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American Family Physician Jan 2011Stress fractures are common injuries in athletes and military recruits. These injuries occur more commonly in lower extremities than in upper extremities. Stress... (Review)
Review
Stress fractures are common injuries in athletes and military recruits. These injuries occur more commonly in lower extremities than in upper extremities. Stress fractures should be considered in patients who present with tenderness or edema after a recent increase in activity or repeated activity with limited rest. The differential diagnosis varies based on location, but commonly includes tendinopathy, compartment syndrome, and nerve or artery entrapment syndrome. Medial tibial stress syndrome (shin splints) can be distinguished from tibial stress fractures by diffuse tenderness along the length of the posteromedial tibial shaft and a lack of edema. When stress fracture is suspected, plain radiography should be obtained initially and, if negative, may be repeated after two to three weeks for greater accuracy. If an urgent diagnosis is needed, triple-phase bone scintigraphy or magnetic resonance imaging should be considered. Both modalities have a similar sensitivity, but magnetic resonance imaging has greater specificity. Treatment of stress fractures consists of activity modification, including the use of nonweight-bearing crutches if needed for pain relief. Analgesics are appropriate to relieve pain, and pneumatic bracing can be used to facilitate healing. After the pain is resolved and the examination shows improvement, patients may gradually increase their level of activity. Surgical consultation may be appropriate for patients with stress fractures in high-risk locations, nonunion, or recurrent stress fractures. Prevention of stress fractures has been studied in military personnel, but more research is needed in other populations.
Topics: Algorithms; Anti-Inflammatory Agents, Non-Steroidal; Bone Density Conservation Agents; Calcium, Dietary; Crutches; Diagnosis, Differential; Diagnostic Imaging; Electric Stimulation Therapy; Etidronic Acid; Fracture Healing; Fractures, Stress; Humans; Orthotic Devices; Pain; Risedronic Acid; Risk Factors; Ultrasonic Therapy; Vitamin D
PubMed: 21888126
DOI: No ID Found -
Yakugaku Zasshi : Journal of the... 2020Since the first report in 2003, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been increasing, without effective clinical strategies. Osteoporosis is... (Review)
Review
Since the first report in 2003, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been increasing, without effective clinical strategies. Osteoporosis is common in elderly women, and bisphosphonates (BPs) are typical and widely used anti-osteoporotic or anti-bone-resorptive drugs. BRONJ is now a serious concern in dentistry. As BPs are pyrophosphate analogues and bind strongly to bone hydroxyapatite, and the P-C-P structure of BPs is non-hydrolysable, they accumulate in bones upon repeated administration. During bone-resorption, BPs are taken into osteoclasts and exhibit cytotoxicity, producing a long-lasting anti-bone-resorptive effect. BPs are divided into nitrogen-containing BPs (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). N-BPs have far stronger anti-bone-resorptive effects than non-N-BPs, and BRONJ is caused by N-BPs. Our murine experiments have revealed the following. N-BPs, but not non-N-BPs, exhibit direct and potent inflammatory/necrotic effects on soft-tissues. These effects are augmented by lipopolysaccharide (the inflammatory component of bacterial cell-walls) and the accumulation of N-BPs in jawbones is augmented by inflammation. N-BPs are taken into soft-tissue cells via phosphate-transporters, while the non-N-BPs etidronate and clodronate inhibit this transportation. Etidronate, but not clodronate, has the effect of expelling N-BPs that have accumulated in bones. Moreover, etidronate and clodronate each have an analgesic effect, while clodronate has an anti-inflammatory effect via inhibition of phosphate-transporters. These findings suggest that BRONJ may be induced by phosphate-transporter-mediated and infection-promoted mechanisms, and that etidronate and clodronate may be useful for preventing and treating BRONJ. Our clinical trials support etidronate being useful for treating BRONJ, although additional clinical trials of etidronate and clodronate are needed.
Topics: Animals; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Clinical Trials as Topic; Clodronic Acid; Diphosphonates; Etidronic Acid; Humans; Inflammation; Jaw; Mice; Nitrogen; Phosphate Transport Proteins; Rats
PubMed: 31902887
DOI: 10.1248/yakushi.19-00125 -
International Endodontic Journal Aug 2019To test whether the incorporation of a chelation powder, etidronate, marketed for root canal irrigation (Dual Rinse HEDP) into a sodium hypochlorite (NaOCl) solution...
AIM
To test whether the incorporation of a chelation powder, etidronate, marketed for root canal irrigation (Dual Rinse HEDP) into a sodium hypochlorite (NaOCl) solution induced additional cytotoxic and genotoxic effects not observed with NaOCl alone.
METHODOLOGY
Fresh and 24-h-old mixtures of 0.9 g of etidronate in 10 mL of 2.5% NaOCl were assessed for their basic chemical features including pH and the ability to chelate Ca from hydroxylapatite. Pure NaOCl and phosphate-buffered saline (PBS) with/without etidronate served as control solutions. Cytotoxic and genotoxic effects of diluted solutions (1:10, 1:100, and 1:1000) were assessed on Chinese hamster lung fibroblast (V79) using the MTT, clonogenic and micronucleus assays, respectively. One-way ANOVA and Tukey's HSD test were applied with an alpha-type error of 5% (P < 0.05).
RESULTS
In mixtures of NaOCl and etidronate, the free available chlorine was lost completely after 24 h, and the pH dropped by more than 3 units. However, the ability of the etidronate to chelate Ca was maintained. The fresh mixtures of NaOCl and etidronate were not more toxic than NaOCl alone (P > 0.05), whilst the 24-h-old mixtures were less toxic (P < 0.05) and statistically similar to pure etidronate. Etidronate per se showed little cytotoxicity and no genotoxicity at the tested dilutions.
CONCLUSIONS
The ability of the used etidronate, Dual Rinse HEDP, to chelate calcium is not affected by NaOCl. Cytotoxicity and genotoxicity of mixed solutions is dictated by the presence of free available chlorine therein.
Topics: Chelating Agents; DNA Damage; Etidronic Acid; Root Canal Irrigants; Root Canal Therapy; Sodium Hypochlorite
PubMed: 30848496
DOI: 10.1111/iej.13110 -
Atherosclerosis Jan 2020In pseudoxanthoma elasticum (PXE), low levels of inorganic pyrophosphate result in extensive arterial calcification. Recently, the treatment of ectopic mineralization in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
In pseudoxanthoma elasticum (PXE), low levels of inorganic pyrophosphate result in extensive arterial calcification. Recently, the treatment of ectopic mineralization in the PXE (TEMP) trial showed that one year of treatment with etidronate halts progression of femoral artery calcification in PXE patients. The aim of this study was to test the efficacy of etidronate on calcification in different vascular beds.
METHODS
In this prespecified post-hoc analysis of the TEMP trial, arterial calcification mass was quantified in the carotid siphon, common carotid artery, thoracic and abdominal aorta, coronary arteries, iliac arteries, and the femoropopliteal and crural arteries using CT at baseline and after one year of etidronate treatment or placebo. In addition, a total arterial calcification score was calculated. The difference in calcification progression was compared between the etidronate and placebo group.
RESULTS
74 PXE patients were enrolled and randomized. Etidronate significantly halted progression of calcification in all vascular beds except for the coronary arteries. For the total arterial calcification score, the median absolute increase in mass score was -63.6 (-438.4-42.2) vs. 113.7 (9.4-377.1) (p < 0.01) and the median relative increase was -2.4% (-10.3-3.8) vs. 6.3% (0.2-15.8) (p < 0.01) in the etidronate and placebo arm, respectively.
CONCLUSIONS
Etidronate treatment halts systemic arterial calcification in PXE. Further research must assess the long term safety and efficacy of etidronate on clinical outcomes in PXE.
Topics: Aged; Arteries; Etidronic Acid; Female; Humans; Male; Middle Aged; Pseudoxanthoma Elasticum; Single-Blind Method; Tomography, X-Ray Computed; Vascular Calcification
PubMed: 31756632
DOI: 10.1016/j.atherosclerosis.2019.10.004 -
The Cochrane Database of Systematic... Jan 2008Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts.
OBJECTIVES
To assess the efficacy of etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women.
SEARCH STRATEGY
We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007.
SELECTION CRITERIA
Women receiving at least one year of etidronate for postmenopausal osteoporosis were compared to those receiving placebo and/or concurrent calcium/vitamin D. The outcome was fracture incidence.
DATA COLLECTION AND ANALYSIS
Study selection and data abstraction was done in duplicate. Meta-analysis of fracture outcomes was performed with data presented as relative risks and a relative change greater than 15% was considered clinically important. Study quality was assessed through the reporting of allocation concealment, blinding and withdrawals.
MAIN RESULTS
Eleven studies representing a total of 1248 patients were included in the review.A significant 41% relative risk reduction (RRR) in vertebral fractures across eight studies (RR 0.59, 95% CI 0.36 to 0.96) was found. The six secondary prevention trials demonstrated a significant RRR of 47% in vertebral fractures (RR 0.53, 95% CI 0.32 to 0.87) and a 5% absolute risk reduction (ARR); compared with the pooled result for the two primary prevention trials (RR 3.03, 95% CI 0.32 to 28.44), which was not significant. There were no statistically significant risk reductions for non-vertebral (RR 0.98, 95% CI 0.68 to 1.42), hip (RR 1.20, 95% CI 0.37 to 3.88) or wrist fractures (RR 0.87, 95% CI: 0.32 to 2.36). For adverse events, no statistically significant differences were found in the included studies. However, observational data has led to concerns regarding potential risk for upper gastrointestinal injury.
AUTHORS' CONCLUSIONS
Etidronate, at 400 mg per day, demonstrated a statistically significant and clinically important benefit in the secondary prevention of vertebral fractures. No statistically significant reductions in vertebral fractures were observed when it was used for primary prevention. In addition, no statistically significant reductions in non-vertebral, hip, or wrist fractures were found, regardless of whether etidronate was used for primary or secondary prevention. The level of evidence for all outcomes is Silver (www.cochranemsk.org.).
Topics: Bone Density; Bone Density Conservation Agents; Etidronic Acid; Female; Hip Fractures; Humans; Osteoporosis, Postmenopausal; Spinal Fractures; Wrist Injuries
PubMed: 18254018
DOI: 10.1002/14651858.CD003376.pub3 -
Biological & Pharmaceutical Bulletin 2016Bisphosphonates (BPs) are typical anti-bone-resorptive drugs, with nitrogen-containing BPs (N-BPs) being stronger than non-nitrogen-containing BPs (non-N-BPs). However,...
Bisphosphonates (BPs) are typical anti-bone-resorptive drugs, with nitrogen-containing BPs (N-BPs) being stronger than non-nitrogen-containing BPs (non-N-BPs). However, N-BPs have inflammatory/necrotic effects, while the non-N-BPs clodronate and etidronate lack such side effects. Pharmacological studies have suggested that clodronate and etidronate can (i) prevent the side effects of N-BPs in mice via inhibition of the phosphate transporter families SLC20 and/or SLC34, through which N-BPs enter soft-tissue cells, and (ii) also inhibit the phosphate transporter family SLC17. Vesicular transporters for the pain transmitters glutamate and ATP belong to the SLC17 family. Here, we examined the hypothesis that clodronate and etidronate may enter neurons through SLC20/34, then inhibit SLC17-mediated transport of glutamate and/or ATP, resulting in their decrease, and thereby produce analgesic effects. We analyzed in mice the effects of various agents [namely, intrathecally injected clodronate, etidronate, phosphonoformic acid (PFA; an inhibitor of SLC20/34), and agonists of glutamate and ATP receptors] on the nociceptive responses to intraplantar injection of capsaicin. Clodronate and etidronate produced analgesic effects, and these effects were abolished by PFA. The analgesic effects were reduced by N-methyl-D-aspartate (agonist of the NMDA receptor, a glutamate receptor) and α,β-methylene ATP (agonist of the P2X-receptor, an ATP receptor). SLC20A1, SLC20A2, and SLC34A1 were detected within the mouse lumbar spinal cord. Although we need direct evidence, these results support the above hypothesis. Clodronate and etidronate may be representatives of a new type of analgesic drug. Such drugs, with both anti-bone-resorptive and unique analgesic effects without the adverse effects associated with N-BPs, might be useful for osteoporosis.
Topics: Acetic Acid; Adenosine Triphosphate; Analgesics; Animals; Bone Density Conservation Agents; Capsaicin; Clodronic Acid; Etidronic Acid; Excitatory Amino Acid Agonists; Foscarnet; Glutamic Acid; Lumbar Vertebrae; Mice; Mice, Inbred BALB C; N-Methylaspartate; Pain; Sodium-Phosphate Cotransporter Proteins; Spinal Cord; Substance P
PubMed: 27150146
DOI: 10.1248/bpb.b15-00882 -
BMJ Clinical Evidence May 2011The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50... (Review)
Review
INTRODUCTION
The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50 years.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of bisphosphonates to prevent fractures in postmenopausal women? What are the effects of pharmacological treatments other than bisphosphonates to prevent fractures in postmenopausal women? What are the effects of non-pharmacological treatments to prevent fractures in postmenopausal women? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 71 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: alendronate, calcitonin, calcium, calcium plus vitamin D, clodronate, denosumab, etidronate, exercise, hip protectors, hormone replacement therapy, ibandronate, multifactorial non-pharmacological interventions, pamidronate, parathyroid hormone, raloxifene, risedronate, strontium ranelate, vitamin D, vitamin D analogues, and zoledronate.
Topics: Administration, Oral; Alendronate; Bone Density Conservation Agents; Calcium, Dietary; Etidronic Acid; Evidence-Based Medicine; Female; Fractures, Bone; Humans; Incidence; Postmenopause; Raloxifene Hydrochloride
PubMed: 21542947
DOI: No ID Found -
Revue Medicale de Liege Jan 1996
Topics: Bone Diseases, Metabolic; Bone Neoplasms; Bone Resorption; Diphosphonates; Etidronic Acid; Humans; Osteitis Deformans
PubMed: 8701122
DOI: No ID Found -
Journal of the American College of... Mar 2018In pseudoxanthoma elasticum (PXE), low pyrophosphate levels may cause ectopic mineralization, leading to skin changes, visual impairment, and peripheral arterial disease. (Randomized Controlled Trial)
Randomized Controlled Trial
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 fluoride positron emission tomography scans as femoral arterial wall target-to-background ratios (TBR). 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 TBR 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 fluoride sodium positron emission tomography activity compared with placebo, without important safety issues. (Treatment of Ectopic Mineralization in Pseudoxanthoma elasticum; NTR5180).
Topics: Aged; Bone Density; Bone Density Conservation Agents; Calcium; Drug Monitoring; Etidronic Acid; Female; Femur; Humans; Male; Middle Aged; Peripheral Arterial Disease; Phosphates; Positron-Emission Tomography; Pseudoxanthoma Elasticum; Tomography, X-Ray Computed; Treatment Outcome; Vascular Calcification
PubMed: 29519353
DOI: 10.1016/j.jacc.2017.12.062 -
Health Technology Assessment... Jun 2005To establish the clinical effectiveness and cost-effectiveness of selective oestrogen receptor modulators, bisphosphonates and parathyroid hormone (subject to licensing)... (Meta-Analysis)
Meta-Analysis Review
A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis.
OBJECTIVES
To establish the clinical effectiveness and cost-effectiveness of selective oestrogen receptor modulators, bisphosphonates and parathyroid hormone (subject to licensing) for the prevention and treatment of osteoporosis and the prevention of osteoporotic fractures in postmenopausal women.
DATA SOURCES
Electronic databases.
REVIEW METHODS
Studies that met the review's entry criteria were eligible for inclusion in the meta-analyses provided that they reported fracture incidence in terms of the number of patients suffering fractures. Meta-analysis was carried out using the random-effects model. A model was constructed to estimate the cost-effectiveness of osteoporosis interventions. The model calculated the number of fractures that occurred and provided the costs associated with osteoporotic fractures, and the quality-adjusted life-years (QALYs). In addition, the conditions of breast cancer and coronary heart disease (CHD) were modelled, as some interventions have been shown to affect the risk of these conditions.
RESULTS
Ninety randomised controlled trials (RCTs) met the inclusion criteria. They related to the five interventions (alendronate, etidronate, risedronate, raloxifene and teriparatide) and to five comparators (calcium, calcium plus vitamin D, calcitriol, hormone replacement therapy and exercise), as well as placebo or no treatment. All five interventions have been shown to reduce the risk of vertebral fracture in women with severe osteoporosis with adequate calcium intakes. However, none of these drugs has been demonstrated, by direct comparison, to be significantly more effective than either each other or the other active interventions reviewed in this report. The intervention costs of treating all osteoporotic women, for a period of 5 years, were in the region of pound 900-1500 million for alendronate, etidronate, risedronate and raloxifene. The cost per QALY ratios fell dramatically with age. Assuming the risks of a woman with severe osteoporosis at the threshold of osteoporosis, no treatment had a cost per QALY below pound 35,000 at 50 years of age. At 60 years of age, the cost per QALY of raloxifene was pound 26,000 assuming no impact on hip fractures, and pound 31,000 assuming an adverse effect. However, these results are driven by the effect on breast cancer and the assumptions made regarding this disease state. No other intervention had a cost per QALY below pound 35,000. When analyses were conducted assuming that the fracture risk is doubled at each site, alendronate and risedronate had cost per QALY ratios below pound 30,000 at all ages. For women at the threshold of osteoporosis, without a prior fracture and aged 70 years, the cost per QALY of the three bisphosphonates ranged from pound 34,000 to pound 41,000. Raloxifene had a cost per QALY of pound 23,000, assuming no effect on hip fracture, given assumptions regarding breast cancer. At 80 years of age, the cost per QALY of alendronate and risedronate was below pound 20,000. This was true for etidronate when incorporating observational data, but the value rose to pound 69,000 when only RCT data were used. No other intervention had a cost per QALY below pound 35,000. It was assumed that doubling the risk of fracture for women without a prior fracture would give results similar to patients at the threshold of osteoporosis with a prior fracture.
CONCLUSIONS
Of the five interventions, only raloxifene appeared to reduce the risk of vertebral fracture in postmenopausal women unselected for low bone mineral density (BMD). However, as the full data have not been made public, there is some uncertainty regarding this result. None of the five interventions has been shown to reduce the risk of non-vertebral fracture in women unselected for low BMD. All of the proposed interventions provided gains in QALYs compared with no treatment in women with sufficient calcium and vitamin D intakes. The size of the QALY gain for each intervention was strongly related to the age of the patient. The estimated costs varied widely for the interventions. These net costs were markedly different by age, with some interventions becoming cost-saving at higher age ranges in patients with a prior fracture. Areas for future research include: the evidence base for the efficacy of fracture prevention in the very elderly, reanalysis of raloxifene using a dedicated breast cancer and CHD model, and more trials considering the cost-effectiveness of teriparatide.
Topics: Age Factors; Aged; Alendronate; Bone Density; Bone Density Conservation Agents; Cost-Benefit Analysis; Etidronic Acid; Evidence-Based Medicine; Female; Fractures, Bone; Humans; Middle Aged; Osteoporosis, Postmenopausal; Quality-Adjusted Life Years; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Risedronic Acid; Teriparatide
PubMed: 15929857
DOI: 10.3310/hta9220