BACKGROUND: Current clinical guidelines recommend a drug holiday after extended use of oral bisphosphonates. However, no studies have investigated the impact of drug holidays before hip fractures on post-fracture mortality.
OBJECTIVE: To investigate the effect of drug holiday on post-fracture mortality in patients with extended use of oral bisphosphonates.
METHODS: Retrospective population-based cohort study.
METHODS: All patients with hip fractures in Victoria, Australia from 2014-18.
METHODS: Patients adherent to oral alendronate or risedronate for ≥5 years prior to hip fracture.
METHODS: Group-based trajectory modelling categorized patients into different bisphosphonate usage after 5-year good adherence.
METHODS: Post-fracture mortality.
RESULTS: We identified 365 patients with good adherence (medication possession ratio ≥80%) to oral alendronate/risedronate for ≥5 years. Most patients (69%) continued to use oral bisphosphonates till admission for hip fracture; 17% had discontinued for one year and 14% had discontinued for two years. Post-fracture mortality was higher in patients who had discontinued risedronate for one year (Hazard ratio [HR] 2.37, 95% confidence interval [CI] 1.24-4.53) and two years (HR 3.08, 95% CI 1.48-6.41) prior to hip fracture. No increase or decrease in post-fracture mortality was observed in patients who had discontinued alendronate for one year (HR 0.59, 95% CI 0.29-1.18) or two years (HR 1.05, 95% CI 0.57-1.93) prior to hip fracture.
CONCLUSIONS: Post-fracture mortality is higher in people who discontinue risedronate, but not alendronate, for 1 or 2 years after being adherent to treatment for at least 5 years. The type of bisphosphonate may be a factor to consider when planning drug holidays.

Bisphosphonates prevent future hip fractures. However, we found that one in six patients with hip fractures had a delay in bisphosphonate initiation and another one-sixth discontinued treatment within 12 months after discharge. Our results highlight the need to address hesitancy in treatment initiation and continuous monitoring.
OBJECTIVE: Suboptimal antiresorptive use is not well understood. This study investigated trajectories of oral bisphosphonate use following first hip fractures and factors associated with different adherence and persistence trajectories.
METHODS: We conducted a retrospective study of all patients aged ≥ 50 years dispensed two or more bisphosphonate prescriptions following first hip fracture in Victoria, Australia, from 2012 to 2017. Twelve-month trajectories of bisphosphonate use were categorized using group-based trajectory modeling. Factors associated with different trajectories compared to the persistent adherence trajectory were assessed using multivariate multinomial logistic regression.
RESULTS: We identified four patterns of oral bisphosphonate use in 1811 patients: persistent adherence (66%); delayed dispensing (17%); early discontinuation (9%); and late discontinuation (9%). Pre-admission bisphosphonate use was associated with a lower risk of delayed dispensing in both sexes (relative risk [RR] 0.28, 95% confidence interval [CI] 0.21-0.39). Older patients ( ≥ 85 years old versus 50-64 years old, RR 0.38, 95% CI 0.22-0.64) had a lower risk of delayed dispensing. Males with anxiety (RR 9.80, 95% CI 2.24-42.9) and females with previous falls had increased risk of early discontinuation (RR 1.80, 95% CI 1.16-2.78).
CONCLUSIONS: Two-thirds of patients demonstrated good adherence to oral bisphosphonates over 12 months following hip fracture. Efforts to further increase post-discharge antiresorptive use should be sex-specific and address possible persistent uncertainty around delaying treatment initiation.

OBJECTIVE: Dental implant treatment is considered contraindicated in patients with cancer on high-dose antiresorptive medication (HDAR). The aim of this prospective, feasibility study was to evaluate implant treatment in patients with cancer on HDAR, in terms of implant survival, implant success, and oral health-related quality of life (OHLQoL) after 2 years of loading.
METHODS: Implants were inserted in three groups of HDAR patients: (1) Previous tooth extraction, no medication-related osteonecrosis of the jaw (MRONJ), (2) Previous MRONJ, now healed, (3) Existing MRONJ, planned surgical resection. Implants were placed without adjunctive bone or soft tissue argumentation. Abutment operation was performed after ≥12 weeks. Prosthetic treatment was initiated ≥14 weeks. Survival and success rate were determined, and OHLQoL was analyzed with OHIP-49 and QLQ-H&N35 questionnaires. Patients were seen for 6 months, 1- and 2 years follow-up.
RESULTS: Twenty-two patients, 39 implants, completed the implant-based prosthetic treatment. Implant-supported crowns and overdentures were fabricated. Thirteen patients (59%) with 23 implants (59%) completed 2 years follow-up. Overall implant survival and success rate after 2 years of loading were 100% and 97.4%, respectively. OHLQoL for the patients increased in all groups after the treatment, a substantial increase was seen in group 3. Two patients developed MRONJ, but not related to the implant treatment.
CONCLUSIONS: Dental implant treatment, with high survival and success rate and increased post-treatment OHLQoL, is feasible in HDAR patients after 2 years of loading. Caution with general recommendations should be exercised.

Background and objectives: The investigation of the pathophysiology behind medication-related osteonecrosis (MRONJ) of the jaw mostly focuses on alterations in osteoclast and osteoblast cell activity, but changes in the organic and inorganic bone matrix have rarely been studied. The aim of this study was to investigate whether collagen, the main organic component of extracellular bone matrix, is destructed in osteonecrosis of the jaw secondary to antiresorptive medication. Material and methods: Bone samples of patients with MRONJ (n = 15, control group n = 3) were demineralized, and collagen fragments were separated from intact collagen pellets by ultrafiltration. The quantification of mature collagen cross-links hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) in pellets and ultrafiltrates was performed by high-performance liquid chromatography (HPLC). The detection of hydroxyproline (Hyp) was carried out using a spectrophotometric assay. In addition, collagen chains were analyzed by sodium dodecylsulfate-polyacrylamide gel (SDS-PAGE). Results: The results revealed significantly higher concentrations of HP, LP and Hyp in pellet samples. In addition, there were no significant differences between samples from MRONJ patients and those of the control group. These results were paralleled by SDS- PAGE. Conclusion: These findings suggest that MRONJ does not involve the destruction of type I and V collagen molecules, in contrast to previously reported destruction by osteoradionecrosis.

Bisphosphonates have been reported to be cardioprotective in some, but not all, studies. It is unknown whether denosumab (Dmab) use protects against cardiovascular events (CVEs).
To determine whether oral bisphosphonate (oBP) or Dmab use is associated with CVEs in persons with incident fracture.
Participants with an incident minimal trauma fracture from the Sax Institute\'s 45 and Up Study, a population-based cohort from NSW, Australia, were followed between 2005/2009 and 2017. Questionnaire data were linked to hospital admissions (Admitted Patients Data Collection [APDC]) by the Centre for Health Record Linkage). Medicare Benefit Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) data sets were provided by Services Australia. Data was stored in a secure computing environment (Secure Unified Research Environment). Fractures, CVEs, and comorbidities were identified from the APDC and oBP and Dmab medication from the PBS. oBP and Dmab users were matched to never users (NoRx) by propensity scores. The main outcome measures were association between oBP and Dmab with CVE (acute myocardial infarction, unstable angina, cerebrovascular accident, and transient ischemic attack) and were determined using a stratified Cox\'s proportional hazards model.
There were 880 pairs of oBP and NoRx (616 women) and 770 pairs of Dmab and NoRx (615 women) followed for ∼4.3 years. CVE risk was similar for oBP and NoRx Hazard Ratios (HR) women, 0.88 [95% CI 0.65-1.18]; men, 1.07 [95% CI 0.72-1.57]). Similar findings were obtained for Dmab (Hazard Ratios (HR) women, 1.08 [95% CI 0.78-1.50]; men, 1.55 [95% CI 0.96-2.48]).
oBP and Dmab use was not associated with CVEs.

To compare the effects of high-intensity resistance and impact training (HiRIT) to low-intensity, Pilates-based exercise (LiPBE) on proximal femur geometry and explore the influence of antiresorptive medication on those effects. Postmenopausal women with low bone mass, on or off antiresorptive bone medications were randomly allocated, stratified on medication intake, to eight months of twice-weekly, supervised HiRIT (Onero™) or LiPBE (Buff Bones®). 3D hip software was used to analyse proximal femur DXA scans. Outcomes included femoral neck (FN) and total hip (TH), volumetric (e.g. vBMC, vBMD) and geometric (e.g. cortical thickness, cross-sectional area [CSA], section modulus [Z]) indices of bone strength. Data were analysed using analysis of variance. Scans of 102 women were examined: LiPBE, 43; HiRIT, 37; LiPBE-med, 11; HiRIT-med, 11. HiRIT improved TH trabecular vBMC and vBMD (3.1 ± 1.1% versus - 1.2 ± 1.2%, p = 0.008; and 1.5 ± 1.0% versus - 1.6 ± 1.2%, p = 0.042, respectively) and FN and TH total vBMC (2.0 ± 0.8% versus - 0.2 ± 0.7%, p = 0.032; and 0.7 ± 0.4% versus - 0.8 ± 0.6%, p = 0.032, respectively), compared to losses in LiPBE. HiRIT also increased Z while LiPBE did not (p = 0.035). The combination of HiRIT and medication achieved greater improvements in FN total and trabecular vBMD, total BMC, CSA and Z than HiRIT alone. HiRIT improved geometric parameters of proximal femur strength, while LiPBE exercise was largely ineffective. Medication may enhance some HiRIT effects. Findings suggest reduced hip fracture risk in response to HiRIT.Trial registration number ACTRN12617001511325.

OBJECTIVE: The aim of the study is to evaluate the results of apical surgery (AS) in patients receiving high-dose antiresorptive medication (HDAR).
METHODS: Retrospective descriptive quality control study conducted in an Oral and Maxillofacial Department at a University Hospital. Fourteen patients on HDAR met the inclusion criteria. Only descriptive statistics were applied.
RESULTS: Fourteen patients had operation on seventeen teeth. Mean HDAR treatment period before apical surgery: 25 months (SD, ± 24.27; range, 1-78 months). Drug holiday during surgery and initial healing: mean, 8 months (SD, ± 5.96; range, 0.4-22 months). Sixteen out of seventeen teeth healed clinically and showed complete or ongoing radiographic healing. All patients except one became free of symptoms. Mean follow-up: 13 months (SD, ± 9.05; range, 2-31 months). Radiographic healing according to Molven and Rud: 7, complete; 6, uncertain; 1, unsatisfactory. Three patients died during follow-up and were considered drop-outs.
CONCLUSIONS: The present case series suggest that apical surgery is a valid treatment option for apical periodontitis in patients on HDAR, where orthograde endodontic retreatment is not possible. None of the patients developed medication-related osteonecrosis of the jaw. Further studies in larger study groups and with longer follow-up periods are needed. The regional scientific ethical committee provided a document exemption, registration date 20 November 2013, and the local data protection agency approved handling of the recorded data (No. 2012-41-0045), registration date 11 January 2012.

Objective: To evaluate the level of knowledge and attitudes among Swedish general dentists regarding the behavior and management of patients treated with bisphosphonates and denosumabMaterials and Methods: A questionnaire was sent to 656 dentists. The web-based survey included questions on demographics, risk perception of osteonecrosis of the jaws (ONJ), the experience of managing patients treated with bisphosphonates and denosumab and requests to acquire new knowledge. Independence and associations were tested using Fisher\'s exact test and the chi-square test function.Results: The overall response rate was 57.6%. Most of the dentists, 69.7%, had been in the profession for more than 5 years. The criteria for ONJ were not known by 43.2% and 86.9% did not feel comfortable with their current level of knowledge when managing the patients in question. The rest of the respondents felt uncertain and more than 70% were unaware of the different stages of ONJ, when to refer a patient to a specialist and when to prescribe antibiotics.Conclusion: Dentists practicing in Sweden express a strong need for an improved level of knowledge when managing patients treated with bisphosphonates and denosumab. The results demonstrate a need for the necessary advancement of education and clinical training at dental schools in order to prepare dentists to provide safe, modern care within the healthcare sector.

OBJECTIVE: The purpose of this study was to determine the efficacy and tolerability of different antiresorptive therapeutic regimens for treating symptomatic bone marrow lesions (BML) of the knee.
METHODS: Patient records of 34 patients with radiologically diagnosed, painful BML of the knee treated with either a bisphosphonate (zoledronic, ibandronic, or alendronic acid) or with a human monoclonal antibody (denosumab) were retrospectively evaluated. Response to treatment was assessed, as change in patient-reported pain, by evaluation of BML expansion on MRI using the Whole-Organ Magnetic Resonance Imaging Score (WORMS), and by laboratory analysis of bone turnover markers: C-terminal cross-linking telopeptide (CTx) and procollagen type 1 amino-terminal propeptide (P1NP). Tolerability was evaluated by documentation of adverse reactions.
RESULTS: Zoledronic acid was more or at least equally effective as the other treatment regimens with response to treatment in 11 of 12 patients (92%). The highest rate of adverse events was noted in 4 of 12 patients (33%) treated with zoledronic acid. CTx and WORMS differentiated well between responders and non-responders, whereas P1NP failed to do so. Changes in pain correlated moderately with change in WORMS (r = - 0.32), weakly with change in CTx (r = - 0.07), and not at all with change in P1NP.
CONCLUSIONS: Zoledronic acid appeared to be more effective than other antiresorptive medications-at the cost of more frequent adverse events. While radiological and laboratory evaluation methods may allow for objective treatment monitoring, they appear to capture different dimensions than patient-reported pain.
METHODS: III.

Osteonecrosis is the devitalization of bone and consequent lytic changes. In the jaws, osteonecrosis is a pathologic consequence of prior radiation therapy (osteoradionecrosis) or certain antiresorptive medications. Herein, we review the pathogenesis and clinical manifestations of these lesions, and describe the spectrum of radiologic findings in these conditions, and highlight the similarities and differences between the imaging appearances of these 2 entities.