Pilot study to evaluate the safety and effectiveness of etidronate treatment for arterial calcification due to deficiency of CD73 (ACDC).

BACKGROUND: Arterial calcification due to deficiency of CD73 (ACDC; OMIM 211800) is a rare genetic disease resulting in calcium deposits in arteries and small joints causing claudication, resting pain, severe joint pain, and deformities. Currently, there are no standard treatments for ACDC. Our previous work identified etidronate as a potential targeted ACDC treatment, using in vitro and in vivo disease models with patient-derived cells. In this study, we test the safety and effectiveness of etidronate in attenuating the progression of lower-extremity arterial calcification and vascular blood flow based on the computed tomography (CT) calcium score and ankle-brachial index (ABI). METHODS: Seven adult patients with a confirmed genetic diagnosis of ACDC were enrolled in an open-label, nonrandomized, single-arm pilot study for etidronate treatment. They took etidronate daily for 14 days every 3 months and were examined at the NIH Clinical Center bi-annually for 3 years. They received a baseline evaluation as well as yearly follow up after treatment. Study visits included imaging studies, exercise tolerance tests with ABIs, clinical blood and urine testing, and full dental exams. RESULTS: Etidronate treatment appeared to have slowed the progression of further vascular calcification in lower extremities as measured by CT but did not have an effect in reversing vascular and/or periarticular joint calcifications in our small ACDC cohort. CONCLUSIONS: Etidronate was found to be safe and well tolerated by our patients and, despite the small sample size, appeared to show an effect in slowing the progression of calcification in our ACDC patient cohort.(ClinicalTrials.gov Identifier NCT01585402).

Safety and effectiveness of risedronate in Paget's disease of bone: postmarketing surveillance study in Japan.

INTRODUCTION: We conducted an all-case postmarketing surveillance study between 2008 and 2017 to evaluate the safety and effectiveness of risedronate for Paget's disease of bone (PDB) in Japan. MATERIAL AND METHODS: This study registered all patients who received once-daily risedronate 17.5 mg for the treatment of PDB and collected data over a 48-week follow-up period per treatment cycle for each patient. RESULTS: The safety analysis set included 184 patients (mean age, 63.7 years), 81 (44.0%) of whom previously received a bisphosphonate. Of them, 41 (22.3%) experienced 72 adverse drug reactions (ADRs), and 8 (4.3%) experienced 14 serious ADRs. Common ADRs included gastrointestinal disorders (20 patients, 10.9%) and hypocalcemia (6 patients, 3.3%). The effectiveness analysis set included 182 patients, 124 of whom completed only one treatment cycle and 58 of whom completed multiple treatment cycles. The proportions of patients who normalized serum alkaline phosphatase (ALP) concentration were 71.1% (113/159 patients) and 67.3% (33/49 patients) for the first and second treatment cycles, respectively. The relapse rate according to ALP levels after the end of treatment for the first cycle was 5.0% (95% confidence interval [CI] = 2.1-11.5) at 24 weeks and 12.9% (95% CI = 7.5-21.7) at 40 weeks. Regarding pain relief, the achievement rates were 70.0% (49/70 patients) and 30.8% (4/13 patients) for the first and second treatment cycles, respectively. CONCLUSION: To conclude, risedronate 17.5 mg/day is safe and effective for treating patients with PDB in daily practice.

Antiresorptive treatments for corticosteroid-induced osteoporosis: a Bayesian network meta-analysis.

INTRODUCTION: Corticosteroid-induced osteoporosis (CIO) is the most common type of secondary osteoporosis, leading to fractures, and increased morbidity and mortality. SOURCE OF DATA: Pubmed, EMBASE, Scopus and Google Scholar databases. AREAS OF AGREEMENT: Prolonged glucocorticoids administration leads to secondary osteoporosis. AREAS OF CONTROVERSY: The optimal management for CIO is controversial. GROWING POINTS: The present study compared bone mineral density, fractures and adverse events in patients undergoing treatment with risedronate, alendronate, zoledronate, denosumab or etidronate for CIO. AREAS TIMELY FOR DEVELOPING RESEARCH: For selected patients with CIO, alendronate performed better overall. These results must be interpreted within the limitations of the present study. LEVEL OF EVIDENCE: I, Bayesian network meta-analysis of randomized clinical trials.

Case report: Osteomalacia due to bisphosphonate treatment in a patient on hemodialysis.

BACKGROUND: No publications have reported on osteomalacia in patients receiving intermittent cyclical therapy with etidronate (a bisphosphonate) and undergoing long-term hemodialysis (HD). CASE PRESENTATION: We report on a 46-year-old Japanese man admitted to our hospital for further examination of left forearm pain. Maintenance HD was started at age 24 years, and the man had been on HD since then. At age 38 years, surgical parathyroidectomy was performed for secondary hyperparathyroidism; iliac crest bone biopsy performed at the same time showed osteitis fibrosa. The active vitamin D3 preparation calcitriol was started, and intermittent cyclical etidronate therapy was introduced 2 years later for osteoporosis. At age 45 years, the patient stopped taking calcitriol because of hypercalcemia but continued with etidronate. At age 46 years, a pseudofracture with a Looser zone occurred in the left ulna, and left femur bone biopsy revealed osteomalacia. Etidronate was discontinued, and calcitriol was restarted; open reduction and internal fixation with an angular stability plate were performed. Union of the bone was achieved 10 months after the operation. At age 49 years, a lumber bone biopsy confirmed improved bone morphometry. CONCLUSIONS: We believe that intermittent cyclical etidronate therapy without administration of active vitamin D3 during long-term HD might have induced osteomalacia, resulting in the ulna insufficiency fracture. Therefore, we propose that administration of active vitamin D3 is essential to prevent osteomalacia in patients on long-term HD who are receiving bisphosphonates and have potential vitamin D3 deficiency.

Bisphosphonates or RANK-ligand-inhibitors for men with prostate cancer and bone metastases: a network meta-analysis.

BACKGROUND: Different bone-modifying agents like bisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are used as supportive treatment in men with prostate cancer and bone metastases to prevent skeletal-related events (SREs). SREs such as pathologic fractures, spinal cord compression, surgery and radiotherapy to the bone, and hypercalcemia lead to morbidity, a poor performance status, and impaired quality of life. Efficacy and acceptability of the bone-targeted therapy is therefore of high relevance. Until now recommendations in guidelines on which bone-modifying agents should be used are rare and inconsistent. OBJECTIVES: To assess the effects of bisphosphonates and RANKL-inhibitors as supportive treatment for prostate cancer patients with bone metastases and to generate a clinically meaningful treatment ranking according to their safety and efficacy using network meta-analysis. SEARCH METHODS: We identified studies by electronically searching the bibliographic databases Cochrane Controlled Register of Trials (CENTRAL), MEDLINE, and Embase until 23 March 2020. We searched the Cochrane Library and various trial registries and screened abstracts of conference proceedings and reference lists of identified trials. SELECTION CRITERIA: We included randomized controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for men with prostate cancer and bone metastases. We included men with castration-restrictive and castration-sensitive prostate cancer and conducted subgroup analyses according to this criteria. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of trials. We defined proportion of participants with pain response and the adverse events renal impairment and osteonecrosis of the jaw (ONJ) as the primary outcomes. Secondary outcomes were SREs in total and each separately (see above), mortality, quality of life, and further adverse events such as grade 3 to 4 adverse events, hypocalcemia, fatigue, diarrhea, and nausea. We conducted network meta-analysis and generated treatment rankings for all outcomes, except quality of life due to insufficient reporting on this outcome. We compiled ranking plots to compare single outcomes of efficacy against outcomes of acceptability of the bone-modifying agents. We assessed the certainty of the evidence for the main outcomes using the GRADE approach. MAIN RESULTS: Twenty-five trials fulfilled our inclusion criteria. Twenty-one trials could be considered in the quantitative analysis, of which six bisphosphonates (zoledronic acid, risedronate, pamidronate, alendronate, etidronate, or clodronate) were compared with each other, the RANKL-inhibitor denosumab, or no treatment/placebo. By conducting network meta-analysis we were able to compare all of these reported agents directly and/or indirectly within the network for each outcome. In the abstract only the comparisons of zoledronic acid and denosumab against the main comparator (no treatment/placebo) are described for outcomes that were predefined as most relevant and that also appear in the 'Summary of findings' table. Other results, as well as results of subgroup analyses regarding castration status of participants, are displayed in the Results section of the full text. Treatment with zoledronic acid probably neither reduces nor increases the proportion of participants with pain response when compared to no treatment/placebo (risk ratio (RR) 1.46, 95% confidence interval (CI) 0.93 to 2.32; per 1000 participants 121 more (19 less to 349 more); moderate-certainty evidence; network based on 4 trials including 1013 participants). For this outcome none of the trials reported results for the comparison with denosumab. The adverse event renal impairment probably occurs more often when treated with zoledronic acid compared to treatment/placebo (RR 1.63, 95% CI 1.08 to 2.45; per 1000 participants 78 more (10 more to 180 more); moderate-certainty evidence; network based on 6 trials including 1769 participants). Results for denosumab could not be included for this outcome, since zero events cannot be considered in the network meta-analysis, therefore it does not appear in the ranking. Treatment with denosumab results in increased occurrence of the adverse event ONJ (RR 3.45, 95% CI 1.06 to 11.24; per 1000 participants 30 more (1 more to 125 more); high-certainty evidence; 4 trials, 3006 participants) compared to no treatment/placebo. When comparing zoledronic acid to no treatment/placebo, the confidence intervals include the possibility of benefit or harm, therefore treatment with zoledronic acid probably neither reduces nor increases ONJ (RR 1.88, 95% CI 0.73 to 4.87; per 1000 participants 11 more (3 less to 47 more); moderate-certainty evidence; network based on 4 trials including 3006 participants). Compared to no treatment/placebo, treatment with zoledronic acid (RR 0.84, 95% CI 0.72 to 0.97) and denosumab (RR 0.72, 95% CI 0.54 to 0.96) may result in a reduction of the total number of SREs (per 1000 participants 75 fewer (131 fewer to 14 fewer) and 131 fewer (215 fewer to 19 fewer); both low-certainty evidence; 12 trials, 5240 participants). Treatment with zoledronic acid and denosumab likely neither reduces nor increases mortality when compared to no treatment/placebo (zoledronic acid RR 0.90, 95% CI 0.80 to 1.01; per 1000 participants 48 fewer (97 fewer to 5 more); denosumab RR 0.93, 95% CI 0.77 to 1.11; per 1000 participants 34 fewer (111 fewer to 54 more); both moderate-certainty evidence; 13 trials, 5494 participants). Due to insufficient reporting, no network meta-analysis was possible for the outcome quality of life. One study with 1904 participants comparing zoledronic acid and denosumab showed that more zoledronic acid-treated participants than denosumab-treated participants experienced a greater than or equal to five-point decrease in Functional Assessment of Cancer Therapy-General total scores over a range of 18 months (average relative difference = 6.8%, range -9.4% to 14.6%) or worsening of cancer-related quality of life. AUTHORS' CONCLUSIONS: When considering bone-modifying agents as supportive treatment, one has to balance between efficacy and acceptability. Results suggest that Zoledronic acid likely increases both the proportion of participants with pain response, and the proportion of participants experiencing adverse events However, more trials with head-to-head comparisons including all potential agents are needed to draw the whole picture and proof the results of this analysis.

Association Use of Bisphosphonates with Risk of Breast Cancer: A Meta-Analysis.

BACKGROUND: Previous studies have investigated the association between the use of bisphosphonates and the development of breast cancer, which presented controversial results. Thus, this meta-analysis was conducted to summarize the current evidence of the association of bisphosphonate use with breast cancer risk. METHODS: A comprehensive search was conducted in PubMed, ISI Web of Knowledge, the Cochrane Library, and Embase from inception to March 2019 by two researches, who independently selected trials, retrieved relevant data, and assessed study quality. The summary relative risk (RR) for the use of bisphosphonates on the risks of developing breast cancer was calculated using a random-effect model. RESULTS: The present meta-analysis, which included four case-control studies, involving 55052 breast cancer cases, and seven retrospective cohort studies, involving 14641 breast cancer cases, assessed the effect of bisphosphonates on breast cancer risk. The random-effect model meta-analysis found a reduced risk of breast cancer with exposure to bisphosphonates with pooled RR of 0.87 (95% confidence interval [CI]: 0.80 to 0.94). The short-term use of bisphosphonates (<1 year) did not render significant alteration (RR = 0.92, 95% CI: 0.82 to 1.03), while a significant 26% risk reduction of breast cancer was noted with long-term use (>1 year) (RR = 0.74, 95% CI: 0.62 to 0.90). A protective effect of bisphosphonates was shown in contralateral breast cancer (RR = 0.41, 95% CI: 0.20 to 0.84). In terms of the type of bisphosphonates, a significant inverse relationship was noted for etidronate, with pooled RR of 0.87 (95% CI: 0.80 to 0.96). CONCLUSION: This meta-analysis suggested that the use of bisphosphonates was associated with reduced risk of breast cancer, including contralateral breast cancer. Compared to other types of bisphosphonates, only etidronate showed a significant inverse relationship. Additionally, the long-term use (>1 year) of bisphosphonates was more significant in lowering breast cancer risk. Further randomized controlled trials are needed to verify this association. This trial is registered with PROSPERO (registration number: CRD42018105024) (registered on 29 August 2018).

Etidronate for Prevention of Ectopic Mineralization in Patients With Pseudoxanthoma Elasticum.

BACKGROUND: In pseudoxanthoma elasticum (PXE), low pyrophosphate levels may cause ectopic mineralization, leading to skin changes, visual impairment, and peripheral arterial disease. OBJECTIVES: The authors hypothesized that etidronate, a pyrophosphate analog, might reduce ectopic mineralization in PXE. METHODS: In the Treatment of Ectopic Mineralization in Pseudoxanthoma Elasticum trial, adults with PXE and leg arterial calcifications (n = 74) were randomly assigned to etidronate or placebo (cyclical 20 mg/kg for 2 weeks every 12 weeks). The primary outcome was ectopic mineralization, quantified with 18fluoride positron emission tomography scans as femoral arterial wall target-to-background ratios (TBRfemoral). Secondary outcomes were computed tomography arterial calcification and ophthalmological changes. Safety outcomes were bone density, serum calcium, and phosphate. RESULTS: During 12 months of follow-up, the TBRfemoral increased 6% (interquartile range [IQR]: -12% to 25%) in the etidronate group and 7% (IQR: -9% to 32%) in the placebo group (p = 0.465). Arterial calcification decreased 4% (IQR: -11% to 7%) in the etidronate group and increased 8% (IQR: -1% to 20%) in the placebo group (p = 0.001). Etidronate treatment was associated with significantly fewer subretinal neovascularization events (1 vs. 9, p = 0.007). Bone density decreased 4% ± 12% in the etidronate group and 6% ± 9% in the placebo group (p = 0.374). Hypocalcemia (<2.20 mmol/l) occurred in 3 versus 1 patient (8.1% vs. 2.7%, p = 0.304). Eighteen patients (48.6%) treated with etidronate, compared with 0 patients treated with placebo (p < 0.001), experienced hyperphosphatemia (>1.5 mmol/l) and recovered spontaneously. CONCLUSIONS: In patients with PXE, etidronate reduced arterial calcification and subretinal neovascularization events but did not lower femoral 18fluoride sodium positron emission tomography activity compared with placebo, without important safety issues. (Treatment of Ectopic Mineralization in Pseudoxanthoma elasticum; NTR5180).

Epidemiología, farmacología y caracterización clínica de la osteonecrosis de los maxilares. Un estudio retrospectivo de 70 casos / Epidemiology, pharmacology and clinical characterization of bisphosphonate-related osteonecrosis of the jaw. A retrospective study of 70 cases

Introducción y objetivos: Los bisfosfonatos son fármacos con un amplio espectro de indicaciones cuya principal capacidad es la inhibición de la función osteoclástica. En el año 2003 se ha descrito una complicación asociada a su empleo, la osteonecrosis de los maxilares por bisfosfonatos (ONMB). Los objetivos del presente estudio son identificar los casos recogidos de ONMB en un hospital de tercer nivel durante 8 años, evaluando las principales variables en relación con la enfermedad, el bisfosfonato empleado y los factores de riesgo locales o generales que pudieran actuar como desencadenante en la patogénesis de la ONMB. Material y método: Se procedió a la selección los pacientes diagnosticados de ONMB en un centro de referencia para una población de 1.100.000 habitantes. Las variables analizadas se dividieron en 3 grupos: pacientes, fármaco (incluyendo el análisis de la dosis aplicada y la ponderación dosis/potencia) y osteonecrosis. Resultados: Se recogieron 70 casos (44 mujeres y 26 varones), con una media de 66,8 años. Dieciocho pacientes habían recibido un aminobisfosfonato oral y 52 por vía intravenosa. El tiempo medio de administración fue de 26,53 meses. En el 67,1% de los pacientes se pudo identificar un factor local desencadenante, siendo el más frecuente la exodoncia (48,6%). Aunque la exposición ósea estaba presente en el 75,7% de los casos, 8 enfermos padecieron una osteonecrosis sin exposición, manifestando la presencia de dolor y/o fístula crónica. El 58,6% experimentaron una resolución completa con un tiempo medio de control de 16,28 meses. Conclusiones: El 25% de las ONMB en nuestra serie se relacionaron con la administración de un bisfosfonato oral, especialmente el alendronato. El ácido zoledrónico es el agente que menos miligramos precisa para desarrollar la enfermedad. La exposición ósea solitaria fue el dato clínico más habitual, afectando especialmente a sectores posteriores mandibulares en pacientes con enfermedad metastásica (AU)

Background and objectives: Bisphosphonates are widely prescribed drugs whose principal capacity is inhibiting the osteoclast function. In 2003 a complication related to their administration, bisphosphonate-related osteonecrosis of the jaw (BRONJ), was described. The objectives of this study were to identify diagnosed cases of BRONJ in a third-level hospital over 8 years, evaluating the main features in relation to the disease, the bisphosphonate and the presence of local or general risk factors that could trigger the BRONJ. Material and method: Patients diagnosed with BRONJ in a centre of reference for a population of 1,100,000 inhabitants were selected. Variables analysed were classified into 3 groups: patients, bisphosphonate (focusing on dose and weighting dose/potency) and osteonecrosis. Results: Seventy cases were studied —44 women and 26 men—, with a mean age of 66.8 years. Eighteen patients received bisphosphonates orally and 52, intravenously. The mean time of administration was 26.53 months. In 67.1% of the patients it was possible to identify a local trigger, with the most common being tooth extraction (48.6%). Bone exposure was present in 89.2% of the cases, while 12 patients developed BRONJ without exposed bone, with only pain and/or chronic sinus tracts. Complete resolution was achieved in 58.6% of the patients, with a mean time of control of 16.28 months. Conclusions: 25% of the BRONJ cases were related to the administration of oral bisphosphonates, especially alendronate. Zoledronic acid was the bisphosphonate that required the fewest milligrams to induce osteonecrosis. Single bone exposure was the most common clinical finding, especially in the molar mandibular region in patients with metastatic disease (AU)

Effects of etidronate on the Enpp1⁻/⁻ mouse model of generalized arterial calcification of infancy.

Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder of spontaneous infantile arterial and periarticular calcification which is attributed to mutations in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) gene. Whilst the bisphosphonate, etidronate, is currently used off-label for the treatment for GACI, recent studies have highlighted its detrimental effects on bone mineralisation. In the present study, we used the Enpp1-/- mouse model of GACI to examine the effects of etidronate treatment (100 µg/kg), on vascular and skeletal calcification. Micro-computed tomography (µCT) analysis revealed a significant decrease in trabecular bone mass, as reflected by the decrease in trabecular bone volume/tissue volume (BV/TV; %), trabecular thickness, trabecular separation, trabecular number and pattern factor (P<0.05) in the Enpp1-/- mice in comparison to the wild-type (WT) mice. Mechanical testing revealed that in the WT mice, treatment with etidronate significantly improved work to fracture and increased work post-failure (P<0.05, in comparison to the vehicle-treated WT mice). This significant increase, however, was not observed in the Enpp1-/- mice. Treatment with etidronate had no effect on bone parameters in the WT mice; however, the Enpp1-/- mice displayed an increased structural model index (SMI; P<0.05). We used a recently developed 3D µCT protocol to reconstruct and quantify the extensive aortic calcification in Enpp1-/- mice in comparison to the WT mice. However, treatment with etidronate did not prevent de novo calcification, and did not arrest the progression of established calcification of the aorta.

Risedronate as an intra-abdominal sepsis mimic: a case report.

UNLABELLED: This case report highlights the potential severity of bisphosphonate-associated reactions. CASE REPORT: A 76-year-old lady underwent several hospital admissions for investigation of fever associated with rigors, abdominal pain, and vomiting. DISCUSSION: Despite multiple investigations, no cause was found, but the timing of the symptoms coincided with monthly risedronate administration.

Gastrointestinal and renal side effects of bisphosphonates: differentiating between no proof of difference and proof of no difference.

BACKGROUND: This study was aimed at comparing the safety of bisphosphonates in women with osteoporosis by application of equivalence testing. METHODS: Gastrointestinal and renal side effects were evaluated based on information published in randomized controlled trials. RESULTS: The data on gastrointestinal side effects (47 trials) indicated that alendronate, risedronate etidronate, and zolendronate have similar rates of the adverse effects; application of Bayesian network meta-analysis showed that equivalence was demonstrated according to margins around ±10%. The data on renal safety were more sparse and suffered from the use of different outcome measures; hence, a single trial could be evaluated. This trial showed a similar effect of alendronate and risedronate on renal function at 12 months; equivalence was based on differences between the two agents in renal function with margins of less than ±10.4 ml/min. CONCLUSION: Our study provided quantitative information to determine to what extent bisphosphonates can be considered equivalent in terms of gastrointestinal and renal side effects.

Epidemiology, pharmacology and clinical characterization of bisphosphonate-related osteonecrosis of the jaw. A retrospective study of 70 cases.

BACKGROUND AND OBJECTIVES: Bisphosphonates are widely prescribed drugs whose principal capacity is inhibiting the osteoclast function. In 2003 a complication related to their administration, bisphosphonate-related osteonecrosis of the jaw (BRONJ), was described. The objectives of this study were to identify diagnosed cases of BRONJ in a third-level hospital over 8 years, evaluating the main features in relation to the disease, the bisphosphonate and the presence of local or general risk factors that could trigger the BRONJ. METHODS: Patients diagnosed with BRONJ in a centre of reference for a population of 1,100,000 inhabitants were selected. Variables analysed were classified into 3 groups: patients, bisphosphonate (focusing on dose and weighting dose/potency) and osteonecrosis. RESULTS: Seventy cases were studied -44 women and 26 men-, with a mean age of 66.8 years. Eighteen patients received bisphosphonates orally and 52, intravenously. The mean time of administration was 26.53 months. In 67.1% of the patients it was possible to identify a local trigger, with the most common being tooth extraction (48.6%). Bone exposure was present in 89.2% of the cases, while 12 patients developed BRONJ without exposed bone, with only pain and/or chronic sinus tracts. Complete resolution was achieved in 58.6% of the patients, with a mean time of control of 16.28 months. CONCLUSIONS: 25% of the BRONJ cases were related to the administration of oral bisphosphonates, especially alendronate. Zoledronic acid was the bisphosphonate that required the fewest milligrams to induce osteonecrosis. Single bone exposure was the most common clinical finding, especially in the molar mandibular region in patients with metastatic disease.

Bone safety with risedronate: histomorphometric studies at different dose levels and exposure.

UNLABELLED: This report describes bone safety and histomorphometric data across different dose levels and dosing frequencies of risedronate. Normal bone structure and histomorphometric data were observed, with ongoing bone remodeling and mineralization regardless of dose. These data are reassuring and do not suggest compromised bone remodeling during treatment with established risedronate regimens. INTRODUCTION: The efficacy and bone safety of risedronate 5 mg daily were established in pivotal phase III randomized, placebo-controlled clinical studies. Histomorphometric analysis of paired biopsies demonstrated bone safety as reflected by presence of fluorescent tetracycline double-labels in all evaluable biopsies. This report describes bone safety and histomorphometric data across studies of various dose regimens of risedronate. METHODS: Bridging studies, with bone mineral density as the primary endpoint, demonstrated non-inferiority of risedronate 35 mg and 50 mg once a week, risedronate 150 mg once a month, and a risedronate 75-mg dose on two consecutive days a month versus risedronate 5 mg daily. The low oral bioavailability and known dosing limitations due to food interactions of bisphosphonates have led to development of an oral delayed-release dose form of risedronate 35 mg to be taken weekly, before or after breakfast. Bone biopsies were collected at 24 months in studies involving these risedronate dosing regimens; bone safety and histomorphometric data were evaluated. RESULTS: Qualitative bone histology showed normal mineralization of newly formed bone without evidence of pathological findings, such as osteomalacia, bone marrow dyscrasia, or bone marrow fibrosis. Importantly, ongoing bone remodeling, based on fluorochrome labeling, was observed in all patients regardless of dose and exposure. Key histomorphometric variables were comparable to those observed with the risedronate 5 mg daily dose and were within the range seen in healthy pre- and post-menopausal women. CONCLUSIONS: Overall, the results are reassuring with respect to bone safety and histomorphometric data, and do not suggest oversuppression of bone remodeling during treatment with these established risedronate regimens.

Design of pH-responsive alginate raft formulation of risedronate for reduced esophageal irritation.

Risedronate sodium (RA), a pyridinyl bisphosphonate, is widely used in the treatment of osteoporosis. However, the free acid form of the bisphosphonate below pH 3.5 has the potential to produce severe impatience of the upper gastrointestinal tract, particularly esophagitis. A pH-responsive raft-forming tablet (PRR-T) was designed to prevent the esophageal irritation, mainly consisting of low-molecular-weight alginate (LFR 5/60, 300 mg) as raft-forming polymer, sodium bicarbonate (1000 mg) as gas-generating agent and citrate and sodium citrate (600 and 200 mg, respectively) as buffer system. A PRR-T was rapidly liquefied in water within 80 s with a low viscosity 8.0 mPa s, offering ease of swallowing in patients. A formulation profoundly neutralized simulated gastric fluid over pH 5.5, leading to an ionization of the bisphosphonate, without raft formation. On the other hand, the raft was rapidly formed on the top layer preventing the reflux of RA, if the contact with acidic medium is much higher than 0.5 N of hydrochloric acid. Nevertheless, the release rate of the drug was equivalent, providing over 95% release within 5 min. Our study demonstrated the potential usefulness of alginate-based PRR-T for an oral therapy with bisphosphonates for reduced esophageal adverse experiences.

Denosumab significantly increases bone mineral density and reduces bone turnover compared with monthly oral ibandronate and risedronate in postmenopausal women who remained at higher risk for fracture despite previous suboptimal treatment with an oral bisphosphonate.

UNLABELLED: Managing osteoporotic patients suboptimally adherent to bisphosphonates (BPs) is difficult. Such patients who remained at higher risk for fracture (≥1 risk factor) were transitioned to denosumab or a monthly oral BP. Denosumab-treated subjects had significantly greater increases in bone mineral density and decreases in bone turnover in this 12-month study. INTRODUCTION: A clinical need exists to manage patients who are suboptimally adherent to oral BPs and remain at higher risk for fracture. Here, we compare the effects on bone mineral density (BMD) and bone turnover of transitioning such patients to denosumab or monthly oral BP (ibandronate or risedronate). METHODS: In two previous multicenter, open-label studies, postmenopausal women ≥55 years previously treated with, though suboptimally adherent to, a daily or weekly BP were randomized to denosumab 60 mg subcutaneously every 6 months (N = 852) or oral BP 150 mg monthly (N = 851) for 12 months. In this combined post-hoc analysis, a subset of higher risk subjects was identified, and the percentage changes from baseline in BMD and serum C-telopeptide of type I collagen (sCTX-1) were assessed. RESULTS: In the overall population, denosumab was associated with greater gains in BMD at 12 months than monthly oral BP at the total hip, femoral neck, and lumbar spine (p < 0.0001 for all). In higher risk subjects, denosumab led to greater gains in BMD than oral BPs at the total hip (2.2 vs 0.8 %), femoral neck (1.8 vs 0.3 %), and lumbar spine (3.7 vs 1.4 %) (p < 0.0001 for all). Denosumab also led to greater decreases in sCTX-1 in the overall population and higher risk subjects at months 1 and 6 (p < 0.0001 for both). Adverse events and serious adverse events were generally similar between treatment groups. CONCLUSIONS: Transitioning to denosumab was well tolerated and more effective in increasing BMD and reducing bone turnover than cycling to a monthly oral BP treatment in subjects who remained at higher fracture risk despite suboptimal BP treatment.

Bisphosphonate-associated atypical subtrochanteric femur fractures in the older patient.

Bisphosphonates, drug of choice in the treatment of osteoporosis, have been associated with unusual skeletal side effects such as osteonecrosis of jaw and atypical femur fractures in recent years. We report two older patients with bisphosphonate-associated atypical femur fracture from a South Australian tertiary care hospital and a brief discussion of potential diagnostic complexities in this patient population.

Efficacy, tolerability and safety of once-monthly administration of 75mg risedronate in Japanese patients with involutional osteoporosis: a comparison with a 2.5mg once-daily dosage regimen.

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).

Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease. METHODS: In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028. FINDINGS: Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7-11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. INTERPRETATION: Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. FUNDING: Alliance for Better Bone Health (Warner Chilcott and Sanofi).

Bisphosphonate-related osteonecrosis of jaw (BRONJ) in Japanese population: a case series of 13 patients at our clinic.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) affects quality of life and is an important problem for dentists. A Japanese position paper on BRONJ was published in 2010. The purpose of this study was to review clinical data on the treatment of BRONJ obtained at the Clinic of Oral and Maxillofacial Surgery, Tokyo Dental College, Chiba Hospital to further our understanding of this disease. A total of 13 patients (6 men and 7 women) were included. All the patients included in this study had received Bisphosphonate (BP) therapy and had BRONJ. Five of them (38.5%) had received oral BP therapy for osteoporosis, while the remaining 8 (61.5%) had received parenteral BP therapy for bone metastases from breast or prostate cancer. Osteoporosis patients were treated with risedronate or alendronate. Breast or prostate cancer patients were treated with zoledronate. Two patients with rheumatoid arthritis were treated with corticosteroid. Three patients had diabetes mellitus. Eleven patients were treated with antibiotics, while 5 underwent surgical treatment. Discontinuation of BP was recorded in 7 patients during dental treatment. Sequestration was observed in 6 patients during an 11-month follow-up. Eventually, healing and improvement of the oral mucosa were observed in 3 patients. The current standard treatment for BRONJ does not always provide good results. It is necessary to accumulate further clinical data to establish more effective treatment strategies for BRONJ.