Pulsed Electromagnetic Fields in Bone Healing: Molecular Pathways and Clinical Applications.

In this article, we provide an extensive review of the recent literature of the signaling pathways modulated by Pulsed Electromagnetic Fields (PEMFs) and PEMFs clinical application. A review of the literature was performed on two medical electronic databases (PubMed and Embase) from 3 to 5 March 2021. Three authors performed the evaluation of the studies and the data extraction. All studies for this review were selected following these inclusion criteria: studies written in English, studies available in full text and studies published in peer-reviewed journal. Molecular biology, identifying cell membrane receptors and pathways involved in bone healing, and studying PEMFs target of action are giving a solid basis for clinical applications of PEMFs. However, further biology studies and clinical trials with clear and standardized parameters (intensity, frequency, dose, duration, type of coil) are required to clarify the precise dose-response relationship and to understand the real applications in clinical practice of PEMFs.

Effects of photobiomodulation in the treatment of fractures: a systematic review and meta-analysis of randomized clinical trials.

Several therapeutic strategies have been proposed to optimize the conventional treatment of fractures. Photobiomodulation (PBM) appears to help reduce pain and control inflammation, and it also accelerates bone repair. This systematic review aimed to evaluate the effectiveness and safety of PBM with low-level laser therapy (LLLT) in the bone fracture healing process. We included randomized controlled trials (RCTs) comparing the effects of PBM with those of any other intervention in adults with lower or upper limb bone fractures. The primary outcomes investigated were pain reduction, radiographic healing, and adverse events. The searches were conducted in October 2018. Two RCTs were included that compared PBM to the placebo. A meta-analysis showed significant difference in favor of PBM for pain reduction (MD 1.19, 95% CI [0.61 to 1.77], 106 participants, two RCTs), but this difference was not clinically significant. One RCT (50 participants) showed a clinical and statistical improvement in physical function (MD - 14.60, 95% CI [- 21.39 to - 7.81]) and no difference in radiographic healing, regarding absence of fracture line (RR 1.00, 95% CI [0.93 to 1.08]) and visible bone callus (RR 0.33, 95% CI [0.01 to 7.81]). The certainty of evidence was classified as low to very low. Based on the evidence of low to very low certainty, PBM seems to be associated with the improvement of pain and function. Therefore, new RCTs are required that meet the recommendations of CONSORT to prove the effectiveness and safety of this intervention and support its recommendation in clinical practice.

Photobiomodulation therapy (PBMT) in bone repair: A systematic review.

BACKGROUND: Photobiomodulation therapy (PBMT) using low-level laser influences the release of several growth factors involved in the formation of epithelial cells, fibroblasts, collagen and vascular proliferation, besides accelerating the synthesis of bone matrix due to the increased vascularization and lower inflammatory response, with significant increase of osteocytes in the irradiated bone. Considering its properties, beneficial effects and clinical relevance, the aim of this review was to analyze the scientific literature regarding the use of PBMT in the process of bone defect repair. METHODS: Electronic search was carried out in PubMed/MEDLINEⓇ and Web of Science databases with combination of the descriptors low-level laser therapy AND bone repair, considering the period of publication until the year 2018. RESULTS: The literature search identified 254 references in PubMed/MEDLINE and 204 in Web of Science, of which 33 and 4 were selected, respectively, in accordance with the eligibility requirements. The analysis of researches showed articles using PBMT in several places of experimentation in the subjects, different types of associated biomaterials, stimulatory effects on cell proliferation, besides variations in the parameters of use of laser therapy, mainly in relation to the wavelength and density of energy. Only four articles reported that the laser did not improve the osteogenic properties of a biomaterial. CONCLUSIONS: Many studies have shown that PBMT has positive photobiostimulatory effects on bone regeneration, accelerating its process regardless of parameters and the use of biomaterials. However, standardization of its use is still imperfect and should be better studied to allow correct application concerning the utilization protocols.

Reliable Radiation Technique to Minimize Ovarian Dose During Radiation Prophylaxis of Heterotopic Ossification.

BACKGROUND/AIM: Scattered radiation during radiotherapy (RT) directed at the hip joint poses concerns about ovarian function in patients of reproductive age. Here, we report the impact of using a split-beam technique (SBT) and different photon energies on the total ovary dose during radiation prophylaxis of heterotopic ossification (HO). PATIENTS AND METHODS: This was a single-institution, retrospective study of 32-patients with traumatic acetabular fractures (TAF). All underwent surgery followed by CT-based-RT within 72 h in a single fraction of 700 cGy. Ipsilateral (IL) and contralateral (CL) ovaries (OV) were contoured separately and dose volume histograms (DVH) generated. Additional planning trials were created for each patient by utilizing a SBT medially and by using different photon energies (6-18 MV) to investigate the difference in ovary dose among these maneuvers. RESULTS: The median Mean-dose delivered to ILOV was 59 cGy and the median Max-dose was 177 cGy. CLOV median Mean-dose was 6 cGy and median Max-dose was 10 cGy. SBT at the medial edge of the field led to a 27% and 22% dose reduction in the median Mean and Max. doses, respectively, to ILOV; 9% and 5% reduction was seen in the median Mean and Max. doses, respectively, to CLOV. Higher photon energies (10-18 MV) led to an additional 28% and 16 % reduction in median Mean and Max. doses, respectively, to ILOV when compared to those from 6 MV. The CLOV median Mean dose was reduced by 18% and the Max. dose was reduced by 12%. CONCLUSION: A biologically significant radiation dose is delivered to the ovaries during HO radiation prophylaxis at the hip joints. Ipsilateral ovarian dose could be reduced by half and contralateral by one-quarter by using CT-based treatment planning with a medial SBT and photon energies above 6 MV. We suggest using no more than 10 MV to minimize neutron contamination. Those techniques should be the standard of care as it provides a reliable method for minimizing the radiation dose to the ovaries, consequently, maximizing female fertility preservation during HO radiation prophylaxis. All female patients in childbearing age should be fully informed about ovarian radiation exposure and possible temporary alteration in ova production and morphology.

WITHDRAWN: Radioisotopes for metastatic bone pain.

BACKGROUND: This is an update of the review published in Issue 4, 2003. Bone metastasis cause severe pain as well as pathological fractures, hypercalcaemia and spinal cord compression. Treatment strategies currently available to relieve pain from bone metastases include analgesia, radiotherapy, surgery, chemotherapy, hormone therapy, radioisotopes and bisphosphonates. OBJECTIVES: To determine efficacy and safety of radioisotopes in patients with bone metastases to improve metastatic pain, decrease number of complications due to bone metastases and improve patient survival. SEARCH METHODS: We sought randomised controlled trials (RCTs) in MEDLINE, EMBASE, CENTRAL, and the PaPaS Trials Register up to October 2010. SELECTION CRITERIA: Studies selected had metastatic bone pain as a major outcome after treatment with a radioisotope, compared with placebo or another radioisotope. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias of included studies by their sequence generation, allocation concealment, blinding of study participants, researchers and outcome assessors, and incomplete outcome data. Two review authors extracted data. We performed statistical analysis as an "available case" analysis, and calculated global estimates of effect using a random-effects model. We also performed an intention-to-treat (ITT) sensitivity analysis. MAIN RESULTS: This update includes 15 studies (1146 analyzed participants): four (325 participants) already included and 11 new (821 participants). Only three studies had a low risk of bias. We observed a small benefit of radioisotopes for complete relief (risk ratio (RR) 2.10, 95% CI 1.32 to 3.35; Number needed to treat to benefit (NNT) = 5) and complete/partial relief (RR 1.72, 95% CI 1.13 to 2.63; NNT = 4) in the short and medium term (eight studies, 499 participants). There is no conclusive evidence to demonstrate that radioisotopes modify the use of analgesia with respect to placebo. Leucocytopenia and thrombocytopenia are secondary effects significantly associated with the administration of radioisotopes (RR 5.03; 95% CI 1.35 to 18.70; Number needed to treat to harm (NNH) = 13). Pain flares were not higher in the radioisotopes group (RR 0.74; 95% CI 0.27 to 2.06). There are scarce data of moderate quality when comparing Strontium-89 (89Sr) with Samarium-153 (153Sm), Rhenium-186 (186Re) and Phosphorus-32 (32P). We observed no significant differences between treatments. Similarly, we observed no differences when we compared different doses of 153Sm (0.5 versus 1.0 mCi). AUTHORS' CONCLUSIONS: This update adds new evidence on efficacy of radioisotopes versus placebo, 89Sr compared with other radioisotopes, and dose-comparisons of 153Sm and 188Re. There is some evidence indicating that radioisotopes may provide complete reduction in pain over one to six months with no increase in analgesic use, but severe adverse effects (leucocytopenia and thrombocytopenia) are frequent.

The effects of photobiomodulation and low-amplitude high-frequency vibration on bone healing process: a comparative study.

This study aimed at investigating the effects of photobiomodulation (PBM) and low-amplitude high-frequency (LAHF) whole body mechanical vibration on bone fracture healing process when metallic plates are implanted in rats' femurs. Forty male rats weighing between 250 and 350 g, 12 weeks old, were employed in this study. A transverse critical size defect (CSD) was made in their right femurs that were fixed by stainless steel plates. After the surgery, the rats were divided equally into four groups: low-level laser therapy group (GaAlAs laser, 830 nm, 40 mW, 4 J/cm2, 0.35 cm beam diameter, LLLT), whole body vibration group (60 Hz, 0.1 mm amplitude, 1.5 g, WBV), a combination of laser and vibration group (LV), and the control group (C). Each group was divided into two subgroups based on sacrifice dates. The rats were sacrificed at intervals of 3 and 6 weeks after the surgery to extract their right femurs for radiography and biomechanical and histological analyses, and the results were analyzed using standard statistical methods. Radiographic analyses showed greater callus formation in the LLLT and WBV groups than in control group at both 3 (P < 0.05 and P < 0.001, respectively) and 6 weeks after surgery (P < 0.05 and P < 0.05, respectively). Histological evaluations showed a higher amount of new bone formation and better maturity in the LLLT and WBV groups than the control groups at 3 and 6 weeks after surgery. Biomechanical tests showed that the maximum force at fracture in the LLLT (P < 0.05 in 3 weeks and P < 0.05 in 6 weeks) and WBV (P < 0.001 in 3 weeks and P < 0.05 in 6 weeks) groups was greater than that in the control groups at both time intervals. But a combination of laser and vibration therapy, LV, did not show a positive interaction on bone fracture healing process. The biostimulation effects of PBM or LLLT and of low-amplitude high-frequency WBV both had a positive impact on bone healing process, for critical size defects in the presence of a stainless steel implant. But their combination, i.e., low-level laser therapy and low-amplitude high-frequency whole body vibration (LV), interestingly did not accelerate the fractured bone healing process.

Effect of low-level laser therapy on bone repair: a randomized controlled experimental study.

The aim of this study was to investigate the effect of low-level laser therapy (LLLT) on bone repair in femoral fractures. Sixty adult Wistar rats were randomly assigned into one of two groups: group A (ostectomy + LLLT) or group B (ostectomy + sham laser). An experimental model of complete bone fracture was surgically created by removing a 2-mm fragment from the middle third of the femoral shaft. Data were analyzed on days 8, 13, and 18 after the fracture (subgroups 1, 2, and 3). Samples were assessed for changes in inflammatory infiltration; trabecular bone matrix, periosteal, and new bone formations; and changes in the expression of particular osteogenic-related proteins (osteocalcin, osteopontin, and osteonectin). Microscopic analysis revealed a significant decrease in inflammatory infiltration, intense trabecular bone matrix and periosteal formation, and an increase in newly formed bone after laser irradiation. We also found an increase in the expression of bone matrix proteins with LLLT, with a significant difference measured for osteocalcin in the LLLT group at day 8 (p = 0.007). We show that LLLT plays an important role in augmenting bone tissue formation, which is relevant to fracture healing. LLLT may therefore be indicated as an adjunct therapeutic tool in clinical practice for the treatment or recovery of nonunion injuries.

The impact of body mass index on heterotopic ossification.

PURPOSE: To analyze the impact of different body mass index (BMI) as a surrogate marker for heterotopic ossification (HO) in patients who underwent surgical repair (SR) for displaced acetabular fractures (DAF) followed by radiation therapy (RT). METHODS AND MATERIALS: This is a single-institution retrospective study of 395 patients. All patients underwent SR for DAF followed by RT ± indomethacin. All patients received postoperative RT, 7 Gy, within 72 h. The patients were separated into four groups based on their BMI: <18.5, 18.5-24.9, 25-29.9, and >30. The end point of this study was to evaluate the efficacy of RT ± indomethacin in preventing HO in patients with different BMI. RESULTS: Analysis of BMI showed an increasing incidence of HO with increasing BMI: <18.5, (0%) 0/6 patients; 18.5-24.9 (6%), 6 of 105 patients developed HO; 25-29.9 (19%), 22 of 117; >30 (31%), 51 of 167. Chi-square and multivariate logistic regression analysis showed that the correlation between odds of HO and BMI is significant, p < 0.0001. As the BMI increased, the risk of HO and Brooker Classes 3, 4 HO increased. The risk of developing HO is 1.0× (10%) more likely among those with higher BMI compared with those with lower BMI. For a one-unit increase in BMI the log odds of HO increases by 1.0, 95% CI (1.06-1.14). Chi-square test shows no significant difference among all other factors and HO (e.g., indomethacin, race, gender). CONCLUSIONS: Despite similar surgical treatment and prophylactic measures (RT ± indomethacin), the risk of HO appears to significantly increase in patients with higher BMI after DAF. Higher single-fraction doses or multiple fractions and/or combination therapy with nonsteroidal inflammatory drugs may be of greater benefit to these patients.

Radioisotopes for metastatic bone pain.

BACKGROUND: This is an update of the review published in Issue 4, 2003. Bone metastasis cause severe pain as well as pathological fractures, hypercalcaemia and spinal cord compression. Treatment strategies currently available to relieve pain from bone metastases include analgesia, radiotherapy, surgery, chemotherapy, hormone therapy, radioisotopes and bisphosphonates. OBJECTIVES: To determine efficacy and safety of radioisotopes in patients with bone metastases to improve metastatic pain, decrease number of complications due to bone metastases and improve patient survival. SEARCH STRATEGY: We sought randomised controlled trials (RCTs) in MEDLINE, EMBASE, CENTRAL, and the PaPaS Trials Register up to October 2010. SELECTION CRITERIA: Studies selected had metastatic bone pain as a major outcome after treatment with a radioisotope, compared with placebo or another radioisotope. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias of included studies by their sequence generation, allocation concealment, blinding of study participants, researchers and outcome assessors, and incomplete outcome data. Two review authors extracted data. We performed statistical analysis as an "available case" analysis, and calculated global estimates of effect using a random-effects model. We also performed an intention-to-treat (ITT) sensitivity analysis. MAIN RESULTS: This update includes 15 studies (1146 analyzed participants): four (325 participants) already included and 11 new (821 participants). Only three studies had a low risk of bias. We observed a small benefit of radioisotopes for complete relief (risk ratio (RR) 2.10, 95% CI 1.32 to 3.35; Number needed to treat to benefit (NNT) = 5) and complete/partial relief (RR 1.72, 95% CI 1.13 to 2.63; NNT = 4) in the short and medium term (eight studies, 499 participants). There is no conclusive evidence to demonstrate that radioisotopes modify the use of analgesia with respect to placebo. Leucocytopenia and thrombocytopenia are secondary effects significantly associated with the administration of radioisotopes (RR 5.03; 95% CI 1.35 to 18.70; Number needed to treat to harm (NNH) = 13). Pain flares were not higher in the radioisotopes group (RR 0.74; 95% CI 0.27 to 2.06). There are scarce data of moderate quality when comparing Strontium-89 ((89)Sr) with Samarium-153 ((153)Sm), Rhenium-186 ((186)Re) and Phosphorus-32 ((32)P). We observed no significant differences between treatments. Similarly, we observed no differences when we compared different doses of (153)Sm (0.5 versus 1.0 mCi). AUTHORS' CONCLUSIONS: This update adds new evidence on efficacy of radioisotopes versus placebo, (89)Sr compared with other radioisotopes, and dose-comparisons of (153)Sm and (188)Re. There is some evidence indicating that radioisotopes may provide complete reduction in pain over one to six months with no increase in analgesic use, but severe adverse effects (leucocytopenia and thrombocytopenia) are frequent.

Stimulation of bone formation and fracture healing with pulsed electromagnetic fields: biologic responses and clinical implications.

Pulsed electromagnetic fields (PEMF) have been used for several years to supplement bone healing. However, the mode of action of this non-invasive method is still debated and quantification of its effect on fracture healing is widely varied. At cellular and molecular level, PEMF has been advocated to promote the synthesis of extracellular matrix proteins and exert a direct effect on the production of proteins that regulate gene transcription. Electromagnetic fields may also affect several membrane receptors and stimulate osteoblasts to secrete several growth factors such as bone morphogenic proteins 2 and 4 and TGF-beta. They could also accelerate intramedullary angiogenesis and improve the load to failure and stiffness of the bone. Although healing rates have been reported in up to 87 % of delayed unions and non-unions, the efficacy of the method is significantly varied while patient or fracture related variables could not be clearly associated with a successful outcome.

Low-dose X-ray irradiation promotes fracture healing through up-regulation of vascular endothelial growth factor.

Compared with high and medium dose irradiation, low-dose irradiation (LDI) revealed different yet healing promotion effects, such as hormesis and adaptive response. A recent milestone work by Zhou demonstrated that LDI at 1 Gy promoted callus formation and mineralization in a rat model, yet without being able to address the underlying mechanism. It is well known that vascular endothelial growth factor (VEGF) is a key cytokine that regulates angiogenesis, especially important found in the process of fracture healing to interplay with other molecules. Furthermore, recent studies revealed that tissue repair might be enhanced by LDI through up-regulation of the level of VEGF. In view of this general phenomenon, we propose the following hypothesis that low-dose X-ray irradiation at ≤ 1 Gy promotes fracture healing through up-regulation of VEGF.

The effects of infrared low-level laser therapy on healing of partial osteotomy of tibia in streptozotocin-induced diabetic rats.

OBJECTIVE: The effects of low-level laser therapy (LLLT) on a bone defect model in streptozotocin-induced diabetic (STZ-D) rats was examined. BACKGROUND DATA: LLLT accelerates bone fracture repair in healthy animals, but its effect in diabetic animals is unclear. METHODS: Twenty-eight rats were divided into five groups: 1 (diabetes, no LLLT), 2 (diabetes, LLLT high dose), 3 (diabetes, LLLT low dose), 4 (no diabetes, no LLLT), and 5 (no diabetes, LLLT low dose) Diabetes was induced by a single injection of STZ in rats of groups 1, 2, and 3. A bone defect was made in the right tibia of rats in all groups. The defect in groups 2, 3, and 5 was treated with LLLT (890 nm, 70 W, 3000 Hz, circular beam shape, and 1 cm(2) spot size). Doses of 23.3 J/cm(2) (530 s) for group 2 and 11.6 J/cm(2) (265 s) for groups 3 and 5 were applied three times a week. The right tibias were collected 42 days after surgery and subjected to three-point bending test on a material testing machine (MTM) until fracture occurred. Data was automatically recorded on the MTM formed the load-deformation curve. RESULTS: Mann-Whitney test showed that LLLT with 11.6 J/cm(2) significantly increased bending stiffness and maximum force in diabetic rats compared with group 1 (both p = 0.041). CONCLUSION: LLLT in an experimental diabetic model enhanced bone repair with a higher bending stiffness and maximum force compared to the control group.

Prophylaxis of heterotopic ossification in patients sedated after polytrauma : medical and ethical considerations.

BACKGROUND AND PURPOSE: Heterotopic ossification (HO) often follows acetabular fractures after multitrauma. Irradiation is a mean for prophylaxis. We established a standard procedure in our hospital for patients under sedation, when obtaining informed consent for HO prophylaxis is impossible. PATIENTS AND METHODS: We reviewed current scientific evidence, calculated the risks of radiation and presented the ethical and legal framework. The subject was scrutinised by an interdisciplinary panel. RESULTS: Irradiation is the most effective means for prophylaxis and has few adverse effects in adult patients with fractures of the acetabulum. The lifetime risk of radiation-induced cancer or infertility are insignificant. CONCLUSIONS: Informed consent for irradiation should be obtained before operation whenever possible. When this cannot be done prophylaxis can be postponed for a maximum of 3 days in order to obtain consent. If the patient is not able to communicate within this period, prophylactic irradiation should be given after consulting the relatives. The patient must be informed as soon as possible.

[Osteoporosis in cancer survivors]. / Osteoporosis tras la curación tumoral.

The detection of late sequelae in survivors of cancer has become increasingly important as developments in diagnostic and therapeutic methods have led to a more and long-term survival rates in tumoral patients. Osteoporosis is one of such problem that has been increasingly identified in patients with cancer. Significant bone loss and increased risk of fractures have been described in these patients. Medical problems associated with the malignancy or caused by the oncologic treatment are the main factors involved in bone loss. Therefore, patients at risk for bone loss should be undergo preventive or therapeutic interventions at an early enough stage to prevent fractures.

[Value of a combined ossification prophylaxis with indomethacin and radiotherapy for acetabular fractures]. / Wertigkeit einer kombinierten Ossifikationsprophylaxe mit Indometacin und Bestrahlung bei Azetabulumfrakturen.

BACKGROUND: Heterotopic ossification is a complication in patients with surgically treated acetabular fractures. The incidence is related to the surgical approach (extended iliofemoral, posterior or a combined approach). The objective of this study was to evaluate the incidence of heterotopic ossification in patients with acetabular fractures who received a combined prophylaxis with both a single dose of radiation and indomethacin compared to those who received only a prophylaxis with radiation or indomethacin. PATIENTS AND METHODS: A total of 24 patients with a combined prophylaxis after surgery were examined retrospectively 24 months after trauma. A systematic literature review was performed and our own results were compared with different methods for prophylaxis of heterotopic ossification from the literature. RESULTS: Only one patient developed a heterotopic ossification. In accordance with the literature, combined prophylaxis showed the least incidence of ossification compared to the other methods. Differences in incidence frequencies were significant between the different prophylaxis methods. CONCLUSION: A combined prophylaxis for heterotopic ossification in surgically treated acetabular fractures seems to be a better alternative than a prophylaxis with radiation or indomethacin alone.

Shock wave treatment shows dose-dependent enhancement of bone mass and bone strength after fracture of the femur.

Shock wave treatment is believed to improve bone healing after fracture. The purpose of this study was to evaluate the effect of shock wave treatment on bone mass and bone strength after fracture of the femur in a rabbit model. A standardized closed fracture of the right femur was created with a three-point bending method in 24 New Zealand white rabbits. Animals were randomly divided into three groups: (1) control (no shock wave treatment), (2) low-energy (shock wave treatment at 0.18 mJ/mm2 energy flux density with 2000 impulses), and (3) high-energy (shock wave treatment at 0.47 mJ/mm2 energy flux density with 4000 impulses). Bone mass (bone mineral density (BMD), callus formation, ash and calcium contents) and bone strength (peak load, peak stress and modulus of elasticity) were assessed at 12 and 24 weeks after shock wave treatment. While the BMD values of the high-energy group were significantly higher than the control group (P = 0.021), the BMD values between the low-energy and control groups were not statistically significant (P = 0.358). The high-energy group showed significantly more callus formation (P < 0.001), higher ash content (P < 0.001) and calcium content (P = 0.003) than the control and low-energy groups. With regard to bone strength, the high-energy group showed significantly higher peak load (P = 0.012), peak stress (P = 0.015) and modulus of elasticity (P = 0.011) than the low-energy and control groups. Overall, the effect of shock wave treatment on bone mass and bone strength appears to be dose dependent in acute fracture healing in rabbits.

Radioisotopes for metastatic bone pain.

BACKGROUND: Bone metastases manifest through pain, which can arise even before the injury is radiologically detected. Pain occurs as a result of bone destruction and, as more destruction ensues, more pain can be experienced. Radiculopathies, plexopathies and shrinkage of spinal nerves due to tumour growth and fractures are very frequent in these patients. Relief of pain from bone metastasis can be achieved by treating the cancer itself; radiotherapy; conventional analgesics; and specific drugs that work on the bone tumour-induced alteration: biphosphonates, calcitonin or radioactive agents. OBJECTIVES: To determine the efficacy of radioisotopes to control metastatic pain in patients with bone metastases and complications due to bone metastases (hypercalcaemia, bone fracture and spinal cord compression) as well as its efficacy in terms of patient survival and adverse effects. SEARCH STRATEGY: Randomised and controlled clinical trials related to this review were retrieved electronically using MEDLINE (1966-2003), EMBASE (1974-2003) and Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1 2003). general strategies to identify RCTs were combined with specific commands to identify trials of radioisotopes and metastatic bone pain. SELECTION CRITERIA: The inclusion criteria were: randomised trials of patients with metastatic bone pain that compared treatment with radioisotopes and placebo, and where the major outcome was either pain or complications of bone metastases (eg, hypercalcaemia, bone fracture, spinal cord compression) assessed at least four weeks after treatment. DATA COLLECTION AND ANALYSIS: The quality of included studies was assessed using the Jadad scale and the Oxford Pain Validity Score. Two independent reviewers extracted the data and completed a standard form designed for that purpose. An intention-to-treat analysis was performed, and global estimates of effect were calculated using a random effects model. MAIN RESULTS: Four trials (325 patients) provided data that suggest a small effect of radioisotopes on pain control both at short and medium term (one to six months). No evidence was available to assess long-term effects (12 months). Only one study provided data on analgesia use and concluded that patients given either radioisotopes or placebo showed similar levels of analgesic use when compared to baseline use. Leukocytopenia and thrombocytopenia are secondary effects associated with the administration of radioisotopes. The incidence of leukocytopenia is significantly greater in patients treated with radioisotopes (RR=4.56, 95% CI (1.22,17.08)). There were also a greater number of thrombocytopenia events in the treatment group, without reaching statistical significance. REVIEWER'S CONCLUSIONS: The efficacy of radioisotopes has been assessed in clinical trials with small sample sizes and short-term evaluations of the outcomes. There is some evidence indicating that radioisotopes may give complete reduction in pain over one to six months with no increase in analgesic use, but adverse effects, specifically leukocytopenia and thrombocytopenia, have also been experienced.