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).

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).

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.

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-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.

Oral bisphosphonate-related osteonecrosis of the jaws in dental implant patients: a case series.

Bisphosphonates have been associated with a serious adverse reaction known as bisphosphonate-related osteonecrosis of the jaws (BRONJ). The aim of this study was to describe its clinical characteristics in patients with dental implants who were taking bisphosphonates orally. We made a retrospective multicentre study in 3 hospitals in Galicia, Spain. The medical records and clinical and radiological follow-up of the oral cavity were reviewed for those patients given bisphosphonates and diagnosed with BRONJ after the placement of dental implants within the previous 3 years. The series comprised 9 white patients (mean age 66 years). The bisphosphonates were alendronate (n=6), ibandronate (n=2), and risedronate (n=1), and the most common indication was osteoporosis (n=7). The mean interval between the initiation of treatment and the onset of BRONJ lesions was 60 months. Most of the lesions were located around the mandibular implants (n=8). The mean interval between placement of dental implants and the onset of BRONJ was 34 (range 1-96) months. After treatment 7/9 patients recovered completely. The prevalence of BRONJ secondary to treatment with bisphosphonates taken orally after placement of dental implants may be higher than expected in a particular geographical region, but to date specific risk factors have not been identified. Clinical characteristics and the outcomes of treatment of lesions are similar to those seen in patients with BRONJ that is unrelated to placement of dental implants.

Analysis of docetaxel therapy in elderly (≥70 years) castration resistant prostate cancer patients enrolled in the Netherlands Prostate Study.

BACKGROUND: Prostate cancer truly is an age-associated disease. Due to the increased life expectancy and more sensitive diagnostic techniques in the Western world, prostate cancer is diagnosed more frequently and with rapidly increasing incidence and prevalence rates. However, age above 65 or 70 years has been an exclusion criterion in clinical trials for decades and the knowledge about chemotherapy tolerance in elderly is limited. METHODS: We performed a retrospective analysis of data acquired from the recently published Netherlands Prostate Study (NePro) to evaluate the influence of advanced age on docetaxel therapy in elderly men (>70 years) with castration resistant prostate cancer (CRPC) and bone metastases. Statistical analyses were performed stratified for age into four categories: <70 (n=315), 70-74 (n=150), 75-79 (n=85), and ≥80 years old (n=18). RESULTS: We analysed 568 patients (median age 68.1 years, range 46-89 years, 44.5% aged ≥70 years). There was no relation between dosage and age (p=0.60). We found no significant differences between the number of dose reductions, time to progression (TTP), overall survival, chemotherapy tolerance and toxicity up to the age of 80 years. However, when compared to younger men, men aged 80 years or above more frequently experienced grade 3/4 toxicity and were five times less likely to complete the first three treatment cycles at the intended dose (Odds ratio (OR) 5.34, p=0.0052) and showed decreased overall survival (15.3 months versus 24.5 months in <80 years group, p=0.020). CONCLUSION: In CRPC patients up to the age of 80 years, docetaxel chemotherapy is well tolerated, with toxicity levels and TTP comparable to those of younger patients. For chemotherapeutic treatment of patients above the age of 80 years an individual assessment should be made.

Randomized, double-blinded, placebo-controlled, trial of risedronate for the prevention of bone mineral density loss in nonmetastatic prostate cancer patients receiving radiation therapy plus androgen deprivation therapy.

PURPOSE: Androgen deprivation therapy (ADT) has been used as an adjuvant treatment to radiation therapy (RT) for the management of locally advanced prostate carcinoma. Long-term ADT decreases bone mineral density (BMD) and increases the risk of osteoporosis. The objective of this clinical trial was to evaluate the efficacy of risedronate for the prevention of BMD loss in nonmetastatic prostate cancer patients undergoing RT plus 2 to 3 years of ADT. METHODS AND MATERIALS: A double-blinded, placebo-controlled, randomized trial was conducted for nonmetastatic prostate cancer patients receiving RT plus 2 to 3 years of ADT. All had T scores > -2.5 on dual energy x-ray absorptiometry at baseline. Patients were randomized 1:1 between risedronate and placebo for 2 years. The primary endpoints were the percent changes in the BMD of the lumbar spine at 1 and 2 years from baseline, measured by dual energy x-ray absorptiometry. Analyses of the changes in BMD and bone turnover biomarkers were carried out by comparing mean values of the intrapatient changes between the 2 arms, using standard t tests. RESULTS: One hundred four patients were accrued between 2004 and 2007, with 52 in each arm. Mean age was 66.8 and 67.5 years for the placebo and risedronate, respectively. At 1 and 2 years, mean (±SE) BMD of the lumbar spine decreased by 5.77% ± 4.66% and 13.55% ± 6.33%, respectively, in the placebo, compared with 0.12% ± 1.29% at 1 year (P=.2485) and 0.85% ± 1.56% (P=.0583) at 2 years in the risedronate. The placebo had a significant increase in serum bone turnover biomarkers compared with the risedronate. CONCLUSIONS: Weekly oral risedronate prevented BMD loss at 2 years and resulted in significant suppression of bone turnover biomarkers for 24 months for patients receiving RT plus 2 to 3 years of ADT.

Bisphosphonate-related enamel hypoplasia in a child with idiopathic arterial calcification of infancy.

We report bisphosphonate-related enamel hypoplasia as a rare side effect in a child with idiopathic arterial calcification of infancy.

[Bisphosphonate related osteonecrosis of the jaw and infection with Actinomyces]. / Osteonecrosis maxilar asociada a bisfosfonatos e infección por Actinomyces.

BACKGROUND AND OBJECTIVE: Bisphosphonate related osteonecrosis of the jaw (BRONJ) has raised considerable interest since its recent description. Its pathogenesis is not yet clarified; formerly it has been considered a non-infectious complication, but recent studies seem to implicate bacteria of the genus Actinomyces. The objective of this study is to analyze the cases of BRONJ in our institution. PATIENTS AND METHODS: Review of medical records of patients diagnosed of BRONJ in the Maxillofacial Surgery Unit of our hospital. RESULTS: We have found 11 cases of BRONJ in our hospital: 4 women taking oral alendronate or risendronate for osteoporosis and 7 cancer patients treated with intravenous zolendronic acid. All of them showed bone invasion by bacteria of the genus Actinomyces. Nine patients underwent prolonged treatment with amoxicillin with favourable clinical outcome in all of them, but 3 died of their malignancy. By contrast, one patient with beta-lactamic allergy and irregular treatment with erythromycin and tetracycline had a chronic evolution of the lesions. There was no information for other patient. CONCLUSIONS: Actinomyces play an important role in the development of BRONJ and specific antibiotic treatment improves the prognosis of this process.

Osteomalacia in a patient with Paget's bone disease treated with long-term etidronate.

A 93 year-old woman with Paget's disease of bone had been treated with etidronate without interruption during 20 years. The daily dose was usual (5mg/kg/day) but this prescription had never been stopped by her physicians. Two fractures had already occurred in pagetic (right tibia) and non pagetic bones (right fibula) within the last 2 years, and she presented rib fractures, another right tibia fracture and right femur fracture during hospitalization time. X-rays films showed major osteolysis of left ulna and right tibia. Blood samples and technetium bone scan brought no evidence for sarcoma or lytic evolution of the disease. A transiliac bone biopsy on non pagetic bone site confirmed the diagnosis of osteomalacia (increased osteoid parameters), with secondary hyperparathyroidism (hook resorption). In Paget's disease of bone, continuous treatment by etidronate may induce generalized osteomalacia, and increase the risk of fracture in both pagetic and non-pagetic bones. Whereas physicians and pharmaceutical industry try to improve the observance of those drugs, this striking observation also points out that a prescription always needs to be updated.

Pharmacovigilance of oral bisphosphonates: adverse effects manifesting in the soft tissue of the oral cavity.

PURPOSE: It is well known that oral bisphosphonates can induce necrosis of the osseous structures of the jaws. However, there seems to be a limited awareness that oral bisphosphonates can also induce adverse effects in the soft tissues of the oral cavity, as indicated by the paucity of reported cases in the literature. Because oral bisphosphonates are widely used drugs for several skeletal conditions, it is reasonable to assume that mucosal adverse effects are more common than the small number of published cases indicates. The purpose of this study was to investigate whether this adverse effect of bisphosphonates is represented as reports from health practitioners in an adverse drug reaction database, as well as to gain knowledge about which substances are being associated with adverse drug reactions affecting the oral mucosa. MATERIALS AND METHODS: The database of the Medical Products Agency-Sweden was searched for adverse effects from oral bisphosphonates manifesting in the oral and maxillofacial region. Reports of reactions limited to the soft tissues of the oral cavity were selected and further analyzed. Only those reports showing recovery or improvement after the cessation of bisphosphonate use were included in the study. RESULTS: A total of 83 cases of adverse reactions to oral bisphosphonates were retrieved from the search. Of these, 12 were included in the study. They were associated with the use of alendronate, etidronate and risedronate, in descending order. Sixteen percent of the reports comprising the oral and maxillofacial region were limited to the oral mucosa and reported recovery or improvement after discontinuation of the drug. CONCLUSIONS: Adverse effects of oral bisphosphonates with manifestations in the soft tissue of the oral cavity seem to be more common than the small number of published cases indicates. However, considering that oral bisphosphonates are widely used drugs, the incidence is still low. These adverse drug reactions are not limited to alendronate and may also be induced by etidronate and risedronate. Still, a significant proportion of the cases are associated with alendronate. Regardless of the substance used, discontinuing the drug is an effective treatment for the mucosal lesions.

Vertebral fracture efficacy during risedronate therapy in patients using proton pump inhibitors.

UNLABELLED: Recent evidence suggests that proton pump inhibitor (PPI) use may affect fracture risk, an important issue for patients being concurrently treated for osteoporosis. The results of our post hoc analysis showed that, regardless of PPI concomitant use, risedronate significantly reduced the risk of new vertebral fractures compared with placebo. INTRODUCTION: Recent evidence suggests that PPI use may affect fracture risk, an important issue for patients being concurrently treated for osteoporosis. Moreover, data suggest that concomitant use of PPIs may wane the anti-fracture effect of bisphosphonates. We explored the relationship between concomitant use of PPIs and incident vertebral fractures among patients treated with risedronate or placebo. Bone mineral density (BMD) and upper gastrointestinal (UGI) adverse events (AEs) were also assessed. METHODS: This study is a post hoc analysis of a subset of patients participating in three prospective, randomized, placebo-controlled clinical trials, with durations of up to 3 years, which evaluated the efficacy of risedronate in reducing fracture risk: Vertebral Efficacy with Risedronate Trial-MultiNational (VERT-MN); Vertebral Efficacy with Risedronate Trial-North America (VERT-NA); and the risedronate Hip Intervention Program (HIP). RESULTS: Total enrollment included 2,729 risedronate and 2,725 placebo patients. Concomitant acid-suppressing drugs were used by 8.8% of the total population (n = 482). Regardless of PPI concomitant use, risedronate significantly reduced the risk of new vertebral fractures compared with placebo (risk reduction: PPI users 57%, p = 0.009; PPI non-users 38%, p < 0.001). BMD increased with risedronate, independent of PPI use. PPI users were at a 2.5-fold greater risk of experiencing at least one UGI AE compared with non-users. CONCLUSIONS: Risedronate significantly reduced the risk of new vertebral fractures compared with placebo, regardless of PPI concomitant use.

A phase I study of combined docetaxel and repeated high activity 186Re-HEDP in castration-resistant prostate cancer (CRPC) metastatic to bone (the TAXIUM trial).

PURPOSE: Bone-seeking radiopharmaceuticals have palliative benefit in castration-resistant prostate cancer (CRPC) metastatic to bone. Recent studies have shown improvement of survival and quality of life when radiopharmaceuticals were given repeatedly or in combination with chemotherapy. We designed a phase I study combining docetaxel and (186)Re-labelled hydroxyethylidene diphosphonate (HEDP) in men with CRPC and bone metastases to evaluate toxicity. METHODS: A dose escalation schedule was designed consisting of four dose levels with a standard dosage of docetaxel (75 mg/m(2) 3-weekly). (186)Re-HEDP was given in increasing activities (1,250 MBq up to 2,500 MBq) after the third and sixth cycle of docetaxel. Dose limiting toxicity (DLT) was defined as any grade 4 toxicity lasting more than 7 days or any grade 3 toxicity that did not recover within 10 days. Three patients were planned for each dose level expanding to six if a DLT occurred. RESULTS: Fourteen patients were recruited with a median age of 64.6 years. One DLT, grade 3 thrombocytopenia lasting >10 days, occurred at dose level 3 leading to expansion of this group to six. One of these patients had an episode of acute renal failure which resolved. Because of production problems of (186)Re-HEDP dose level 4 was not started. CONCLUSION: Combined therapy with docetaxel and (186)Re-HEDP is generally well tolerated in patients with CRPC metastatic to bone. We will conduct a randomized phase II study using three cycles of docetaxel 75 mg/m(2) 3-weekly followed by (188)Re-HEDP 40 MBq/kg body weight, followed by another three cycles of docetaxel 75 mg/m(2), followed by (188)Re-HEDP 20 MBq/kg body weight.

The tolerance and therapeutic efficacy of rhenium-188 hydroxyethylidene diphosphonate in advanced cancer patients with painful osseous metastases.

PURPOSE: This study evaluated the tolerance and therapeutic efficacy of rhenium-188 hydroxyethylidene diphosphonate ((188)Re-HEDP) in patients with different types of advanced cancer suffering from bone pain caused by osseous metastases. METHODS: Sixty-four patients received a single injection of escalating doses of (188)Re-HEDP with various dosages. Vital signs were observed before and after treatment for 8 weeks; adverse effects and rebound pain were recorded within 8 weeks after injection. Blood counts, biochemical parameters, and electrocardiogram were also measured over a period of 8 weeks. Clinical follow-up studies including the bone pain score and the Karnofsky performance score were performed. Pain response was scored by a four-point pain-rating scale as complete, marked, mild, and no response. RESULTS: No adverse effects or clinically significant changes in vital signs, electrocardiograms, and biochemical parameters in patients were observed, and there was no statistical change in alkaline phosphate levels in patients before or after treatment. The overall nadir of thrombopenia was at week 4, leucopoenia at week 3, and anemia at week 8. At week 8, the mean level of platelets and leukocytes returned to baseline levels. The pain score descended from 8.11 to 7.74 on the day of therapy, with a nadir of 4.89 at week 4, and up to 6.67 at week 8 after therapy (p < 0.05). The Karnofsky performance score continually increased from 74.81 before therapy to 82.31 at 8 weeks (p > 0.05 Pain palliation was reported by 73.33% of patients, with a mean duration of 6.85 weeks and a mean start time of 4.05 days. Of the specific tumor types, pain relief was achieved in 84.62% of patients with prostate cancer, 78.57% with breast cancer, 62.50% with lung cancer, and 55.56% with liver cancer. CONCLUSIONS: (188)Re-HEDP is a useful radiopharmaceutical agent for improving bone pain in patients with advanced cancer with painful bone metastases.