Long-term efficacy and safety of neridronate treatment in patients with complex regional pain syndrome type 1: a pre-specified, open-label, extension study

Background: No data on the permanent and curative effect of bisphosphonate treatment in patients with complex regional pain syndrome type-1 (CRPS-1) are currently available. The aim of this pre-specified, open-label, observational study was to evaluate the long-term efficacy and safety of neridronate treatment. Design: A pre-specified, open-label, extension study. Methods: Patients treated with intramuscular (IM) placebo in the double-blind phase of the study were assigned to 100 mg intravenous (IV) neridronate treatment administered 4 times over 10 days. These patients, together with those previously treated with 400 mg IM neridronate, were followed for 1 year. Efficacy was assessed using a visual analogue scale (VAS) pain score. Changes in clinical signs and symptoms, quality of life (QoL) using the Short Form Health Survey (SF-36), and the McGill Pain Questionnaire were also assessed. Results: Benefits on pain, clinical and functional measures were maintained and further improved over 12 months in most patients treated with neridronate administered either IM or IV. In IM-treated patients, the percentage of those defined as responders (VAS score reduction ≥ 50%) progressively increased up to day 360 to 32 of 35 patients (91.4%). Among the 27 patients referred to as responders at the end of the double-blind phase, 26 reported the same result at day 360 (96.3%). In IV-treated patients, a responder rate of 88% (22 out 25) was found at day 360 (p = 0.66 between groups). Consistent improvements were also observed for all clinical signs and functional questionnaire. No drug-related adverse events were reported during the study. Conclusion: In patients with acute CRPS-1, the benefit in pain, clinical, and functional measures observed a few weeks after neridronate treatment administered either IM or IV is maintained and further improved over 12 months. Parenteral neridronate induces permanent disease remission preventing chronic pain and motor dysfunction. Trial registration: EU Clinical Trials Register (EudraCT Number): 2014-001156-2

Safety profile of drugs used in the treatment of osteoporosis: a systematical review of the literature.

The range of osteoporosis treatments is increasingly large and, like any disease, the pharmacological management of patients should involve a risk/benefit evaluation to attain the greatest reduction in risk of fracture with the lowest incidence of adverse events. The aim of this review is to critically appraise the literature about the safety issues of the main pharmacological treatments of osteoporosis. This document is the result of a consensus of experts based on a systematic review of regulatory documents, randomized controlled trials, metaanalyses, pharmacovigilance surveys and case series related to possible adverse drug reactions to osteoporosis treatment with calcium and vitamin D supplements, bisphosphonates, strontium ranelate, selective estrogen receptor modulators, denosumab, and teriparatide. As expected, randomized controlled trials showed only the most common adverse events due to the samples size and the short observation time. Case series and observational studies are able to provide data about uncommon side effects, but in some cases a sure cause-effect relationship needs still to be confirmed. Consistently with methodological limitations, the newer drugs have a tolerance profile that has not been fully explored yet. Osteoporosis treatments showed an overall good tolerance profile with rare serious adverse events that, however, must be well known by the clinician who prescribes these drugs. The concern about possible adverse events should be weighed against the reduction of morbidity and mortality associated with a significant fracture risk reduction

Intramuscular neridronate for the treatment of complex regional pain syndrome type 1: a randomized, double-blind, placebo-controlled study

Background: Complex regional pain syndrome type-1 (CRPS-1) is a severely disabling painful disease challenging to treat. This multicenter, randomized, double-blind placebo-controlled trial examined the efficacy of intramuscular (i.m.) neridronate in CRPS-1 patients. Methods: A total of 78 patients diagnosed with CRPS-1 (aged 59.5 ± 10.3, 66.7% female) were randomly assigned to 25 mg (i.m.) neridronate (N = 41) given once daily for 16 consecutive days or placebo control (N = 37). Efficacy was assessed after 30 days using a visual analogue scale (VAS) pain score and the number of patients achieving ⩾50% reduction in VAS score. Change in clinical signs and symptoms, quality of life (QoL) using Short Form Health Survey (SF-36) and the McGill Pain Questionnaire were also assessed. Results: After 30 days, VAS score decreased significantly to a greater extent in neridronate-treated patients versus placebo (31.9 ± 23.3 mm versus 52.3 ± 27.8 mm, p = 0.0003). Furthermore, the proportion of patients achieving a VAS reduction of ⩾50% was greater in the neridronate group (65.9% versus 29.7%, p = 0.0017). Clinical signs and symptoms were improved significantly in the neridronate group versus placebo for edema (72.5% versus 79.9%, p = 0.03), pain during motion (70% versus 83.3%, p = 0.0009), allodynia (20% versus 63.3%, p = 0.0004), and hyperalgesia (20% versus 56.7%, p = 0.0023). Whereas no difference was observed for QoL measures using the SF-36 questionnaire, three of the four pain variables using the McGill Pain Questionnaire improved significantly in the neridronate group. No serious drug-related adverse events were reported during the study. Conclusion: In patients with acute CRPS-1, i.m. injections of 25 mg neridronate were associated with clinically relevant benefit compared with placebo controls. Trial registration: EU Clinical Trials Register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001156-2

Expert opinion on the management of patients with osteoporosis with anabolic drugs in Italy

Objective. Fragility fractures (FF) resulting from osteoporosis pose a significant public health challenge in Italy, with considerable socio-health and economic implications. Despite the availability of safe and effective drugs, osteoporosis remains underdiagnosed and undertreated, leaving over 2 million high-risk Italian women without treatment. This paper aims to identify and propose key improvements in the management of osteoporosis, focusing particularly on the critical issues related to the use of anabolic drugs in secondary prevention, according to the current Italian Medicines Agency (AIFA) Note 79. Methods. The Expert Panel, composed of nine recognized Italian experts in rheumatology, analyzed current practices, prescribing criteria, and the most recent literature. Three main reasons for revising the indications on pharmacological treatment of osteoporosis were identified: inadequate treatment of osteoporosis, new evidence regarding frontline placement of anabolics in high-risk conditions, and emerging sequential or combined strategies. Results. The proposed improvements include the adoption of the Derived Fracture Risk Assessment algorithm for accurate fracture risk assessment, revision of AIFA Note 79 to reflect current evidence, improved prescribing appropriateness, broader access to anabolic agents, and the provision of sequential therapies with antiresorptives for teriparatide. These changes aim to enhance patient outcomes, streamline healthcare processes, and address the high percentage of undertreated individuals. Conclusions. This expert opinion emphasizes the importance of the appropriate use of anabolic drugs to reduce FF and associated costs while ensuring the sustainability of the National Health Service. The proposed recommendations are in line with the latest scientific evidence, providing a comprehensive strategy to optimize the management of osteoporosis in Italy

Expert opinion on the management of patients with osteoporosis with anabolic drugs in Italy

Objective. Fragility fractures (FF) resulting from osteoporosis pose a significant public health challenge in Italy, with considerable socio-health and economic implications. Despite the availability of safe and effective drugs, osteoporosis remains underdiagnosed and undertreated, leaving over 2 million high-risk Italian women without treatment. This paper aims to identify and propose key improvements in the management of osteoporosis, focusing particularly on the critical issues related to the use of anabolic drugs in secondary prevention, according to the current Italian Medicines Agency (AIFA) Note 79. Methods. The Expert Panel, composed of nine recognized Italian experts in rheumatology, analyzed current practices, prescribing criteria, and the most recent literature. Three main reasons for revising the indications on pharmacological treatment of osteoporosis were identified: inadequate treatment of osteoporosis, new evidence regarding frontline placement of anabolics in high-risk conditions, and emerging sequential or combined strategies. Results. The proposed improvements include the adoption of the Derived Fracture Risk Assessment algorithm for accurate fracture risk assessment, revision of AIFA Note 79 to reflect current evidence, improved prescribing appropriateness, broader access to anabolic agents, and the provision of sequential therapies with antiresorptives for teriparatide. These changes aim to enhance patient outcomes, streamline healthcare processes, and address the high percentage of undertreated individuals. Conclusions. This expert opinion emphasizes the importance of the appropriate use of anabolic drugs to reduce FF and associated costs while ensuring the sustainability of the National Health Service. The proposed recommendations are in line with the latest scientific evidence, providing a comprehensive strategy to optimize the management of osteoporosis in Italy.   On behalf of the Study Group on Osteoporosis and Skeletal Metabolic Diseases of the Italian Society of Rheumatology

Improvement of pain and regional osteoporotic changes in the foot and ankle by low-dose bisphosphonate therapy for complex regional pain syndrome type I: a case series

<p>Abstract</p> <p>Introduction</p> <p>Complex regional pain syndrome is characterized by pain, allodynia, hyperalgesia, edema, signs of vasomotor instability, movement disorders, joint stiffness, and regional osteopenia. It is recognized to be difficult to treat, despite various methods of treatment, including physiotherapy, calcitonin, corticosteroids, sympathetic blockade, and nonsteroidal anti-inflammatory drugs. Pathophysiologically, complex regional pain syndrome reveals enhanced regional bone resorption and high bone turnover, and so bisphosphonates, which have a potent inhibitory effect on bone resorption, were proposed for the treatment of complex regional pain syndrome.</p> <p>Case presentation</p> <p>A 48-year-old Japanese man with complex regional pain syndrome type I had severe right ankle pain with a visual analog scale score of 59 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-inflammatory drugs for five months. Radiographs showed marked regional osteoporotic changes and bone scintigraphy revealed a marked increase in radioactivity in his ankle. One month after the start of oral administration of risedronate (2.5 mg per day), his bone pain had fallen from a VAS score of 59 out of 100 to 18 out of 100. Bone scintigraphy at 12 months showed a marked reduction in radioactivity to a level comparable to that in his normal, left ankle. On the basis of these results, the treatment was discontinued at 15 months. At 32 months, our patient had almost no pain and radiographic findings revealed that the regional osteoporotic change had returned to normal.</p> <p>A second 48-year-old Japanese man with complex regional pain syndrome type I had severe right foot pain with a visual analog scale score of 83 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-inflammatory drugs for nine months. Radiographs showed regional osteoporotic change in his phalanges, metatarsals, and tarsals, and bone scintigraphy revealed a marked increase in radioactivity in his foot. One month after the start of oral administration of alendronate (35 mg per week), his bone pain had fallen from a visual analog scale score of 83 out of 100 to 30 out of 100 and, at nine months, was further reduced to 3 out of 100. The treatment was discontinued at 15 months because of successful pain reduction. At 30 months, our patient had no pain and the radiographic findings revealed marked improvement in regional osteoporotic changes.</p> <p>Conclusions</p> <p>We believe low-dose oral administration of bisphosphonate is worth considering for the treatment of idiopathic complex regional pain syndrome type I accompanied by regional osteoporotic change.</p

The relationship between educational level and bone mineral density in postmenopausal women

BACKGROUND: This study describes the influence of educational level on bone mineral density (BMD) and investigating the relationship between educational level and bone mineral density in postmenopausal women. METHODS: A total of 569 postmenopausal women, from 45 to 86 years of age (mean age of 60.43 ± 7.19 years) were included in this study. A standardized interview was used at the follow-up visit to obtain information on demographic, life-style, reproductive and menstrual histories such as age at menarche, age at menopause, number of pregnancies, number of abortions, duration of menopause, duration of fertility, and duration of lactation. Patients were separated into four groups according to the level of education, namely no education (Group 1 with 209 patients), elementary (Group 2 with 222 patients), high school (Group 3 with 79 patients), and university (Group 4 with 59 patients). RESULTS: The mean ages of groups were 59.75 ± 7.29, 61.42 ± 7.50, 60.23 ± 7.49, and 58.72 ± 7.46, respectively. Spine BMD was significant lower in Group 1 than that of other groups (p < 0.05). Trochanter and ward's triangle BMD were the highest in Group 4 and there was a significant difference between Group 1 and 4 (p < 0.05). The prevalence of osteoporosis showed an inverse relationship with level of education, ranging from 18.6% for the most educated to 34.4% for the no educated women (p < 0.05). Additionally, there was a significant correlation between educational level and spine BMD (r = 0.20, p < 0.01), trochanter BMD (r = 0.13, p < 0.01), and ward's BMD (r = 0.14, p < 0.01). CONCLUSIONS: The results of the study suggest that there is a significant correlation between educational level and BMD. Losses in BMD for women of lower educational level tend to be relatively high, and losses in spine and femur BMD showed a decrease with increasing educational level

Pain prediction by serum biomarkers of bone turnover in people with knee osteoarthritis: an observational study of TRAcP5b and cathepsin K in OA

Objectives: To investigate serum biomarkers, tartrate resistant acid phosphatase 5b (TRAcP5b) and cathepsin K, indicative of osteoclastic bone resorption, and their relationship to pain and pain change in knee osteoarthritis (OA). Methods: Sera and clinical data were collected from 129 people (97 with 3-year follow-up) with knee OA from the Prediction of Osteoarthritis Progression (POP) cohort. Knee OA-related outcomes in POP included: WOMAC pain, NHANES I (pain, aching and stiffness), subchondral sclerosis, and radiographically determined tibiofemoral and patellofemoral OA. Two putative osteoclast biomarkers were measured in sera: TRAcP5b and cathepsin K. Medial tibia plateaux were donated at knee arthroplasty for symptomatic OA (n=84) or from 16 post mortem controls from the Arthritis Research UK (ARUK) Pain Centre joint tissue repository. Osteoclasts were stained for TRAcP within the subchondral bone of the medial tibia plateaux. Results: Serum TRAcP5b activity, but not cathepsin K-immunoreactivity, was associated with density of TRAcP-positive osteoclasts in the subchondral bone of medial tibia plateaux. TRAcP-positive osteoclasts were more abundant in people with symptomatic OA compared to controls. Serum TRAcP5b activity was associated with baseline pain and pain change. Conclusions: Our observations support a role for subchondral osteoclast activity in the generation of OA pain. Serum TRAcP5b might be a clinically relevant biomarker of disease activity in OA