there are inconsistent results. Similarly, the effect of calcium supplementation on CAVD remains controversial. Purpose The aim of this study was to assess the effects of bisphosphonate therapy on the normal aortic valve and vitamin D induced in vivo rabbit aortic stenosis (AS) model. Methods The impact of calcium supplementation on the rabbit AS model was also evaluated. A total of 30 New Zealand white rabbits were divided into five equal groups: no treatment (Group I); 25,000 IU/day vitamin D3 (cholecalciferol) (Group II, rabbit AS model); 25,000 IU/day cholecalciferol plus 2500 mg/day calcium carbonate (Group III); 20 μg/kg/week intravenous alendronate (Group IV) and 25,000 IU/day cholecalciferol plus 2500 mg/day calcium carbonate plus 20μg/kg/week alendronate (Group V). Echocardiography was performed at baseline and after 12 weeks of treatment. The left ventricular mass index (LVMI), aortic valve area (AVA), transvalvular velocities and gradients were recorded. Radiologic and histopathologic examination was performed at the end of the 12th week. Control animals displayed no abnormalities of the aortic valve. Results There was no echocardiographic change in Group IV. In Groups II, III and V, there was a significant decrease in AVA and increases in transvalvular velocities and gradients. However, these stenotic changes were significantly prominent in Group V (p=0.001 for all, via repeated measures ANOVA). Moreover, LVMI was only increased in Group V (p&amp;lt;0.05). Calcification of aortic valvar complex was detected in 14 (46.7%) cases by radiologic imaging and 10 (33.3%) cases by histopathologic examination. Most frequent calcification was found in Group V (5 for each method, 83.3%). Agatston, volume and equivalent mass scores of calcific foci in Group V were significantly higher than other groups (p&amp;lt;0.05 for all). There was no significant difference between groups regarding with presence of osteoclasts in calcific foci. Conclusion Calcium supplementation has no effect on the in vivo rabbit AS model. Alendronate treatment aggravates the stenosis and increases the calcification in the rabbit AS model. Alendronate treatment has no effect on the normal valve in which there was no osteogenesis and osteoclastogenesis. Based on these findings, in patients with CAVD, alendronate treatment should be given with regular echocardiographic follow-up or may not be preferred. Central figure Funding Acknowledgement Type of funding source: None

Acceptability of bisphosphonates among patients, clinicians and managers: a systematic review and framework synthesis

ObjectiveTo explore the acceptability of different bisphosphonate regimens for the treatment of osteoporosis among patients, clinicians and managers, payers and academics.DesignA systematic review of primary qualitative studies. Seven databases were...

As fraturas associadas aos bifosfonatos demoram mais para cicatrizar?

Introdução: Os bisfosfonatos evoluíram como a base para o tratamento da osteoporose, reduzindo a incidência de fraturas. Recentemente, várias publicações descreveram a ocorrência de fraturas de fêmur atípicas de baixa energia associadas ao uso de bifosfonatos. O objetivo deste estudo foi avaliar o tempo médio de cicatrização de fraturas atípicas de fêmur associadas ao tratamento com bifosfonatos em comparação com um grupo controle. &#x0D; Materiais e métodos: Avaliamos retrospectivamente 34 mulheres (idade média de 74 anos) com fraturas atípicas; 16 deles haviam recebido bisfosfonatos por pelo menos cinco anos. Foram tratados entre 2006 e 2017 e estabilizados com haste cefalomedular. Este grupo foi comparado a um grupo controle com características semelhantes. &#x0D; Resultados: Vinte e dois tiveram fraturas subtrocantéricas e 12 tiveram fraturas diafisárias. 14% daqueles que tomaram bifosfonatos e foram submetidos à cirurgia necessitaram de uma revisão em comparação com 5,5% do grupo de controle. O tempo médio de consolidação foi maior nos tratados com bifosfonatos (8,5 vs. 6 meses), com diferença estatisticamente significativa (p &lt;0,001).&#x0D; Conclusões:O benefício do tratamento com bisfosfonatos na prevenção de fraturas é maior do que o risco de fraturas atípicas; entretanto, é importante avaliar a relação risco-benefício de cada paciente no início e durante o tratamento, lembrando que, apesar disso, o tempo de cicatrização é maior.

Risk factors for medication-related osteonecrosis of the jaw and salivary IL-6 IN cancer patients

IntroductionMedication-related osteonecrosis of the jaws is a severe complication of the use of antiresorptive and antiangiogenic therapy, with limited treatment options and great impact on patient’s quality pf life. ObjectiveThe aim of this study was to assess the risk factors associated with medication-related osteonecrosis of the jaws in oncologic patients undergoing bisphosphonate treatment. In addition, salivary levels of interleukin-6, IL-6, were measured to investigate their association with severity and risk of medication-related osteonecrosis of the jaws. MethodsCase-control study with 74 patients with bone metastases from solid tumors and multiple myeloma was included. Patients were divided into three groups: 1) those undergoing bisphosphonate treatment with medication-related osteonecrosis of the jaws; 2) those undergoing bisphosphonate without medication-related osteonecrosis of the jaws; and 3) those with bisphosphonate pretreatment. The demographic and medical data of the patients were collected to assess risk. The clinical evaluation was performed to diagnose medication-related osteonecrosis of the jaws and unstimulated saliva was collected for quantification of IL-6. ResultsAs result, it was observed that patients diagnosed with medication-related osteonecrosis of the jaws were submitted to higher number of bisphosphonate doses (p = 0.001) and monthly infusion protocol (p = 0.044; OR = 7.75). Patients who did not have routine followup with specialized dentists during therapy with bisphosphonate and smoking were associated with medication-related osteonecrosis of the jaws (p = 0.019; OR = 8.25 and p = 0.031; OR = 9.37 respectively). Group 1 had a higher frequency of treatment with chemotherapy and corticosteroids concomitant with bisphosphonate, and surgical dental procedures (p = 0.129). Salivary IL-6 levels showed no statistically significant difference between the groups (p = 0.571) or association with medication-related osteonecrosis of the jaws severity (p = 0.923). ConclusionA higher number of bisphosphonate cycles, monthly infusion protocol, no dental follow-up for oral health maintenance and smoking were associated with medication-related osteonecrosis of the jaws. Specialized dental follow up during bisphosphonate treatment has been shown to be an important factor in preventing this complication.

Bisphosphonates in veterinary medicine: The new horizon for use.

Bisphosphonates (BPs) are characterized by their ability to bind strongly to bone mineral and inhibit bone resorption. However, BPs exert a wide range of pharmacological activities beyond the inhibition of bone resorption, including the inhibition of cancer cell metastases and angiogenesis and the inhibition of proliferation and apoptosis in vitro. Additionally, the inhibition of matrix metalloproteinase activity, altered cytokine and growth factor expression, as well as reductions in parameters of pain have also been reported. In humans, clinical BP use has transformed the treatment of post-menopausal osteoporosis, rare bone diseases such as osteogenesis imperfecta, as well as multiple myeloma and metastatic breast and prostate cancer, albeit not without infrequent but significant adverse events. Despite the well-characterized health benefits of BP use in humans, the evidence-base for the therapeutic efficacy of BPs in veterinary medicine is, by comparison, limited. Notwithstanding, BPs are used widely in small animal veterinary practice for the medical management of hyperparathyroidism, idiopathic hypercalcemia in cats, as well as for the palliative care of bone tumors which are common in dogs, and in particular, primary bone tumors such as osteosarcoma. Palliative BP treatment has also recently increased in veterinary oncology to alleviate tumor-associated bone pain. In equine veterinary practice, non-nitrogen-containing BPs are FDA-approved to control clinical signs associated with navicular syndrome in adult horses. However, there are growing concerns regarding the off-label use of BPs in juvenile horses. Here we discuss the current understanding of the strengths, weaknesses and current controversies surrounding BP use in veterinary medicine to highlight the future utility of these potentially beneficial drugs.

Risk factors for atypical forearm fractures associated with bisphosphonate usage.

The purpose of this study was to find the diagnostic factors for atypical forearm fractures additional to atypical femur fractures, via a retrospective case-control study. Thus, our authors performed a complete enumeration survey for patients under the treatment of bisphosphonate (BP). We identified 53 patients that met the following inclusion criteria between March 2009 and February 2019: a BP therapy history or ongoing administration of at least 1 year, presence of simple radiographs of bilateral femurs and forearms, and availability of complete medical records and radiological data. The patients were divided into two groups: those with any lesion of atypical fractures of ulna or radius, regardless of the displacement of at least one side extremity in simple radiographs (group 1, 20 patients); and those without any lesions of pathognomonic finding or fractures in either forearm in simple radiographs (group 2, 33 patients). Univariate analyses of basic demographic characteristic such as age, smoking, comorbidity of diabetes mellitus or any connective tissue disease needing steroid treatment, and BMD showed no significant differences between the groups (P>0.05). The co-morbidity of malignant cancer inevitably needing BP usage was not different between the two groups. Multivariate analyses of the several variables that differed significantly between the two groups in univariate analyses demonstrated that total period and single prescribing physician/surgeon were significantly associated with forearm fractures. A cut-off value of 65 months for the total period predicted the presence atypical forearm fractures. Atypical forearm fractures are probably more common than reported in the literature to date, and all forearm lesions were accompanied by preceding atypical femur fractures. The period of BP administration had the main effect on the occurrence of atypical forearm fractures, particularly if more than 65 months. Also, the prescription by multiple physician was predicting factor for forearms lesion additionally to AFFs, however, more evidence-based study is needed to understand the effects of cancer-related BP usage on the forearm. Level III, retrospective case-control study.

Antimicrobial peptide gene expression in medication-related osteonecrosis of the jaw

Bisphosphonates and denosumab are commonly used antiresorptive therapies in patients with bone metastasis and osteoporosis. Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect of these drugs, and infection has been recognized as a contributing factor. Current therapeutic options for MRONJ show limited effectiveness, therefore necessitating novel treatment strategies. Bisphosphonates have recently been reported to induce the expression of antimicrobial peptides (AMPs), an inherent component of the immune system. Therefore, the aim of the present study was to investigate and compare the influence of the anti-RANKL antibody denosumab and bisphosphonates on the gene expression of selected AMPs: human α-defensin-1, human α-defensin-3, human β-defensin-1, and human β-defensin-3. Bone specimens were collected from patients with MRONJ who had been treated with bisphosphonates (n = 6) or denosumab (n = 6), and from healthy subjects (n = 6) with no history of treatment with bone metabolism-influencing drugs. Reverse transcription-quantitative polymerase chain reaction was used to quantify the expression levels of selected AMPs. Samples from patients treated with denosumab showed significantly higher mRNA expression of human α-defensin-3 and human β-defensin-3 than those from healthy subjects. This finding is similar to previously described upregulated expression of human defensins in patients with MRONJ after bisphosphonates treatment. This suggests that the elevated expression of defensins may be at least a part of the mechanism underlying the pathogenesis of osteonecrosis induced by antiresorptive therapies, which can serve as a new target for potential treatment of MRONJ.

Root canal treatment of compromised teeth as alternative treatment for patients receiving bisphosphonates: 60-month results of a prospective clinical study.

This 60-month prospective study aimed to evaluate tooth survival and healing rates after root canal treatment in patients taking bisphosphonates (BPs). Secondary outcomes were complications and clinical variables observed during and after treatment. Root canal treatment was performed using manual K-file canal instrumentation and a carrier-based filling technique with an epoxy resin-based sealer. Teeth without adequate root/crown integrity were restored by trained operators at the tissue level (TL group) to prevent occlusal/mechanical stress and to enable periapical lesion healing without the risk of root fracture. Other teeth were restored with normal occlusal contacts (OC group). Healthy patients who had undergone one or more root canal treatments of the same type constituted the control group. The relationships of the following variables to survival and health status were examined (chi-squared test and multivariate analysis, P=0.05): age, gender, smoking habit, tooth location, treatment type, BPs treatment, BPs exposure, initial periapical index (PAI) and occlusal restoration. Survival curves were constructed using Kaplan-Meier analysis, with extraction serving as the end-point. In total, 65 patients with 109 root canal-treated teeth who were taking BPs were included. At 60months, data from 57 patients (52F, 5M; median age 65.7±8.6years) who had undergone 96 root canal treatments were analysed (drop-out rate=16.9%). The survival rate was 85%, and the success rate was 76%. The control group consisted of 46 patients (21F, 25M; median age 60.3±7.2years) who had undergone 102 root canal treatments. The survival rate was 88%, with 12 teeth lost during follow-up. The success rate was 73%. In the BP group, 55 teeth were restored normally (OC group) and 41 teeth were restored at the tissue level (TL group). No difference in the success or survival rate was observed between the BP and control groups (P>0.05). Univariate Kaplan-Meier analysis revealed that only tooth type significantly affected survival status in the BP group. The analysis revealed the clinical relevance of smoking, tooth location and initial PAI on patients' health status (P<0.05). Root canal treatments and post-endodontic restoration with tissue-level filling procedures represent a safe approach for severely damaged teeth in patients receiving BPs having comparable results to root filled teeth restored with occlusal contacts and to the control group.

Femoral Bowing and Femoral Neck-Shaft Angle Evaluation Can Reduce Atypical Femoral Fractures in Osteoporotic Patients: A Scientific Report.

Bisphosphonates (BPs) are the mainstay of osteoporosis treatment due to their safety and efficacy. There is evidence that BPs medication may be complicated by atypical femoral fractures (AFFs). Prolonged administration of BPs is even more strongly associated with AFFs. AFF is a relatively rare complication of BPs when taking into account the huge population worldwide that benefits from this pharmacotherapy. AFF is, however, a serious complication of BPs treatment, which includes prolonged healing time and high revision rate when operative treatment is required. Less frequently, AFFs occur even without BPs administration, while these fractures have all the characteristics of “stress” or “insufficiency” fractures. The critical point of view in AFFs pathogenesis seems to be not only the biology of cortical bone, but also the mechanical issue. It has been proven that BPs, glucocorticoids and proton pump inhibitors (PPIs) can cause bone turnover suppression and affect the biological parameter of AFFs pathogenesis. Specific mechanical femoral bone properties predispose to AFFs pathogenesis. Several studies have already reported that increased femoral bowing > 5.250 degrees or decreased femoral neck-shaft angle <125 degrees, are associated with increased risk for diaphyseal and subtrochanteric AFFs respectively, regardless of BPs uptake. If these two parameters are simultaneously present, the probability for AFFs occurrence increases dramatically. Our scientific report, which is based on the current evidence about AFFs, is that if both femoral bowing angle and femoral neck-shaft angle are evaluated before BPs administration, this intervention may reduce the incidence of AFFs. Thus, in cases with excessive lateral femoral shaft bowing or very small femoral neck-shaft angle, the prescription of another anti-osteoporotic treatment than BPs should be recommended. If, however, BPs can’t be avoided, clinicians should be aware of the fact that long-term administration may be implicated with AFFs occurrence. In these cases, short term BPs administration with timely drug holiday between three and five years may be reasonable. Finally, roentgenographic evaluation of both femurs every six months and medical reference in case of any emerging thigh pain are also logical interventions to prevent and reduce AFFs.

A Review on the Role of Denosumab in Fracture Prevention.

Denosumab is a receptor activator of nuclear factor kappa-Β ligand inhibitor, which suppresses the bone resorption process to preserve bone mass. It is usually recommended to postmenopausal women and men with high fracture risk. With the recent publication of the results from FREEDOM study and its extension, the long-term effect of denosumab in preventing fragility fractures has been put forward. This review aims at summarising the evidence of denosumab in reducing fracture risk and its safety derived from clinical studies. Most of the evidence are derived from FREEDOM trials up to 10 years of exposure. Denosumab is reported to prevent vertebral and non-vertebral fractures. It is also proven effective in Japanese women, patients with chronic kidney diseases and breast cancer patients receiving antineoplastic therapy. Denosumab discontinuation leads to high remodeling, loss of bone mineral density and increased fracture risk. These negative effects might be preventable by bisphosphonate treatment. The safety profile of denosumab is consistent with increased years of exposure. In conclusion, denosumab is a safe and effective option for reducing fracture risk among patients with osteoporosis.

Characteristics of micro-fracture healing events in trabecular bone (microcalli) from human vertebrae remain unaffected by bisphosphonate treatment

Characteristics of micro-fracture healing events in trabecular bone (microcalli) from human vertebrae remain unaffected by bisphosphonate treatment

Paget's disease of bone-acurrent review of clinical aspects, diagnostics and treatment

Paget's disease is amonostotic or polyostotic progressive skeletal disease with a genetic predisposition. The affected bone areas show osseous swelling and often grotesque deformation, chronic pain and fractures. Many cases are asymptomatic for along time resulting in alate diagnosis. The pathogenesis is still unknown. In addition to agenetic predisposition, viral factors are also discussed. Laboratory tests and imaging are used for diagnosis. The effective principle of medicinal bisphosphonate treatment is to inhibit osteoclastic bone resorption and should be initiated early to prevent secondary complications. This article presents the current knowledge about this rare osteological disease.