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Background: Discontinuation of anti-osteoporotic medications (AOM), except for bisphosphonates (BP), is not favorable for the bone, being especially negative for Prolia® (60 mg denosumab-DMAb). DMAb withdrawal leads to a rapid and significant increase in bone turnover markers, and to an important loss in bone mineral density, which has been associated with an increased risk of multiple vertebral fractures (MVF)., Objective: To assess the risk of MVF (≥2 VF) recorded at the same time) after discontinuation of different AOM., Methods: A case-control analysis nested in a cohort of new users of DMAb, BP, Teriparatide (TPTD), Strontium Ranelate (SrRan), or selective estrogen receptor modulators (SERM), aged ≥18 years from 2011 to 2018 with ≥1 year of prior available data, was performed using the Pharmacoepidemiological Research Database for the Public Health System (BIFAP) in Spain. Cases were first MVF recorded after AOM initiation (index date). Up to 4 controls per case, matched on index date, age, sex, and location, were randomly selected among non-cases from the cohort. Adjusted conditional OR (AOR) and 95 % CI: between discontinuation of a given AOM (supply of the last prescription ended >90 days before the index date) and occurrence of MVF was assessed compared with their current use and alternatively, with discontinuation of BP, among individuals who did not switch therapy in the study., Results: A total of 532 incident cases of MVF were identified and matched to 2121 controls (86 % women; median age 73 years). AOR of MVF after DMAb discontinuation was 2.82 (1.73-4.60) compared with DMAb current use. No risk was seen for the other AOM. The AOR was highest between 3 and 9 months after discontinuation of denosumab (8.58; 3.98-18.48) and after >1 year of cumulative use (5- and 11-times increased risk when discontinuing after 1-2 years and 2-5 years of use, respectively). Compared with BP discontinuers, discontinuation of DMAb (2.73, 1.66-4.50), TPTD (2.06, 1.09-3.88) and SrRan (1.93, 1.23-3.05) showed an increased risk of MVF; current use of DMAb showed no protective effect (1.44; 0.95-2.17)., Conclusions: Discontinuation of DMAb was associated with an immediate increased risk of MVF, especially after longest treatments compared with patients who continued therapy or discontinued BP. Although there were increased risks after discontinuation of other AOM in comparison with first- line therapy (BP), these were not found when the reference was current users. Confounding by indication cannot be discarded. Larger studies should investigate reasons for discontinuation and preventive retreatment options., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Romosozumab is an anti-sclerostin antibody that increases bone formation and decreases bone resorption. It became available for patients at high risk of osteoporotic fractures in Japan in 2019. The aim of this study was to clarify the clinical effects, safety, and predictors of the effectiveness of 12 months of romosozumab therapy. The study had an observational pre-post design and included 460 patients. Romosozumab was administered at a dose of 210 mg subcutaneously every 4 weeks for 12 months. The incidence of new fractures, safety, and changes in bone mineral density (BMD) and bone turnover markers were recorded. New fractures occurred in 11 cases (3.0 %). Nine patients (2.0 %) experienced cardiovascular events, which were fatal in 3 (0.65 %). Percent changes in BMD at the spine and total hip at 12 months from baseline were +7.7 % and +1.8 %, respectively. Romosozumab had better effects in patients with good renal function, low spine BMD, and high TRACP-5b at baseline and low TRACP-5b or high P1NP after 1 month of treatment. The percent change in spine BMD at 12 months was significantly lower in patients transitioning from denosumab than in those not previously treated with other anti-osteoporosis agents. Romosozumab is considered to be relatively safe in patients with primary osteoporosis compared to those with secondary osteoporosis. Romosozumab resulted in larger increases in spine BMD in patients with primary osteoporosis who were not previously treated with other anti-osteoporosis therapies and those with low spine BMD at the start of treatment., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Antiresorptive treatment is currently used in millions of patients with osteoporosis and cancer worldwide. Early studies of denosumab suggested a small signal in ovarian cancer incidence and emerging data suggest that denosumab stimulates germ cell proliferation in the gonads. This study aims to determine the association between the use of denosumab and the risk of reproductive cancers compared with the use of alendronate., Research Design and Methods: Using a cohort study design, we used the Danish nationwide registries to identify a population of subjects ≥50 years of age during 2010-2017 who started denosumab after being on alendronate treatment for at least six months. The cohort was matched 1:2 with patients who had been treated with alendronate alone for at least six months. The risk of reproductive cancers and the risk difference between groups were estimated using the Longitudinal Targeted Maximum Likelihood Estimation (L-TMLE) method., Results: We identified 6054 Danish individuals who underwent treatment with denosumab. These individuals were matched with 12,108 receiving alendronate. The absolute risk of reproductive cancer was 1.05 % (95 % CI 0.75-1.34) after three years for denosumab users and was not different 0.03 % (-0.34-0.39) than for alendronate users. In supplemental analyses, there was no increased risk of non-reproductive cancers associated with the use of denosumab (risk difference of 0.54 % (-0.41-1.19). Analysis comparing denosumab users with the general population gave similar results., Conclusion: There was no difference in the risk of cancer following treatment with denosumab compared to treatment with alendronate assessed after a short follow-up of 3 years., Competing Interests: Declaration of competing interest All authors have no relevant financial or non-financial interests to disclose except Sam Kafai Yahyavi and Rune Holt who are current co-principal investigators on an RCT with denosumab and Martin Blomberg Jensen, who holds two patents on the use of RANKL inhibitors to treat male infertility., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Osteogenesis imperfecta (OI) is a congenital disease comprising a heterogeneous group of inherited connective tissue disorders. The main treatment in children is bisphosphonate therapy. Previous animal studies have shown that bisphosphonates delay tooth eruption. The aim of this study is to determine whether patients with OI treated with pamidronate and/or zoledronic acid have a delayed eruption age compared to a control group of healthy children., Methods: An ambispective longitudinal cohort study evaluating the age of eruption of the first stage mixed dentition in a group of children with OI (n = 37) all treated with intravenous bisphosphonates compared with a group of healthy children (n = 89). Within the study group, the correlation (Pearson correlation test) between the type of medication administered (pamidronate and/or zoledronic acid) and the chronology of tooth eruption is established, as well as the relationship between the amount of cumulative dose received and tooth eruption., Results: The age of eruption of the study group was significantly delayed compared to the age of eruption of the control group for molars and lateral incisors (p < 0.05). Patients who received higher cumulative doses had a delayed eruption age compared to those with lower cumulative doses (p < 0.05). There is a high positive correlation between age of delayed tooth eruption and Zoledronic acid administration., Conclusion: Patients with OI have a delayed eruption of the 1st stage mixed dentition compared to a control group of healthy children. This delayed eruption is directly related to the cumulative dose of bisphosphonates and the administration of zoledronic ac., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

An 81-year-old Caucasian man who had commenced thrice weekly hemodialysis (HD) three months earlier, presented with a hip fracture, two vertebral fractures and a bone mineral density T-score of -3.6. He had received weekly iron sucrose infusions for 6 weeks and alphacalcidol on dialysis days. Although he suffered from coeliac disease and cirrhosis, he was fully ambulatory and well-nourished. He was normocalcaemic with a marginally low plasma phosphate and the PTH was 11.8 pmol/L (<2-times the upper range of the assay). In view of his severe osteoporosis, it was decided to treat him with denosumab (dmab). Laboratory assessment 2 weeks post dmab showed severe hypophosphatemia and hypocalcemia; phosphate 0.11 mmol/L and ionized calcium 0.83 mmol/L, and he was admitted for intravenous phosphate infusion. Three months later he remained on a phosphate supplement. The case illustrates that, in addition to the risks of hypocalcemia in patients with kidney failure and high bone turnover, kidney failure patients without evidence of high bone turnover, can also be at risk of hypocalcemia and severe hypophosphatemia requiring acute hospitalization and phosphate infusion. The potential role of compromised phosphate absorption versus increased deposition will be discussed. We recommend a cautious approach to dmab therapy in patients on dialysis, with evaluation of bone turnover and serum phosphate levels prior to initiation of treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Grahame J Elder reports a relationship with Amgen that includes: funding grants. Grahame J Elder reports a relationship with Shire that includes: funding grants. Grahame J Elder reports a relationship with Sanofi that includes: funding grants. Grahame J Elder reports a relationship with Théramex that includes: funding grants. Bo Abrahamsen reports a relationship with UCB that includes: consulting or advisory, funding grants, and speaking and lecture fees. Bo Abrahamsen reports a relationship with Pharmacosmos that includes: consulting or advisory, funding grants, and speaking and lecture fees. Bo Abrahamsen reports a relationship with Kyowa-Kirin that includes: consulting or advisory, funding grants, and speaking and lecture fees. Bo Abrahamsen reports a relationship with Gedeon Richter that includes: speaking and lecture fees. Bo Abrahamsen reports a relationship with Amgen that includes: speaking and lecture fees., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a potentially intractable disease with no definitive pathophysiology and no treatment and prevention strategies. This study aimed to investigate whether time-selective depletion of macrophages worsens BRONJ-like lesions in mice. A murine model of high-prevalence BRONJ-like lesions in combination with zoledronate/chemotherapeutic drug administration and tooth extraction was created according to the methods of our previous studies. Daily intra-oral submucosal administration of clodronate-loaded liposomes, which temporarily depletes systemic macrophages, was performed immediately after tooth extraction. Spleens, femora, tibiae, and maxillae were dissected 2 weeks after extraction to evaluate BRONJ-like lesions and systemic conditions by micro-computed tomography analysis, histomorphometric and immunofluorescent analyses, and serum chemistry with ELISA. Depletion of macrophages significantly decreased the numbers of local and systemic macrophages and osteoclasts on the bone surface, which markedly worsened osseous healing, with increased necrotic bone and empty lacunae in the existing alveolar bone and newly formed bone in the extraction sockets, and soft tissue healing, with decreased collagen production and increased infiltration of polymorphonuclear cells. Interestingly, the depletion of macrophages significantly shifted macrophage polarization to M1 macrophages through an increase in F4/80 + CD38 + M1 macrophages and a decrease in F4/80 + CD163 + M2 macrophages, with decreases in the total number of F4/80 + macrophages. These data demonstrated that severe inhibition of osteoclasts in bone tissue and polarization shifting of macrophages in soft tissue are essential factors associated with BRONJ., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study was to retrospectively examine predictors of fracture risk when adult patients experienced a denosumab treatment lapse or discontinuation in a real-world clinic setting., Materials and Methods: Eligible patients were adults who had received ≥2 doses of denosumab at an academic health center in the United States. Demographics, treatment doses, reasons for missed doses, and fractures, were collected retrospectively from electronic health records, from an 8-year period (2010-2018). The number of times each patient incurred a treatment lapse, defined as ≥240 days between two doses (excluding lapse due to discontinuation, death, or transfer of care) was computed. The occurrence of denosumab discontinuation (excluding discontinuation due to death or transfer of care), whether the patient initiated alternative therapy, and the reason for each lapse and discontinuation were collected. Cox proportional hazards models assessed characteristics associated with risk of fracture and treatment discontinuation. A logistic regression model was used to determine if cumulative amount of time off medication (i.e., cumulative lapse time) was associated with a higher likelihood of incurring a fracture., Results: We included 534 patients: 95 % White, 86 % women, 33 % tobacco users, 13 % diagnosed with diabetes, median age 69 years (Interquartile Range (IQR): 62-77), and median Body Mass Index (BMI) 25 kg/m 2 (IQR: 22-28). Thirty-six percent of patients incurred 250 lapses; 10 % discontinued therapy. Dental problems/procedures and logistical barriers were the most common reasons for lapses and discontinuations. Nineteen percent (n = 103) incurred a total of 190 fractures; of these, 121 were osteoporotic, 50 were vertebral. Risk of any, osteoporotic, and vertebral fractures were associated with off-treatment status (hazard ratio [HR] = 1.7, p = 0.043; HR = 2.0, p = 0.026; and HR = 4.2, p = 0.001, respectively) and older age (HR = 1.3, p = 0.015; HR = 1.5, p = 0.001; and HR = 1.8, p = 0.005, respectively). Older age was associated with higher risk of discontinuation (HR = 1.4, p = 0.022). There was a non-significant trend of a nonlinear association between incurring a fracture and cumulative lapse time (p = 0.087)., Conclusion: Denosumab treatment lapses are common, and off-treatment status may be associated with a higher risk of fractures. Clinical teams should proactively identify and address adverse effects and potential logistical barriers to reduce the risk of treatment lapses., Competing Interests: Declaration of competing interest Dr. Hosteng, Dr. Peter, Dr. Chakrabarti, Dr. Gipson, Dr. Gregory, Mr. DeClercq, and Dr. Choi declare that they have no conflict of interest. Dr. Tanner serves on the advisory board/speakers bureau for CSL Behring, AMGA, Ultragenyx, and Regeneron., (Copyright © 2023. Published by Elsevier Inc.)

Long-term usage of bisphosphonates, especially zoledronic acid (ZA), induces osteogenesis disorders and medication-related osteonecrosis of the jaw (MRONJ) in patients, thereby contributing to the destruction of bone remodeling and the continuous progression of osteonecrosis. Menaquinone-4 (MK-4), a specific vitamin K 2 isoform converted by the mevalonate (MVA) pathway in vivo, exerts the promotion of bone formation, whereas ZA administration suppresses this pathway and results in endogenous MK-4 deficiency. However, no study has evaluated whether exogenous MK-4 supplementation can prevent ZA-induced MRONJ. Here we showed that MK-4 pretreatment partially ameliorated mucosal nonunion and bone sequestration among ZA-treated MRONJ mouse models. Moreover, MK-4 promoted bone regeneration and inhibited osteoblast apoptosis in vivo. Consistently, MK-4 downregulated ZA-induced osteoblast apoptosis in MC3T3-E1 cells and suppressed the levels of cellular metabolic stresses, including oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and DNA damage, which were accompanied by elevated sirtuin 1 (SIRT1) expression. Notably, EX527, an inhibitor of the SIRT1 signaling pathway, abolished the inhibitory effects of MK-4 on ZA-induced cell metabolic stresses and osteoblast damage. Combined with experimental evidences from MRONJ mouse models and MC3T3-E1 cells, our findings suggested that MK-4 prevents ZA-induced MRONJ by inhibiting osteoblast apoptosis through suppression of cellular metabolic stresses in a SIRT1-dependent manner. The results provide a novel translational direction for the clinical application of MK-4 for preventing MRONJ., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This study investigated the incidence, risk factors, and outcome of medication-related osteonecrosis of the jaw after dental extractions in patients receiving antiresorptive agents for osteoporosis or bone metastases. 240 patients with a median drug exposure of 43 months were retrospectively studied. The incidence of MRONJ after dental extraction in the osteoporosis cohort was 2.7 % per person-year (95 % CI 1.6-4.6 %) (n = 13/126), and for the bone metastases cohort 26.4 % per person-year (95 % CI 20.4-34.2 %) (n = 58/114). 92 % of MRONJ cases were stage 1. Dental infection as the reason for extraction increased the osteonecrosis risk in the osteoporosis (OR 22.77; 95 % CI 2.85-181.62; p = 0.003) and bone metastases cohorts (OR 2.72; 95 % CI 1.28-5.81; p = 0.010). Using leukocyte and platelet-rich fibrin reduced this risk by 84 % (p = 0.003), as did antibiotics use by 86-93 % (p = 0.013). Within the bone metastases cohort, an interval since last administration of at least 3 months reduced risk of MRONJ (OR 0.83; 95 % CI 0.72-0.97; p = 0.018). Mucosal healing occurred in 11/13 patients (84.6 %; 95 % CI 54.5-98.1 %) with osteoporosis and 31/58 patients (53.4 %; 95 % CI 40.0-66.7 %) with bone metastases. In conclusion, though the MRONJ risk in this selected population taking antiresorptive agents and presenting to the Oral Maxillofacial Surgery clinic for a dental extraction is considerable and higher in those with dental infections, preventive measures such as antibiotics and use of LRPF membranes may significantly reduce that risk., (Copyright © 2023. Published by Elsevier Inc.)

Background: Cardiovascular effects of osteoporosis medications have recently been highlighted. Although oral and intravenous bisphosphonates are assumed to have similar cardiovascular safety, few head-to-head comparisons exist. The cardiovascular safety of teriparatide is unknown. Aim We conducted a pharmacovigilance safety study of cardiac events using real-life adverse event reports from alendronate, zoledronic acid and teriparatide users., Methods: Adverse drug reactions were obtained from Vigibase, a WHO database of individual case safety reports (ICSRs) from 130 countries (1967-2020). ISCRs for atrial fibrillation (AF), angina pectoris, arteriosclerosis coronary artery (ACA), cardiac arrhythmias, coronary artery disease (CAD), thromboembolic events (TE), ischaemic heart disease (IHD), torsade de pointes/QT prolongation (TDP) associated with alendronate, zoledronic acid and teriparatide use were extracted. Data were included in a disproportionality analysis where the lower end of the 95 % credibility interval for the information component (IC 025 ), showing a statistical association when >0. Head-to-head comparisons of ISCRs were estimated by age-adjusted odds ratios and 95 % confidence intervals., Results: 465 episodes of angina, 287 ACA, 13,385 arrhythmias, 792 CAD, 6743 TE, 3264 IHD, 1037 myocardial infarcts, and 3714 TDP events were recorded across 50,365 alendronate, 52,436 zoledronic acid and 137,629 teriparatide users. There was a significant association between alendronate and zoledronate with all outcomes except MI. Teriparatide use was associated with AF, arrythmias and angina only. In head-to-head comparisons, teriparatide use was associated with fewer ACA and CAD events than alendronate and fewer ACA than zoledronic acid., Discussion: Osteoporosis medication use is associated with adverse cardiac events, except for MI, and these appear to be more common with oral and intravenous bisphosphonates than teriparatide. Our data do not support differential effects of oral and intravenous bisphosphonates on cardiac events. Mechanisms whereby teriparatide may be cardio-protective warrant further investigation., Competing Interests: Declaration of competing interest The salary of AJR is supported by a National Health and Medical Research Council Australia Investigator Grant (GNT1197958). PRE has received grant funding to his institution from Amgen, Eli-Lilly and Alexion, and honoraria from Amgen and Sanofi., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest Vanessa Costa de Sousa Ferreira, Amanda Pimentel Lopes, Nicholas Militão Alves, Fátima Regina Nunes Sousa, Raquel Felipe Vasconcelos, Conceição Silva Martins, Karuza Pereira Alves, Delane Viana Gondim, Vírginia Claúdia Carneiro Girão, Renata Ferreira Carvalho Leitão, Gerly A. C. Brito and Paula Goes have nothing to disclose.

The balance between osteoclastic bone resorption and osteoblastic bone formation is ultimately responsible for maintaining a structural and functional skeleton. Despite their strength, bones do break and the main cause of fractures are trauma and decreased bone mineral density as a result of aging and/or pathology that weakens the bone's microarchitecture and subsequently, its material properties. Osteoporosis is a disease marked by increased osteoclast activity and decreased osteoblastic activity tipping the remodeling balance in favor of bone resorption and can be caused by aging, glucocorticoids, disuse and estrogen-deficiency. Ultimately, this leads to brittle and weaker bones which become more prone to trauma or stress-induced fractures. The current treatment for preventing and treating osteoporotic fractures is the use of antiresorptive drugs such as bisphosphonates (BPs) and denosumab, but unfortunately, their long-term use, especially with alendronate and ibandronate, has been associated with increased risk of atypical femoral fractures (AFFs); femoral diaphyseal fractures distal to the lesser trochanter but proximal to the supracondylar flare. The purpose of this review is to examine the information that exists in the literature examining the effects of BPs on fracture repair of long bones in rodent (rat and mouse) models. The focus on rodents stems from the scientific community's unresolved need to develop small animal models to examine the molecular, cellular, tissue and biomechanical mechanisms responsible for the development of AFFs and how best they can be treated., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Romosozumab is a potent drug for treating postmenopausal osteoporosis but has a limited dosing period of 12 months. Bone mineral density (BMD) decreases soon after romosozumab discontinuation, thus emphasizing the importance of appropriate sequential treatment. The present VICTOR randomized controlled study compared the efficacy of ibandronate and denosumab as sequential therapy options following 12-month romosozumab treatment. Subjects completing 12 months of romosozumab administration for severe postmenopausal osteoporosis were randomly assigned to receive either ibandronate or denosumab for an additional 12 months. The primary outcome of interest was the percentage changes in BMD at the lumbar spine, total hip, and femoral neck from 12 months (completion of romosozumab) to 18 and 24 months of total treatment (6 and 12 months, respectively, after the conversion to sequential therapy). Secondary outcomes included alterations in serum bone turnover markers and the incidence of adverse events. Sixty-two subjects each in the ibandronate and denosumab groups completed the sequential therapy. The respective percentage changes in BMD at the lumbar spine from 12 months to 24 months were 2.5 % in the ibandronate group and 5.4 % in the denosumab group. At 24 months, we observed significant differences versus 12 months for both groups as well as between the groups (all P < 0.01), showing a superior ability to increase BMD at the lumbar spine for denosumab over ibandronate. BMD gains at the total hip and femoral neck exhibited comparably favorable trends. P1NP and TRACP-5b were significantly decreased from 12 to 24 months (-64.9 % and - 26.8 % in the ibandronate group and - 67.4 % and - 36.3 % in the denosumab group, respectively; all P < 0.001 versus 12 months). Several minor adverse events were recorded in both groups, none of which led to the discontinuation of the trial. The VICTOR study revealed that denosumab could be considered more effective than ibandronate, with few severe adverse events, for the enhancement of BMD as a sequential agent after romosozumab in postmenopausal osteoporosis patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Teriparatide, a recombinant human parathyroid hormone analogue, is associated with increased bone mineral density and a decreased risk of fractures. A dose-dependent increase in the incidence of osteosarcoma was observed in toxicology studies conducted in rats. The primary objective of this study was to estimate the incidence of osteosarcoma over a 10-year period among teriparatide-treated patients versus patients unexposed to teriparatide with osteoporosis and patients in the general population using national pharmacy dispensing data linked with data from participating state cancer registries (SCRs) in the US., Methods: Patients aged 18 years or older with a dispensed teriparatide prescription formed two different cohorts: Teriparatide-Osteoporosis (Teriparatide-OP) was formed by matching teriparatide patients to unexposed patients with osteoporosis and Teriparatide-General Population (Teriparatide-GP) was formed by matching teriparatide patients to general population patients with a dispensed prescription for a medication other than teriparatide. Matching was performed using select demographics and other variables. Study cohorts were linked to SCR data to ascertain osteosarcoma status. To account for missing outcome data from non-participating SCRs, two analytic approaches were used: the first adjusted the person-time at-risk using a coverage fraction and the second restricted the analyses to patients from states with participating SCRs., Results: There were 18 osteosarcoma cases across four study cohorts: the same three cases in the Teriparatide-OP and Teriparatide-GP cohorts, six cases in the Osteoporosis cohort, and nine cases in the General Population cohort. For the analysis using the coverage fraction the incidence rate ratio (IRR) comparing the Teriparatide-OP and Teriparatide-GP cohorts to the Osteoporosis and General Population cohorts was 1.0 (95% CI: 0.2, 4.5) and 1.3 (95% CI: 0.2, 5.1), respectively. When restricting the analysis to patients from states with participating SCRs, the IRR was 0.6 (95% CI: 0.1, 3.6) and 0.8 (95% CI 0.1, 4.0), respectively., Conclusion: The estimates of association between teriparatide and osteosarcoma were imprecise due to the small number of observed osteosarcoma cases. However, the incidence of osteosarcoma observed in each study cohort was within the expected range given background rates for the US general population. The evidence generated by this study, in conjunction with other real-world studies evaluating the risk of osteosarcoma, was used to support changes to the US teriparatide label (including removal of the black box warning regarding potential risk of osteosarcoma) and expand treatment options for patients with osteoporosis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Central giant cell granulomas (CGCG) are rare osteolytic, benign but often locally aggressive tumours of bone. Surgical curettage may not be possible in extensive lesions and resection carries high morbidity, especially in growing children, and previous medical therapies have had variable efficacy and high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours., Aims: To evaluate the efficacy and safety of our protocol for denosumab treatment of CGCG in children., Methods: Retrospective review of 4 patients treated with denosumab using a standardised protocol for CGCG in a tertiary paediatric centre. Denosumab 70 mg/m 2 was given 4-weekly, followed by 2 doses of zoledronate 0.025 mg/kg, aimed at preventing rebound hypercalcaemia., Results: Treatment of CGCG resulted in metabolic remission in all patients, but recurrence, detected by positron emission tomography (PET), occurred at 6 months in three patients and 12 months in one patient. Three patients developed symptomatic hypercalcaemia 4-5 months and one patient asymptomatic hypercalcaemia 7 months after cessation of denosumab, with 3 requiring additional bisphosphonate treatment., Conclusions: Denosumab produced a radiological and metabolic response in our patients, but metabolic recurrence occurred in all patients. PET imaging was effective for monitoring treatment response and early detection of recurrence. Incidence of rebound hypercalcaemia in this paediatric cohort was high. We present proposed changes to our protocol with the aim of producing sustained remission and preventing rebound hypercalcaemia., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Bisphosphonates are effective in reducing hip and other fractures. However, concerns about atypical femur fractures (AFFs) have contributed to substantially decreased bisphosphonate use, and hip fracture rates may be increasing. Despite this impact, important uncertainties remain regarding AFF risks including the association between bisphosphonate use and other risk factors such as BMD, age, weight, and race. To address this evidence gap, a cohort study of 196,129 women ≥50 years of age in the Southern California Kaiser Permanente HMO women (with ≥1 bisphosphonate prescription) were studied; the primary outcome was radiographically-adjudicated AFF between 2007 and 2017. Risk factors including bisphosphonate use and race were obtained from electronic health records. Multivariable Cox models were used for analysis. Benefit-risk was modeled for 1-10 years of bisphosphonates to compare fractures prevented vs. AFFs associated. Among 196,129 women, 277 (0.1%) sustained AFFs. After multivariable adjustment, AFF risk increased with longer bisphosphonate duration: hazard ratio (HR) increased from HR = 8.9 (95%CI: 2.8,28) for 3-5 years to HR = 43.5 (13.7138.1) for >8 years. Hip BMD, surprisingly, was not associated with AFF risk. Other risk factors included Asian ancestry (HR = 4.8 (3.6, 6.6)), short stature, overweight, and glucocorticoid use. Bisphosphonate discontinuation was associated with rapid decrease in AFF risk. Decreases in osteoporotic and hip fractures risk during 1-10 years of bisphosphonates far outweighed the increase AFF risk in Caucasians, but less so in Asians. In Caucasians, after 3 years 149 hip fractures were prevented with 2 AFFs associated compared to 91 and 8 in Asians. The evidence for several potential mechanisms is summarized with femoral geometry being the most likely to explain AFF risk differences between Asians and Caucasians. The results from this new study add to the evidence base for AFF risk factors and will help inform clinical decision-making for individual patients about initiation and duration of bisphosphonate therapy and drug holidays., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Once-yearly infusions of zoledronic acid (ZA) 5 mg may be optimal for secondary fracture prevention after hip fracture (HF), but there are crucial side effects of ZA. This study assessed the tolerability of the first infusion of once-yearly ZA within one to two weeks after HF surgery and to identify risk factors for acute-phase reactions (APRs) and the decrease in serum calcium (Ca) concentration., Methods: We analyzed 84 patients (average age: 83 years, 18 men and 66 women) who met the inclusion criteria. The patients underwent the first infusion of ZA one to two weeks after HF surgery and received antipyretic analgesics and active vitamin D analog., Results: APRs occurred in ten patients (11.9%) and all these patients had pyrexia (>37.5 °C) and/or other symptoms. The asymptomatic hypocalcemia (serum Ca < 8.3 mg/dL) incidence was 6.0% at 7 days after ZA infusion. Compared with female patients without APRs, female patients with APRs had significantly higher levels of serum 25-dihydroxyvitamin D at baseline and serum C-reactive protein on the day ZA was administered (day 0). Multiple linear regression analyses showed that serum level of tartrate-resistant acid phosphatase-5b were significantly associated with an absolute decrease in serum corrected Ca from day 0 to day 7., Conclusions: The first infusion of ZA within one to two weeks after HF surgery was well tolerated with the combined use of antipyretic analgesics and active vitamin D analog. Higher inflammatory condition after surgery which is more likely sensitized by ZA administration may increase the risk of APRs, and high bone turnover may increase hypocalcemia risk., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Denosumab is the world's first human monoclonal antibody for the treatment of osteoporosis and shares an active pathway with bisphosphonates, strongly suppressing osteoclast activities. This is the first case report describing a possible relationship between the development of osteonecrosis of external auditory canal and denosumab administration. We herein report an 81-year-old woman diagnosed with left osteonecrosis of external auditory canal who had a history of denosumab administration. She underwent left radical mastoidectomy due to being refractory to conservative treatment. No major complications or recurrence were observed in the left ear after surgery, but bone erosion in the right ear has continued to progress slowly despite the cessation of denosumab administration. Otolaryngologists should be aware of the association between osteonecrosis of external auditory canal and denosumab administration and consider performing long-term observation even after cessation., (Copyright © 2020. Published by Elsevier B.V.)

Background: Atypical femur fractures are widely recognized and associated with anti-resorptive therapy, most commonly bisphosphonates. These fractures generally occur in the femoral shaft or subtrochanteric region. Cases of atypical fractures at non-femur sites, including the ulna, have been reported., Case Report: Here we report a probable atypical ulnar fracture in a man receiving denosumab, who had been using his upper extremities for transfers and ambulation. Radiographs demonstrated a non-comminuted, transverse fracture somewhat similar to findings of atypical femur fractures. He was deemed a poor surgical candidate and treated with teriparatide. To our knowledge, this is the first reported probable atypical ulnar fracture potentially associated with denosumab use., Conclusion: We believe it important that clinicians be aware of the association of anti-resorptive therapy with atypical fractures not only of the femur, but also at other skeletal sites. In patients on long-term anti-resorptive therapy, it is appropriate to consider that persistent "prodromal" pain might indicate an impending atypical fracture at an atypical skeletal site., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Bone turnover suppression agents are widely used for prophylaxis of bone metastases from cancer and osteoporosis; the occurrence of their side effect, antiresorptive agent-related osteonecrosis of the jaw (ARONJ), has been increasing. We investigated the relationships between opacification in the nasal sinuses, rhinosinusitis, and ARONJ based on data obtained from oral surgeons., Methods: We examined 132 patients who had been clinically diagnosed with ARONJ based on clinical observations; all patients had undergone treatment at the Departments of Otorhinolaryngology and Oral Surgery. In 16 of the 132 patients, we confirmed a diagnosis of osteonecrosis of the upper jaw and the presence of ipsilateral opacification of the maxillary sinus. We analyzed the data of these 16 patients in detail., Results: Five of the 16 patients had some nasal symptoms and had been diagnosed with rhinosinusitis. The opacification of the rhinosinuses improved, partially improved, and remained unchanged after treatment in 10, three, and two patients, respectively; notably, imaging assessment could not be conducted after treatment in one case., Conclusions: Although there is no consensus regarding the treatment of sinusitis accompanying ARONJ, attempts to improve the causal foci and conservative treatment may offer favorable results; thorough investigation is necessary in refractory cases before determining the use of surgery., Competing Interests: Declaration of Competing Interest All authors confirm that they have no funding information, financial relationships, or other conflicts of interest that should be disclosed., (Copyright © 2020 Oto-Rhino-Laryngological Society of Japan Inc. Published by Elsevier B.V. All rights reserved.)

Zoledronate is the most potent and most long-acting bisphosphonate in clinical use, and is administered as an intravenous infusion. Its major uses are in osteoporosis, Paget's disease, and in myeloma and cancers to reduce adverse skeletal related events (SREs). In benign disease, it is a first- or second-line treatment for osteoporosis, achieving anti-fracture efficacy comparable to that of the RANKL blocker, denosumab, over 3 years, and it reduces fracture risk in osteopenic older women. It is the preferred treatment for Paget's disease, achieving higher rates of remissions which are much more prolonged than with any other agent. Some trials have suggested that it reduces mortality, cardiovascular disease and cancer, but these findings are not consistent across all studies. It is nephrotoxic, so should not be given to those with significant renal impairment, and, like other potent anti-resorptive agents, can cause hypocalcemia in patients with severe vitamin D deficiency, which should be corrected before administration. Its most common adverse effect is the acute phase response, seen in 30-40% of patients after their first dose, and much less commonly subsequently. Clinical trials in osteoporosis have not demonstrated increases in osteonecrosis of the jaw or in atypical femoral fractures. Observational databases are currently inadequate to determine whether these problems are increased in zoledronate users. Now available as a generic, zoledronate is a cost-effective agent for fracture prevention and for management of Paget's disease, but wider provision of infusion facilities is important to increase patient access. There is a need to further explore its potential for reducing cancer, cardiovascular disease and mortality, since these effects could be substantially more important than its skeletal actions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Asian race, younger age, higher body mass index (BMI) and antiresorptive drugs have all been associated with atypical femur fractures (AFFs). This increased risk of AFF in Asians is important as by 2050, >50% of hip fractures globally will occur in Asia, with an increased demand for antiresorptive drugs being likely. It is also currently unclear whether AFF risk is increased in all Asian subgroups. We therefore aimed to identify the incidence of AFFs in an Australian tertiary hospital, the contribution of ethnic origin to AFF risk, and determine other clinical risk factors for AFF. From January 1, 2009 to December 31, 2017, 97 AFFs (82 complete and 15 incomplete) occurred in 71 individuals in the overall study population of 204,358. Patients with AFF were more likely to be female (88.7% vs 69.1%, p < 0.001) and younger [median (IQR): 74(52-92) years vs 83(75-88) years, p < 0.001] than the "typical" femur fracture group (n = 3330). The cumulative incidence rate of AFF was 4.2 per 100,000 person-years, far lower than for any ICD-10 AM coded "typical" femur fracture (202.9 per 100,000 person-years). Asians were 3.4 (95%CI, 2.1-5.6) times more likely to sustain an AFF than non-Asians, the highest incidence being in those from South East Asian countries (16.6 per 100,000 person years), suggesting differences in risk between Asian countries. In the nested case-control study, bisphosphonate use was an independent association with AFF development. We conclude Asian ethnicity is an important association with AFF in this large Australian cohort., Competing Interests: Declaration of competing interest PRE: has received research funding or honoraria from Amgen, Eli-Lilly and Theramex. AJV has received research funding or honoraria from Amgen. RZ has received research funding or honoraria from Amgen, MSD, Servier, GENZYME & AKP. He is a Director of StraxCorp Pty Ltd. All other authors state they do not have other conflicts of interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: This observational safety study used national registers to compare the real world cardiovascular and skeletal safety of zoledronic acid (ZA) against oral bisphosphonates (oBP) and untreated population controls., Methods: Propensity score matched cohort study in Sweden and Denmark., Results: Matched cohort 1 included 8739 ZA users and 25,577 oBP users while matched cohort 2 included 8731 ZA users and 25,924 untreated subjects. In comparison to oBP users, heart failure risk was higher in ZA users, with an adjusted HR (adj) (95%CI) of 1.17 (1.04;1.32) and a higher all-cause mortality (adj HR 1.24 (1.15; 1.34)), however, there was no increased risk of cardiovascular mortality. In the comparison to untreated subjects, ZA users showed a higher risk of atrial fibrillation, adj HR 1.18 (1.05;1.32), arrhythmias adj HR 1.18 (1.06;1.31), and heart failure, adj HR 1.38 (1.24;1.54). Cardiovascular mortality was lower in ZA users (adj HR 0.87 (0.77; 0.98)) and risk of adverse skeletal outcomes was significantly higher, reflecting more severe osteoporosis in these patients. There was no association of cardiovascular risk with increasing exposure time. Sensitivity analyses produced similar findings with no substantial changes in event rates., Conclusions: We noted an increased risk of heart failure, fractures and death among ZA users compared with oral BP. The risk of cardiovascular and skeletal outcomes was higher in ZA users than in matched population controls, but there was no increase in cardiovascular mortality in ZA users compared to oral BP or untreated controls. Despite propensity score matching, it is not possible to determine with certainty whether the increased risk of cardiovascular outcomes is consistent with a true drug effect or higher baseline risk in patients who begin ZA treatment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Antiresorptive therapies reduce fracture risk; however, long-term bone turnover inhibition may raise concerns about rare, but serious, skeletal adverse events-atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). Denosumab, a fully human monoclonal antibody against RANKL, has demonstrated sustained low vertebral and nonvertebral fracture rates with low skeletal adverse event rates in the 3-year FREEDOM trial and its 7-year Extension (in which all subjects received open-label denosumab). In this analysis, we aimed to estimate fractures prevented relative to skeletal adverse events observed with 10 years of denosumab therapy. We modeled a hypothetical placebo group using the virtual-twin method, thereby allowing calculation of fractures prevented with denosumab treatment (relative to the virtual-placebo group) in the context of AFF or ONJ events observed in the long-term denosumab group. Estimated virtual-placebo and observed long-term denosumab exposure-adjusted fracture rates per 100,000 subject-years were calculated for fractures classified as clinical (3180 and 1777, respectively), major osteoporotic (2699 and 1525), vertebral (1879 and 901), and nonvertebral (2924 and 1528), and compared with observed AFF and ONJ in the long-term denosumab group (5 and 35 per 100,000 subject-years, respectively). The skeletal benefit/risk ratio (fractures prevented per adverse event observed) for clinical fractures was 281 (AFF) and 40 (ONJ). Based on this model, denosumab treatment for up to 10 years has a favorable skeletal benefit/risk profile when comparing fractures prevented per skeletal adverse event observed. Clinical trial registration: NCT00089791, NCT00523341., Competing Interests: Declaration of competing interest S Ferrari has received research grants from Amgen, UCB Pharma, and Agnovos; has received consulting fees from Amgen, UCB Pharma, Eli Lilly, Agnovos, and LAbatec; and has given expert testimony for Novartis. EM Lewiecki has received research grants from Radius, Amgen, Mereo, and Bindex; has received consulting fees and served on the advisory board for Amgen, Radius, Alexion, Sandoz, and Samsung Bioepis; and has served on the speaker's bureau for Radius and Alexion. PW Butler, DB Crittenden, and N Pannacciulli are former employees and stockholders of Amgen Inc. DL Kendler has received research grants from Amgen and AstraZeneca; has received consulting fees from Amgen and Eli Lilly; and has served on the speaker's bureau for Amgen, Eli Lilly, and Pfizer. N Napoli has received consulting fees from Abiogen, Eli Lilly, and UCB Biopharma; and has served on the speaker's bureau for Eli Lilly. S Huang is an employee and stockholder of Amgen Inc. E Siris has received royalties from Up To Date as a peer reviewer for denosumab. N Binkley has received research grants from Radius, RTI Health Solutions, and GE Healthcare; and has received consulting fees/served on an Advisory Board for Amgen and Taurus., (Copyright © 2020. Published by Elsevier Inc.)

Background: Vertebral fractures (VF) upon Denosumab (DMAB) discontinuation were first described as a distinct phenomenon in 2015, yet the magnitude of this event remains undetermined., Objectives: To estimate fracture risk after DMAB discontinuation, in a real-world setting., Methods: The computerized database of a 2.3-million members' state-mandated health organization was utilized to detect osteoporotic patients with at least two DMAB dispenses. Treatment discontinuation was defined as a refill gap of 3 months or more, while the discontinuation date was defined as an anticipated missed purchase date. Fractures were identified by an osteoporosis registry and individually adjudicated by an expert's review. Fractures occurring within one year from discontinuation among DMAB discontinuers (DD) and from the 2nd year of treatment onwards for persistent users (PU) were included., Results: A total of 1500 DD (92% females, mean ± SD age = 71.8 ± 9.5y), and 1610 PU (91%, 71.7 ± 8.8) were identified. At baseline, the groups were comparable in fracture- history, bisphosphonate exposure, smoking, and bone density. Multiple VF occurred in 12 (0.8%) DD vs. 2 (0.1%) PU (p = 0.006). The overall rate of fractures per 100 patient-years of follow-up was significantly higher in DD than PU (RR 3.2, 95% CI 2.2-4.8), as well as the rate of VF (RR 4.7, 95% CI 2.3-9.6) and multiple VF (RR 14.6, 95% CI 3.3-65.3, effect size 1.06)., Conclusions: Patients who discontinue DMAB are at greater risk of major OP fractures than those who persist with treatment. Same is true for clinical multiple vertebral fractures, yet the incidence of the latter was low. These findings demonstrate a need for greater awareness and thoughtful management of DMAB discontinuation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Zoledronic acid (ZOL), a nitrogen bisphosphonate (N-BP), is currently used to treat and control pediatric osteolytic diseases. Variations in the intensity of the effects and side effects of N-BPs have been reported with no clear explanations regarding their origins. We wonder if such variations could be associated with different levels of RANKL signaling activity in growing bone during and after the treatment with N-BPs. To answer this question, ZOL was injected into neonate C57BL/6J mice with different genetically-determined RANKL signaling activity levels (Opg +/+ \Rank Tg- , Opg +/+ \Rank Tg+ , Opg +/- \Rank Tg- , Opg +/- \Rank Tg+ , Opg -/- \Rank Tg- and Opg -/- \Rank Tg+ mice) following a protocol (4 injections from post-natal day 1 to 7 at the dose of 50 μg/kg) that mimics those used in onco-pediatric patients. At the end of pediatric growth (1 and half months) and at an adult age (10 months), the bone morphometric and mineral parameters were measured using μCT in the tibia and skull for the different mice. A histologic analysis of the dental and periodontal tissues was also performed. At the end of pediatric growth, a delay in long bone and skull bone growth, a blockage of tooth eruption, some molar root alterations and a neoplasia-like structure associated with incisor development were found. Interestingly, the magnitude of these side effects was reduced by Opg deficiency (Opg -/- ) but increased by Rank overexpression (Rank Tg ). Analysis of the skeletal phenotype at ten months confirmed respectively the beneficial and harmful effects of Opg deficiency and Rank overexpression. These results validated the hypothesis that the RANKL signaling activity level in the bone microenvironment is implicated in the modulation of the response to ZOL. Further studies will be necessary to understand the underlying molecular mechanisms, which will help decipher the variability in the effects of N-BPs reported in the human population. SIGNIFICANT STATEMENTS: The present study establishes that in mice the RANKL signaling activity level is a major modulator of the effects and side-effects of bisphosphonates on the individual skeleton during growth. However, the modulatory actions are dependent on the ways in which this level of activity is increased. A decrease in OPG expression is beneficial to the skeletal phenotype observed at the end of growth, while RANK overexpression deteriorates it. Far removed from pediatric treatment, in adults, the skeletal phenotypes initially observed at the end of growth for the different levels of RANKL signaling activity were maintained, although significant improvement was associated only with reductions in OPG expression., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Intravenous bisphosphonates (IV BP) have been used to treat children with osteoporosis for many years. Favorable side effect profile and improvements in bone mineral density (BMD) have been demonstrated in patients with osteogenesis imperfecta (OI), a primary form of osteoporosis in pediatrics. Less is known about the safety of IV BP in children with secondary osteoporosis or glucocorticoid-induced osteoporosis (GIO). We aimed to determine the prevalence of both acute and long-term side effects and assess the efficacy of IV BP treatment to increase bone mineral density in pediatric patients with varying presentations of compromised bone health., Methods: We conducted a retrospective chart review of pediatric patients (<21 years old) treated for osteoporosis with intravenous pamidronate (PAM) or zoledronic acid (ZA) at Cincinnati Children's Hospital Medical Center from 2010 to 2017. Patient demographics, diagnosis, infusion type and dose, acute phase reactions (APR), electrolyte abnormalities, and bone density measurements were collected from the electronic medical records. Diagnoses were grouped into 3 categories: primary osteoporosis, secondary osteoporosis, and GIO. Descriptive characteristics and adverse events were compared among categories. Change in bone mineral density (BMD) over time was compared among groups., Results: 123 patients (56% male) received 942 infusions (83% PAM and 17% ZA). APR was reported in 7% of all infusions and more common in secondary osteoporosis (16%, p < 0.0001). There was a higher percentage of acute adverse events after the first infusion (27% vs 5%, p < 0.0001). Hypocalcemia following IV BP infusions occurred in 7% (27/379) of infusions and was significantly associated with ZA use (p = 0.04). Severity of hypocalcemia was generally mild, requiring intravenous calcium in 3% (13/379) of infusions. Hypophosphatemia occurred frequently, however rarely required intravenous supplementation. In 468 patient years of IV BP exposure, there were no reports of osteonecrosis of the jaw (ONJ) nor atypical femoral fracture (AFF). Lumbar spine (LS) aBMD Z-score 1 year after IV BP initiation increased overall for all groups (p < 0.0001) but did not significantly differ for those who did or did not fracture following IV BP treatment., Conclusions: APR due to intravenous BP treatment for pediatric osteoporosis were infrequent and generally mild. APR were more likely to occur in patients with secondary osteoporosis, a group who may require closer monitoring. A higher proportion of hypophosphatemia occurred in the patients with GIO. Long-term serious adverse events including ONJ and AFF were not identified in our patient population. LS aBMD Z-score increased following initiation of IV BP. However, the change in BMD was not associated with risk of fracture during the follow-up interval. These data provide reassurance and suggest that IV BP can be safely used in pediatric patients with osteoporosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Declining use of bisphosphonates (BP) in the United States and Europe may lead to a widening of the treatment gap for osteoporosis and an increase in fracture rates. However, a shift to non-bisphosphonates and to hospital administered i.v. BPs could lead to overestimation of the treatment gap if analyses are based exclusively on BP prescriptions. When a healthcare system successfully narrows the treatment gap by making appropriate use of anti-osteoporosis drugs, we would expect to see declining rates of osteoporotic fractures with much of the decrease being statistically attributable to medication uptake. We analysed a best-case scenario where all use of BPs, denosumab, raloxifene and PTH analogues - including the oncology area - was contrasted with the trend in hip fracture rates. This scenario also considered users of raloxifene and teriparatide as covered by osteoporosis drugs though the primary RCT for raloxifene showed no risk reduction in nonvertebral fractures and the RCT for teriparatide risk reductions for non-vertebral fractures but not hip fracture specifically. Sensitivity analyses were also done., Methods: We used aggregate statistics on hip fracture events and total use of the above medications estimating the number of persons potentially covered. The reduction in hip fracture rates attributable to treatment was estimated using the absolute risk reduction (ARR) found in real-world users of oral alendronate in Denmark with the ARR in the FIT primary prevention arm as an alternative scenario., Results: A plateau in use of osteoporosis medications occurred in 2014. Between 2005 and 2015, hip fracture rates declined by 30%. However, only up to 20% of the observed reduction in hip fracture rates was statistically attributable to treatment even in a best-case scenario. Sensitivity analyses where raloxifene and teriparatide were excluded did not impact on this finding., Discussion: Anti-osteoporosis treatment in Denmark reached a plateau in 2014 even in a best-case scenario where all dispensations were assumed to be for osteoporosis. Future studies may be able to distinguish between the oncology area and the osteoporosis indication as well as provide a delineation of age and gender demographics among users of hospital administered osteoporosis medications. About 80% of the decline in hip fracture rates appears to be due to factors other than osteoporosis medication. The plateau in use of osteoporosis treatment at a level that is too low to make a meaningful impact on societal fracture burden is problematic given the predicted increased age-specific hip fracture rates., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A method for the extraction and quantification of zoledronic acid (ZA) from human bone was set up and validated. This method allowed the quantification of ZA from jawbone sequestrations of patients affected by bisphosphonate-related osteonecrosis of the jaw (BRONJ) associated with ZA treatment. The analyte was extracted from the bone tissues with phosphoric acid and derivatized using trimethylsilyl diazomethane (TMS-DAM). ZA tetramethyl phosphonate was then quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), showing high accuracy, repeatability and selectivity. Lower limits of quantification and detection (LLOQ and LLQD) were 3.4 ng/mL and 1 ng/mg, respectively. This study fully described the analytical process for the determination of ZA in human bone sequestrations, representing a pivotal step for further biomedical research on ZA and BRONJ., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: High-resolution peripheral quantitative computed tomography (HR-pQCT) represents a three-dimensional tool for the screening of osteoporosis patients i.e., regarding fracture risk. The purpose of this study was to determine the baseline and follow-up bone microarchitecture in relation to incident fracture risk in postmenopausal women on denosumab treatment., Methods: We have retrospectively evaluated data from 182 postmenopausal women treated with denosumab that underwent an initial HR-pQCT scan before the initiation of the treatment; and at least one second HR-pQCT after 12 months. Women were assigned to two groups based on documented fragility fractures for the following 2.9 ± 1.1 years: fracture (n = 22) and no fracture (n = 160). Baseline parameters from DXA, HR-pQCT and bone turnover were compared between the two groups. Furthermore, ROC and multiple regression analyses of the baseline and follow-up data were performed to evaluate the predictive value regarding incident fractures., Results: At baseline, trabecular parameters were significantly reduced in the fracture group and showed the best predictive value for new fractures, while DXA results could not predict fractures. A multiple regression model identified BV/TV and age as the best baseline parameters for incident fracture risk. At 12 months, cortical and trabecular parameters increased in the non-fracture group, while no significant increase was noted in the fracture group. However, no significant differences regarding the changes of these parameters could be detected between the non-fracture and fracture cohort., Conclusions: Trabecular bone microstructure at baseline is crucial for incident fracture risk in postmenopausal women on denosumab treatment, especially in comparison to DXA values. In this context, the microstructural follow-up results seemed to be of lesser importance regarding fracture risk. The results of this exploratory study should be validated in independent populations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) worsens oral health-related quality of life. Most BRONJ occurs in multiple myeloma or metastatic breast cancer patients treated with bisphosphonate/chemotherapeutic combination therapies. Cyclophosphamide (CY), an alkylating chemotherapeutic drug, is used to treat multiple myeloma, although its use has been recently reduced. The aim of this study was to clarify the effects of CY dose on tooth extraction socket healing when CY is used with or without bisphosphonate in mice. Low-dose CY (50 mg/kg; CY-L), moderate-dose CY (100 mg/kg; CY-M), high-dose CY (150 mg/kg; CY-H), and bisphosphonate [Zometa (ZA): 0.05 mg/kg] were administered for 7 weeks. Each dose of CY and ZA in combination was also administered for 7 weeks. Both maxillary first molars were extracted at 3 weeks after the initiation of drug administration. Euthanasia was performed at 4 weeks post-extraction. Gross wound healing, microcomputed tomography analysis, histomorphometry, and immunohistochemistry were used to quantitatively evaluate osseous and soft tissue wound healing of tooth extraction sockets. ZA monotherapy induced no BRONJ-like lesions in mice. CY monotherapy rarely induced open wounds, though delayed osseous wound healing occurred in a CY dose-dependent manner. In contrast, CY/ZA combination therapy prevalently induced BRONJ-like lesions with compromised osseous and soft tissue healing in a CY dose-dependent manner. Interestingly, anti-angiogenesis was noted regardless of CY dose and ZA administration, even though only CY-M/ZA and CY-H/ZA combination therapies induced BRONJ-like lesions. Our findings suggest that high-dose CY may be associated with the development of BRONJ following tooth extraction only when CY is used together with ZA. In addition to anti-angiogenesis, other factors may contribute to the pathoetiology of BRONJ., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Bisphosphonates can cause mucosal irritation. Although esophageal ulceration is a well-recognized adverse effect of bisphosphonates, pharyngolaryngeal ulcers associated with the improper use of oral bisphosphonates have rarely been described. A previously healthy 78-year-old woman presented with refractory pharyngolaryngeal ulcers. Extensive evaluation, including biopsy, bacterial culture, and blood tests did not identify any findings that indicated a specific disease diagnosis. Antibiotics and oral prednisolone were ineffective. Ultimately, it was found that the patient regularly took a tablet of alendronate, a type of bisphosphonate, by dissolving it in the oral cavity. Within 2 weeks after withdrawal of the use of the medication, her symptoms were eliminated, and the lesions were completely healed. This case illustrates the importance of correct administration of bisphosphonates. Given the widespread use of bisphosphonates, physicians need to be aware that their improper use can cause pharyngolaryngeal ulcers., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Osteoporosis is one of the most prevalent forms of age-related bone diseases. Increased bone loss with advancing age has become a grave public health concern. This study examined whether phlorizin and phloretin, dihydrochalcones in apple peels, inhibited senile osteoporosis through enhancing osteoblastogenic bone formation in cell-based and aged mouse models. Submicromolar phloretin and phlorizin markedly stimulated osteoblast differentiation of MC3T3-E1 cells with increased transcription of Runx2 and osteocalcin. Senescence-accelerated resistant mouse strain prone-6 (SAMP6) mice were orally supplemented with 10 mg/kg phlorizin and phloretin daily for 12 weeks. Male senescence-accelerated resistant mouse strain R1 mice were employed as a nonosteoporotic age-matched control. Oral administration of ploretin and phorizin boosted bone mineralization in all the bones of femur, tibia and vertebra of SAMP6. In particular, phlorizin reduced serum RANKL/OPG ratio and diminished TRAP-positive osteoclasts in trabecular bones of SAMP6. Additionally, treating phlorizin to SAMP6 inhibited the osteoporotic resorption in distal femoral bones through up-regulating expression of BMP-2 and collagen-1 and decreasing production of matrix-degrading cathepsin K and MMP-9. Finally, phlorizin and phloretin antagonized GSK-3β induction and β-catenin phosphorylation in osteoblasts and aged mouse bones. Therefore, phlorizin and phloretin were potential therapeutic agents encumbering senile osteoporosis through promoting bone-forming osteoblastogenesis via modulation of GSK-3β/β-catenin-dependent signaling., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Osteoporosis is a metabolic bone disease that is characterized by heightened state of bone resorption accompanied by diminished bone formation, leading to a reduction of bone mineral density (BMD) and deterioration of bone quality, thus increasing the risk of developing fractures. Molecular insight into bone biology identified cathepsin K (CatK) as a novel therapeutic target. CatK is a lysosomal cysteine protease secreted by activated osteoclasts during bone resorption, whose primary substrate is type I collagen, the major component of organic bone matrix. Available anti-resorptive drugs affect osteoclast survival and influence both resorption and formation of bone. CatK inhibitors are distinct from the existing anti-resorptives as they only target the resorption process itself without impairing osteoclast differentiation and do not interfere with bone formation. An inhibitor of CatK, odanacatib, robustly increased both trabecular and cortical BMD in postmenopausal osteoporosis patients. The phase III fracture prevention trial with odanacatib ended early due to good efficacy and a favorable benefit/risk profile, thus, enhancing the opportunity for CatK as a pharmacological target for osteoporosis. So far, all the inhibitors that reached to the stage of clinical trial targeted active site of CatK to abrogate the entire proteolytic activity of the enzyme in addition to the desired blockage of excessive elastin and collagen degradation, and could thus pose safety concerns with long term use. Identification of selective exosite inhibitors that inhibit CatK's elastase and/or collagenase activity but do not affect the hydrolysis of other physiologically relevant substrates of CatK would be an improved strategy to inhibit this enzyme., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Antiresorptive drugs have been widely used to treat patients with hypercalcemia caused by malignancy, bone metastasis, multiple myeloma, and osteoporosis. However, it is well known that antiresorptive drugs can cause osteonecrosis of the jaw (ONJ). Herein, we report a rare case of nasal septal abscess caused by medication related osteonecrosis of the jaw (MRONJ) in a breast cancer patient. A 69-year-old woman was referred to our clinic for evaluation of nasal obstruction. Physical examination revealed a cherry-like swelling of the nasal mucosa emanating from the septum that obstructed both nasal cavities and a fistulous tract showing pus discharge after extraction of the bilateral maxillary central incisors (MCI) and the right maxillary lateral incisor (MLI). Computed tomography and panoramic radiography revealed extensive osteonecrosis of the maxilla and swelling of the nasal mucosa. The clinical diagnosis was nasal septal abscess caused by osteonecrosis of the maxilla. Surgical procedure was undertaken for this case. An indwelling drain was placed in the oral cavity, and sequestrectomy was performed with incision and drainage of the anterior portion of left nasal septum. The patient was doing well at the 7-month follow-up. The patient had a medical history of breast cancer with bone, lung, liver metastases, and had received intravenous bisphosphonate, which is one of the antiresorptive medicines, over the past 4 years. We suspect that this history played an important role in MRONJ induced nasal septal abscess., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Prolonged bisphosphonate use has been associated with increased risk of atypical femoral fractures. Very few cases of atypical femoral fractures have been reported with denosumab. We report a case of bilateral tibial stress reactions in a 60-year-old man with no history of osteoporosis who was on prolonged high-dose denosumab for the treatment of giant cell tumor of bone. He presented with a 3-month history of pain in his bilateral shins worsening with activity and improving with rest. Although initial radiographs were unremarkable, he was found to have changes consistent with a stress reaction on magnetic resonance imaging of the distal tibia. To our knowledge, bilateral tibial stress reactions have not been previously reported with anti-resorptive therapies (neither bisphosphonates nor denosumab). Our case is intriguing in terms of the development of stress reactions as a precursor to stress fractures which may also relate to atypical fractures. Our case suggests a possible association between denosumab use and stress reactions. Of note the indication for denosumab in our case was for the treatment of giant cell tumor of bone where the Food and Drug Administration (FDA) approved dose is substantially higher than the FDA approved dose for osteoporosis treatment. Although rare, clinicians should consider the possibility of stress fractures in patients on anti-resorptive medications such as denosumab, especially when a patient presents with new onset thigh pain, hip pain or pain over an area affecting the long bones. Evaluation by imaging of affected areas should be pursued to enable early detection and intervention, as well as prevention of morbidity and associated ongoing risk to the patient., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Despite the fact that the medications used to treat abnormal bone conditions often induce osteonecrosis of the jaw (ONJ), previous attempts to establish an animal model for ONJ have shown insufficient consideration for this important prerequisite for the development of the disease. The purpose of this study was to establish an animal model with the most common metabolic bone disease, osteoporosis. Ninty-six rats were randomly divided into ovariectomy (Ov) group (n=48) and sham-operated group (n=48). Six weeks after Ov or sham surgery, rats in each group were subdivided into bisphosphonate group (n=36 each) and control group (n=12 each) and injected with zoledronic acid and normal saline, respectively, once a week. After additional 6weeks, surgical intervention was performed, and the injections were continued for 8 more weeks. The animals were then sacrificed for further macroscopic, histological, histomorphometric, radiological, and bone biomarker investigations. As histologically determined, the Ov group (77.8%) showed higher ONJ prevalence compared to the sham group (47.2%; P<0.05). Micro-structural and histomorphometric assessments revealed that rats with ONJ (ONJ group) presented with deteriorated bone architectures with higher necrotic bone fraction and lower number of osteoclasts (P<0.05). Compared to the sham-operated ONJ group, the Ov ONJ group showed significantly lower values of Tb.N, Tb.Sp, Conn.D, N.Oc/T.Ar, and TRACP 5b and CTX/TRACP (P<0.05). The ovariectomized rat model in this study successfully mimicked human ONJ lesions with an underlying bone disease and showed different bone characteristics than that of the previous ONJ model. Based on the differences, further researches for investigating pathophysiology of ONJ, including various pharmacological responses for deteriorated bone environment, are required., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy., Objective: Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients., Design, Setting, and Participants: This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial., Intervention: Patients were grouped by concomitant BTT use or no BTT use., Outcome Measurements and Statistical Analysis: Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models., Results and Limitations: While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p=0.01) and increased the time to ECOG deterioration (HR 0.75; p<0.001) and time to opiate use for cancer-related pain (HR 0.80; p=0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients., Conclusions: AA with concomitant BTT was safe and well tolerated in men with chemotherapy-naïve mCRPC. The benefits of AA on clinical outcomes were increased with concomitant BTT., Patient Summary: Treatment of advanced prostate cancer often includes bone-targeted therapy. This post hoc analysis showed that in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone in combination with bone-targeted therapy, there was a continued trend in prolongation of life when compared with patients treated with prednisone alone., Trial Registration: ClinicalTrials.gov NCT00887198., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Atypical femoral fractures (AFF) tend to occur in Asian women with prolonged bisphosphonate exposure. Hip geometry is thought to contribute to the risk of AFF formation. We examined the hip structural geometry parameters in Asian female chronic bisphosphonate users who sustained an AFF and compared them to chronic bisphosphonate users who did not sustain any femoral fracture (NFF) and bisphosphonate-naïve patients who sustained an osteoporotic femoral fracture (OFF)., Materials & Methods: Thirty-one patients with AFFs were gender and age-matched to 31 patients with NFFs and 49 patients with OFFs. The Hip Structural Analysis parameters analyzed were bone mineral density (BMD), cross-sectional area (CSA; a metric of resistance to axial compression), section modulus (SM; a metric of resistance to tensile loads), average cortical thickness (ACT; mean thickness of the femoral cortices), buckling ratio (BR; an index of likelihood of local buckling), and neck shaft angle (NSA; the angle between the neck and shaft axes). The regions analyzed were three cross-sections measured at the narrowest femoral neck diameter, the intertrochanteric area, and the proximal femoral shaft. One-way ANOVA with Bonferroni adjustment for multiple comparisons was used to compare parameters between the three patient groups, with statistical significance defined as p<0.05., Results: There were no statistical differences in parameters between patients with AFFs and patients with NFFs at all measured regions. Patients with AFFs and NFFs had statistically higher BMD, CSA, ACT, SM values and lower BR values at the NN and IT regions than patients with OFFs. Additionally, patients with NFFs had statistically higher SM values at the IT region than patients with OFFs, while patients with AFFs had statistically higher BMD, CSA, and ACT values at the FS region. All other measured parameters were not statistically different between the groups., Conclusions: Chronic bisphosphonate users with and without AFFs had similar femoral structural geometries. Unlike in other populations, varus neck shaft angles were not found to be associated with AFFs in Asian female chronic bisphosphonate users. Thus, bone cross-sectional geometry is not likely to be associated with AFFs in Asian female chronic bisphosphonate users. Hip Structural Analysis does not show an increased predilection for tensile failure in AFFs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Patients with high-risk localised prostate cancer (PCa) are at risk of developing bone metastases (BMs). Zoledronic acid (ZA) significantly reduces the incidence of skeletal complications in castration-resistant metastatic PCa versus placebo., Objective: To investigate ZA for the prevention of BMs in high-risk localised PCa., Design, Setting, and Participants: Randomised open-label multinational study with patients having at least one of the following: prostate-specific antigen ≥20 ng/ml, node-positive disease, or Gleason score 8-10., Intervention: Standard PCa therapy alone or combined with 4mg ZA intravenously every 3 mo for ≤4 yr., Outcome Measurements and Statistical Analysis: BMs were assessed using locally evaluated bone-imaging procedures (BIPs), with subsequent blinded central review. Patients with BMs, time to BMs, overall survival, and adverse events were compared between treatment groups., Results and Limitations: A total of 1393 of 1433 randomised patients were used for intention-to-treat (ITT) efficacy analyses, with 1040 patients with BIP-BM outcome status at 4±0.5 yr. The local urologist/radiologist diagnosed BIP-BMs in 88 of 515 patients (17.1%) in the ZA group and 89 of 525 patients (17.0%) in the control group (chi-square test: p=0.95), with a difference between proportions of 0.1% (95% confidence interval [CI], -4.4 to 4.7) in favour of the control group. In the ITT population (n=1393), the Kaplan-Meier estimated proportion of BMs after a median follow-up of 4.8 yr was 14.7% in the ZA group versus 13.2% in the control group (log-rank: p=0.65). Low hot spot numbers on bone scans were confirmed as metastases with additional imaging. Central reviews of BIPs were possible only on a subset of patients., Conclusions: ZA administered every 3 mo was demonstrated to be ineffective for the prevention of BMs in high-risk localised PCa patients at 4 yr., Patient Summary: Zoledronic acid administered every 3 mo was demonstrated to be ineffective for the prevention of bone metastases in high-risk nonmetastatic PCa patients at 4 yr., Trial Registration: The ZEUS trial is registered in the Dutch trial register www.trialregister.nl and the ISRCTN register at http://www.controlled-trials.com/ISRCTN66626762., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Bone metastases (BMs) are frequently present in patients with metastatic renal cell carcinoma (mRCC) and cause significant morbidity., Objective: The purpose of this analysis was to assess the impact of BMs and bisphosphonate therapy (BT) on outcomes in mRCC., Design, Setting, and Participants: We conducted a pooled analysis of patients with mRCC treated from 2003 to 2011 in phase 2 and 3 trials., Outcome Measurements and Statistical Analysis: Statistical analyses were performed using Cox regression and the Kaplan-Meier method., Results and Limitations: We identified 2749 patients treated with sunitinib (n=1059), sorafenib (n=355), axitinib (n=359), temsirolimus (n=208), temsirolimus plus interferon-α (IFN-α) (n=208), or IFN-α (n=560), with 28% (n=781) having BMs. A total of 285 patients (10.4%) received BT. The presence of BMs in patients was associated with shorter overall survival (OS) when compared with patients without BMs (13.2 vs 20.2 mo, respectively; p<0.0001) and shorter progression-free survival (PFS) (5.1 vs 6.7 mo, respectively; p<0.0008). When stratified by risk groups, the presence of BMs was associated with shorter OS in all risk groups. The use of BT in patients with BMs was not associated with improved OS compared with patients who did not receive BT (13.3 vs 13.1 mo, respectively; p=0.3801) or improved PFS (5.1 vs 4.9 mo, respectively; p=0.1785). Bisphosphonate users with BMs did not have a decreased rate of skeletal-related events (SREs) compared with nonusers (8.6% vs 5.8%, respectively; p=0.191). In addition, BT was associated with increased rates of hypocalcemia, renal insufficiency, and osteonecrosis of the jaw (p<0.0001). Data were analyzed retrospectively., Conclusions: We confirm that the presence of BMs is associated with shorter survival in mRCC. BT did not affect survival or SRE prevention and was associated with increased toxicity., Patient Summary: In this analysis, we demonstrate that bone metastases are associated with shorter survival in patients with metastatic renal cell carcinoma. In addition, we call into question the utility of bisphosphonate therapy in this population., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Osteoclast-induced bone resorption and wear-particle-induced osteolysis leads to prosthetic loosening, one of the most common causes of joint implant failure, resulting in revision surgery. Thus, inhibition of osteoclastic bone resorption, which further prevents wear particle-induced osteolysis, is a potential treatment strategy for prosthetic loosening. Here, we examined the therapeutic effect of hypericin (HP), which was photosensitive, on osteoclastogenesis and wear particle-induced osteolysis in the absence of visible light. HP inhibited RANKL-induced osteoclast differentiation in bone marrow macrophages (BMMs) and RAW264.7 cell line without any evidence of cytotoxicity. The bone-resorbing activity of mature osteoclasts was significantly inhibited by HP. As HP has been previously reported to inhibit signalling pathway such as ERK and NF-κB in other cells, which is also important in osteoclast differentiation. We thus examined the molecular mechanism and showed that HP significantly inhibited the ERK/mitogen-activated protein kinase (MAPK) signalling pathway without affecting nuclear factor kappaB (NF-κB), c-Jun N-terminal kinase (JNK) and p38 signalling in RANKL-stimulated BMMs. Further in vivo studies revealed HP attenuated osteoclast formation and subsequently prevented wear particle-induced bone erosion. Taken together, the results suggest that HP inhibits RANKL-mediated osteoclastogenesis via affecting ERK signalling in vitro and suppresses wear particle-induced osteolysis in vivo. We therefore conclude that HP may be an innovative and safe alternative treatment for osteoclast-related prosthetic loosening., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Atypical fractures of the diaphyseal femoral shaft have been reported in the literature at an increasing rate over the past few years. They have been observed mostly in patients who have been on prolonged courses of bisphosphonates, with no reported cases of atypical femoral fractures in those treated with other anti-resorptive medications. A 59 year old woman sustained an atypical fracture of her right femur in March 2013. She had a past medical history of rheumatoid arthritis and osteoporosis. She had been on alendronate but it was discontinued after five years in 1999. She received denosumab by subcutaneous injection in December 2012. At follow up, she complained of pain in her left femur and a radiograph revealed atypical appearances. She was admitted in June 2013 for prophylactic nailing of the left femur. To our knowledge, this is the first reported case of bilateral atypical femoral changes in a patient prescribed denosumab. Given that denosumab has been on the market for a short time period, we expect that the number of these cases will increase with time. We emphasise previous guidance that patients who present with new onset hip or thigh pain should be screened for atypical femoral fractures., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Oral risedronate has been shown to be effective in the treatment of osteoporosis when administered once-daily or once-weekly in Japan. This randomized, double-blind, multicenter 12-month study was conducted to compare the efficacy and tolerability of oral risedronate 75mg once-monthly with 2.5mg once-daily in Japanese patients with involutional osteoporosis. Bone mineral density (BMD), biochemical markers of bone metabolism, fractures, and adverse events (AEs) were evaluated. At the end of the study (Month 12, last observation carried forward [M12, LOCF]), mean percent change (SD) from baseline in lumbar spine (L2-L4) BMD, measured by dual energy X-ray absorptiometry (primary endpoint), was increased by 5.69 (4.00)% in the 2.5mg once-daily group (n=428), and 5.98 (4.54)% in the 75mg once-monthly group (n=422). In the non-inferiority t-test (non-inferiority margin Δ=1.5%), the 75mg once-monthly group was non-inferior to the 2.5mg once-daily group (p<0.0001). The difference between treatment groups was 0.28% (95% CI, -0.31% to 0.88%). Changes in biochemical markers of bone metabolism were generally comparable in the two groups, although decreases in the percent change from baseline in urinary NTX/CRN and CTX/CRN were statistically greater in the 2.5mg once-daily group than the 75mg once-monthly group. The frequency of new vertebral fractures (including aggravation of prevalent fractures) at the end of the study (M12, LOCF) was also similar in the two groups: 1.2% in the 2.5mg once-daily group and 1.3% in the 75mg once-monthly group. The incidence of mild/moderate/severe AEs was 75.5%/6.3%/0.5% in the 2.5mg once-daily group and 77.7%/8.1%/0.7% in the 75mg once-monthly group. AEs associated with gastrointestinal symptoms occurred in approximately 30% of subjects in each group but with no severe cases. AEs potentially associated with acute phase reaction (including symptoms of influenza-like illness or pyrexia starting within 3days of the first dose of the study drug and with a duration of 7days or less) only occurred in the 75mg once-monthly group (2.1%, 9/422 subjects; influenza-like symptoms in 1 subject and pyrexia in 8 subjects), although the incidence was low without any severe cases. In conclusion, risedronate 75mg once-monthly (a dosage which is 30 times higher than risedronate 2.5mg once-daily) had non-inferior efficacy in terms of BMD and was similarly well tolerated compared to the once-daily regimen in Japanese patients with involutional osteoporosis. Consistent with the once-daily and once-weekly dosage, the once-monthly dosage of risedronate 75mg was half that used outside Japan (150mg)., (© 2013. Published by Elsevier Inc. All rights reserved.)

Context: Advanced prostate cancer (PCa) is associated with skeletal complications, both as a result of bone metastases and because of fractures associated with fragility due to androgen-deprivation therapy (ADT). Osteoclast inhibitors are commonly used to reduce skeletal complications but are associated with a number of potential adverse events., Objective: To review clinical trials of osteoclast inhibitors in advanced PCa, to discuss the adverse event profile of these agents, and to discuss strategies to address specific adverse events., Evidence Acquisition: PubMed was searched for reports of clinical trials of osteoclast inhibitors in advanced PCa. As zoledronic acid and denosumab are used most commonly in this disease, these trials were the focus. The literature was reviewed to identify key publications addressing the prevention and management of adverse events associated with these drugs., Evidence Synthesis: The major findings of the trials and the adverse events are discussed. Prevention and management of common adverse events are addressed., Conclusions: Zoledronic acid prevents loss of bone mineral density associated with ADT and delays skeletal-related events in metastatic castration-resistant PCa (mCRPC). Denosumab reduces the incidence of fragility fractures associated with ADT, delays the onset of bone metastases in nonmetastatic castration-resistant disease, and is superior to zoledronic acid in the prevention of skeletal complications in mCRPC. Adverse events associated with both agents include osteonecrosis of the jaw and hypocalcemia. Hypocalcemia is more common with denosumab. Zoledronic acid requires dose modifications for renal insufficiency, is contraindicated in severe renal insufficiency, and has been associated with deterioration of renal function. Appropriate patient selection with close attention to dental health, supplementation with calcium and vitamin D, and monitoring of laboratory values are effective strategies to minimize the impact of adverse events associated with osteoclast inhibitors in advanced PCa., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the cost-effectiveness of denosumab versus other treatments in men with osteoporosis who are ≥75years old from a payer perspective in Sweden., Methods: A lifetime cohort Markov model was developed with seven health states: well, hip fracture, vertebral fracture, other osteoporotic fracture, post-hip fracture, post-vertebral fracture, and dead. During each cycle, patients could have a fracture, remain healthy, remain in a post-fracture state or die. Background fracture risks, mortality rates, persistence rates, utilities, medical and drug costs were derived using published sources. Estimates of fracture efficacy were drawn from available studies in post-menopausal osteoporotic (PMO) women as BMD improvements have been shown to be similar across male osteoporosis (MOP) and PMO populations, and a recent clinical trial suggested that the fracture risk reduction from bisphosphonate therapy in men is similar to that seen in women in comparable studies. Lifetime expected costs and quality-adjusted life-years (QALYs) were estimated for denosumab, generic alendronate, generic risedronate, ibandronate, zoledronate, strontium ranelate and teriparatide. On average, patients in the model were 78years old, with bone mineral density T-score at the femoral neck of -2.12. Prevalent vertebral fractures were present in 23% of patients. In the base-case, the model assumed that patients would experience treatment-related effects up to 2years after discontinuation. Costs and QALYs were discounted at 3% annually. Extensive sensitivity analyses were conducted., Results: Total lifetime costs for denosumab, alendronate, strontium ranelate, zoledronate, risedronate, ibandronate and teriparatide were €31,004, €33,731, €34,788, €34,796, €34,826, €35,983 and €37,461, respectively. Total QALYs were 5.23, 5.15, 5.15, 5.17, 5.13, 5.12 and 5.22, respectively. Compared to other treatments, denosumab had the lowest costs and highest QALYs. In the one-way sensitivity analyses, when compared to alendronate (next least expensive strategy), the ICER for denosumab was most sensitive to the relative risk of hip fracture on denosumab. The probability of denosumab being cost-effective compared to the other treatments at a threshold of €66,000/QALY was 96.1%., Conclusion: Denosumab dominated all comparators, including generic bisphosphonates, in the treatment of osteoporosis in men who were ≥75years old in Sweden., (Copyright © 2013 Elsevier Inc. All rights reserved.)