High Doses Of Bisphosphonates Research Articles

Acute Tubular Necrosis Attributed to High-Dose Everolimus with High-Potency Bisphosphonates for Advanced Breast Cancer – A Case Report

Introduction: Everolimus (EVR)-induced kidney injury is rarely reported. Conversely, acute tubular necrosis (ATN) is a recognized complication of high-dose bisphosphonate therapy. Case presentation: SM, a 69-year-old female patient with advanced breast cancer, who developed severe kidney injury necessitating renal replacement therapy (RRT) shortly after initiating EVR treatment, while concurrently receiving chronic high-potency bisphosphonate therapy. Kidney biopsy confirmed ATN. Upon discontinuation of both EVR and bisphosphonates, her renal function gradually improved over several months, leading to the cessation of RRT. At a two-year follow-up, her kidney function has returned to baseline. Conclusion: In this case report, we outline the patient's clinical course and provide a pathophysiological rationale for the synergistic effect of EVR and bisphosphonates in promoting ATN. With the increasing use of EVR in various oncologic indications, we emphasize the reversible nature of this kidney injury and stress the importance of timely recognition and intervention.

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.

Weight-Based Bisphosphonate Administration for Multiple Myeloma Patients and the Risks of Skeletal Complications

High-dose bisphosphonate for multiple myeloma patients might elevate risks of skeletal complications earlier than general expectations. This study aims to find incidences of atypical femoral fracture (AFF) and medication-related osteonecrosis of the jaw (MRONJ), elucidate their risk factors, and suggest cut-off values for the safer dosing of high-dose bisphosphonate treatment. By using the clinical data warehouse of a single institute, retrospective cohort data of multiple myeloma-diagnosed patients with high-dose bisphosphonate (pamidronate or zoledronate) treatment from 2009 to 2019 was extracted. Among 644 patients, the incidence of prominent AFF requiring surgery was 0.93% (6/644) and MRONJ was diagnosed in 11.8% (76/644) of the study population. For both AFF and MRONJ, the total potency-weighted sum of total dose per body weight (OR = 1.010, p = 0.005) were significant on logistic regression. Cutoffs of the potency-weighted total dose (mg) per body weight (kg) for AFF and MRONJ were 77.00 and 57.70 mg/kg, respectively. After roughly one year of treatment with high-dose zoledronate (about four years for pamidronate), an earlier thorough re-evaluation of skeletal complications should be taken. Body weight adjustments for accumulative dose calculation in terms of permissible dosing should be taken into consideration.

A nested case-control study of factors contributing to the development of medication-related osteonecrosis of the jaw in patients using bone resorption inhibitors in Mishima City

Medication-related osteonecrosis of the jaw (MRONJ) is characterized by necrosis of the jawbone with intraoral bacterial infection and has a significant negative impact on oral health-related quality of life. Risk factors for the onset are unknown, and definitive therapeutic approaches have not yet been defined. A case-control study at a single institution in Mishima City was conducted. The purpose of this study was to examine in detail the factors that contribute to the development of MRONJ. Medical records of MRONJ patients who visited Mishima Dental Center, Nihon University School of Dentistry, during the period 2015-2021 were extracted. Counter-matched sampling design was used to select participants matched for sex, age, and smoking for this nested case-control study. The incidence factors were statistically examined by logistic regression analysis. Twelve MRONJ patients were used as cases and 32 controls were matched. After adjustment for potential confounders, injectable bisphosphonates (aOR = 24.5; 95% CI = 1.05, 575.0; P < 0.05) were significantly associated with the development of MRONJ. High-dose bisphosphonates may be a risk factor for the development of MRONJ. Patients who use these products require careful prophylactic dental treatment against inflammatory diseases, and dentists and physicians should maintain close communication.

Adherence of bisphosphonate and decreased risk of clinical vertebral fracture in osteoporotic patients: A propensity score matching analysis

ObjectivesBisphosphonate is associated with a decreased risk of vertebral fractures due to osteoporosis. However, there are limited studies on how poor compliance with bisphosphonate affects the risk of vertebral fractures in a nationwide cohort. We aim to evaluate whether adherence to bisphosphonate affects the risk of fracture in osteoporosis patients.MethodsWe used the data of the Korean National Health Insurance Service Senior Cohort. A total of 33,315 (medication possession ratio [MPR]: 50) osteoporosis patients were matched using the propensity score matching method: those who received low-dose bisphosphonate and those who received high-dose bisphosphonate. Twenty-two confounding variables, including age, socioeconomic status, medications prescribed, and underlying diseases that may affect the risk of fracture were adjusted for propensity score matching. The risk of vertebral fracture was assessed by Cox proportional hazards regression.ResultsPatients with a higher MPR showed a decreased vertebral fracture risk than those with a lower MPR (MPR 50 = hazard ratio [HR] 0.909; 95% confidence interval [CI] 0.877–0.942 P < 0.001; MPR 70 = HR: 0.874, 95% CI: 0.838–0.913, P < 0.001; MPR 90 = HR: 0.822, 95% CI: 0.780–0.866, P < 0.001). MPR was associated with a decreased vertebral fracture risk in both groups with or without history of fracture. In the subgroup analysis, MPR was associated with a decreased vertebral fracture risk in women, in all ages, with or without T2DM, and with or without hypertension.ConclusionsHigher MPR is associated with a lower vertebral fracture risk.

Zoledronic Acid Deteriorates Soft and Hard Tissue Healing of Murine Tooth Extraction Sockets in a Dose-Dependent Manner.

The pathophysiology, histopathology, and immunopathology of bisphosphonate-related osteonecrosis of the jaw (BRONJ) Stage 0 remain unclear. The aim of this study was to investigate the effects of high-dose bisphosphonates on tooth extraction socket healing by creating a murine model of BRONJ Stage 0-like lesions using 8-week-old female C57BL/6J mice. Zoledronic acid (Zol) was administered subcutaneously twice a week for 7weeks at doses of 0.1mg/kg/week (moderate dose; Zol-M), 0.5mg/kg/week (high dose; Zol-H1), and 1.0mg/kg/week (higher dose; Zol-H2). Saline was used as a control (VC). Both maxillary first molars were extracted 3weeks after drug treatment. Maxillae, long bones, and sera were collected 4weeks post-extraction (n = 7 mice/group). Microcomputed tomography, histological, immunohistochemical, and ELISA analyses were performed. A ceiling effect for Zol was noted at the Zol-H1 dose. Osseous healing of extraction sites was significantly impaired with increased necrotic bone and the number of empty lacunae in a Zol dose-dependent manner. Zol significantly decreased epithelial thickness, due to a decrease in thickness of the stratum spinosum, in both Zol-H1 and Zol-H2. Both Zol-H1 and Zol-H2 significantly suppressed the distribution of F4/80+ macrophages in the connective tissue of tooth extraction sockets, although gross healing appeared to be normal. Intriguingly, both Zol-H1 and Zol-H2 significantly increased the numbers of TRAP+ mononuclear cells and detached osteoclasts in the connective tissue and bone marrow of extraction sites compared to VC and Zol-M, correlated with serum TRAcP5b levels. The created murine model of BRONJ Stage 0-like lesions becoming more severe in a dose-dependent manner may help to understand the pathophysiology and histopathology of BRONJ Stage 0 in humans.

Influence of Medical and Geriatric Factors on Implant Success: An Overview of Systematic Reviews.

To provide an overview of the influence of medical and geriatric factors on implant survival in order to form clinical recommendations for the practitioner. This narrative literature review was performed to address the following questions: (1) Is age (> 75 years) a risk factor for implant survival?; (2) Is diabetes mellitus a risk factor for implant survival?; and (3) Is antiresorptive therapy a risk factor for implant survival? The PubMed, Web of Knowledge (Thomson Reuters), and Google Scholar databases were searched for systematic reviews and research papers of evidence level II and above that were published up to February 2019 for each topic. (1) Age > 75 years does not affect implant survival according to short-term follow up (1 to 5 years). However, polypharmacy should be considered in this patient group. (2) Diabetes mellitus is not a risk factor for implant survival in the short term, but there is no information on appropriate perioperative treatment and wound closure. There is little evidence in the literature on the success of bone grafting and progressive loading protocols in diabetic patients. (3) Implant therapy cannot be recommended in patients under high-dose bisphosphonate and antibody therapy. Bone grafting should be avoided under antiresorptive therapy. There are no treatment regimens available for patients with peri-implantitis receiving antiresorptive medication. This review suggests that the risk assessment for an implant patient should not be based on age, but rather on the patient's specific risk factors, such as former and current diseases and medication.

Abstract P2-18-02: Fractures in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG S0307 trial (ClinicalTrials.gov Identifier: NCT00127205)

Abstract Background: Evidence from randomized trials, including a recent meta-analysis, suggests that adjuvant bisphosphonates can decrease recurrence and death in postmenopausal women with early-stage breast cancer. Bisphosphonates (BP) have been included as adjuvant therapy for postmenopausal breast cancer patients in multiple guidelines. SWOG S0307 compared efficacy of 3 BPs in early stage breast cancer, with no evidence of differences in efficacy on breast cancer outcomes by type of bisphosphonate, either in the overall analysis or subgroups. BPs are generally well tolerated, with a relatively low risk of serious adverse effects. Treatment for hormone sensitive breast cancer frequently includes treatment with an aromatase inhibitor (AI) or ovarian function suppression (OFS), both of which can accelerate bone loss, decrease bone density, and increase fractures. In addition to decreasing breast cancer events, BPs have been shown to decrease fractures in breast cancer patients receiving AIs or OFS. However, concerns have been raised about the risk of atypical femur fractures (AFF), a rare subtype of fragility fractures, which appear to increase with longer BP use (3-100/100,000 person-years) (Shane 2013). This substudy evaluated all fractures occurring in patients enrolled on S0307. Methods: Patients with stage I-III breast cancer who were receiving adjuvant systemic therapy were randomized to receive 3 years of intravenous zoledronic acid (ZA) 4 mg IV given every 4 weeks for the first six months, and then every 3 months for the following 2.5 years, oral clodronate (CLOD) 1,600 mg/day orally, or oral ibandronate (IBAN) 50 mg/day orally. The primary endpoint was disease-free survival (DFS). On-treatment data collection forms specifically queried whether a fracture had occurred during the reporting period, the site of the fracture, and whether or not it was associated with trauma. Results: A total of 6,097 patients were randomized to S0307, with a median age of 53 years. Rates for overall fractures at 7.7 years were higher for CLOD (9.3%) compared to IBAN (7.4%) and ZA (7.1%) (p=0.02), with differences being mostly in the spine. Traumatic fracture differences were not significant (CLOD 2.0%, ZA 1.9%, IBAN 1.7%; p=0.83). Fragility fracture rates were 5.2% with ZA, 7.2% with CLOD, and 5.6% with IBAN. Ankle fractures were the most common fracture site at 2.8% overall. Leg fractures, including femur fractures, were relatively low with a rate of 1.5% overall and not different between agents. AFF were not specifically queried/determined. Conclusion: In S0307, BPs were used in higher doses than is recommended for treatment of postmenopausal osteoporosis. There is limited data comparing the long-term effects across BP drugs used at these higher doses on the skeleton. In S0307, an overall fracture rate of 8% was seen in early stage breast cancer patients despite receiving BPs along with conventional systemic therapy. Fracture rates were slightly higher for CLOD than ZA and IBAN for fragility and overall fractures, but similar for traumatic fractures. This may reflect the potency of CLOD or the dosing schedule. Rates of femur fractures were relatively low in all arms without evidence of excess femur fractures. Funding: NIH/NCI CA180888, CA180819, CA180820, CA180821, CA180868, CA180863, CA196175; BCRF, Komen, Berlex (Bayer), Roche/Genentech, Novartis. Citation Format: Rachel L (MD) Yung, Jieling Miao, Alexander HG Paterson, Mark Clemons, Elizabeth C Dees, James N Ingle, Carla I Falkson, William Barlow, Gabriel N Hortobagyi, Julie R Gralow. Fractures in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG S0307 trial (ClinicalTrials.gov Identifier: NCT00127205) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-18-02.

Factors associated with osteonecrosis of the jaw in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG 0307 trial.

552 Background: Bisphosphonates reduce the risk of bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of osteonecrosis of the jaw (ONJ). We used the data collected in the S0307 trial to describe factors associated with provoked and unprovoked ONJ. Methods: In S0307, 6097 patients with Stage I-III breast cancer who had surgery were randomized to receive zoledronic acid (ZA) 4mg IV monthly for 6 months, then every 3 months, clodronate (CL) 1600mg daily, or ibandronate (IB) 50mg daily for three years, with no difference in bone metastases or disease-free survival. Patients completed dental procedures prior to and had a dental exam at enrollment. Pearson’s Chi-squared and Student’s T-test were used to test differences in categorical and continuous variables, respectively; logistic regression was used test independent association. Results: Of 5836 evaluable women, 48 developed ONJ, which was associated with bisphosphonate type (28/2124 (1.26%) for ZA, 8/2185 (0.36%) for CL and 12/1527 (0.77%) for IB (p = 0.002). Median time to onset of ONJ was 24.9 (1.4-66.6) for ZA, 41.2 months (range 33.8-67.4) for CL, 23.9 (2.1-75.3) for IB (p = 0.0447). Infection was present in 21 (43.8%) and absent in 20. ONJ was considered unprovoked in 20 (41.7%) and provoked by dental extraction in 20 (41.7%), periodontal disease in 14 (29.2%), denture trauma in 6 (12.5%), other dental surgery in 3 (6.3%). ONJ was associated with dental calculus (OR 2.03 (95% CI: 1.08-3.81), gingivitis (OR 2.11, 95% CI: 1.12-3.98), and periodontal disease (OR 2.87, 95% CI 1.45-5.53) that were moderate/severe and &gt; 4mm periodontitis (OR 2.20, 95% CI 1.18-4.08). Patients with provoked and unprovoked ONJ had similar amounts of dental disease and lesion location. ONJ was not associated with dentures, plaque, chemotherapy, corticosteroids or renal adverse events. In multivariate analysis (limited by small sample), only bisphosphonate type was associated with ONJ. Conclusions: ONJ prevalence was low, likely due to patients completing dental procedures before enrollment. ZA carried a higher risk of ONJ (though current adjuvant dosing interval recommendations are less frequent), with time to onset similar to IB. Oral CL and IB (not currently available in the United States) are thus likely more appropriate for patients with poor dental health. Clinical trial information: NCT00127205.

Symposium: Imaging modalities for drug-related osteonecrosis of the jaw (6), assessment of mandibular metabolism due to long-term administration of an anti-resorptive agent by bone scintigraphy (secondary publication)

SummaryIt is not yet known why anti-resorptive agent-related osteonecrosis specifically affects the jaw. Here we assessed changes in the bone metabolism of the mandible in response to long-term bisphosphonate (BP) therapy, and we compared the bone metabolism changes of the mandible with those of other bone sites using a quantitative analysis by bone scintigraphy. The region of interest was selected by identifying without an abnormal accumulation of the mandible, humerus, second and fourth lumbar vertebrae, iliac crest, intertrochanteric femur and diaphysis. Bone scintigraphy images were quantified using a value we termed the ‘bone uptake value (BUV)’. In the low-dose bisphosphonate (LBP) group (n = 21), the patients were undergoing osteoporosis treatment with low-dose BP. The high-dose BP (HBP) group consisted of 12 bone metastasis patients undergoing high-dose BP treatment. The Control group was 47 subjects with oral disease who had never been treated with an anti-resorptive agent. Our analyses demonstrated that with long-term BP administration, the bone metabolism of the iliac crest and intertrochanteric femur was suppressed but that of the mandible was enhanced. There was no significant difference in bone metabolism with either the low-dose BP or high-dose BP treatment. The effects of the long-term administration of BP were site-specific.

The effect of antiresorptive drugs on implant therapy: Systematic review and meta-analysis.

A considerable portion of the adult population has received and/or is receiving treatment with antiresorptive drugs (ARDs). It is thus relevant to assess possible side effects of ARD intake in connection to various aspects of implant therapy. The aim of this study was to answer the focused question "In patients with systemic intake of ARDs, what is the outcome and complication rate of implant therapy including associated bone grafting procedures comparing to patients without systemic intake of ARDs?" Original studies fulfilled predefined inclusion criteria (e.g., case series, cohort studies, case-control studies, and controlled and/or randomized controlled clinical trials; retro- or prospective design; and ≥10 patients with systemic intake of ARDs). Various patient-, medication-, and intervention-related parameters [i.e., implant loss, grafting procedure complication/failure, peri-implant marginal bone levels/loss, medication-related osteonecrosis of the jaws (MRONJ), and peri-implantitis] were extracted, and meta-analyses and quality assessment were performed. Twenty-four studies with bisphosphonate (BP) intake (mainly low dose for osteoporosis treatment) and seven studies on hormone replacement therapy (HRT), including ≥10 patients, and controls not taking the medication were identified. Furthermore, seven studies on MRONJ associated with implants were included. Meta-analyses based on four studies reporting on patient level and eight studies reporting on implant level showed no significant differences in terms of implant loss between patients on BPs (mainly low dose for osteoporosis treatment) and controls. Furthermore, low-dose BP intake did not compromise peri-implant marginal bone levels. Based on two studies, no negative effect of HRT was observed on the implant level, while HRT appeared to exert a marginally significant negative effect regarding implant survival on the patient level and regarding peri-implant marginal bone levels. Based on six studies reporting single-patient data, MRONJ in patients on BP for osteoporosis appeared in 70% of the cases >36months after start of drug intake, while in patients with cancer, MRONJ appeared in 64% of the cases ≤36months after first BP intake. Low-dose oral BP intake for osteoporosis treatment, in general, does not compromise implant therapy, that is, patients on ARDs do not lose more implants nor get more implant-related complications/failures comparing to implant patients without BP intake. There is almost no information available on the possible effect on implant therapy of high-dose BPs or other widely used ARDs (e.g., denosumab), or on the success or safety of bone grafting procedures. Patients with high-dose ARD intake for management of malignancies, patients on oral BP over a longer period of time, and patients with comorbidities should be considered as high-risk patients for MRONJ.

Development of Medication-Related Osteonecrosis of the Jaw After Extraction of Teeth With Experimental Periapical Disease

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but severe side effect of antiresorptive medications. Most animal models use tooth extraction as an instigating local factor to induce MRONJ, with varied results. However, these teeth are healthy and absent of dental disease, a rare finding that does not reflect clinical practices. The authors hypothesized that extraction of teeth with periapical inflammation would lead to MRONJ in rats treated with high-dose bisphosphonates. Rats were pretreated with zoledronic acid (ZA) for 1week. Pulp exposure (PE) was established by exposing the pulpal chamber of the first and secondmolars. Experimental periapical disease (EPD) was induced by PE and bacterial inoculation into pulp chambers of the first and second mandibular molars. The mandibular molars were extracted 4weeks after PE or EPD, and animals were euthanized 4weeks after tooth extraction. Extraction sockets were assessed clinically, radiographically, and histologically. Clinically, radiographically, and histologically, socket healing was observed in all vehicle-treated animals and in ZA-treated animals after extraction of healthy teeth or teeth with PE. In contrast, bone exposure, lack of socket healing, and osteonecrosis were present in most ZA-treated animals after extraction of teeth with EPD. Bacterial presence was noted in areas of osteonecrotic alveolar bone. These data support a synergistic contribution of severe dental disease and tooth extraction to MRONJ pathogenesis. Importantly, this model is amenable to manipulation of methodologic conditions for the dissection of parameters involved in MRONJ pathogenesis.

Factors affecting development of medication-related osteonecrosis of the jaw in cancer patients receiving high-dose bisphosphonate or denosumab therapy: Is tooth extraction a risk factor?

Methods for preventing medication-related osteonecrosis of the jaw (MRONJ) in cancer patients who have received high-dose bisphosphonate (BP) or denosumab (Dmab) have not yet been established. Tooth extraction after starting medication has been believed to be a major risk factor for MRONJ, and therefore this procedure tends to be avoided. This study investigated the risk factors for MRONJ, with a special reference to the correlation between tooth extraction and development of MRONJ. One hundred and thirty-five cancer patients who were administrated high-dose BP or Dmab were enrolled in the study. Demographic factors, general condition, treatment factors, and dental findings were examined retrospectively using medical records and panoramic X-ray findings. The cumulative occurrence rate of MRONJ was calculated using the Kaplan–Meier method, and the correlation between these variables and development of MRONJ was analyzed by univariate and multivariate Cox regression analysis. MRONJ developed in 18 of 135 patients. The 1-, 2-, and 3-year cumulative occurrence rates were 8.6%, 21.5%, and 29.2%, respectively. The duration of medication before first visit to the dental unit and the presence of a tooth with clinical symptoms were significantly correlated with the development of MRONJ. The rate of MRONJ occurrence in patients who had teeth with clinical symptoms, but who did not undergo tooth extraction, became higher 2 years later than that in patients who underwent extraction of teeth with symptoms, although not significant. Early dental examination and effective preventative care to avoid infection/inflammation are important for preventing MRONJ.

Submental Perforator Flap for Soft-Tissue Reconstruction in Bisphosphonate-Related Osteonecrosis of the Jaws

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) has emerged as an important and increasingly common comorbidity, especially in patients undergoing long-term treatment with high doses of bisphosphonates. The management of BRONJ remains controversial. Surgical treatment is necessary in severe cases. Treatment of the bone requires sequestrectomy or resection. Given the lack of sufficient mucosa to perform the operation and fragility of margins in many patients, local flaps are crucial. We report two cases of stage-3 BRONJ presenting secondary infection with Actinomyces , receiving treatment consisting of marginal resection of the necrotic bone, reinforcement with a reconstruction plate, and reconstruction of soft tissues using a submental perforator artery flap ipsilateral to the lesion. Total cure was achieved in both cases, achieving favorable aesthetic and functional outcomes.

Non-destructive NIR spectral imaging assessment of bone water: Comparison to MRI measurements

Bone fracture risk increases with age, disease states, and with use of certain therapeutics, such as acid-suppressive drugs, steroids and high-dose bisphosphonates. Historically, investigations into factors that underlie bone fracture risk have focused on evaluation of bone mineral density (BMD). However, numerous studies have pointed to factors other than BMD that contribute to fragility, including changes in bone collagen and water. The goal of this study is to investigate the feasibility of using near infrared spectral imaging (NIRSI) to determine the spatial distribution and relative amount of water and organic components in whole cross-sections of bone, and to compare those results to those obtained using magnetic resonance imaging (MRI) methods. Cadaver human whole-section tibiae samples harvested from 18 donors of ages 27-97years underwent NIRSI and ultrashort echo time (UTE) MRI. As NIRSI data is comprised of broad absorbances, second derivative processing was evaluated as a means to narrow peaks and obtain compositional information. The (inverted) second derivative peak heights of the NIRSI absorbances correlated significantly with the mean peak integration of the water, collagen and fat NIR absorbances, respectively, indicating that either processing method could be used for compositional assessment. The 5797cm-1 absorbance was validated as arising from the fat present in bone marrow, as it completely disappeared after ultrasonication. The MRI UTE-determined bound water content in tibial cortical bone samples ranged from 62 to 91%. The NIRSI water peaks at 5152cm-1 and at 7008cm-1 correlated significantly with the UTE data, with r=0.735, p=0.016, and r=0.71, p=0.0096, respectively. There was also a strong correlation between the intensity of the NIRSI water peak at 7008cm-1 and the intensity of the collagen peak at 4608cm-1 (r=0.69, p=0.004). Since NIRSI requires minimal to no sample preparation, this approach has great potential to become a gold standard modality for the investigation of changes in water content, distribution, and environment in pre-clinical studies of bone pathology and therapeutics.

Effects of the basic multicellular unit and lamellar thickness on osteonal fatigue life

A remodeling cycle sets the size of the osteon and associated lamellae in the basic multicellular unit. Treatments and aging affect these micro-structural features. We previously demonstrated decreased fatigue life with an unexplained mechanism and decreased osteon size in cortical bone treated with high-dose bisphosphonate. Here, three finite element models were examined: type-1: a single osteon, as a homogeneous unit and with heterogeneous lamellae and interlamellae, type-2: a control, interstitial-only tissue and type-3: the osteon with cement line, set within the interstitial tissue. Models were loaded in simulated, sinusoidal bending fatigue. As osteon size was decreased, lamellar number and lamellar thickness were incrementally adjusted for each model. As hypothesized, lamellae within the larger type-1 models attained greater cycles to failure and the addition of an osteon to type-2 models (generating a type-3 model set) yielded increased fatigue life. However, as the osteon size was decreased, the potential for compressive damage nucleation was increased within the lamellae of the osteons versus the interstitium. Also, osteons with fewer, thicker lamellae displayed increased fatigue life. Osteonal microstructure plays a role in damage initiation location, especially when BMU size is smaller. Previous findings by us and others could partially be explained by this further understanding of increased probability for damage nucleation in smaller osteons.

La sindrome algodistrofica o Complex Regional Pain Syndrome type 1

Complex regional pain syndrome (CRPS) includes a wide range of conditions affecting a peripheral limb characterised by chronic disabling pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. Pain is regional and it is typically associated with abnormal sensory, motor, sudomotor, vasomotor and/or trophic findings. The pathophysiology is still poorly understood. The disease shows a female preponderance with a peak age of incidence around the 5th and 6th decade. The available diagnostic criteria for CRPS-I rely exclusively on clinical criteria, that are unfortunately focused on the signs and symptoms of the chronic and late disease, while little emphasis is given to the typical imaging (X-rays, bone scintigraphy, MRI) findings of the early phase. Over the last decades, several therapies have been proposed but the few studies available are often too small to be conclusive and rarely evolved to randomised controlled trials (RCTs). On the basis of the results of a few RCTs, only bisphosphonate therapy appears to provide substantial benefits, especially in patients in the early phase of the disease, often leading to persistent remission or complete healing. In conclusion, short courses of high doses of bisphosphonates should be considered the treatment of choice for patients with CRPS-I.

Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus.

This work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is estimated at 0.001% to 0.01%, marginally higher than the incidence in the general population (<0.001%). New insights into the pathophysiology of ONJ include antiresorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and macrophage function, as well as the role of local bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging, bone scanning, and positron emission tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures, as well as other drugs, including antiangiogenic agents. Prevention strategies for ONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical debridement is indicated in advanced nonresponsive disease and has been successful. Early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell intralesional transplantation, low-level laser therapy, local platelet-derived growth factor application, hyperbaric oxygen, and tissue grafting.

RANKL Inhibitors Induce Osteonecrosis of the Jaw in Mice With Periapical Disease

Antiresorptive medications are essential in treating diseases of pathologic osteoclastic bone resorption, including bone cancer and osteoporosis. Bisphosphonates (BPs) are the most commonly used antiresorptives in clinical practice. Although inhibition of bone resorption is important in regulating unwanted malignant and metabolic osteolysis, BP treatment is associated with potential side effects, including osteonecrosis of the jaws (ONJ). Recently, non-BP antiresorptive medications targeting osteoclastic function and differentiation, such as denosumab, have entered the clinical arena. Denosumab treatment results in a similar rate of ONJ as BPs. Animal models of ONJ, using high-dose BP treatment in combination with tooth extraction or dental disease, provide valuable tools and insight in exploring ONJ pathophysiology. However, the ability of other antiresorptives to induce ONJ-like lesions in animal models has not been explored. Such studies would be beneficial in providing support for the role of osteoclast inhibition in ONJ pathogenesis versus a direct BP effect on oral tissues. Here, we tested the ability of the receptor activator of NF-κB ligand (RANKL) inhibitors RANK-Fc (composed of the extracellular domain of RANK fused to the fragment crystallizable [Fc] portion of immunoglobulin G [IgG]) and OPG-Fc (composed of the RANKL-binding domains of osteoprotegerin [OPG] linked to the Fc portion of IgG) to induce ONJ in mice in the presence of periapical disease, but in the absence of dental extractions. We demonstrate radiographic evidence of ONJ in RANK-Fc-treated and OPG-Fc-treated mice, including inhibition of bone loss, increased bone density, lamina dura thickening, and periosteal bone deposition. These findings closely resembled the radiographic appearance of an ONJ patient on denosumab treatment. Histologic examination revealed that RANK-Fc treatment and OPG-Fc treatment resulted in absence of osteoclasts, periosteal bone formation, empty osteocytic lacunae, osteonecrosis, and bone exposure. In conclusion, we have successfully induced ONJ in mice with periapical disease, using potent osteoclast inhibitors other than BPs. Our findings, coupled with ONJ animal models using high-dose BPs, suggest that osteoclast inhibition is pivotal to the pathogenesis of ONJ.

Ninety-One Osteoporosis Patients Affected with Bisphosphonate-Related Osteonecrosis of the Jaw: A Case Series

Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) presents with necrotic bone in the mouth in the setting of BP exposure. It has been studied in cancer patients taking high-dose BP, but BRONJ has also been noted in patients taking lower-dose BP for osteoporosis. The purpose of this study was to characterize the phenotypes and outcomes in a large series of patients with osteoporosis and BRONJ in the setting of BP exposure. We conducted a retrospective case series. The sample was composed of subjects with BRONJ and osteoporosis. Subjects with a history of BP treatment for myeloma or metastatic cancer to the bones were excluded. Descriptive statistics were computed for the study variables. Ninety-one cases of BRONJ met the inclusion criteria. Subjects had a median age of 71 years and were predominantly female (94.5 %). The median time of BP exposure was 60 months (range 2-120). Most subjects were treated with alendronate (82.4 %). The mandible was involved more frequently (58.2 %) than the maxilla (37.3 %). Subjects commonly (65.9 %), but not universally, reported pain. For subjects with treatment outcome data (n = 0), most reported improvement (80.0 %). Although BRONJ is an uncommon condition, the absolute number of cases is fairly large due to the very large number of patients taking BPs for osteoporosis. The findings of this study confirm that BRONJ primarily affects the mandible, a substantial minority present without pain, and patients typically improve with treatment.